Drug Dissolution, Drug Release and Dissolution Part 3, Drug Characteristics for Dissolution, 3. 13 Beer-Lambert Law, Absorption Spectra and Beer-Lambert Law, PHAR120 - Drug Packaging CHAP 46, Drug packaging, Drug Packaging, Solid State, Solid State,...
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Pertaining to the ear.
If reaction rate CHANGES, it follows __________ Order Reaction.
First
_________ Order: rate depends on initial concentration of reactant.
First
First Order Kinetics: rate = rate Rate is ___________-dependent Rate constant (k) units:
First Order Rate Law: rate = k[A] A → B rate = -d[A]/dt = d[B]/dt Rate is concentration-dependent Rate constant (k) units: 1/time (ex. 1/s)
lozenges
Flat disks containing a medicinal agent with a suitably flavor base that dissolve slowly in the mouth for a long period of time, releasing therapeutic ingredients.
Who is the Stokes Radius named after?
George Gabriel Stokes
What are dissolution profiles?
Graphs that show the percent of a drug dissolved vs time
For poorly soluble drugs, decreasing particle size can significantly improve dissolution. Give examples of 2 of these cases covered in lecture.
Griseofulvin and Nitrofurantoin
Absorption
It is a process by which drug molecules travel from the site of administration to the site of measurement.
Adsorption
It is a surface phenomenon where powder particles of a chemical will bind with the powder particle of another chemical or molecules from a solution may bind to the powder particle.
What is the best way to describe Cs?
It is an aqueous diffusion layer or stagnant liquid film that forms when a drug is first subjected to dissolution
Higher K favors what?
absotption
What are examples of drugs that have been found to be still be potent and safe years beyond their expiration date?
acetaminophen, hydrocodone
elixer
hydroalcoholic liquids for oral use
prone to taking on water
hydroscopic
In an emulsion, microbes grow in the aqueous phases where the (ionized/unionized) form of preservatives accumulate.
ionized
the best known example of a drug given by sublingual administration is
nitroglycerin
biocompatibility
not irrigating; does not promote infection or abscess
ophthalmic
pertaining to the eye
Lag-Time is the time required by the drug to __________ the tissue BEFORE it is absorbed into the blood stream.
saturate
startum corneum
the outermost cell layer of the epidermis
when c is expressed as a percentage solution, what is E termed?
the percentage absorption coefficient
Shelf-life is defined as the time it takes for ___% of the drug to degrade
10
Incorporated
Drug can be ____ into a granule
Dissolution is (endothermic/exothermic)
endothermic
elastromeric pump
intravenous devices for intermittent or very slow continuous infusion
lattice
network constructed of basic repeating pattern
What letter represents the RATIO between Cd, C₁, C₂, and Cr?
(big) K
Active transport (aka what?)
(carrier-mediated) -requires input of E= active transport -transport against conc gradient (low to high)
trouche
(lozenge) a flat round dosage form containing medication, flavor, sugar, and mucilage. dissolves in mouth to release medication
irrigation
(medicine) cleaning a wound or body organ by flushing or washing out with water or a medicated solution
Orally
(of drugs) through the mouth rather than through injection
tincture
(pharmacology) a medicine consisting of an extract in an alcohol solution
Psuedo-first order kinetics
-
Solid products (packaging)
- solid dosage forms may be packaged in opaque glass or opaque plastic - the closure should exclude water - powder dosage forms can be packaged in sachets - freeze dried sterile powders can be packaged in glass vials
Convenience
- the packaging must be convenient to use and encourage patient compliance with usage instructions - the protective functions of the packaging should not inhibit the ease of use
Describe sublingual delivery.
-API is absorbed from under the tongue -enter directly to systemic circulation and bypasses the liver -sublingual mucosa is thin and more permeable compared to buccal mucosa -tablets are designed to disintegrate and dissolve rapidly in saliva without aid of water
Chemical stability
-Active(s) retain chemical integrity and potency within limits - Degradation of active lead to inaccuracy in dosing and possible therapeutic failure - Product specifications have limits usually ± 2-10% of label - Tighter control if degradants toxic i.e. tetracycline forms toxic by product
Oral route dosage forms
-tablets -capsules -bulk powders (BC powder) -solutions -suspensions -elixirs -syrups -emulsions
There is an equal amount of octanol and water when Log P is?
0
The acceptable Buffer Capacity used in the human body is:
0.01 - 0.1 [choose 0.05 on test to find βmax]
using USP Apparatus I or II in a volume of ≤ 900 ml in each of these medias
0.1 N HCl or Simulated Gastric Fluid USP without enzymes pH 4.5 buffer pH 6.8 buffer or Simulated Intestinal Fluid USP without enzymes
In the following graph for a co-solvent system: - What is the SOLUBILITY of Phenobarbital at Glycerin 0% and Alcohol 0%?
0.1g/100mL
The index of refraction (n) for air is equal to _________.
1
what does the length usually equal?
1 cm
the pH of the stomach is around
1 to 2
Diffusion Coefficient (D) is a constant that measures what 2 things?
1) How well a solute can diffuse in a diffusional barrier. 2) Permeability of a diffusant across a membrane.
Buffers depend what on 3 things?
1. C [TOTAL concentration] 2. Ka [dissociation constant] 3. pH
Lubricants effect on: 1. Ka 2. tmax 3. AUC
1. Decrease 2. increase 3. decrease to no effect
What are 2 limitations of the determined expiration date using the Arrhenius Equation?
1. Degradation is purely chemical. 2. MECHANISM of degradation does NOT change with increase/decrease in temperature.
Drug absorption may be affected if there is what?
1. Delay in gastric emptying 2. Stimulation of bile flow 3. Change in the pH of the GI tract 4. Increase in splanchnic blood flow 5. Change in luminal metabolism of the drug 6. Physiochemical interaction of the meal with the drug
Advantages of Intrathecal injection
1. Direct access to cerebrospinal fluid for uptake into brain 2. single dose narcotics
1. P-gp is important in what? 2. P-gp is found where?
1. Drug efflux and drug resistance 2. Many tissues including jejunum, colon, rectum, brain
4 Goals of Preformulation
1. Establish physical characteristics 2. Establish physicochemical parameters of new drugs 3. Establish compatibility with common excipients 4. Determine stability
Graphite Covalent C-C bond length
1.42A close to the expected value for C=C double bond
contribution of atom on face
1/2
Contribution of atom on edge
1/4
contribution of atom on vertex
1/8
why was it necessary to zero the spectrophotometer using distilled water?
"zeroing" takes into account the sum of the absorbances from the air, plastic cuvette and water so that the only thing we measure is the absorbance of BB/MO
Defects in crystals
(1)Point defects:irregularities or deviations from ideal arrangement around a point or an atom in a crystal (a)Stoichiometric defects (A)in covalent crystals (i)Vacancy defects (ii)Interstitial defect (B)in ionic crystals (i)Frenkel defect (ii)Schottky defect (2)Line defects:irregularities or deviations from ideal arrangement for a whole row or column in the crystal.
Cell membranes are composed of?
(7-10nm) -Composed of phospholipid bilayers interspersed with carbohydrates and protein groups
Markers to study transit times
(ex: mannitol, codeine, lactulose) -tools to study mechanism of drug absorption
Why are large particles delayed from emptying?
(ex: tablets, capsules) -delayed for 3-6 hours by the presence of food in the stomach
What is the Dissolution rate constant (k)?
(small) k = D/h
Graph of Thermomechanical Analysis (refer to slide 25)
- (Green arrow) Tg: Intersection point of tangential lines - (Red box on right): Linear Expansion Coefficient
Polymorphism is common in these 3 types of drugs.
- 63% barbiturates - 67% steroids - 40% sulfonamides
Reclosable Packaging
- AFTER initially opening, it is capable of being reclosed with a similar degree of security and is capable of being reused multiple times w/out loss of security - *** Child Resistant Capabilities***
Disadvantages of Rectal Route
- Absorption is much slower - Low patient compliance
Drug
- An agent intended for the use in diagnosis, mitigation, treatment, cure, or prevention of diseases in humans or other animals - it can either DECREASE or INCREASE the existing function of an organ, tissue, or cell ( i.e. decrease BP, increase bone density)
Preservative Excipients
- Antimicrobial preservatives are added to nonsterile dosage forms to protect them from microbial growth or from microorganisms that are introduced - Sterile articles packaged in multiple-dose containers: antimicrobial preservatives are added to inhibit growth of microorganism that be introduced from repeatedly withdrawing individual doses - 15% alcohol is adequate for the preservation of products with a pH of 5 - 18% alcohol has been considered adequate for neutral or slightly alkaline preparations
Types of Excipients: Stabilizers
- Antioxidant - Coating - Preservatives - Cryoprotectant
Advantages of Parenteral Route
- Avoid First Pass - Subcutaneous, intramuscular, intraperitoneal: a lag time before the drug reaches the blood stream (shorter than the oral route)
Advantages of Transdermal Route
- Avoid pre-systemic metabolism (GI tract and liver) - Maintain drug level within the therapeutic window for prolonged periods of time in the blood stream - Less frequent dosing
Reservoir Transdermal Patch
- Backing - Drug Reservoir - Rate controlling membrane (does NOT contain drug) - Adhesive/Drug Layer Rate controlling membrane is there to separate the drug in the drug reservoir and the drug in the adhesive layer to prevent them from touching and causing degradation.
Antimicrobial Preservatives USP 30-NF 25
- Benzalkonium Chloride - Benzoic Acid - Cetrimonium Bromide - Chlorocresol - Methylparaben - Phenoxyethanol - Phenylmercuric Nitrate - Propylparaben - Sodium Dehydroacetate - Thimerosal - Benzalkonium Chloride Solution - Benzyl Alcohol - Cetylpyridinium Chlroide - Cresol - Methylparaban Sodium - Phenylethyl Alcohol - Potassium Benzoate - Propylparaben Sodium - Sodium Propionate - Thymol - Benzethonium Chloride - Butylparaben - Chlorobutanol - Ethylparaben - Phenol - Phenylmercuric Acetate - Potassium SOrbate - Sodium Benzoate - Sorbic Acid
USP-NF
- Book that can be used to learn more about the API and inactive ingredients of a drug
**On Exam Example of Non-polar solvents:
- Chloroform - Ethyl Ether - Benzene - Carbon Tetrachloride
Optical Crystallography
- Degree of stability of metastable form - Transition Temperature - Melting point - Rates of transition - Whether to use polymorphism to improve dosage form
Ideal Drug
- Desirable pharmacological action - no side effects - reaches intended location giving the right amount of the right time - Rapidly & completely removed when no longer needed - Minimal dosage & frequency - affordable
Delivery System
- Device used to deliver drugs ( i.e. teaspoon, syringe) - Design feature of the dosage form that affects the delivery of the drug ( i.e. enteric coated tablet, sustained release tablet) - Example: Burpless Fish Oil Capsule
USP-NF: Monograms
- Drug substances, dosage forms, compounding procedures, preparations - Includes the name of the ingredient or preparation; the definition; packaging, storage, and labeling requirements, and the specification
Acceptable tamper evident packaging
- Film Wrappers - Transparent - Blister or Strip Packs - Plastic bubbles - Heat Shrink Bands - Pouches, Sachets - Container Mouth Inner Seals - Tape seals - Breakable Caps - Tear-away Caps - Banding on a 2 piece hard shell capsule
Characteristics of Crystalline solids:
- Fixed structure - Less soluble than amorphous - Less tendency to change form
Types of Excipients: Aesthetics
- Flavors - Colorants - Sweeteners
What 2 drug examples are in Class IV of the BCS?
- Furosemide - Hydrochlorithiazide
**On Exam Example of a Semipolar solvent:
- Glycerin - Propylene glycol - Ethanol - Acetone
Preserving Syrups
- High sugar concentrations protect syrup from bacterial contamination - In 1 L of Syrup USP there is 850 grams of sucrose that PRESERVES 463 mL of water - 850 grams of sucrose is equivalent to 537 mL of sucrose: Equivalent factor of 0.63 mL/g (for every 1 gram of sucrose there is 0.63 mL of sucrose) - For every 1 L of syrup the ratio is 463 mL water preserved/850 g sucrose: Equivalent factor of 0.54 mL/g (for every 1 g of sucrose, 0.54 mL of water is preserved) - For any unpreserved water, use 18% alcohol
PREgelatinized STARCH
- Highly Digestible - Bulking Agent - Disintegrant (when wet) - Binder (when dry)
Advantages of Pharmaceutical Solutions
- Homogenous (uniform dose) - Drug is IMMEDIATELY available for absorption (no dissolution needed) - Can be used via different routes of administration - Easy to administer to patients with difficulty in swallowing (pediatrics) - Easy to adjust dose
Disadvantages of Pharmaceutical Solutions
- LESS stable than solids - Intrinsic solubility may limit - Have to mask unpleasant taste or odors - Difficult to handle, package, transport and store - LESS accurate than unit dose forms (i.e. tabs, caps)
Types of Excipients: Bulking Agent or Diluent
- Lactose - Microcrystalline Cellulose
What are the limitations to the pH-Partition Theory?
- Large epithelial SA of small intestine - Long stay in small intestine - Drug ions interact with oppositely-charged ions - Some drugs absorbed via active pathways - Drug absorption affected by lipid solubility
Advantages of Nasal Route
- Local Action - Less metabolic activity - Easy to administer
Which plot is MORE favorable? - Log k vs. 1/ε with a (-) slope - Log k vs. 1/ε with a (+) slope
- Log k vs. 1/ε with a (-) slope
what was the difference between the 2 dyes?
- MO's wavelength max was lower than BB's - BB has a lot more double bonds
Polyethylene Glycol (PEG)
- MW of 200-800: Viscous liquids - MW > 1000: Wax-like solids ALL are water - miscible/soluble
Physiological Features of the Small Intestines
- Main region for drug absorption - Extremely large surface area - Relatively long residence time
✰✰✰ (IMPORTANT) In Fasting & Nonfasting: - The time it takes for NONDIGESTABLE materials to pass through the STOMACH is _________min. to _________hr.
15 minutes to 2 hours
Rule of thumb: pH is STABLE within _________ units of pKa.
2
the maximum amount of medication that can be administered subcutaneously is
2 ml
The shelf life of a drug is at least how many years?
2 years
Q10 values of ______ or ______ represent estimates at room temperature for shelf-life when Ea is unknown and for a conservatively shorter value than t90%.
2,5
what percent of an administered ophthalmic solution is actually delivered to the eye
20% about 80% of a dose is lost from the eye by overflow
Question from lecture: What is the possible composition for compound A and compound B in the following picture when the temperature is lower than the eutectic point?
25% solid A and 75% solid B
Number of voids in different packings 1)CCP/FCC
2N tetrahedral voids N octahedral voids where N is number of atoms For just one unit cell, N=4 so Tetrahedral voids/unit cell=8 Octahedral voids/unit cell=4 Octahedral voids are present (1/4) at each edge and 1 at center therefore total 4 Tetrahedral voids are present 1 at each corner (contribution 1 each) so 8 tetrahedral voids.
london edinburgh dublin
3 cities of bp
SI transit time
3-4 hr
Unit cell types
(a)Primitive (SCC) (b)Centered unit cells (BCC,FCC,ECC)
Sublingual dosage forms
-tablets -lozenges
contribution of atom on body center
1
Advantages of IM
1. easier to give than IV 2. larger volumes than SC
Why do we ignore C in the dissolution rate equation?
Because it is too small
Flavor H+
Sour
What are ways drugs cross intestinal epithelium
Through or between the epithelial cells
a linear relationship
What is relationship does the plot of absorbance vs. concentration produce?
LA
long-acting
Define S in Fick's First Law
Surface area
What is S in the dissolution rate equation?
Surface area of exposed solid
Span, Tween, SLS are examples of what agent?
Surfactant
Thermal analysis utilizes DSC, TGA, and _________.
TMA
True/False: isomerization is a type of degradation
TRUE
T/F: 90-99% of an administration drop in the eye will be lost.
TRUE: due to tear turnover, drainage, metabolism, and protein binding
Radical Chain Mechanism: when all radicals are paired
Termination
General Chapters
Tests and procedures referred to in multiple monographs are described in DETAIL
Equilibrium or Saturation solubility
The MAXIMUM amount (mg) of a solute or drug that is present in a solution per unit volume (mL) of a solvent at a constant temperature and pressure.
Hygroscopicity
The ability of a powder to adsorb moisture from the atmosphere.
Solution
The absorption rate of a drug is most rapid when the drug is formulated as:
Heat of Vaporization - δHV
The amount of heat absorbed when 1g of a liquid vaporizes.
Deliquescence
The amount of moisture adsorbed is so high that the powder will dissolve and form a solution.
Frenkel defect or Dislocation defect
The cation is dislocated and is displaced to interstitial site. Thus atom remains neutral This happens in compounds with 1)Low coordination number 2)Large difference in size of cation and anion Examples ZnS, AgBr, AgI, AgCl In these 1)Density remains the same 2)Increases electric conductance. Compound might originally be an insulator but because of displacement of anion might become a conductor. This happens by ionic mechanism. This property of conversion from insulator to conductor is called dielectric property and is measure by dielectric constant of a material. Frenkel defect thus causes increase in dielectric constant. Dielectric constant increases due to closeness of like charges
Transmembrane movement of drugs is influenced by?
The composition and structure of the plasma membranes
Approximate Solubility Descriptive Terms (defined by USP)
The descriptive terms is based on the amount (mL) of solute needed to dissolve 1 gram of solvent
In the following graph: What does B indicate in a co-solvent system?
The dielectric constant of a mixture of DMI and PEG400
What is Class I Bioclassification?
The drug has high solubility and high permeability
What is Class III Bioclassification?
The drug has high solubility, but low permeability
What is Class IV Bioclassification?
The drug has low solubility and low permeability
What is Class II Bioclassification?
The drug has low solubility but high permeability
Food effect most pronounced when what?
The drug is taken shortly after a meal
Transcellular transport determined by?
The ease of drug permeability across lipid membranes--> best for small lipophilic drugs
Elimination rate constant can be determined from what? (first-order oral absorption)
The elimination phase of the plasma level-time curve after completion of GI absorption
Define J in Fick's First Law
The flux, amount of materials passing a unit area in unit time
Bravais lattices
The fourteen possible lattices that can be created in three dimensions using lattice points
propellant
The gas used to expel materials from aerosol containers.
Molar Heat of Vaporization - (cal/gram; cal/mole)
The heat absorbed by 1 mole of liquid when it passes into vapor phase.
Heat of Fusion - δHf - (cal/gram; cal/mole)
The heat absorbed when a solid becomes liquid and heat is liberated when liquid freezes.
Penetration; Coating
The method for slowing drug release from the dosage form is to COAT its surface with a material (polymers) that slow ____ by the dispersion fluid. Drug release depends on the physiochemical nature of ____ material
Multi dose packaging
The nursing floor or into may receive large stock containers of medications from which doses are poured. Although this type of packaging reduces the pharmacy's workload, it adds to the preparation time and increases the possibility of error
What is the extent of dissolution?
The percent of drug dissolved relative to the original amount
Porosity
The percentage of open space in a powder sample or tablet.
Therapeutic Range
The plasma or serum concentration (ng/mL) range, within which, the drug is likely to produce the therapeutic activity or effect.
Diffusion
The process by which drug molecules move from a region of high concentration to a region of low concentration.
What is drug dissolution?
The process by which solid dosage forms dissolve so they can be absorbed by the body
Physical instability: (4)
polymorphs formation of eutectic mixture crystallization vaporization adsorption absorption complexation
Oral elixers contain ______________ APIs.
poorly soluble
EDTA, a chelator is a
preservative
what will the different physical properties of polymorphs have an affect on
procesing of raw materials, chemcialy stability, physcial stability and bioavailability
Define dissolution.
process by which a solid drug substance becomes dissolved in a solvent
Define iontophoresis.
process of TD API delivery where API penetration is increased by use of low voltage current on skin for few hours
Instability may result in changes in _________ ____________ and ________________
product appearance and composition
british pharmacopoeia
product of merging of the pharmacopoeia of 3 cities
Dissolution
The process of powder particles dissolving in the surround fluid to form a solution.
Physicochemical Properties; Biological Properties
The properties of drugs can be described as being either?? or ??
Solubility of a substance
The quantity that will dissolve in a specified quantity of a solvent to form a saturated solution at given temperature and pressure.
What is the purpose of disintegrating agents?
promote break-up of tablets; swell in water
Functions of packaging - convenience
promotes compliance with the directions for taking medicine
In Fick's First Law, the the diffusion flux along direction x is (proportional/directly proportional) to the concentration gradient.
proportional
pastes are generally used for their ---- action
protective
Well- Closed Container
protects the contents from contamination by extraneous solids and from the loss of the article
Tight Container
protects the contents from contamination by liquids, solids, or vapors; from loss of the article; and from efflorescence, deliquescence (Absorb water from the air), or evaporation under the ordinary or customary conditions of handling, shipment, storage, and distribution, and is capable of tight reclosure
The proteins in the cell membrane do what?
provide a pathway for the selective transfer of polar molecules and charged ions through the lipid bilayer
What can develop after continuous exposure of a photoallergy?
pruritic and eczematous
international pharmacopoeia
published by WHO
What is meant by a drug undergoing dissolution in a first-order process?
The rate of dissolution decreases as drug concentration decreases
Use accelerated stability testing for chemical stability testing because:
quick detection of drug degradation Prediction of shelf-life rapid quality control
Diffusitivity reflect the _________ at which a diffusant is transported between 2 regions.
rate
The Order of a Reaction refers to how concentration of the reactant influences ___________.
rate
When Ea, A, and k (rate constant) at one temperature are KNOWN, the ___________ ____________ at a different temperature can be determined using Arrhenius Equation.
rate constant (k)
The release of drug from the delivery system is dictated by the transport/release properties of the __________ _________ membrane.
rate controlling
Buffer Capacity is defined as:
The ratio of change in gram equivalent weight of an acid or base needed to produce a particular change in pH in 1L of the buffer system.
Bioavailability
The relative amount of administered dose that reaches the general circulation and the rate at which it reaches the general circulation.
What does the value of D in the dissolution rate equation depend on?
The size of the molecules and viscosity of the dissolution medium
Membrane controlling reservoir systems
rate controlling membrane has constant thickness (x) and diffusivity (D) and solubility coefficient
What is passive transport flux?
rate of transfer -measure in mass per unit area (Ex: mg/cm^2)
schiffs base
reaction with drug containing primary amine and one with aldehyde or ketone functional group
Dose response
response vs. conc of drug -as the conc of the drug increases, typically the response increases as well
Inducers of CYP3A
rifampin
homeopathy
safe, gentle and natural system of healing that works with your body to relieve symptoms, restore itself and improve your overall health
Solubility is defined as the concentration of a solute in a ___________ solution at a certain temperature.
saturated
Solid state
The state of matter having a fixed volume and fixed shape
Micromeritics
The study of science of small particles.
Termination of Action
The time (hr ,min, etc...) at which the drug concentration in the plasma falls below MEC.
Onset of Action
The time (hr, min, etc...) at which the administered drug reaches the therapeutic range OR the drugs begin to produce the effect.
Duration of Action
The time (hr, min, etc...) span beginning at the onset of action and up to the termination of action.
For most drugs, the optimum site for drug absorption after oral administration is where?
The upper portion of the SI or duodenum region
Paracellular transport goes through where?
The water filled junctions between cells
Schottky defect in NaCl
There are approximately 10⁶ Schottky pairs per cm³ at room temperature. In 1cm³ there are about 10²² ions. Thus there is one schottky defect per 10¹⁶ ions⁶
What is meant by a drug undergoing dissolution in a zero-order process?
There is a fixed amount of drug released per unit time
This type of analysis is a branch of materials science where the properties of materials are studied as they change with temperature.
Thermal Analysis
This technique relates to TMA and is the measurement of a change of a dimension of the sample with a negligible force acting on the sample while it is subjected to a temperature regime.
Thermodilatometry (TD)
This type of analysis is commonly used to determine selected characteristics of materials that exhibit either mass loss or gain due to decomposition, oxidation, or loss of volatiles (such as moisture).
Thermogravimetric Analysis (TGA)
This type of analysis is the measurement of a change of a dimension or a mechanical property of the sample against temperature.
Thermomechanical Analysis (TMA)
How are compressed tablets obtained?
They are obtained from granules (drug + excipients) into unit dose form.
Viscosity Inducing Agents
Think ABCD -Acacia, Agar, Alginic acid, Aluminum monostearate -Bentonite -Carbomers, Carboxymethylcellulose sodium, Cellulose -Dextrin
USP
Think API
NF
Think inactive ingredients
1 in 10
Though you can use any ratio, which one is most common?
How can you decrease h in the dissolution rate equation?
Through agitation (stirring) or through using disintegrents
What is the goal of the cube-root law?
To quantify the dissolution rate
What is the difference between topical and transdermal?
Topical delivers drug to the skin layers (target); Transdermal delivers the drug through the skin (not the target).
Differences in solids disappear in the liquid or vapor state. (T/F)
True
Dissolution is faster with metal salt forms. (T/F)
True
The Frequency Factor (A) is a CONSTANT. (T/F)
True
The liquid film constitutes a stationary diffusion layer in which the concentration of the drug is equal to the drug solubility (Cs). (T/F)
True
Under normal condition, only a small fraction of total molecules are in an activated state. (T/F)
True
How can you increase Cs?
Use a salt form of a drug so it better interacts with the solution medium
Advantages of SC
Used for insulin
Transcytosis is primarily for transport of macromolecules and small particles such as?
Virus and Bacteria
Parameters affecting dissolution: Diffusion layer thickness (h)
Viscosity Motility, increases mixing, decreases h
You can only accurately determine the concentration of a colored solution for visible light spectroscopy
When conducting an experiment, what is something to keep in mind?
Why is pseudo or apparent zero-order kinetics observed?
When the concentration of the reactant is constant either by excess initial concentration or by rapid replenishment of the reactant.
more light has been absorbed, there are more molecules in that solution to absorb that light and so it's going to appear darker to us
Why is it that the more concentrated a solution is the darker the color appears?
If reaction rate is the SAME, it follows __________ Order Reaction.
Zero
__________ Order: rate is NOT dependent on concentration of reactant.
Zero
Lag-Time and Burst Effects follow (Zero Order/First Order) release.
Zero Order
What order are most solid drugs delivered as?
Zero and First order reactions
First Order Integrated Rate Law
[A]t = [A]0*e^-kt ln[A]t = ln[A]0 - kt
β reaches MAXIMUM when Ka = ____________
[H+]
Biological
____ Factors: 1. Absorption 2. Distribution 3. Metabolism 4. Biological Half Life (Excretion) 5. Margin of Safety
Why is absorption of a compressed tablet slower than that of solution?
a compressed tablet has both a disintegration and dissolution phase
High perfusion in the duodenum maintains what?
a conc gradient between the intestinal lumen and plasma circulation
tablet
a dose of medicine in the form of a small pellet
What types of drugs can be passively diffused through the stomach?
a few fat-soluble, acid-stable drugs (a drug that is absorbed in the stomach is most often by passive diffusion)
Solutions
a homogeneous mixture of one or more solutes, or dispersed phase, dissolved in a medium (solvent) in a molecular or an ionic level - Thermodynamically stable, one phase system (one of which is completely dissolved in the other) - composed of a solid, liquid, or gas dissolved in a liquid solvent
wheal
a raised blister like area in the skin, as caused by an intradermal injection
a raised blister like area on the skin cause from an intradermal injection is call
a wheal
what is the absorbance equation?
absorbance = Ecl
hydrates
absorbs water
Higher A favors
absorption (duodenum)
Disadvantage of SC
absorption depends on blood flow and injection volume
Indomethacin is a weak ____________.
acid
Stomach is (basic/acidic).
acidic
molecules need energy to react
activation energy (Ea)
What is the API of a drug?
active pharmaceutical ingredient
metered dose inhaler
aerosols that use special metering valves to deliver a fixed dose when the aerosol in actuated
When the dissolution medium has poor wetting properties, micronization results in poor dissolution rates due to __________.
agglomeration
which will not be caused by particulate material in an intravenous injection?
air emboli
Spirits and Essences
alcoholic or hydroalcoholic solutions of volatile substances (usually volatile oils) - Alcohol content 62-86% - convenient means of obtaining a proper amount of flavoring oil - Non aqueous solution containing alcohol
random packing arrangement
amorphous structure
IUD
an intrauterine contraceptive device that is placed in the uterus for a prolonged period of time
powder
any of various cosmetic or medical preparations dispensed in the form of a powder, a solid substance in the form of tiny loose particles
parenteral
any route that does not involve that alimentary tract
Dispersion forces
arises from instantaneous transient dipoles
why does increasing thermodynamic favourability of the packing arrangement decrease solubility
as molecules are less likely to leave the crystal packing structure
Hydrogen bonds form a network of
attractive intermolecular interactions throughout the crystal structure
slow process that is uncatalyzed, under the action of oxygen
auto-oxidation
type of oxidation:
auto-oxidation
Orthorhombic/rhombic system (Bravias Lattice)
a≠b≠c α=β=γ=90° 1)Primitive 2)Face centred 3)Body centred 4)End centred
Monoclinic system (Bravais Lattice)
a≠b≠c α=γ=90° β≠90° 1)Primitive 2)End centred
why were their wavelength max's different?
both of their structures were complex; one contained more conjugated bonds than the other and different functional groups mean different wavelength absorbances
Signs of instability: emulsions
breaking, creaming, gas formation, discoloration or microbial growth
when administering a nasal spray...
breath through the nostril while spraying the solution
inspiration
breathing in
Diffusion results in mixing or mass transport WITHOUT needing __________ motion.
bulk
Diffusion results in mixing or mass transport without needing __________ motion.
bulk
How is therapeutic range determined?
by studying drug effects in large patient population and noting plasma concentration at which patient experience therapeutic effects and side effects
dimension of unit cell
ca
Signs of instability: suspensions
caking, difficultly resuspending, crystal growth, discoloration microbial growth
C₁ and C₂ (can/cannot) be measured since these are values INSIDE the membrane.
cannot
In which dosage form is API encased in either hard or soft gelatin.
capsule
---- contain the drug and other ingredients packaged in a gelatin shell
capsules
Heavy metals are _____________.
catalysts
Signs of instability: ointments
change in consistency or demonstrate separation
In Fick's Second Law, the concentration profile and concentration gradient (stays the same/changes) with time in real situations.
changes
Stability considerations in dispensing practice can be: (5)
chemical physical microbiological therapeutic toxicological
polymorph
chemically the same, but the alignment has changed (if it is a crystalline structure) which can change its physical properties
wash
cleanse with a cleaning agent, such as soap, and water eyes or mouth
film-coated
coated with thin layer of water-insoluble polymer
DMI, an organic solvent, is (partially/completely) soluble in water.
completely
Osmotic pump
composed of a reservoir containing drug a rigid semi-permeable membrane, an osmotic agent and a flexible impermeable wall
syrup
concentrated solutions of sugar in water
At higher conc's the rate of drug absorption remains what during active transport?
constant or zero order
CD
controlled diffusion
CR
controlled release
Bond type in diamond
covalent
Bond type in Graphite
covalent in plane, non-covalent between planes
Ordered packing arrangement
crystal structure
What is the modified dissolution rate equation?
dM/dt=(DSCs)/h
june 30 1906
date nf of unofficial prep title was changed to national formulary
alkyl group missing: carboxyl group missing:
dealkylation decarboxylation
pres theodore roosevelt
declared usp and nf as standards for medicinal and pharmaceutical substances
Isomerization is pH (dependent/independent) and catalyzed by various buffers.
dependent
Solubility depends on crystal structure expanded
depends on 3D packing arrangement of molecules in the solid
plasters are generally used with the ----- route of administration
dermal
different polymorphs
different packing arrangements, intermolecular interactions and cohesive packing energies
The RATE of dissolution is (directly/inversely) proportional to SA of drug particles.
directly ⬆ dissolution rate, ⬆ SA
What is the course of drug in product to drug in body?
drug in product disintegration and drug release solid drug particles drug in solution absorption drug in body
Signs of instability: creams
emulsion breakage, crystal growth, shrink
Energy absorbed from the excipient will transfer the ________ to the ______ ______ causing it to ________ (____ ______ or _____ _______)
energy active drug degrade (free radical or reactive intermediate)
If physical, chemical and microbiological stabilities are maintained, therapeutic and toxicological stabilities are ___________
ensured
GI transit time of what two tablets are affected by food?
enteric-coated and non-disintegrating tablets
Pharmacist Responsibility: Store products under recommended ________ conditions
environmental
Biopharmaceutics Classification System is an essential tool to
establish BE for Generic drug product approval
Efflux drug transporters are located where?
ex: P-gp Membranes to protect body from undesirable compounds
If there is prolonged contact with the GI tract what can happen?
ex: aspirin may irritate the gastric mucosa
Step 2: Food & Drug Interactions (Competition between food components & drugs reduce specialized transport)
examples: cephalosporin & di/tripeptides
Photosensitizing _________ may absorb light and indirectly transfer the absorbed energy to a drug.
excipients
Buccal administration is a parenteral route of administration
false
parenteral administration always involves the use of needles
false
with oral formulations, drugs administered by solid dosage forms generally reach the systemic circulation faster than liquid dosage forms
false
Powder patterns can be used to
fingerprint polymorphic forms
Extravascular absorption is typically what?
first order process
dec 15 1820
first usp was published
Step 2: Food & Drug Interactions (Alteration of pH)
food tends to increase pH of the stomach
Advantages of inhalation and intranasal
for local and systemic effects
torsion angles
formed by three consecutive bonds
Drug release depends on
formulation & matrix
steril
free of microorganisms
Order of close packing principle
gas, liquid, amorphous solid, crystalline solid
Enteric Coated (EC) tablets does NOT disintegrate. They are released in the ________ fluid.
gastric (stomach)
unit dose parenteral route: amuple
glass container that holds a single sterile dose of drug either a liquid, powder, or crystal. container has a narrow neck that must be broken to reach the drug. nurses use sterile syringe to withdraw medication. once glass is broken, drug can't be kept sterile.
intramuscular injection sires
gluteal, deltoid, and vests lateralis muscles
What are hydrocarbon ointment bases?
greasy, no water, stay on skin and keep medications contact with skin
Question from lecture: A smaller ion may have a __________ Stokes Radius than a larger ion.
greater
L-glutamic acid
has 8x1017 molecules and 2x1017 unit cells
a spacer with an MDI aerosol will
help coordinate actuation and inspiration
Drugs with ________ log P values are easily bound to protein, have low aqueous solubility, and bind to extraneous sites.
high
Drugs with low log P values has __________ aqueous solubility.
high
Low Activation energy (Ea) = _______________ degradation rate, and stability problems may arise.
high
Effects of pressure on CN of compounds
high pressure changes 4:4 CN → 6:6 CN High temperature changes 8:8 CN → 6:6 CN
Melting Point Depression is used to determine the __________ of a compound.
identity
when is a molecule polymorphic
if a molecule crystallises in more than one 3D packing arrangement
unit dose packaging
in an institutional setting, each dose is individually wrapped and labeled, and a 24 hour supply is prepared by the pharmacy and dispensed
non-crystalline --> crystalline when
in contact with H2O
For a drug absorbed by carrier mediated process the rate of absorption ___ in what kind of relationship?
increases with drug conc until the carrier molecules are completely saturated
Why do carboxylic acids have higher melting pnts than alkanes
increasing intermolecular interactions, increases thermodynamic favourability decreases the tendancy for the molecules to leave the solid state
using the most stable polymorph
increasing stability, decreasing solubility
Extended release profile
initial release of the drug to provide therapeutic drug after intake, followed by gradual release over an extended period of time to maintain effect
intraventricular
injected directly into a ventricle of the brain
enema
injection of a liquid through the anus to stimulate evacuation
intracardiac
inside the heart
-------- injections are administered into the top layer of the skin at a slight angle using short needles
intradermal
why do different IR spectra arise
intramolecular geometry (conformation) and intermolecular geometry (3D packing arrangement)
-----= injections are administered directly into the veins
intravenous
a dissolution stop would not be necessary for drug absorption from a/an
intravenous solution
a gel:
is a network of interlacing particles
Driving force for dissolution
is the concentration gradient across boundary (diffusion) layer (Cs-C)
same atoms and number of atoms, but rearranged differently
isomerization
Why is the alcohol content in elixirs important?
it helps solubility but may form precipitate in GI lumen that slows absorption
specific rate constant for a reaction
k
Rate constant for pseudo zero order:
k0'
Rate constant for pseudo first order:
k1'
________ is the Zero-Order rate constant with units of concentration (or mass)/time-1
k₀
Mixing ____________, a hygroscopic compound, in a solution with primary amine keeps the amine stable even when stored at 90°C for 12 weeks.
lactose
homeopathic pharmacopoeia of the us
law of similarities; cornerstone of regulatory framework for homeopathy and homeopathic drugs products in the us
What is the unit for the Permeability coefficient (P)?
length.time-¹ (cm.s-¹)
In an emulsion, the unionized preservatives are (water/lipid) soluble.
lipid
Free radicals formed by heat or light can cause oxidation of drugs, leading to
lipid peroxides, inactive drug
For the same compound, the more impurities present, the broader the melting point range, and the (higher/lower) the melting point.
lower
For weak BASES, the lower the pKa, the (lower/higher) the log Papp.
lower
poiein
make
In solid state atoms oscillate about
mean position
Diffraction geometry and braggs law
measure 2q calculate d, measure I associated w each reflection
spray
mist against mucous membranes of the nose and throat
emulsions
mixture of two liquids that do not dissolve into each other in which one liquid is spread through the other by mixing and using a stabilizer called an emulsifier
emulsions
mixture of two non-miscible liquids where one is dispersed throughout the other as tiny droplets
suspension
mixture of water and nondissolved materials
Accelerated stability testing focuses on:
moisture/humidity light temperature
multidose packaging: parenteral route - multidose vials
multidose vials contain either sterile liquid or powder to be reconstituted using sterile technique. if reconstituted, nurse must write date/time of prep on the label and must note the expiration date and storage
which device would be used to administer a volatile drug intranasally?
nasal inhaler
Saliva is (acidic/basic/neutral)
neutral
are polymorph 1 and solvate 1 chemically similar
no
would a crystal comprising 24 molecules in 6 unit cells be visible to the naked eye
no
Zero-order absorption
not common, only when--> -drug is absorbed by a saturable process -zero-order controlled-release delivery formulation is used
which dermal formulation is a base with drug incorporated into in
ointment
why do we look at kinetics
optimize yield, understand mechanism, slow reaction down (to stabilize)
Which route of administration is most common and why?
oral; it is convenient, economical, and high acceptance among patients
In Cell Diffusion: Donor compartment (Cd) is (inside/outside) of the cell membrane
outside
Addition of oxygen or removal of hydrogen
oxidation
Characterized by change in color, precipitation or odor
oxidation
loss of at least one electron when two or more substances interact
oxidation
What is the next common pathway for drug breakdown after hydrolysis?
oxidation Ex: Phenolic compounds
Controlling what reduces degradation from isomerization?
pH
Buffer system is at MAXIMUM CAPACITY when:
pH = pKa
H-bonds in phenylphrine HCl
positive charge on N delocalised onto H atoms of NH3 group ie H atoms have a partial +ve charge
In the Log K vs. 1/ε plot, opposite charges gives a ___________ slope and the same charges gives a _____________ slope.
positive, negative
buccal
pouch between the teeth and cheek in the mouth
___________ is the most common ingredient form used to compound other pharmacological dosage forms.
powder
Burst Effect is observed in systems that have been stored for a long time and the rate controlling membrane is ______________ with the drug.
pre-saturated
chewable
preferred form for vitamins, antacids, childrens med, quickly dissolves in the mouth
According to the law of mass action, the rate of chemical reaction is ____________ to the product of molar concentration of reactants eacch carried to the power equal to moles in substance.
proportional
nonaqueous solutions often contain glycerin, alcohol, and
propylene glycol
For atom to be placed inside void
radius of the atom must be less or equal to void ratio
Close packing principle amorphous solid
random (short range order) more tighly packed
Close packing principle gas
randomly oreintated, fast moving, large inermolecular/atomic distances
Close packing principle liquid
randomly orientated, fast moving, smaller intermolecular/ atomic distances
Bioavailability of Buccal or sublingual (SL)
rapid absorption of lipid soluble drugs
pharmacopoeia
recipe or formula or standards required to prepare a drug
international pharmacopoeia
recommendation to natl pharmacopoeia revisions
Alteration of the dielectric constant (ε) by non-aqueous, water miscible solvents (i.e. alcohol, glycerin, propylene glycol) (increase/reduce) the hydrolysis.
reduce
What is enteral route and what forms does it include?
refers to anything involving the alimentary tract (mouth to rectum) -oral -buccal -sublingual -rectal
Diffraction of x-rasy can be described by
reflection of the incident radiation from planes within the crystal
Ionic crystals
regular repeating pattern = long range 3D order = crystalline
ophthalmic
related to the eye
Describe delayed release (DR) dosage forms.
release active drug at a time other than immediately after administration at desired site in GI
If the RATIO of salt/acid or base/salt is IDENTICAL, then the pH will (remain unaffected/change)
remain unaffected
A major assumption of Noyes-Whitney relationship is that the Surface Area of the particle (remains constant/changes).
remains constant
Elimination
removal of the drug product (or metabolite) from the body
A buffer's presence in a solution ________ change in pH after addition of small amounts of BOTH acids and bases.
resist
Degradation mechanisms can be
reversible parallel consecutive
The Stokes Radius of a solute is the radius of a hard sphere that diffuses at a (same/different) rate as the solute.
same
The rate of the reaction is determined by the concentration of two chemical reactions or the square of the concentration of one chemical reaction
second order kinetics
Diffusion coefficients of MOST small molecules [MW: 100-500] are (similar/different) and the thickness is the same.
similar
Design of lipid matrix systems
simple formulation design, needs a: Matrix former Channeling agents Solubilizers
The ZERO-ORDER Dissolution Profile is under (sink/non-sink) condition
sink (straight positive slope)
example of overall rate equation
slide 42
Indigestible solids empty ___ and when?
slowly -mainly during the interdigestive phase when food is NOT present and the stomach is less motile but periodically empties its content due to housekeeper wave contraction
within the alimentary tract, pHs of 5-7 are typically found in the:
small intestine
Brownian Diffusion
small particles, randomized motion. Reach the desired site
Absorption through lymphatics (lacteals under microvilli) is possible for what type of drug?
some lipophilic drugs
international pharmacopoeia
source material for reference or adaptation by any WHO Member State to establish pharmaceutical reqs
a device that goes between an aerosol's mouthpiece and the patients mouth is a/an
spacer
Electrolytes increase the ionic strength of a formulation and can cause a ____________ problem.
stability
How do manufacturers determine expiration date?
stability testing under good manufacturing practices
multidose packaging: oral route - stock bottles
stock bottles contain a liquid or solid form such as tablets, capsule or powders. large stock bottles hold medication that's dispensed over a period of days. when reconstituting powders, nurse must write the date/time of prep on the container's label and carefully note storage direction and expiration date. powders once dissolved begin losing potency
Gastric Emptying Time
stomach empties faster during fasting state than when being fed
What is the most important layer of skin to consider when it comes to absorption of drugs?
stratum corneum
a solution MUST be ----- before crystallisation can occur ie it is not thermodynamically favourable before then
supersatured
What are the different forms of medications that can be administered rectally?
suppositories, gels, ointments, creams
List the hierarchy of stability of different dosage forms.
tablets/capsules (most stable) granules/powders suspensions solutions (least stable)
parenteral
taken into the body in a manner other than through the digestive canal
depot
the area in the muscle where the formulation is injected during an intramuscular injection
subcutaneous injection sites
the back of the upper arm, the front of the thigh, the lower portion of the abdomen and the upper back
disintegration
the breaking apart of a tablet into smaller pieces
nasal cavity
the cavity behind the nose and above the roof of the mouth that filters air and moves mucous and inhaled contaminants outward and away from the lungs
nasal mucosa
the cellular lining of the nose
Define solubility.
the concentration of solute in a saturated solution at equilibrium
what does the c in the equation stand for?
the concentration of the colored compound
injectability
the ease of flow when a suspension is injected into a patient
syringeability
the ease with which a suspension can be drawn demo a container using a syringe
Solubility
the expression of the quantity of a drug that can be maintained in solution in a given solvent at a given temperature and pressure: expressed as the number of mL's required to dissolve 1 gram of the drug
what does the l in the equation stand for?
the length of the light path
Glass, plastics and metal are
the most commonly used primary packaging materials.
Where is the drug most important?
the site of action (rarely measured)
in fingerprint diffraction the peak positions are determined by
the size and shape of the unit cell
alveolar sacs (alveoli)
the small sacks of specialized tissue that transfer oxygen out of inspired air into the blood and carbon dioxide out of the blood and into the air for exhalation
Unit cell
the smallest group of particles within a crystal that retains the geometric shape of the crystal
What is the parenteral route and what forms does it include?
the term means next to, or beside the enteral. refers to any sites of administration that are outside of or beside the alimentary system -intraocular -intranasal -inhalation -intravenous -intramuscular -intradermal -dermal -subcutaneous -vaginal
the absorption coefficient's value (E) depends on what?
the units of concentration
If large I
then more atoms in that plane of the crystal structure
If small I
then only a few atoms in or close to the plane
Lacking antibiotic activity is a ________ instability
therapeutic
Manufacturers and pharmacists have legal and moral obligation to ensure products maintain ______ ________
therapeutic efficacy
In active transport what happens if the drug conc gets very high?
there is a fixed number of carrier molecules available, all the binding sites on the carrier may become saturated
unit dose packaging parenteral route
these drugs come in solid of liquid forms and are given by injection via the route specified in the medication order (IV, IM, sub q, IVPB). drugs packaged in the containers are sterile. parenteral means aside intestines, so not administered orally
unit dose topical administration: plastic, disposable, squeezable containers
these hold either prepared solutions for the vagina or enema solutions that are administered rectally. to ease insertion, the containers for enemas that a lubricated nozzle. squeezing the container forces the solution out
Mucilages
thick, viscous macromolecular solutions produced by dispersing vegetable gums in water - commonly used as a suspending or thickening agents
Transcellular pathway is (through/between) the cells.
through
When a solute encounters a cell or tissue it has to cross, it can either travel through the cells OR between the cells through __________ ___________.
tight junction
Dissolution RATE is the drug dissolved per unit _________ under standardized conditions.
time
Dissolution testing provides information regarding the TOTAL ________ for the release of a drug.
time
In USP dissolution testing, CUMULATIVE AMOUNT of drug dissolved and PERCENT of labeled drug dissolved are plotted as a function of ________.
time
In-vitro dissolution test predicts the amount of drug available for absorption with respect to _________.
time
TD
time delay
chemical stability testing limitations of observing stability over entire shelf-life:
time-consuming uneconomical
multidose packaging: topical administration
topical medications are used over an extended period of time, so it's important to avoid contaminating them. nurses should label container w/patient's name and reserve the container's use for only that patient
Degradation products that cause adverse effects cause ______ instability
toxicological
Describe absorption
transfer of drug from its site of administration to the general circulation
Absorption
transfer of drug from its site of administration to the general circulation -the first process after we administer drug to a pt -depends on the route of administer -IV fusion administration is immediate and complete
Metabolism
transformation from one drug product to another
aqueous solutions are water based
true
insulin is routinely administered by the subcutaneous route
true
ophthalmic ointment tubes typically hold about 3.5g of ointment
true
oral administration is the most frequently used route of administration
true
phlebitis can be complication of intravenous administration
true
toxic shock syndrome is a disease caused by a bacterial infection
true
true or false: there are many degradation pathways of epinephrine
true: oxidation, photolysis, and chemical incompatibility (racemization, sulfonation) -most important is oxidation because of its 2 hydroxyl groups (slide 17)
sublingual
under the tongue
Basic repeating pattern is
unit cell
What kind of drugs degrae if gastric emptying is delayed?
unstable drugs (penicillin)
Energy from Active Transport moves (up/down) the concentration gradient.
up
The radius ratios in the cation is to anion ratio table can be obtained by
using the equations in the previous flashcard (the sums of r+ and r-) and writing d in terms of the cation or anion forming the Unit cell This can be used to obtain the radius of the void i.e. the radius of the largest ion which can fit in it.
every 10 years
usp convention and usp revision
What is OraVescent technology?
utilizing an effervescent reaction which is thought to enhance the rate and extent of fentanyl absorption through the buccal mucosa
Relative Humidity (φ) depends on temperature and _________.
vapor pressure of water
volatile drugs are susceptible to
vaporization Example: Nitroglycerin
The process of deliquescence is dictated by _______ diffusion and _______ transport rates.
vapour, heat
What are the junctions like in the GI?
very tight -very minor role in drug absorption
Aromatic Waters
volatile oils in water and are used to provide a pleasant flavor or aroma - peppermint water, USP
aqueous
water based
Question from lecture: TGA can measure the _______ change of the materials when the temperature changes.
weight
mucilage
what is a semisolid mixture of an organic substance and a medicinal agent, vegetable matter.
What is pharmacokinetics?
what the body does to the drug (effected by compliance, absorption, med errors, interactions, and elimination)
What is pharmacodynamics?
what the drug does to the body (effected by drug receptor status, genetic factors, interactions, and tolerance)
jan 6 1817
when dr spalding suggested the creation of natl pharmacopoeia
injection
when someone puts a liquid, especially a drug, into a person's body using a needle and a syringe from small tube
sublingual administration
when tablets are placed under the tongue
Rubbing Alcohol USP
~ 70% v/v
Lag-time Effect AND Burst Effect are dependent on what 2 coefficients?
⓵ Diffusion coefficient (D) ⓶ Membrane thickness (h)
C₁ and C₂ can be calculated by what 2 coefficients?
⓵P and ⓶Papp of the solute
When moisture is absorbed to the extent that deliquescence takes place, the liquid film surrounding the solid is ______________
saturated (becomes soluble)
Thermogravimetric Analysis (TGA) can provide information about physical phenomena such as _______-_______ phase transitions.
second-order
topical
semi-solid dosage direct application of a medication to the skin, eye, ear, or other parts of the body on mucous membranes or body cavities
Cell membranes are ___ that act as?
semipermeable partitions -selective barriers to the passage of molecules
ointment
semisolid preparation (usually containing a medicine) applied externally as a remedy or for soothing an irritation
Food delays stomach emptying of enteric coated tablets for?
several hours
✰✰✰ (IMPORTANT) In Fasting & Nonfasting: - Emptying time is much (shorter/longer) in FASTED state than FED (absorptive) state.
shorter
Signs of instability: gels
shrinkage, separation of liquid from the gel, discoloration or microbial contamination
alveoli
small scars of a liquid
unit dose parenteral route: prefilled cartidges
small vials with a needle or needleless device attached. they fit into a metal or plastic holder and eject 1 unit dose of sterile drug in liquid form
Why is particle size important for water solubility?
smaller particle size means the particles have a larger surface area available for aPI dissolution
Signs of instability: troches
softening or hardening, crystallization, microbial contamination or discoloration
Signs of instability: suppositorites
softening, drying, hardening or shriveling
whats the most widely used dosage forms
solid
bulk powders
solid formulations to be mixed with water or juice
Define amorphous solid.
solid in which there is no long range order of the positions of molecules/atoms; higher free energy, therefore higher apparent solubility and dissolution rate
dissolution depends on
solubility
Oral syrups contain ____________ APIs.
soluble
What are water-soluble ointment bases?
soluble in water, easily removed
How does the seed crystal grow
solute molecules will be deposited onto it
For a drug to be absorbed into systemic circulation and distributed to site of action, it has to be present in (solid/solution) form at the site of ABSORPTION.
solution
what is happening at 2
solution is supersaturated seed crystals will grow, no spontaneous crystal growth
lotion
solution or suspension of soothing substances to be applied on the skin in acute inflammation to relieve pain
describe what is happening at 3
solution supersaturated & crystal growth occurs
List the hierarchy of dissolution and absorption rates of different dosage forms.
solutions (fastest) suspensions/emulsions ODTs/divided powders tablets/capsules (slowest)
Glycerins or Glycerites
solutions composed of no less than 50% glycerin by weight - extremely viscous and are generally used in topical products
Liniments
solutions of various substances in oil, alcoholic solutions of soap or emulsions which are intended for external application
Water Miscible Cosolvent Systems
solutions of water and water miscible solvents such as alcohol, glycerin, propylene glycol, PEG 400 - used to improve the solubility of poorly soluble organic substances and may be formulated for oral, topical, or parenteral administration (i.e. phenytoin injections)
The dielectric constant (ε) is used in the equation that predicts the effect of ___________ on hydrolysis rate.
solvent
In the Diffusion Layer Model: A ________ liquid film forms on the surface of a particle with thickness 'h'.
stagnant (still/inactive)
influence of posture on gastric emptying
standing & lying on right side favors, while lying on left side & supine position retards gastric emptying
What is biopharmaceutics?
study of the relation of the physical and chemical properties of a drug to its bioavailability, PK, PD, and toxicology effects
the most common injection route for insulin is
subcutaneous
which of the following routes is least likely to give a systemic effect?
sublingual oral, rectal and intradermal would be more likely to give a systemic effect
what route of administration is not enteral?
sublingual rectal, inhalation and buccal are all enteral
Syrups
sucrose in water 60-80% sucrose, less than 10% alcohol - simple syrup (syrup USP) - Cherry syrup, acacia syrup - Medicinal syrups (guaifenesin syrup)
dr lyman spalding
suggested to the med society of ny the creation of natl pharmacopoeia
cohesive packing energied
sum of intermolcular interactions
unit dose topical administration: suppositories
suppositories in foil or plastic wrappers are molded in form that can be inserted into the rectum or vagina. they hold medication in a substance such as cocoa butter that melts at body temp and releases the drug. suppositories may be used for unconscious patients or those unable to swallow
which parenteral route of administration would typically use the longest needle with the smallest gauge?
suspension
SA
sustained action
Describe extended release (XR) dosage forms.
sustained plasma concentration that avoids toxicity; provided immediate release and slower sustained release
SR
sustained release
Matrix system design (hydrophilic matrix system)
swelling, slow-dissolving matrix Swell upon contact with body fluids, forming Drug release may be close to zero-order kinetics
What are some disintegration mechanisms?
swelling, wicking, strain recovery
First-order shelf-life equation
t90% = 0.1054/k
summary of 0. 1st, 2nd
table on slide 31
enteric coated
tablets coated by a special chemical that resists gastric secretion but disintegrates in the intestines
Delayed Release (DR) by time or targeted site
targeted release
lacrimal canalicula
tear ducts
The Arrhenius equation is a formula for the ___________-__________ of reaction rates
temperature dependence
chemical reactions will occur at a various rates based on ________
temperatures
Pharmaceutical Crystals
tend to be small organic molecules
when molecules are more relcuctant to leave the solid and enter solution than another polymorph what does this show
that that particular polymorph has the more thermodynamically favourable packing arrangement
what does the E in the equation stand for?
the absorption coefficient
percutaneous
the absorption of drugs through the skin, often a systemic effect
percutaneous absorption
the absorption of drugs through the skin, often for a systemic effect
The physiochemical properties of solid dosage forsm are correlated to
the crystal structure of the raw materials
Stability
the extent to which a preparation retains, within specified limits, and throughout its period of storage and use, the same properties and characteristics that it possessed at the time of compounding
conjuctivia
the eye lid opening
lacrimal gland
the gland that produces tears for the eye
I in braggs law
the intensity, tells us about the contents of these planes
The primary pack (also called the container closure system) is in direct contact with the medicine. It must be compatible with
the medicine, and must not change it in any way.
when c is expressed as molarity, what is E termed?
the molar absorption coefficient
The intensities of powder x -ray diffraction are determiend by
the position of atoms within the unit cell
buccal cavity
the pouch between the cheeks and teeth
water soluble
the property of a substance being able to dissolve in water
Permeability, solubility and dissolution rate determine
the rate and extend of bioavailability and IVIVC
Bioavailability
the rate at and the extent to which a nutrient is absorbed and used
In a First-Order Reaction, over the SAME TIME period, the fraction of UNCHANGED drug REMAINING will ALWAYS be (the same/different).
the same
when administering ophthalmic drops, why is instilling 2 drops at a time not recommended?
the second drop will cause corneal abrasions
viscosity
the thickness of a liquid a measure of thickness or resistance to flow
Pharmacist Responsibility: Properly ______ and _______ admixtures
treat and label
a low pH value such as 1 or 2 indicates a high acidity
true
Define sonophoresis.
ultrasound waves stimulate micro vibrations within skin epidermis and overall KE of molecules, therefore increasing absorption
Dissolution Testing is used as a quality control tool to evaluate batch->batch __________ of formulations, which is mandated by the FDA.
uniformity
Preservatives in oral liquid are (ionized/unionized).
unionized
types of solids and definitions of important terms
update
lititz pharmacopoeia
used by military hosp of the us army
unit dose parenteral route: flexible plastic bag or glass containers
used to hold sterile medication for IV use. nurses administer fluids via IV tubing connected to a needle or catheter placed in patient's blood vessel
Gamma Scintigraphy
used to track dosage form movement from one region of the GI tract to another
Hexagonal closed packing (HCP)
uses hexagonal packing layers in AB-AB structure In metals like Zn, Mg
CCP (Cubic closed packing) or FCC
uses hexagonal packing layers placed in ABC-ABC pattern (also called FCC packing structure) In metals like Cu and Ag
Square closed packing
uses square packing layers in A-A-A-A pattern
body center closed packing
uses square packing layers in AB-AB structure
visible light spectroscopy
uses visible light to detect the absorbance of a solution at a particular wavelength
synstemic effect
when a drug is introduced into the circulatory system by any route of administration and carried to the site of activity
dissolution
when the smaller pieces of a disintegrated tablet dissolve in a solution
intra-arterial
within a artery
intra-articular
within a joint
multidose packaging
within an institutional setting, the unit may receive large stock containers from which doses are poured. while this reduces pharmacy's workload, it adds prep time and increases possibility of error
Van der Waals Forces applies to compounds (without/with) a permanent dipole (i.e. CCl4)
without
1864
year british pharmacopoeia was made
1888
year nf of unofficial prep was published
1940
year revision of usp was changed from 10 yrs to 5 yrs
Can one polymorph be bioavailable and the other one not?
yes
Can temperature changes during manufacture and storage can have significant effects upon polymorphic form ?
yes
Is crystallisation from a supersaturated solution is thermodynamically favourable process
yes
Is nucleation a kinetic process
yes
are polymoreph 1 and polymorph 2 chemically idenitcal
yes
for carboxylic acids do even numbered chains have higher melting points than odd numbered chains
yes
is an ordered close packed structure thermodynamically favoured
yes
will different polymorphs of the same chemical compoud hjave different solubilities
yes
Will nature transform polymorphs
yes if it the theromodynamically favoured direction of change
Sink Condition is when Cr is near _________ or much LOWER than Cd.
zero
rate is constant and independent of concentration of reactant
zero-order
time required for half of a substance to degrade
zero-order half life t½ = [A]/2k
autooxidation examples
• RH → R∙ + H∙ (initiation) • R∙ + O2 → ROO∙ (propagation) • ROO∙ + RH → ROOH + R∙ • R∙ + R ∙ → R-R (termination) • ROO∙ + H∙ → R-OH • R∙ + X → non reactive product (X is an inhibitor)
⬆ log P, ⬆ absorption, ⬆ protein binding (harder for drug to be released), ____ aqueous solubility.
⬇
What are some ways to enhance solubility?
- Modify structure - Reduce particle size - Adding co-solvent, complexing agent, surfactant - Adjust pH - Advanced formulation
dermal dosage forms
-solutions -tinctures -collodions -liniments -suspensions -ointments -creams -gels -lotions -pastes -plasters -powders -aerosols -transdermal patches
Nonaqueous solutions-
-solutions which predominately contain solvents other than water, either alone or in addition to water.
solubility effects
-some drug products may be stabilizes by preparing insoluble salts and formulating them as suspensions -reduced solubility in a suspension decreases amount of drug available for reaction -when in solution drug may undergo apparent first order reaction, but when formulated as a suspension it decomposes through apparent 0 order (why antibiotics are made into suspension-> more stable as the trihydrate version has little solubility)
Vaporization
-some drugs possess high vapour pressure and drug is lost through vaporization -severe changes in tablet content and uniformity may occur
protect product from light
-statement on the label and package should exclude light -amber glass, opaque plastics and some come in foil wrapping when given by IV infusion (nitroprusside)
You can prevent oxidation by:
-storing in nitrogen or carbon dioxide -use an excipient that is more readily oxidized than drug (antioxidant) -use an excipient that intercepts a free radical in propagation
Describe oral syrups.
-sweet, aqueous, viscous solution -great for children -commercial syrup vehicles are available for compounding syrups (usually contain 85% w/v sucrose)
Buccal route dosage forms
-tablets -solutions
Membranes surround what and what is it's function?
-the entire cell -acts as a boundary between the cell and the interstitial fluid
infusion
-the gradual intravenous injection of a volume or fluid into a patient
intramuscular injections
-the principle sites of injection are the gluteal maximus, deltoid, and vastus lateralis -generally result in lower but longer lasting blood concentrations than with IV administration
oral administration
-the stomach has a pH around 1-2. some drugs can't be orally taken because they are degraded or destroyed by the stomach acid and intestinal enzymes.
intravenous sites
-the veins of the antecubital area (in front of the elbow), the back of the hand, and some of the larger veins in the foot.
how could you get rid of copper or iron as a catalyst
-these are catalysts in oxidation -put in a kelating agent (EDTA)-> hangs on to these di or trivalent metals -can put into drug r into water supply (perform a limit test to make sure there are minimal amounts)
excipient
-things we add to the drug to make it usable
what do we use to determine the shelf life for a product
-use the general of chemical kinetics
Lipinski's Rule of 5
-used to predict oral drug absorption -rules for drug molecules that would improve the chance for oral absorption: 1. MW </= 500 Da 2. Not more than 5 H-bond donors (NH, OH) 3. Not more than 10 H-bond acceptors (N,O) 4. Octanol-water partition coefficient. log P </= 5.0
exclusion of oxygen
-useful in parenteral -purged with inert gas (usually N) and sealed
control of pH
-usually a pH of 3-4 is useful providing this pH range has no deleterious effect on product and is physiologically acceptable
Describe urethral drug delivery.
-usually in males -Alprostadil is only drug administered by this route (pellet)
What are absorption ointment bases?
-water in oil emulsion, not easily removed with water -useful as pharmaceutical adjuncts to incorporate small volumes of aqueous solutions into hydrocarbon bases
can changes in solvent composition be helping for stabilization
-yes, depending on nature of transition product
3D molecule + ordered packing arrangement --->
3D molecule + unit cell ---> crystal structure
✰✰✰ (IMPORTANT) In Fasting & Nonfasting: - Intestinal transit time varies from ______ to ______ hours in the upper intestine.
1 to 4
USP and FDA requirements
Drug release profile Uniformity between doses IVIVC (in vitro in vivo correlation) -- Predictability Labeling & patient counseling
In the Diffusion Layer Model: What is the stationary (unchanged) diffusion layer on the liquid film of a drug called?
Drug solubility (Cs)
Parameters affecting dissolution: diffusivity (D)
Drug structure Viscosity of GI fluids Presence of Food Secretions
Timing of Preformulation
Drug synthesized ➔ Toxicity studies ➔ Analytical work ➔ Preformation work ➔ Phase I ➔ Phase II ➔ Phase III ➔ NDA ➔ Production
For topical administration
Drugs applied to the skin or mucous membranes can achieve a local effect. They ca also achieve a systemic effect because they can be absorbed into the circulation.
Aqueous Solutions
Drugs are dissolved in WATER (solvent) along with necessary flavorings, preservatives, or buffering salts
Safety; Large
Drugs suitable for Oral Extended release: Good margin of ____ (____ therapeutic index)
Uniformly
Drugs suitable for Oral Extended release: ____ absorbed from the gastrointestinal tract
T/F: Highly potent drugs are given via matrix patch as opposed to a reservoir patch.
FALSE: highly potent drugs are given through reservoir patches
T/F: The stratum corneum is the outermost layer of skin and maintained the same thickness throughout the body regions.
FALSE: stratum corneum thickness changes regionally
For small molecules, their diffusion coefficients (D) are the major determinant of cell membrane permeability. (T/F)
False
Question from lecture: Differences between polymorphs exists in all states of matter. (T/F)
False
Question from lecture: Monotrophism is a phenomena that one polymorph is stable over certain pressure and temperature range, while the other polymorph is stable over different pressure and temperature range. (T/F)
False
In class Question: Slide 36 Fick's First Law describes Non-steady-state diffusion. (T/F)
False The 2nd Law of Diffusion follows Non-Steady-State Diffusion
In class Question: Lag-time effect is observed in systems that have been stored for a long time and the rate controlling membrane is pre-saturated with the drug. (T/F)
False This is the definition for Burst Effect
In FTRI, only liquids can be used to identify polymorphs. (T/F)
False! Only SOLIDS can be used.
In class Question: The permeability coefficient (P) represents the inherent permeability of a membrane. The unit of P is length²/time. (T/F)
False! The unit of P is length/time
Question from lecture: A COMPLETELY Amorphous compound does not show any crystallization dip, but shows the melting peak in a DSC graph. (T/F)
False. - Amorphous has NO crystals.
Both P and Papp can change. (T/F)
False. P NEVER changes but Papp can change.
A compound has the enthalpy of fusion (△Hf) of more than 0. When we increase the temperature of the solution, the solubility of this compound decreases. (T/F)
False. The solubility increases
T/F: Stirring, which effects h, will decrease the rate of dissolution.
False: stirring will increase dissolution rate
In hygroscopicity, what does moisture affect?
Flow, compaction, dissolution, stability, storage, and packaging.
Irritating drugs are taken with what?
Food even through absorption rate is decreased (extent of absorption and efficacy are often unchanged)
Modulation of Pre-systemic Metabolism
Food/drug that induce or inhibit enzymes in the gutwall or liver: Substrates: verapamil, cyclosporin, testosterone
Crystalline solid
Formed by repition of of a single patter Eg:Quartz, NaCl
Non-stoichiometric defect
Formula of crystal changes Example FeO→Fe₀.₉₅O Usually present in transition metals, lanthanides and actinides It can be a METAL EXCESS or METAL DEFICIENT defect. METAL EXCESS→ Cation>Anion (i)ANION VACENCIES:Anions are missing and replaced by electrons. Example, This can be created by placing NaCl in sodium vapours. Na from the vopours will lose one electron which will replace Cl from the crystal This electron is called an F-CENTER or Farb center from german Farbenzenter meaning colour center. This electron absorbs white light and emits light of specific colours example, NaCl+Na→Yellow LiCl+Li→Pink KCl+K→Violet (ii)EXTRA CATION IN INTERSTITIAL SITES An extra cation is added to the interstitial sites. To balance this, an electron is also added to another interstitial site. Example of ZnO ZnO+∆→Zn⁺²+2e⁻+½O₂↑ So oxygen will leave the crystal. The Zn⁺² wil occupy the interstitial sites and so will the 2e⁻ Yellow colour of ZnO when hot is due to these trapped electrons. Due to these Metal excess defects, free electrons created make the material a SEMICONDUCTOR METAL DEFICIENT→ Cation<Anion An extra cation is removed because of which equivalent number of anions are removed Example on removing 1A²⁺, 2 B⁻ are removed. EXAMPLES:FeO,FeS,NiO Shown in compounds where cation has variable valency
Beads; Microencapsulated; Hydrophilic; Plastic; Complex; Osmotic Pump
Formulations of Extended-release oral dosage forms: -Coated ____, Granules, and Microspheres -____ Drug -Embedding Drug in Slowly Eroding or ____ Matrix System -Embedding Drug in Inert ____ Matrix -____ Formation and Ion-Exchange Resins -____ ____
Extended
Formulations of ____-release oral dosage forms: -Coated Beads, Granules, and Microspheres -Microencapsulated Drug -Embedding Drug in Slowly Eroding or Hydrophilic Matrix System -Embedding Drug in Inert Plastic Matrix -Complex Formation and Ion-Exchange Resins -Osmotic Pump
A technique used to obtain an infrared spectrum of absorption, emission, photoconductivity, or Raman scattering of a solid, liquid, or gas.
Fourier Transform Infrared Spectroscopy (FTIR)
_________ ________ is used to analyze the release of drugs from Semi-Solid dosage forms.
Franz cell
Signs of Instability: solutions/elixirs/syrups
Free of precipitates, discoloration, haziness, gas formation and microbial growth
What factor indicates how many collisions have the correct orientation for molecules to react and form products?
Frequency Factor (A)
a stock solution
From where can a series of serial dilutions be made from?
Drugs may be absorbed form most areas of the ___?
GI tract
Most drugs are ABSORBED in the __________ __________ by passive diffusion.
GI tract
Low density polyethylene vs High density polyethylene
HDPE - has greater rigidity compared to LDPE - more likely to undergo stress cracking - higher melting point - lower gas permeability - used of bottles and jars LDPE - used in the heat sealing layers in laminates Additives in the plastics are usually antioxidants and antistatic agents
BCS III
High solubility Low permeability permeation across barrier is limiting step penetration enhancers may improver BA difficulty to make extended release ex: ranitidine, atenolol
Temperature
High temperatures can degrade drugs and damage dosage forms - suppositories can melt if heated - creams can crack and separate - pack breakdown can accelerate compound decomposition Low temperatures can degrade plastics by making them brittle - selection of the plastic used in packaging is important - some plastics are not suitable for heat treatment - some plastics cannot be stored in the freezer
What kind of meals are mostly likely to affect GI physiology?
High-calorie and high-fat meals FDA recommendation: use high-calorie and high-fat meals to study the effect of food on bioavailability
The ________ square root of time equation is used to calculate the AMOUNT of Semi-Solid dosage forms released.
Higuchi
Who used the weight technique to modify the Noyes Whitney Equation?
Hixson-Crowell
Plastic, disposable, squeezable containers
Hold either prepared solutions for the vagina (douches) or enema solutions that are administered rectally.
KNOW! The lipophilicity/ partition coefficient (P) of the SOLUTE is a MAJOR of determinant of cell membrane _____________.
PERMEABILITY
Dosage; Partition Coefficient; Size; Solubility; Stability; Protein; pKA
PHYSIOLOGICAL Factors: 1. ____ Size 2. ____ ____ and molecular ____ 3. Aqueous ____ 4. Drug ____ 5. ____ Binding 6. ____
packing efficiency
Packing efficiency=Z(4/3)πr³/a³ replace r and Z with values based on type of unit cell.
How to assess drug release and dissolution? (QC) USP Method II
Paddle apparatus No stirring
Fatal
Pain killers = Crushing Morphine for example could lead to a faster release that is potentially ____
Non-Systemic Drug Administration Route
Parenteral -Intracardiac -Intrathecal -Intralumbar Rectal Buccal Dermal Pulmonary Nasal Vaginal Opthalmic Otic Urethral
T/F: the rate of dissolution can be increased by a decrease in particle size of drug powder which increasing surface area.
TRUE
Na₂O (Anti-flourite structure)
4:8 coordination compound structure O occupies FCC lattice and Na occupies tetrahedral voids. Basically opposite of flourite structure.
If shelf life (t90%) is known at a cooler temperature and to be estimated at a warmer temperature, use Q10 value _________.
5
What is the optimal volume to administer, based on eye capacity?
5-10 uL
Biopharmaceutics of Stomach
50 mL of gastric fluids Small surface area pH~1-3.5 Contain hormones, Protein & mucus Reduces solids to a uniform cream to increase contact with membrane little absorption Temporary reservoir Motility - Gastric Emptying Time
the normal commercial eyedropper dispenses ---- of solution
50 microliters
When pH = pKa, _______% of the solution is ionized and _______% is unionized.
50, 50
Packing fraction SCC
58.4%
Refrigerated condition is at _______°C.
5°C
GI tract is a muscular tube that contains
6 m and varying diameter tissues & cells pH, components, food Gastric & small intestine
Number of voids in different packings 2)HCP
6 octahedral voids 12 tetrahedral voids
Intestinal pH varies from _______ to _______.
6.5 to 7
Ratio of half life to shelf life for first order reactions:
6.577
Buffers in blood maintain pH at ___________.
7.4
Eye fluids are maintained at pH __________.
7.4
Packing fraction FCC
74%
USP requires determination of time for _______% of the labeled amount of drug to dissolve.
75% (t75)
Breast Cancer
____ ____ meds = Cancer medication Tamoxifen is dangerous if inhaled by the person crushing it. Other chemo drugs should not be crushed because it could be fatal.
Blood Pressure
____ ____ meds = Nifedipine for example increases the risk of stroke if crushed
Repeat Action
____ ____ systems usually contain two single doses of medication, one for immediate release and the second for delayed release (i.e. initial dose, then, 4-6 h later, second dose)
Functions of packaging - identification
allows patients/consumers to identify the medicine
Triclinic System (Bravais lattice)
a≠b≠c α≠β≠γ≠90° 1)Primitive
adhesive transdermal patch
backing and adhesive/drug layer
Amlodipine and Cimetitine are weak _____________.
bases
Unit cell is an abstract concept
basic builiding block of the crystal lattice and describes the minimum repeating structure
How to assess drug release and dissolution? (QC) USP Method I
basket apparatus, no stirring
A pack can
be a single-unit pack (e.g. a sachet) or a multiple-unit pack (e.g. a bottle containing many tablets).
Preformulation investigate physicochemical properties of drugs and excipients ____________ formulation.
before
subcutaneous
beneath the skin, type of suspension, inject-able, depot therapy.
Paracellular pathway is (through/between) the cells.
between
Where is the buccal pouch?
between mandibular arch and oral mucosa
buccal
between the cheek and the gum
Date after which a repackaged or compounding preparation should not be used; determined from the date the preparation is repackaged or compounded
beyond use date
enteric coated
coating that will not let the tablet disintegrate until it reaches the high pHs of the intestine
samuel hahnemann
coined homeopathic pharmacopoeia of the us
international pharmacopoeia
collection of recommended procedures for analysis and specifications for the determination of pharmaceutical substances and dosage forms
Nucleation and crystallistion
collisions occur betweeen molecules in solution, a critical cluster is reached and a stable nucleus is formed. Further molecules attach and crystal growth ensues, if critical size is not reached unstable clusters fall apart
unit dose packaging oral route
comes in number of forms: capsule/tablets; plastic or glass containers that hold a single dose of liquid or powder (powder is reconstituted into liquid form by following directions of label); sealed medication cup containing a liquid
zero-order half-life is ____________ __________-
concentration dependent
what factors influence rate?
concentration, reaction order, temperature, solvent
What are the units of rate?
concentration/time (M/s)
Zero order rate constant (k) units
concentration/time (M/s)
What are the benefits of parenteral drug delivery?
faster onset of action, permits titration of dosage, ideal for enzymes by bypassing gastric acid
Higher equilibrium saturated solubility correlates to
faster rate of dissolution
IV emulsions
fat emulsions and TPN emulsions are used to provide triglycerides, fatty acids. and calories for patients who can not absorb them from the gastrointestinal tract
what drugs could possibly absorbed through the stomach?
fat soluble, acid stable drugs
Photons from UV light have enough energy to induce ________ of a _____ __________
formation free radical (or another reactive intermediate)
Step 2: Food & Drug Interactions (Influence on gastric emptying)
gastric residence time usually varies from 5 min to 2 h
intravenous administration needle:
gauge: 16-20 length: 1-1.5"
intramuscular administration needle:
gauge: 19-22 length: 1-1.5"
subcutaneous administration needle:
gauge: 24-27 length: 3/8-1"
intradermal administration needle:
gauge: 25-26 length: 3/8"
unit dose parenteral route: vial
glass or plastic container with sealed rubber top. container may have sterile liquid or powder that must be reconstitute with sterile diluent and syringe
Unit for Buffer Capacity
gram equivalent liter-1.pH-1
Inhibitors of CYP3A
grapefruit juice, pomegranate juice, cimetidine, metronidazole, diltiazem, erytromicin
hydrophilic
having a strong affinity for water
BCS I
high solubility high permeability rapid dissolution good bioavailability ex: propranolol P eff > 4 x 10 ^ -6 m/s
For the same compound, the purer the compound, the narrower the melting point range, and the (higher/lower) the melting point.
higher
For weak ACIDS, the lower the pKa, the (lower/higher) the log Papp.
higher
Question from lecture: (Refer to slide 20 of lecture) In a DSC graph, compounds have a _________ heat capacity above the glass transition temperature than below it.
higher
Highly soluble
highest dose strength soluble in < 250 ml aqueous media over pH range of 1-7.5.
Duodenal region is ____ perfused with what?
highly network of capillaries and lymphatic vessels
solutions
homogeneous mixtures, a mixture where substances are distributed evenly. Has a solvent & solute
What forces bind molceules together in the solid state
hydrogen bonding, electrostatic, dipole - dipole, dispersion
The most common chemical reaction that leads to instability is
hydrolysis
reactions of decomposition:
hydrolysis oxidation photodecomposition isomerization
Addition of (hydrophilic/hydrophobic) drugs in modified cyclodextrin increase dissolution rate by increasing water solubility.
hydrophobic
Polymeric materials (PEG, PVP) can affect the rate of dissolution of (hydrophilic/hydrophobic) drugs.
hydrophobic
example of loss of volatiles
ie nitroglycerine- has a very high vapour pressure as a chemical -make paste with water, alcohol, lactose and drug-> make the tablet -it is very volatile - when you open the bottle up, some of the nitro leaves- each time you open it you lose more -ibuprofen is also like this so we put a coating around it -cant put a coating on nitro, so instead we added PVP into it- stabilized it; can also use spray
When is nucleation not needed
if a seed crystal is added to a saturated solution
Partition Coefficient is the ratio of the concentration of the compound in the two phases of a mixture of two ____________ solvents at equilibrium..
immiscible
Solubilizers
improve drug dissolution: surfactants, PEG, pH modifiers
Paper is used mainly
in the secondary packaging. The latter holds/covers the primary pack.
Solvates arise from
inclusion of solvent crystalisation
As temperature increases, degradation rates:
increase
Decreasing Particle Size by micronization (increases/decreases) Surface Area.
increase
In Solid dosage forms: Binding agents (increase/decrease) dissolution rate by increasing wetting.
increase
Pregnancy has the potential to do what?
increase Tmax and decrease Cmax
influence of food on gastric emptying
increase fat (fatty meals) can delay gastric emptying & absorption of drugs
Step 2: Food & Drug Interactions (Stimulation of GI secretions)
increase fat stimulates secretion of bile bile salts are surfactants, increase drug dissolution bile salts form non-absorbable complex with neomycin
necrosis
increase in cell death
Adding wetting agents
increase wettability, increase solvent contact and decrease particle aggregation
Inducers of CYP3A ______ CYP3A activity, _______ drug metabolsim and ______ bioavailabilty.
increase, increase and decrease
In pregnancy decreased absorption=
increased stomach pH and increased mucus production
Addition of surface active agents in the dissolution medium (increases/decreases) the rate of dissolution by wetting the particles.
increases
As Temperature increases, Degradation _______________.
increases
As temperature increases, a greater fraction of molecules become activated and reaction rate ____________.
increases
Electrolytes ___________ tonicity of a solution.
increases
In Zero-Order Reactions, as DEGRADATION decreases, HALF-LIFE _____________.
increases
In Zero-Order Reactions, as INITIAL CONCENTRATION increases, HALF-LIFE _____________.
increases
Increase in solvent (increases/decreases) epsilon (ε)
increases
Q10 is the factor by which the rate constant (decreases/increases) for a 10°C temperature increase.
increases
For a drug absorbed by passive diffusion the rate of absorption ____ in what kind of relationship?
increases -linear relationship to drug conc (first-order rate)
The Frequency Factor is (dependent/independent) of Temperature.
independent
excipients
inert inactive additives to a drug formulation that affect the bulk, delivery, or availability of a drug.
the gradual intravenous injection of a volume of fluid into a patient is called
infusion
inactive ingredient
ingredients beside the active drug that include binders, effervescent salts, lubricants, fillers, diluents and disintegrates
buffer system
ingredients designed to control the pH of a product
MDIs are used to deliver drugs by
inhalation
z-tract injections
injection technique for medications that stain the skin generally 2-3 inches deep
How do we determine if a material is crystalline or amorphous
inpect visually - well defined angles, flat faces and sharp edges all present on crystalline substances
In Cell Diffusion: Receptor compartment (Cr) is (inside/outside) of the cell membrane
inside
Aqueous solubility of less than 10ug/mL and 10-100ug/mL are practically (soluble/insoluble)
insoluble
In SUSPENSIONS, there is an equilibrium between (soluble/insoluble) solid drug and saturated solution of the drug.
insoluble
Step 2: Food & Drug Interactions (Complexation)
insoluble complexes decrease rate of absorption Tetracycline with Ca or Fe Promazine with charcoal Cyanocobalamin with talc
Oral suspension contain ________________ APIs.
insoluble/poorly soluble
Pharmacist Responsibility: Observe products for evidence of ___________
instability
Food can affect the physical ____ of the dosage form
integrity
d in braggs law
interplanar spacing provides the separation between many different planes thousands in the crystal structure
Where does Disintegration, Dissolution, and Absorption occur?
intestine
intraperitoneal
into abdominal cavity
intraocular
into an eye
intrapleural
into sac surrounding the lung
intradermal
into the skin
intrathecal
into the space around spinal canal/cord
intravaginal
into vagina
What are some less common routes for parenteral drug delivery?
intra-arterial, intra-thecal, intra-articular, ESI
Heat of fusion of solids
is definite for crystalline solids and not definite for amorphous solids
The upper stomach is (more/less) acidic than the lower stomach.
less
The villi are ___ abundant in other areas of the GI tract
less
When impurities are present, it takes (more/less) energy to disrupt crystal lattice.
less
The dissolution rate is important for drugs with dissolution rate (less than/more than) absorption rate.
less than
Drug concentration is higher in water than octanol when Log P is?
less than 0 (more water soluble)
Carbon nanotubes
lighter than aluminium stronger than steel andmore conductive than copper
Prednisolone, Dexamethasone, and Prednisone are (lipophilic/hydrophilic)
lipophilic
what drugs could possibly absorbed through limp haptics (lacteals under microvilli)?
lipophilic drugs
pH affects hydrolysis of drugs in ___________ formulations.
liquid
Collodion
liquid preparation containing nitrocellulose pyroxylin in a mixture of ethanol and ethyl ether. - leaves a filmy residue of pyroxylin - provides occlusive protective coating to the skin
____are generally emptied faster than _____ from the stomach
liquids digested solids
What is not retained in the stomach and why?
liquids and small particles (<1 mm) -emptied due to higher basal pressure in the stomach over the duodenum
national formulary of unofficial preparations
list of popular drugs and formulas not included in usp
Close packing principle crystalline solid
long range order (lattice, unit cell) close packed structure
multidose packaging: topical administration - lozenges and pastilles
lonzenges and pastilles can be packaged in multidose
what is the first effect of photochemical decomposition?
loss of potency
Drugs with ________ log P values have high aqueous solubility, and are too hydrophilic to have affinity for membranes, therefore poorly absorbed.
low
Drugs with high log P values has __________ aqueous solubility.
low
High Activation energy (Ea) = ____________ degradation rate.
low
Conc of the drug in the blood is ___ relative to the conc at the site of ___
low drug absorption thus C GI (conc in GI) >> Cp (conc in plasma)
In a Eutectic Mixture, a mixture of 2 compounds has a (higher/lower) melting point than any other ratio of mixture.
lower
In most pharmaceutical systems, the concentration of drug in the receptor (Cr) is MUCH (lower/higher) than the donor (Cd).
lower
Question from lecture: An individual SOLUTE molecule can move from __________ concentration to _________ concentration.
lower, higher
Transcytosis is an important pathway in drug transport. Transcytosis involves __________.
lysosomes
What is the SLOPE for the Zero-Order Process of diffusion?
m = (PSCd)(t)
What is the purpose of an enteric coating?
made of acid insoluble polymers, it helps resist disintegration in the gastric acid environment. It affects dissolution and bioavailability
Matrix system design (Biodegradable particulate systems)
materials degrade (hydrolysis) within the body as a result of natural biological processes: polylactides, polyglycolides Drug release may vary depending on material: zero or pseudo-first order
MTC
maximum tolerated conc -want to be below that conc because that is where we starting getting or seeing toxic side effects
difference in physiochemical properties
may be significant but not always
pH
measure of acidity or alkalinity of a substance
The effective surface area depends on the ability of the _________ to wet the particle's surface.
medium
multidose packaging: topical administration - metal or plastic tube
metal or plastic tube often contains ointment or creams for application to the skin or mucous membranes. squeezing tube releases medication. avoid contamination by using sterile tongue blade or sterile glove to remove medication
Some polymorphs are ___________ and convert to a more stable form.
metastable
Define electroporation.
method where high voltage electrical field is applied to cells for short period of time (milliseconds) to increase permeability of cell membrane
influence of drugs on gastric emptying
metoclopramide promotes faster gastric emptying
how to identify polymorphs
microscopy, melting point determination and solubility determination FT IR
WHat is MEC
minimum effective concentration
Cosolvents must be biocompatible and ____________ in each other.
miscible
what is the concentration (c) usually expressed as?
molarity
Fick's Law of Diffusion
molecules diffuse from a region of high conc to low conc
For a weak acid, the higher the pH, the _______ soluble it is.
more
For a weak base, the higher the pH, the _______ soluble it is.
more
Salt forms of WEAK electrolytes are (more/less) water soluble.
more
CaF₂ (Flourite) structure (AB₂ type)
8:4 coordination number compound Here cation is bigger than anion. 0.225<r⁻/r⁺<o.414 FCC position is occupied by Ca F occupy all tetrahedral voids Effective number of formula unit=4 a=(4/√3)(r⁺+r⁻) CN of Ca=8 CN of F=4
At ____% of the active ingredient, EXPIRED
90
Alcohol USP
95% ethanol
What is clop P?
A group additivity approach for partition coefficients.
Supersaturated Solution
A solution containing more of the dissolved solute than it would normally contain at a definite temperature.
inhaler
A spray device with a mouthpiece that contains an aerosol form of a medication that a patient can spray into his airway.
What is the biopharmceutical classification system?
A system that serves as guidance for predicting the intestinal drug absorption
Melting Point
A temperature at which a solid passes into a liquid state or, strictly speaking, A temperature at which pure liquid and solid exist in equilibrium.
What are the transported molecules in Simple Diffusion? A) Mostly lipophilic small molecules B) Ions (Na+, K+, Ca²+, etc.) C) Most small molecules, certain ions, (Na+ K+ pump) D) Mostly proteins, certain small molecules, and small particles
A) MOSTLY LIPOPHILIC small molecules
In class Question: Slide 53 The Y-axis of Hixson-Crowell plot is the cube root of the amount of the drug remaining. What is the Y-intercept of the line of Mt ⅓ vs. time? A) M₀ ⅓, the cube root of the amount of drug at time zero. B) K, the cube root dissolution rate constant. C) M₀, the amount of drug at time zero. D) 1/K, the reciprocal of the cube root dissolution rate constant.
A) M₀ ⅓, the cube root of the amount of drug at time zero. B) K, the cube root dissolution rate constant. C) M₀, the amount of drug at time zero. D) 1/K, the reciprocal of the cube root dissolution rate constant.
Which of the following drugs belong to BCS class I? (Select all that apply) A) Propranolol B) Metoprolol C) Piroxicam D) Naproxen
A) Propranolol B) Metoprolol C) Piroxicam D) Naproxen
Which transcellular pathway(s) require(s) chemical or biological energy? (Select all that apply) A) Simple Diffusion B) Facilitated Diffusion C) Active Transport D) Transcytosis
A) Simple Diffusion B) Facilitated Diffusion C) Active Transport D) Transcytosis
Which of the following 3 mechanisms can transport small molecular weight solutes? A) Simple Diffusion B) Facititated Diffusion C) Active Transport D) Transcytosis
A) Simple Diffusion ✔ B) Facititated Diffusion ✔ C) Active Transport ✔ D) Transcytosis
In class Question: Slide 45 The liquid film constitutes a stationary diffusion layer in which the concentration of the drug is __________. A) greater than the drug solubility (Cs) B) smaller than the drug solubility (Cs) C) equal to the drug solubility (Cs) D) unknown
A) greater than the drug solubility (Cs) B) smaller than the drug solubility (Cs) C) equal to the drug solubility (Cs) ✔ D) unknown
In class Question: Diffusivity reflects the rate at which a diffusant is transported between two regions. Diffusivity of a diffusant: A) is higher when the diffusant diffuses in a diffusional barrier with a higher viscosity. B) is smaller when the temperature of the whole system is higher. C) has a unit of length/time D) is higher when the Stokes radius of the diffusant is smaller
A) is higher when the diffusant diffuses in a diffusional barrier with a higher viscosity. B) is smaller when the temperature of the whole system is higher. C) has a unit of length/time D) is higher when the Stokes radius of the diffusant is smaller ✔
Which of the following is the unit for the Diffusion Coefficient (D)? A) length.time-¹ (cm.s-¹) B) length².time-¹ (cm².s-¹) C) time².length-¹ (s².cm-¹)
A) length.time-¹ (cm.s-¹) B) length².time-¹ (cm².s-¹) ✔ C) time².length-¹ (s².cm-¹)
The Stokes radius is closely related to __________ __________, factoring in not only size but also solvent effects. A) solute mobility B) solute permeability C) solute temperature
A) solute mobility ✔ B) solute permeability C) solute temperature
Question from lecture: According to logP, which drug may have the highest aqueous solubility? A. Ampicillin B. Ritonavir C. Penicillin G D. Acetaminophen
A. Ampicillin ✔ B. Ritonavir C. Penicillin G D. Acetaminophen
Which of the following phase in DSC has NO Latent Heat? A. Crystallization phase B. Melting phase C. Glass transition temperature phase
A. Crystallization phase B. Melting phase C. Glass transition temperature phase ✔
Which of the following phase in DSC HAS Latent Heat? A. Crystallization phase B. Melting phase C. Glass transition temperature phase
A. Crystallization phase ✔ B. Melting phase ✔ C. Glass transition temperature phase
Question from lecture: (Review slide 54) Minocycline has a solubility of 50mg/mL. It is a ____________drug according to the definition in USP? A. Insoluble B. Very slightly soluble C. Slightly soluble D. Soluble
A. Insoluble B. Very slightly soluble C. Slightly soluble D. Soluble ✔
(Acid/Basic) buffers are composed of weak acid and its conjugate base.
ACID
Transporters (Efflux)
ATP-binding cassette family (ABC transporters)
(Absorption/Dissolution) rate is limiting if absorption < dissolution.
Absorption
Lipinksi's rule of 5 is not applicable to drugs whose?
Absorption involves transporters
Lactulose marker does what?
Accelerates GI transit, increases stool water content, and increases drug absorption
What is the amount of energy required by the compound to put the molecules in an activated state from which they react to form the product of a reaction.
Activation Energy (Ea)
What are the 2 types of Apparatus in USP Equipment?
Apparatus I and II (basket and paddle --> use either one)
_________________ is the effective lipophilicity of a compound at a given pH, and is a function of both the lipophilicity of the unionized compound and the degree of ionization.
Apparent Partition Coefficient
Polycrystalline solids
Appear amorphous but have microcrystalline structures. Metals often occur in polycrystalline form. Individual crystals are often randomly oriented so a metallic sample may appear to be isotropic even though a single crystal is anisotropic.
Uncatalyzed reaction of a drug with molecular oxygen
Autooxidation
What is a chain reaction that proceed slowly under the influence of molecular oxygen called?
Autoxidation
Absorption is very much dependent on what?
Availability SA for absorption
In the Bioavailability of A and B forms of Chloramphenicol Palmitate plot, (A/B) has a higher Plasma Concentration (Cp), therefore better dissolution.
B
What are the transported molecules in Facilitated Diffusion? A) Mostly lipophilic small molecules B) Ions (Na+, K+, Ca²+, etc.) C) Most small molecules, certain ions, (Na+ K+ pump) D) Mostly proteins, certain small molecules, and small particles
B) IONS (Na+, K+, Ca²+, etc.)
(Acid/Basic) buffers are composed of weak base and its conjugate acid.
BASIC
Biopharmaceutics Classification System (BCS)
BCS Systems Bio-pharmaceutics research
Biopharmaceutics Classification System
BCS is a regulatory tool to better correlate in vivo bioavailability with in vitro tests, by classifying drugs into 4 groups
Compositions; Thickness
BEADS have coats of different ____ to control release or same coating with different ____
Absorption; Distribution; Metabolism; Half-Life; Safety
BIOLOGICAL Factors: 1. ____ 2. ____ 3. ____ 4. Biological ____ (Excretion) 5. Margin of ____
Why is it important to know about the dissolution equation and the factors that influence it?
Because we can use these factors of influence to manipulate the dissolution rate of a drug
A =abc
Beer-Lambert Law Equation
At what level does dissolution occur, in vitro, or in vivo?
Both
Question from lecture: Differential Scanning Calorimetry (DSC) is a Thermoanalytical technique in which:
Both the sample and reference are maintained at nearly the same temperature throughout the experiment.
X-ray Diffraction uses what law?
Bragg's Law
Crystalline properties
Braggs Diffraction of Xrays and Unit cell
Dangerous
Breast cancer meds = Cancer medication Tamoxifen is ____ if inhaled by the person crushing it. Other chemo drugs should not be crushed because it could be fatal.
Sink condition for dissolution
C < 20% of its saturation concentration (which depends on solubility)
What are the transported molecules in Active Transport? A) Mostly lipophilic small molecules B) Ions (Na+, K+, Ca²+, etc.) C) Most small molecules, certain ions D) Mostly proteins, certain small molecules, and small particles
C) MOST SMALL MOLECULES, certain ions
Why should you not use drugs beyond their expiration date?
Cannot be sure how potent the drug is Cannot guarantee that the product is safe
Radius Ratio rule
Case 1 Radius of anion>Radius of catiion Cation exists in voids of anion lattice R.R.= Radius of catiom/ Radius of anion =r⁺/r⁻ In the table, Right limit (i.e. smaller limit) is included in the range it is written against. Eg is ratio is exact 0.414 then it is octahedral void.
Disadvantage of IV
Chance of adverse reaction, anaphylaxis
Signs of instability in capsules:
Change in physical appearance or consistency Hardening, brittleness, softening Discoloration Expansion/distortion
What is the Principle of Thermal Analysis?
Change in thermal energy as a function of temperature.
Absorption; Excretion
Characteristics of drug for formulation as sustained release dosage form: Drug should exhibit neither very fast rate of ____ nor ____-- Ex. Diazepam and Phenytoin
under what conditions are chemical reactions done under
Chemical reactions done under conditions to optimize reactions, conditions in pharmaceutical products different - low concentrations, room temperature and pH around neutrality aka unoptimizing it
Thickness
Coated Beads, granules and microspheres: Variation in the coating ____ affects the dissolution rate of the drug
3; 4
Coated beads combined to have ____-____ release groups in the dosing unit
Describe coated compressed tablets.
Coated compressed tablets have sugar, film, or enteric coats to protect from moisture, mask the taste, etc. The coating may affect the bioavailability of the drug but help it "go down" easier.
Droppers
Come in two forms; monodrop containers, which are squeezed to release the medication, and containers with removable droppers. Separate, packaged droppers are also available to administer medications; these are sometimes calibrated .
pH; Electrolyte
Complexes and Ion Exchange Resins: Drug release depends on ____ and ____ concentration in GI tract
Permeable
Complexes and Ion Exchange Resins: Example: Tussionex Pennkinetic extended release suspension - contains ion-exchange polymer matrix combined with a diffusion rate limiting ____ coating
Tableted; Encapsulated
Complexes of drugs with ion-exchange resins - can be ____ or ____
Slowly; Extended
Complexes of drugs with other chemical agents can be ____ soluble in body fluids, which provides ____ drug release
Caffeine, EDTA, Cyclodextrin are examples of what agent?
Complexing agent
What parts of a molecule are susceptible to reaction with light?
Conjugated double bonds
Most drugs degrade by first-order mechanism. For a drug that degrades by first-order kinetics, half life is _________-
Constant (independent of concentration) t½ = ln(2)/k = 0.693/k
Day
Controlled release systems include a component that can be engineered to regulate essential characteristic (e.g., rate or duration of release) and have a duration of action longer than a ____
CRT
Controlled-Release Tablet
Immediate
Conventional ____ release forms cause sequential therapeutic blood level peaks and valleys
Others: e.g. Osmotic Pump Designs
Core structure + Drug Semi-permeable membrane Osmogents: Absorbs water and helps drug to get out Sodium Chloride, Magnesium sulfate, Sodium sulfate Laser-drilled orifice
What system is used when a drug is not completely soluble in water?
Cosolvent System
In vivo studies of drug absorption and permeability are?
Costly and technically challenging
In Cell Diffusion: C₂ is the drug concentration that interacts with (Cd/Cr)
Cr
Types of Excipients: Disintegrant
Cross-linked polyvinylpyrrolidone (PVP)
Sublingual; Buccal
Crushing a ____ or ____ tablet may cause the drug to be ineffective
Carcinogenic; Teratogenic
Crushing products with ____/____ may expose handlers to health risks through aerosolization of the product
Cutting property
Crystalline solids give clean cleavage whereas amorphous solids give irregular cut
Difference between crystalline and amorphous solids
Crystalline solids have a particular MP whereas amorphous solids don't. Amorphous solids melt over a range of temperature
The initial dissolution rate is proportional to
Cs
What are the transported molecules in Transcytosis? A) Mostly lipophilic small molecules B) Ions (Na+, K+, Ca²+, etc.) C) Most small molecules, certain ions, (Na+ K+ pump) D) Mostly proteins, certain small molecules, and small particles
D) MOSTLY PROTEINS, certain small molecules, and small particles
In a co-solvent system: There is NO water on the Dielectric Constant (ε) side, only ________.
DMI
A thermoanalytical technique in which the difference in the amount of heat required to increase the temperature of a sample and reference is measured as a function of temperature.
Differential Scanning Calorimetry (DSC)
____________ are molecules that migrate from one location to another.
Diffusants
What is the main driving force for the release of drugs from sustained release (SR) and controlled release (CR) products?
Diffusion
What happens to dissolution and absorption rates as a drug becomes more hydrophilic?
Dissolution increases, but absorption decreases
Inertial Impaction
Dominant deposition mechanism for particles > 5-10 micrometers or with high density in the upper tracheobronchial regions
Extended Release (ER)
Dosage forms that release drug slowly by design Therapeutic levels maintained for 8-12h FDA: provide reduction in dosing frequency compared to conventional dosage forms
DR + ER
Dose conversion and total dose is??
Dosing unit of 100 beads made of 3-4 release groups; Dosing unit of 100 beads made of 1 release group
Dosing unit of 100 beads made of 3-4 release groups vs. Dosing unit of 100 beads made of 1 release group...which one represents the extended release drug?? Which one represents the immediate release drug??
Making salts of active ingredients (a)
Drug with acidic centre
unit-dose packaging
Each dose is individually wrapped and labelled, and a 24 hour supply is prepared by the pharmacy and dispensed.
Hydration; Gel; Erosion; Release
Embedding drugs in eroding matrices: Mechanism of ACTION is based on successive ____ of the cellulose polymer, ____ formation, ____, and drug ____
The melting point of a Eutectic Mixture is ___________ __________.
Eutectic Point (°C)
T/F: All drugs given orally are meant to be absorbed.
FALSE (vancomycin, warfarin)
T/F: Viscosity of gastric contents will increase the rate of dissolution.
FALSE: viscosity of gastric contents will decrease rate of dissolution
Diffusivity is higher when the diffusant diffuses in a diffusional barrier with a higher viscosity. (T/F)
False
Fick's First Law describes non-steady-state diffusion. (T/F)
False
Lag-time effect is observed in systems that have been stored for a long time and the rate controlling membrane is pre-saturated with the drug. (T/F)
False
Example of non ionised organic molecular crystals
Famotidine
Bioavailability of intradermal injection
Faster than IM and SC
dr lyman spalding
Father of USP
What Equation is used to Calculate the diffusion coefficient (D) of a drug cross a diffusion cell, given (dM/dt), S, dC, and dx?
Fick's First Law
What solid form of drug undergoes the fastest dissolution? why?
Fine particles; Because they have the most surface area
Other new design concepts
Gastric retentive systems Tablets or beads Alginates, carbopol Floating or bioadhesive
capsules
Gelatin shells containing drugs in beads, powders, or liquids.
What is the hierarchy of onset of action rates among parenteral dosage routes?
IV (fastest) IM SQ (slowest)
What are the 4 primary routes for parenteral drug delivery?
IV, IM, SQ, intradermal (not intended to be absorbed)
When would you drop C from the equation?
If C is 20% or smaller than Cs, then you can ignore it
Complex; Incubating; Drug-resin Solution; Column; Ion
In chemically reacting the drug with material such as an ion-exchange resin, the ____ can be prepared by ____ the ____ ____ or passing the drug solution through a ____ containing ____ exchange resin
Slowly; Resin
In chemically reacting the drug with material such as an ion-exchange resin, the drug is released ____ by diffusing through the ____ particle structure
so that the absorbance is proportional to the concentration which is a way for us to measure the concentrations of different color solutions in a lab
In the Beer-Lambert law why are b and c held constant in most experiments
Where does most drug absorption take place?
In the Small Intestine
Associated Component
Intended to deliver the drug article to the patient but is not stored in contact with the article for its entire shelf life (spoons, dosing cups, and dosing syringes)
nasal
Into the nose
What happens to the concentration as time goes on?
It decreases on a gradient over the distance (h)
If a drug has a constant slope over a dissolution profile, what does that mean?
It dissolves controlled over time and is probably a zero-order reaction
If a drug has a steep slope and then flattens out on a dissolution profile, what does that mean?
It dissolves very fast and is probably a first order reaction
What is significant about disintegration of solid dosage forms to granules?
It dramatically increases the surface area and thus increases rate of dissolution
What happens when a drug is uniform/heterogeneous with the solution?
It enters the bulk solution (C) phase, in which the concentration will remain constant for the most part
What is the biphasc dissolution model?
It is the simulation of drug dissolution and absorption in the GI tract through the addition of an organic phase on top of the aqueous one
How doe you find the dissolution rate on a dissolution profile?
It is the slope before the dissolution plateaus
Pharmacokinetics
It is the study of kinetics of ADME (absorption, distribution, metabolism, and elimination) of drugs and their corresponding pharmacologic, therapeutic, or toxic response in man and animals.
Biopharmaceutics
It is the study of the factors influencing the bioavailability of a drug and the use of this information to optimize pharmacological and therapeutic activity of drug products.
Disintegrating tablets, small particles, and fine granules are not delayed from stomach emptying by food =
more consistent duodenal absorption
Density of unit cells
Let Z=number of atoms per unit cell m=mass of one atom=molar mass/Avagadro's No =m/N₀ r=radius of atom a=side length of unit cell Therefore density of unit cell=p=Zm/a³ p=zM/a³N₀ it is usually expressed in g/cm³
What 2 solids are used in eutectic mixture of local anesthetics (EMLA)?
Lidocaine and Prilocaine
Food increases absorption of what?
Lipid soluble drugs
Small Intestine
Longest (4-5 m) Sub-mucosal folds: Villi & Microvilli Large surface area (200 m2) -- Main absorption site Intestinal fluids: pH~6-7.5, contain enzymes, lipids, salts, bicarbonate - secreted by several sources Transit Time (Small & large intestine)
BCS II
Low solubility High permeability dissolution is limiting step formulation to modify dissolution rate can improve or control bioavailability ex: ketoprofene
BCS IV
Low solubility Low permeability poor oral BA most problematic ex: furosemide
Drug absorption barriers
Lumen Mucus Cells (Apical ) Cells (basal) Blood
____________ products are more "fluffy", amorphous, and dissolves faster.
Lyophilized (dry frozen)
What is dM/dt in the dissolution rate equation?
Mass of solute dissolved in time, t
Define "Chemical Kinetics"
Mathematical study of the RATE of APPEARANCE and DISAPPEARANCE of a chemical in a reaction.
what is MTC?
Maximum tolerated concentration
What are P-Glycoproteins?
Membrane proteins that exist in the small intestine that push drug back into the lumen; reduces the drugs bio-availability
What are the involved Proteins in Transcytosis?
Membrane targeting proteins and receptors
Metallic crystals
Microscopic (atomic ) structure reflected in macroscopic properties
What does the Stokes-Einstein Equation determine?
Molecular Size and Volume
Repeat Action Design
Multi-tablet systems Multi layer tablets
Which is larger? Mt or M₀?
M₀
Drugs that have a larger K value are what?
more lipid soluble
Is the radius of a particle undergoing dissolution constant?
No
simple cubic cell (SCC)/ Primitive unit cell
No. of atoms per unit cell: 1 a=unit cells edge r= radius of atom Taking the edge, a=2r r=a/2 d=distance between nearest atoms d=2r=a
End centered cell (ECC)
No. of atoms per unit cell: 2
What are the involved Proteins in Simple Diffusion?
None
What happens if there is no drug dissolution?
Nothing can happen; the drug doesn't get absorbed
Nucleation
Nucleation, the initial process that occurs in the formation of a crystal from a solution, a liquid, or a vapour, in which a small number of ions, atoms, or molecules become arranged in a pattern characteristic of a crystalline solid, forming a site upon which additional particles are deposited as the crystal grow
HCP unit cell analysis
Number of particles per unit cell-6 CN-12 Packing effeciency=74% See video for literally the best explanation https://youtu.be/WncF47rbu8M
Which dosage forms do not have to go through disintegration?
ODT, effervescent tablets, sustained release
Monotrophs
ONLY one polymorph is stable at all temperature below the melting point. ALL OTHERS are unstable.
Amorphous silicon
One of the best photovoltaic material available for conversion of sunlight into electricity
Enantiotrophs
One polymorph is stable under certain pressure and temperature range, while the other polymorph is stable under different pressure and temperature range.
Eye medications are labeled
Ophthalmic or for the eye
Limitation of therapeutic range?
Optimal for most people and NOT everyone
Systemic Drug Administration Route
Oral Parenteral -IV - IM - Subcutaneous - Intraarterial Rectal Sublingual Transdermal Pulmonary Nasal
Multilayer Tablets
Oramorph SR- morphine sulfate sustained release tablets are an example of what kinds of tablets??
Others
Osmotic pumps Complex formation, e.g. ion exchange Gastric floating beads Bio-adhesive Mechanical controlled (device); bioresponsive-release
What are other common chemical reactions that lead to instability?
Oxidation, photolysis and sometimes isomerization
What is Verapamill?
P-GP inhibitor
ATP-binding cassette family (ABC transporters)
P-glycoprotein (P-gp) Breast cancer-resistance proteins (BCRP) Multidrug resistant protein 1 (MRP1)
Example of binding agent covered in lecture.
PVP Sodium CMC
How can you prevent photodegredation?
Package in light-resistant or opaque containers that exclude UV light (amber glass)
All forms of drugs need to dissolve around the site of administration/absorption to be absorbed. What are 2 exceptions?
Parenteral and Oral SOLUTION dosage forms
rectal
more reliable than the oral method. Is advised for unconscious patients, infants, small children, and mouth-breathing patients.
why do even numbered chains have higher melting points than uneven numbered chains
more stable packing arrangement as two points of contact
Drug concentration is higher in octanol than water when Log P is?
more than 0 (more lipid soluble)
a drug is administered by inhalation using a metered dose inhaler aerosol. which pathway will the drug follow?
mouth, trachea, bronchioles, alveoli
Caco-2 cultures are used to study what?
Permeability of passively transported drugs
In the Log K vs. √μ plot, opposite charges gives a ___________ slope and the same charges gives a _____________ slope.
negative, positive
Coatings effect on: 1. Ka 2. tmax 3. AUC
no effect on any of these PK parameters
Passive diffusion means what in terms of E?
no external E
Photo _____: Chemically-induced reactions when the drug absorbs UV light and causes cellular damage No cross-sensitivity Manifests as an exaggerated sunburn on sun-exposed areas and can be seen with initial exposure May be dose-releated
Phototoxicity
For oral administration, unit-dose packaging comes in a number of forms
Plastic bubble, foil, or paper wrappers containing tablets or capsules. Plastic or glass containers that hold a single dose of a liquid or a powder. The powder is reconstituted to a liquid form by following the directions given on the label. A sealed medication cup containing a liquid.
**On Exam What solvents exhibit strong dipolar bonds and hydrogen bond property?
Polar Solvents
____________ is the process when 2 or more identical molecules combine to form a complex molecule.
Polymerization
What is the ability of a solid material to exist in MORE THAN 1 form of crystal structure?
Polymorphism
Zwitterion
Positive and negative groups
If you poured a powder into a liquid, what would happen?
Powders tend to float because they have lots of entrapped air.
In the following graph: What does A indicate in a co-solvent system?
Prediction of Solubility?
Examples of Delayed Release (DR)
Prilosec (enteric coated granules of omeprazole in capsules, AstraZeneca) E-mycin (enteric coated erythromycin tablets, Abbott)
Bioavailability of subcutaneous injection (SC)
Prompt from aqueous solutions
How quickly reactant goes to product
Rate of reaction
What relationship does the August Equation describe?
Relationship between the log of pressure its reciprocal temperature.
The gamma scintigraphy study can be used to correlate what?
Residence time of the drug in a given region after capsule breakup to drug absorption
Disadvantage of Intrathecal injection
Risk of bacterial contamination (preservatives NOT allowed to avoid nerve damage)
are solids chemically inert materials
no, decomposition can occur due to weak intermolecular bonds, need to store at 15-30 and protect from air and lights
Flavor Anions and Cations
Salty
For topical administration with multi dose packaging
Since these containers are used over an extended period of time, it's important to avoid contaminating them. The nurse must label the container with the patients name and reserve the container's use for only that patient.
Delay in gastric emptying tends to do what?
Slow the rate of drug absorption because it delays drugs reaching the duodenum
BCS Systems
Solubility (S) and permeability (LogP & more) IVIVC BCS application and future directions
Soft gelatin capsules may contain the drug in _________________ solution, powder, or drug suspension in oil.
non-aqueous
Can we archive zero-order release?
non-disintegrating dosage forms semisolids for topical and transdermal Some advanced controlled-release systems
What are pharmaceutical crystals
non-ionised or ionised molecules eg salt not zwitterion
The FIRST-ORDER Dissolution Profile is under (sink/non-sink) condition
non-sink (concave slope)
Rank of a unit cell
number of atoms per unit cell
Types of Excipients: Binder
Starch
Example of lubricating agent covered in lecture.
Stearate
Increasing the temperature leads to increase in _______ and ________
number of collision reaction rate
Braggs Law
nλ=2dsinθ
Lidocaine and Prilocaine, both solids at room temperature, form a eutectic _______ with a 16(°C) melting point.
oil
What are water-removal ointment bases?
oil in water emulsions; both hydrophilic and lipophilic drugs can be included
Dissolution from an EMULSION results from partitioning of the drug from oil phase ➞ aqueous phase ➞ _________ _________.
oil phase ➞ aqueous phase ➞ dissolution medium
which opthalmic formulation will maintain the drug in contact with the eye for the longest?
ointment
Pharmacist Responsibility: Dispense _____ stock first and observe __________ dates
oldest expiration
The pH-rate profile is used to identify the _______ of optimum stability.
pH
The interrelationship among pH and pKa parameters is known as what theory?
pH-Partition Theory
Delayed Release (DR) by GI conditions
pH-triggered release (e.g. enteric coating)
What is the duodenal pH and what is this pH optimal for?
pH= 6-6.5 -enzymatic digestion of proteins and carbohydrates with pancreatic enzymes
hemorrhoid
painful swollen veins in the anal or rectal area, generally caused by strained bowel movements from hard stools
hemorrhoid
painful/swollen veins in the anal/rectal area
Relative Humidity (φ) is the ratio of the ___________ pressure of water vapor (ew) to the ____________ pressure of water vapor (ew*) at the same temperature.
partial, equilibrium
The Diffusion Layer Model explains dissolution of a drug from a __________ into a large bulk medium.
particle
colloids
particles up to a hundred times smaller than those in suspensions that are, however, also suspended in a solution
Question from lecture: Which drug has the highest aqueous solubility according to the table?
Streptomycin at -7.7 logP
The carrier molecule in active transport may be highly selective for the drug molecule. If the drug...?
Structurally resembles a natural substrate that is actively transported, then it is likely to be actively transported by the same carrier mechanism--> --> therefore drugs of similar structure may compete for sites of adsorption on the carrier
Antioxidants
Substances that prevent or inhibit oxidation - Added to protect components of the dosage form that are subject to chemical degradation by oxidation - Examples: Ascorbic acid, Ascorbyl palmitate, Monothioglycerol, Sodium bisulfate, Sodium sulfite, Tocopherol
How can you reduce or eliminate water from formulation?
Substitute glycerin, propylene glycol, ethanol, anhydrous vegetable oils Suspend in nonaqueous vehicle Supply as dry powder for reconstitution
Example of Enantiotroph:
Sulfur
Crystalline solids examples
Sulphur Phosphorus Iodine Metals Napthaline NaCl ZnS
What absorptions mechanisms are involved with sublingual delivery?
passive diffusion, carrier mediated transport, and endocytosis
----- absorption is the absorption of drugs through the skin, often for systemic effect
percutaneous
Hydrogen Bonds are the result of the ____________, positively charged dipole of a hydrogen atom. (H-bond donors or acceptors)
permanent
inflammation of a vein is also known as ------ and can be a complication associated with intravenous administration
phlebitis
Diethylstillbestrol and ketoprofen are examples of
photoinduced reactions
Dosage Form
physical manifestation of a drug as a solid, liquid, semi-solid, etc. that can be used in a particular way ( i.e. tablets, capsules)
the primary reason to use a vaginal applicator is to
place the formulation high in the vaginal tract
Intraocular dosage forms
-solutions -suspensions -ointments -inserts
different 3D packing arrangements can give rise to
different physiochemical properties
Different constituents of a meal empty from the stomach at?
different rates
different polynorphs have
different unit cells
the more electrons in the plane the greater the
diffracted density
What is gastric emptying delayed by?
1. high fat meals 2. cold beverages 3. anticholinergic drugs
A radical is any chemical species that contains one or more unpaired electrons
Reactive oxygen species
T/F: Capsules can also deliver divided powders but must disintegrate.
TRUE
T/F: Excipients help with tablet aging.
TRUE
T/F: Gastric contents might decrease the rate of dissolution.
TRUE
T/F: Gastric pH will increase or decrease the rate of dissolution based on ionization of the drug.
TRUE
T/F: Pulmonary vasculature forms a separate circuit from the systemic circulation.
TRUE
T/F: Skin is a rate limiting barrier for drug absorption.
TRUE
____________ ___________ is the concentration profile of the diffusants in the diffusional barrier.
Concentration gradient
In the Diffusion Layer Model: What is the driving force for dissolution?
Concentration gradient (Cs - Cb)
T/F: Suspensions and ointments can be retained on eye surface for longer than solutions.
TRUE
Inhalation dosage forms
-solutions -aerosols -powders
Advantages to Oral Route
- Most common, convenient, patient - preferred route of administration - Many dosage forms available: powders, granules, tablets, capsules, solutions, suspensions, emulsions, gels
Advantages to Rectal Route
- Most drugs given orally can also be administered rectally - Reserved for situation in which oral administration is difficult
Characteristics of Amorphous solids:
- NO fixed structure - Greater solubility than crystalline - Revert to more stable form during storage
Opthalamic Route
- ONLY for the treatment of local conditions of the eye, CANNOT enter systemic circulation -Concentration gradient is the major determinant of absorption of drugs - Must be sterile and must be physically stable, bioadhesive, biodegradable, and in pH range of 7.0-7.7
Semi-Solids
- Ointment - Cream - Gel
Disadvantages of Nasal Route
- Physical barrier of the mucus layer may limit drug diffusion - Ideal for potent drug molecules (effective plasma concentration ~ ng range) - Nasal epithelia are highly sensitive and fragile
What 2 drug examples are in Class II of the BCS?
- Piroxicam - Naproxen
Which of the following are used in USP Equipment and Produce? - Porosity - Composition - Volume of dissolution medium - Bulk Density - pH - Temperature
- Porosity - Composition - Volume of dissolution medium - Bulk Density - pH - Temperature
Solids
- Powders - Granules - Capsules - Tablets - Suppositories
What are the 2 types of DSC?
- Power Compensated DSC (individual heaters) - Heat Flux DSC (single heat source)
What 2 drug examples are in Class I of the BCS?
- Propranolol - Metoprolol
Purpose of Dosage Forms and Drug Delivery Systems
- Protect drug from atmospheric oxygen or humidity (coated tablets, sealed ampules) - Protect drug from destructive gastric acid after oral administration (enteric coated) - Conceal the bitter, salty, or offensive taste or odor of a drug to improve compliance and adherence ( Caps, Coated tabs, flavored syrup) - Provide time controlled drug actions - Provide insertion of a drug into a body orifice
What 2 drug examples are in Class III of the BCS?
- Ranitidine - Cimetidine
Rate the Transport Selectivity of each Mechanism below with (NONE, MODERATE, or HIGH) - Simple Diffusion - Facilitated Diffusion - Active Transport - Transcytosis
- Simple Diffusion ⟹ None - Facilitated Diffusion ⟹ High - Active Transport ⟹ High - Transcytosis ⟹ Moderate
Disadvantages to oral route
- Slow absorption and onset of drug action (20-45 min) - May not be stable in GI fluids - may irritate gastric or intestinal epithelial - pH/food effects on ionization and solubility
Liquids
- Solution - Suspension - Emulsion
Factors that affect Polymorphism (Select all that apply) - Temperature and humidity - Photostability - pH - Effect of solvent - Effect of grinding - Pressure - Effect of tablet compression
- Temperature and humidity - Photostability - pH (x) - Effect of solvent - Effect of grinding - Pressure (x) - Effect of tablet compression
Type II (Treated Soda - Lime Glass)
- Type of glass container which is a soda - lime glass which, by means of a special treatment, reaches the hydrolytic stability of type I glass on its surface later - suitable for acidic and neutral parenteral preparations - can be sterilized before or after filling
Type I (Neutral borosilicate glass)
- Type of glass that has borosilicate structure - Ideal for containing all injectable preparations with acid, neutral, and alkaline pH - Good resistance to thermal shocks and can be sterilized before or after filling
Solvents
- USP Purified Water (Non-sterile) - USP water for injection (Sterile) - USP sterile water for injection - USP sterile water for inhalation - USP bacteriostatic water for injection (sterile) - USP sterile water for irrigation - Alcohol (ethyl alcohol, ethanol) - Isopropyl alcohol (External Use ONLY) - Glycols - Oils
Principles of child resistant packaging
- a degree of strength is required to access the medicine - a degree of coordination is required to access the medicine - 90% of adults should be able to open the device - 85% of children should not be able to open the device
Packaging
- a drug and its packaging are intimately linked - the package plays a key role in controlling the delivery and integrity of drug - changing the packaging creates a new medicine in the eyes of the regulatory authorities
An example of the effects of carbon dioxide
- a neutral unbuffered solution was stored in a polyethylene bottle for 4 weeks - it gradually acidified to pH 4.5 then reverted to neutral pH upon heating - the pH change was due to carbonic acid build up through carbon dioxide permeation. - possible solutions included a plastic overlap, a change in plastic or the inclusion of a buffer
Packaging System
- also referred to as a Container - closure system
Packaging materials - Closures
- are an integral part of the pack - primary function are to * prevent leakage or loss of product * prevent exposure to people * to ensure stability and retain quality of the medicine * to prevent contamination of the medicine - the integrity of a closure can vary from a simple dust cover to a total hermetic seal - may be attained by pressure * mechanical pressure between a rigid and non rigid surface (screw lids, plug seal) * atmospheric pressure (vacuum seal) - closure may also be formed by heating (blister packs, induction heating, ampoules) - closures may be formed using adhesives
Packaging materials - Plastics
- are polymers usually prepared from petrochemical products * have some permeability to gases and moisture * some ingredients used in the plastics can be extracted out * some drugs can partition into the plastic and be absorbed - common plastics found in pharmaceutical packaging include * Polypropylene and polyethylene (LDPE) and (HDPE) * polystyrene and polyvinylchloride
Rectal dosage forms
-solutions -ointment -suppositories
Layered Transdermal Patch
- backing - polymer/drug matric -adhesive/drug layer The polymer and adhesive layers may contain the same drug or two different drugs. - Adhesive layer drug gets absorbed first then the drug in the polymer layer gets slow absorbed after
Non-reclosable child resistant packaging
- blister packs and individual dosage units that are not formed from cellulose (paper) * plastic blister packaging * foil strips (non flimsy) * film strips Blister packs are acceptable as tamper evident packaging and also as child resistant packaging - continuous strips or continuous blister packs are acceptable
Liquids (packaging)
- can be packaged in glass or plastic - permeability of the plastic to the liquid is a concern * certain cosolvents can extract plastic additives out of the plastic - liquids which are often used for sterile products and the container should be suitable for autoclaving
Non-Reclosable Packaging
- cannot be closed again after all or part of the contents have been removed Examples: - Blisters - Sachets - Strips - Single-unit containers - Cold-formed foil blisters - Foil strip packs - PVC/Aclar
Child-Resistant Packaging requirements for medicines
- child-resistant packaging is in addition to any other requirements - the goods must remain child-resistant for the life of the goods - sight, unusual strength or dexterity should not be required to open or reengage the child resistant features
Elixirs
- clear, sweetened, hydro-alcoholic liquids intended for oral use - Alcohol content (5-40%) - less effective than syrups in masking the taste of medicinal substances - Non aqueous solution containing alcohol
Child-Resistant goods
- compound listed in the first schedule of the order must have child resistant packaging - compounds may be a reclosable or non-reclosable pack - the first schedule includes all compounds that are likely to cause serious harm or death to a child that consumes the packaged dose
Laminates
- consisting of plies (layers) of different materials such as paper, plastic and metal - combine the advantages of the different materials, and are used, for example, in sachets.
Packs aid consumer choice
- crucial for OTC medicines to attract customers to the product - an attractive pack may convince a consumer to pay more for the same drug
Secondary Packaging Component
- direct contact with a primary packaging component and may provide additional protection for the article Examples: - wrapper to contain primary pack - Carboard: box to contain primary pack - Paper: Labels, patient information leaflet
Packaging materials - Hermetic closures (seals)
- do not allow any exchange with the outside environment (gases, microorganisms, liquids) - the nature of the material determines if a true hermetic seal is attained - sterile products must be hermetically sealed Common hermetic seals include - unbroken glass surfaces (ampoules) - glass with a rubber bung (injection vials) - heat sealed plastic - aluminium cans
Protection from the environment
- drugs and excipients can undergo degradation in the presence of oxygen and water - packaging protects products from microbiological contamination - stability testing of a product in its final packaging must be performed
Functions of packaging - protection from the environment
- drugs can undergo decomposition if exposed to the environment - a primary role of the packaging is to slow or eliminate the decomposition of the medicine
Pharmaceutical Packaging
- economical means of providing presentation, protection (against climatic & biological conditions, physical & chemical hazard) identification information, containment, convenience and compliance for a product during storage, carriage, display and until the product is consumed
Packaging materials - Glass
- excellent for sterile materials - totally impermeable to air, moisture and microorganisms - disadvantages are its weight and low tensile strength - 4 different varieties of glass are used in pharmaceuticals Glass varieties - Type 1 (borosilicate glass) is used for all parenterals and blood products - Type 3 (soda glass) is suitable for non-aqueous parenteral products - Type 4 glass is not suitable for any parenteral product
Oxygen and carbon dioxide (packaging)
- exclusion of gases may be necessary * oxygen can react with sensitive organic functional groups giving oxidised products * carbon dioxide can react with water yielding carbonic acid changing the pH of solutions - all plastics have some permeability to gases and will allow the passage of carbon dioxide and oxygen
Type III ( Soda - Lime Glass)
- has average hydrolytic resistant - Suitable for containing non-aqueous injectable preparations and those in powder form (moisture sensitive) - Sterilized by dry heat before filling
Multiple-Dose Container
- holds STERILE medication for parenteral administration has met antimicrobial effectiveness testing requirements - intended to contain more than one dose of a drug product - contain 30 mL or less of medication - Beyond use date for an opened or entered (needle punctured) container is 28 days - Example: Vial - Needs preservatives
Single-Dose Container
- holds a STERILE medication for parenteral administration (injection or infusion) NOT required to meet the antimicrobial effectiveness testing requirements. - used for a single patient as a single injection/infusion Examples: - vials, ampules, prefilled syringes - NO preservatives needed
Physiological Features of the Stomach
- important role in solubility/dissolution - Drug must dissolve rapidly enough in the intestinal fluids - Drug in its ionized form will dissolve more (high solubility) than a drug in unionized form (weak bases dissolve more in gastric fluid than weak acids)
Excipients
- intended to be inert (should not interrupt API when it comes to inducing therapeutic actions) - to promote manufacturability - to promote chemical and physical stability - to improve solubility - to assure the desired drug release and bioavailability - to improve patient acceptance & convenience
Primary Packaging Component
- is in direct contact with or may come into direct contact with the article - glass: metric medical bottle, ampoule, vial - plastic: ampoule, vial, infusion fluid container, dropper bottle
Tertiary Packaging Component
- is in direct contact with secondary packaging component and may provide additional protection for the article during TRANSPORTATION and/ or STORAGE
Heat treatment of packaging
- is most often performed when sterilising - some plastics are not suitable for the high temperatures found in autoclaves (121C) and so cannot be sterilised.
Type 3 - soda glass
- is much cheaper but is more reactive and is not suitable for all types of pharmaceutical products
Type 1 - borosilicate glass
- is the kind of heat stable glass found in cookware in the kitchen also known as pyrex - it is a non reactive glass and is the most exepensive
Semi solids (packaging)
- jars or tubes can be used for packaging creams, gels and ointments - the wide mouth allows microorganisms to enter and so the material must have adequate preservative in it - flexible tubes can be filled and crimped * aluminium * plastic
Functions of packaging - presentation
- marketing and brand awareness - helps sales of similar or identical products
Tamper-Evident Packaging
- may not be accessed without obvious destruction of the seal or some portion of the Packaging system -Must be used for sterile drug products intended for opthalamic and otic use - required for drug products intended for sale w/out prescription
Microbiological hazards (packaging)
- microbiological contamination of products should be minimised, even in non-sterile products - microorganisms must be excluded from sterile preparations with a hermetic seal - microorganisms in sterile products must be eliminated by sterilisation, usually with heat and products should be used immediately after opening
Packaging materials - Natural and synthetic rubber
- most often used in closures and bungs - the properties of rubber make it suitable for use in multi-injection containers Advantages of rubber - impermeable to microorganisms - relatively impermeable to gases and moisture Problems with rubber - decomposition on ageing - rubbers contain extractable compounds which may contaminate product
Functions of packaging - compliance
- must be compliant with regulations - in Australia, there are regulations on the types of tamper evident seals, child resistant closures and package labeling that must be evident on the packaging
Light degradation (packaging)
- photodegradation can be reduced using amber bottles or opaque containers - amber containers remove all of the damaging short wavelength UV light from the spectrum
possible errors that could have been done during the experiment?
- pipetting/instrument errors - not calibrating instrument - use of incorrect wavelengths
Functions of packaging
- presentation (marketing) - identification - convenience - protection from the environment - compliance (tamper evidence) - containment (child resistant closures)
temperature effects
- reaciton rates proportional to the # of collisions so expect reaction rate to increase with increasing temp k= A e^(-Ea/RT) =arrhenius equation k=reaction rate constant for any order A= pre-exponential constant Ea= activation energy T= temp in K R= gas constant(1.987cal.deg-1.mol-1)
ways to overcome these erros?
- repeat the experiment - ensure correct pipettes and volumes are used - use smaller intervals
Disadvantages to Parenteral Route
- requires sterile preparation technique and proper equipment/tools
Child-resistant packaging
- should restrict access to a child for a prolonged period of time
Australian guidelines on tamper evident packaging
- the Code of Practice applies to therapeutic goods including medical devices that are unscheduled or in Schedule 2 or Schedule 3 of the Poisons Standard which are administered transdermally, ingested orally or come into contact with the mucous membranes - pressurised containers, ampoules, lozenges and dentrifices are exempted - compounds listed must be packaged in tamper evident packaging - 2 piece hard shell capsules must have 2 tamper evident security devices
Types of packaging - general considerations
- the type of package chosen for a product should match the intended use of the product - it should be convenient to use - it should not react with the drug - it should be amenable to manufacturing - it should fulfil the legal and regulatory guidelines
Reclosable packages
- there are 5 international standards that list acceptable child-resistant packaging used in Australia and some 24 approved manufacturers - basic types are * push down and turn * squeeze sides and turn * align arrows - problems are often encountered with adults that have arthritis
Information on the drug that must be provided on the packaging
- type of product - product trade name e.g. Herron gold - official name e.g. paracetamol - strength - quantity - mode of usage/route of administration - batch number - expiry date - contra-indications - warnings - manufacturing licence number
Moisture and light
- water in the gaseous state can easily enter containers and increase the rate of drug decomposition - the size of the packaging material and the opening of the package is minimised - silica gel desiccant can be added
Emulsions-
-"oil and water don't mix" -some formulations contain both aqueous and oleaginous (oil based) components.
difference between pharmaceutical reactions and synthetic reactions
-Decomposition in a pharmaceutical may take months or years while synthetic reactions conducted under conditions to run in minutes or hours -Range of reactions in products is also much smaller then what would be found in synthetic chemistry.
Class 4: Biopharmaceutical Classification system
-Difficulty in formulating a drug product that will deliver consistent drug bioavailability -An alternate route of administration may be needed (amphotericin B, neomycin)
Class 2: Biopharmaceutical Classification system
-Drug dissolution is limited and well absorbed -bioavailability is controlled by the dosage form and rate of release of the drug substance (Ibuprofen, naproxen)
Class 1: Biopharmaceutical Classification system
-Drug dissolves rapidly and is well absorbed -Bioavailability problem is not expected for immediate-release drug products (Acetaminophen)
Class 3: Biopharmaceutical Classification system
-Drug permeability is limited -bioavailability may be incomplete if drug is not released and dissolved within absorption window (atenolol, penicillin)
drug stability
-Extent to which a product retains, within specified limits and throughout its period of storage and use, the same properties and characteristics it possessed at the time of manufacture.
When is active transport important?
-GI absorption -renal and biliary secretion of drugs and metabolites
Describe pulmonary delivery.
-MDI, DPI, nebulizers -avoids first pass metabolism -Inertial impaction (>6um) -gravitational sedimentation (2-6um) -Brownian diffusion (<0.5um)
most drugs are ___ and involve ______
-Most drugs are organic molecules and degradations involve chemical reactions which follow classical chemical kinetic principles (by adding our excipients we can change these classical problems)
Describe divided powders.
-NO DISINTEGRATION STEP, FASTER ONSET OF ACTION -can be dry, bitter, or have a bad smell which can lead to decreased patient compliance -can be mixed with water or pudding -newer dosage forms -- chewable tablets and ODT -example: Miralax
**On Exam What are the substituents that DECREASE the Partition coefficient (P)?
-OH (hydroxyl) -COOH (carboxylic acid) -NH₂ (amine) -O (oxygen) -CO (carbon monoxide)
physical stability
-Properties like dissolution, appearance are retained -May lead to reduced bioavailability and reduced efficacy (ie tablet hardening over time) - May be due to physicochemical changes to active or excipient -Polymorphs, loss of volatiles, dissolution changes from aging -Changes like mottling (discolouration in patches), caking or color change may or may not affect efficacy but elegance and patient confidence lost -ie in suspension, if particle size gets too big it will settle faster than it should
What are the advantages of sublingual delivery?
-RAPID ONSET AT LOW DOSE -enhanced bioavailability -Increased patient compliance -highly effective for emergency treatments
Microbiological
-Sterility or resistance to microbial growth retained Refers to product remaining sterile or resisting microbial growth -Preservatives must retain efficacy over entire shelf-life (i.e. preservative in eye drops, or making containers tightly sealed) - Product stability considered for variety of criteria - chemical, toxicological, therapeutic, physical and microbiological - Problems should be anticipated and steps taken to circumvent them by use of various stabilization techniques.
What is pharmacokinetics (PK)?
-Study of drug movement into, around, and out of the body (how rapidly they are eliminated and how rapidly they are absorbed) -Study of the time course of drug concentrations in body compartments
Disadvantages of suspensions-
-Tend to settle over time leading to a lack of dose uniformity -unpleasant oral texture
Types of Excipients: Surfactants
-Tweens - Spans (increase solubility)
identifiable curves in pH-rate profiles
-V shaped -sigmoid shaped
Solutions-
-a clear liquid (not necessarily colorless) made up of one or more ingredients dissolved in a solvent -aqueous solutions are the most common of the oral solutions -water, alcohol, glycerin, propylene glycol can be used for oral solutions
Following the rules of the pH partition hypothesis then how do a weak acid and a weak base compare in absorbtion?
-a weak acid will be rapidly absorbed from the stomach (pH 1.2) -a weak base will be poorly absorbed from the stomach
What is the purpose of diluents/fillers?
-add bulk to API to prepare tablets to reasonable size -can be soluble or insoluble -Insoluble increasing disintegration
Tinctures-
-alcoholic or hydroalcoholic solutions of nonvolatile substances -tintures of potent drugs have 10 grams of the drug in each 100 ml of tincture (called 10% tinctures)
Spirits/essences-
-alcoholic or hydroalcoholic solutions of volatile substances with alcohol contents ranging from 62-85%. -most frequently used as flavoring agents, some are used for their medicinal effect
**On Exam What are the substituents that INCREASE the Partition coefficient (P)?
-alkyl (alkane missing 1 H) -aryl (derived from aromatic ring)
Describe modified release tablets.
-alter the rate or timing of drug release -multiple doses packed in single tablet -dose dumping can be a problem
What are some advantages of rectal administration?
-alternative to IV -avoids first pass -rapid absorption -better bioavailability than oral route
inactive amide
-beta lactam group of penicillins/cephalosporins with amino group of an amino glycoside antibiotic
Advantages of suspensions-
-can orally administer drugs that are insoluble in acceptable solvents -can be taken or administered to patients who cannot swallow tablets or capsules -masks objectionable taste of some drugs -drugs are chemically more stable than in solution
What are some disadvantages of film strips?
-cannot contain large doses -total weight usually <150 mg -fragile so it needs special packaging, therefore is expensive
what are the most common functional groups in hydrolysis
-carboxyl derivatives- lactams, esters, and amides (lactam are part of beta-lactam-> antibiotics)
Catalysis
-catalyst is a substance which increases rate constant of a reaction but does not change the equilibrium constant -it is not transformed or consumed but interacts with the reactants to facilitate reaction -want to recognize possible catalysts in formulation and minimize effects on drug stability (diagram on slide 37)
Racemization
-change in optical activity may result in very significant changes in biological activity -body can only metabolize l-aa's; the d-isomer of lactic acid is metabolized to liver glycogen while the l-isomer is metabolized to bicarbonate (sodium lactate can be given to patients that have a low pH-> lactic acid goes through krebs cycle -> nrg, water and co2 this co2 will be metabolized into bicarbonate (the l-isomer)) -ie levomethorphan vs dextromethorphan (natcotic vs OTC)
Elixirs-
-clear, sweetened, hydroalcoholic liquids intended for oral use. -can contain either alcohol soluble or water soluble drugs. -usually less sweet and less viscous that syrups, generally less effective in masking taste. -alcohol content ranges from 5-40%
what are some ways to prevent vaporization
-coating -PVP
Advantages of solutions-
-completely homogenous doses -immediately available for absorption -for patients who cannot swallow tablets or capsules -doses can be easily adjusted
Syrups-
-concentrated or nearly saturated solutions of sucrose in water -more viscous (thicker) than water, and contain less than 10% alcohol
Describe oral suspensions.
-contain micronized particles of API dispersed in liquid medium -a suspending agent minimizes settling -must be shaken -good for patients with trouble swallowing -may be used for prolonged acting liquid dosage forms by using slightly soluble salts or coated ion exchange resins
Bulk powders-
-contain the active drug in a small powder paper or foil envelope
Capsules-
-contain the drug and the other ingredients packaged in a gelatin shell. -the gelatin shell dissolves in the stomach and releases the contents of the capsule. -still undergo disintegration and dissolution before the drug is absorbed in the circulatory system
oral formulations
-contain various ingredients beside the active drug. these inactive ingredients include binders, lubricants, fillers, diluents, and disintegrants
controlling what can control hydrolysis rate
-control of pH allows some control over hydrolysis rate and use of pH-rate profile allows determination of pH value where reaction rate at a minimum -buffering to optimal pH may not always be possible due to solubility and physiological limitations -sometimes compromise pH must be used and pH control could be combined with another stabilizing technique such as a cosolvent (e.g. diazepam injection
What are the requirements for transdermal delivery?
-daily dose <20 mg/day -half-life < 10h -MW < 500 Da -melting point < 200*C -log P between 1 and 4 -drug should be non-irritating and non-sensitizing to skin
hydrolysis
-decomposition of the drug through reaction with water -reaction rates can vary and some molecules like ampicillin can be quite unstable
What are some disadvantages of oral administration of drugs?
-decreased absorption -GI ADRs -destruction by gastric acid -high first pass metabolism -varying absorption across patients
dehydration
-degration of tetracycline and prostaglandin E2 involves loss of a molecule of water (epidehydrotetracycline and prostaglandin A2) -form of dehydration instability also seen with hydrates such as ampicillin trihydrate (has poor water solubility which makes it ideal for suspensions) -not all chemical change but changes the crystal habit of the drug (pseudo polymorphism) which may result in solubility changes -formation of pseudo polymorphism may effect bioavailability due to solubility changes; may also affect stability
What are the benefits of transdermal delivery?
-delivered at a controlled rate -REMAIN IN PLASMA UP TO 7 DAYS -avoids first pass and GI -self-administered and terminated
Describe buccal delivery.
-designed for release and absorption of drug in the buccal pouch -release drug slowly over extended period of time for prolonged action -bypasses first pass metabolism -buccal is three-fold thicker than sublingual -not continuously affected by saliva -follows same vein path as sublingual
gastrointestinal action
-disintegration and dissolution of tablets, capsules, and powders generally begins in the stomach.
Describe oral emulsions.
-disperse system of two immiscible liquids (oil and water) -stabilized by emulsifying agent -liquid API -most always used topically -2 types: water in oil and oil in water -can hide taste of orally administered oils
intravenous formulations
-dosage forms are administrated directly into a vein (blood supply). -most are aqueous (water based), but may also have glycol, alcohols, other non-aqueous solvents in them
inhalation formulations
-dosage forms are intended to deliver drugs to the pulmonary systems (lungs) -most of the dosage forms are aerosols that depend of the power of compressed or liquefied gas to expel the drug from the container.
Describe nasal delivery.
-drops and sprays for local and systemic effect -nasal absorption is facilitated by high permeability -produces rapid blood levels -provides direct route to brain and CSF -can bypass first pass metabolism -convient
What are some disadvantages ophthalmic delivery?
-drops have limited or no penetration to back of eye, rapid dissolution, and short contact time -Injection is traumatic and invasive
Describe oral solutions.
-drug is dissolution in solvent -readily available for absorption, consistent bioavailability -no dissolution -easy to swallow, good for NPO, children, geriatric -may include excipients (coloring, taste, buffers)
Adsorption
-drug loss to packaging materials and well documnted in IV solutions in poly-vinyl chloride plastic -process usually adsorption e.g. diazepam, insulin, hydrazine and in some cases actual partitioning occurs, e.g. nitroglycerin -care must be taken with container selection to avoid these problems
Maillard reacion
-drug with amine functional group and hydroxyl group of a sugar =browning reaction
vaginal dosage forms
-solutions -ointments -creams -aerosol foams -powders -suppositories -tablets -IUDs
Disadvantages of solutions-
-drugs and chemicals are less stable in solution than in dry dosage forms -some drugs are not soluble in solvents that are acceptable for therapeutic use -may require special additives or techniques mask objectionable taste -more difficult to handle, transport and store because of bulk and weight -solutions in bulk containers require dosage measurement devices
levomethorphan vs dextromethorphan
-dxm, a cough suppressant has almost no psychoactive effects at medically-recommended doses -has euphoric, psychedelic, and dissociative properties when administered in high doses -reacreational use sometimes referred to as "robot-tripping" or "triple Cs" -effects classified into plateaus -levo is an opioid analgesic
Describe the otic or aural route of administration.
-ear drops -treats infections, pain, and removes wax -formulated into suspension or solution in vehicle of anhydrous glycerin or propylene glycol -NO WATER = BETTER STABILITY AND NO MICROBES
What are characteristics of granules?
-easily wetted by liquids as opposed to powders -no disintegration step -oral products for reconstitution use granules as finished dosage forms
What are the advantages of buccal delivery?
-easy accessibility -oral mucosa more permeability than skin -less prone to irritation than nasal mucosa
What is the purpose of glidants/lubricants?
-enhance the flow of granules in the tablet machine -may increase disintegration time -generally have no effect on dissolution of water soluble drugs but will adversely affect dissolution of water-insoluble drugs -use only a small amount
ophthalmolic formulation
-every product must be manufactured to be sterile in its final container -a major problem administration is the immediate loss of a dose by natural spillage from the eye
modified-release formulations
-extend dissolution over a period of hours and provide a longer duration of effect compared to plain tablets.
Describe the different bases used in suppositories.
-fatty bases release drug by melting at body temperature (<10 min) -water soluble bases release drug by dissolving in rectal fluids (~1 hr) -fatty bases are preferred for rectal suppositories
arrhenius equation
-formula for the temperature dependence of reaction rates -plot of log k as function of the inverse of absolute temp gives a straight line with a slope of -Ea/2.303R -for 2 temps, following relationship is seen: log(k2/k1)= (Ea/2.303R)x((T2-T1)/(T1T2)) (slide 35)
vaginal administration
-formulations for this route of administration are: solutions, powders for solutions, ointments, creams, aerosol foams, suppositories, tablets, and IUDs -leads to variable absorption since the vagina is a physiologically and anatomically dynamic organ with pH and absorption characteristics is that administration of a formulation during menstruation could predispose the patient to the Toxic Shock Syndrome.
Suspensions-
-formulations in which the drug does nor completely dissolve in the solvent -the drug particles are suspended in the formulation -intended for oral administration they are sweetened and flavored
what does an increase in solvent polarity do
-generally it accelerates the rate when a charge is developed in the activated complex -decreases the rates when there is less charge in the activated complex compared to the starting materials -change in solvent polarity will have little or no effect on the rates of reaction when there is little or no difference in charge between the reactants and the activated complex -solvents may also affect the pKa of the drug by shifting the dissociation equilibrium (pKas on slide 45)
Cell membranes consists of ___ proteins embedded in ___?
-globular -dynamic fluid, lipid bilayer matrix
Tablets-
-hard formulations in which the drug and other ingredients are machine compressed under high pressure. -multiple compressed tablets contain one drug in an inner layer an another drug compressed at a lower pressure around it as an outer layer. -repeat action tablets initially release one dose of the drug and then release a second dose sometime layer
why is lidocaine so stable
-has 2 methyl groups around the nitrogen -this creates steric hinderance and is difficult for water to get into this area -we can add functional groups like this to make a drug more beneficial for us
What are the characteristics of Class I in the Biopharmaceutics Classification System?
-high solubility -high permeability -rate of dissolution limits absorption
What are the characteristics of Class III in the Biopharmaceutics Classification System?
-high solubility -low permeability -permeability is rate limiting
formulations
-how drugs are contained
what are some miscellaneous reactions
-hydration, decarboxylation, additions, and schiff's base formation -some form basis for various drug incompatibilities and instability when drugs are mixed together (admixtures)
Describe vaginal drug administration.
-ideal for both local region and systemic delivery due to large surface area of vagina and presence of dense network of blood vessels -somewhat similar to buccal mucosa -bypass first pass -local delivery of hormones, reduces systemic side effects -erratic and unpredictable -dose can be expelled -low patient compliance -water soluble bases very common; fatty base generally not used because it melt melt and leak out
pH partition hypothesis
-if the pH on one side of barrier differs then 1. drug will ionize to different degrees on either side 2. total drug conc's on the two sides will be equal 3. the side where the drug is more ionized will contain greater portion of the drug
Aging
-important aspect in tablets and changes occur in the disintegration/dissolution properties of the formulation -not always easily explained but hardening or softening alters disintegration/dissolution and bioavailability
Intravenous, intramuscular and intradermal dosage forms
-solutions -suspension -colloids -emulsions
Intranasal dosage forms
-solutions -suspension -ointments -gels
order of reaction
-in drug stability the order of a process generally treated as "apparent" order (pseudo order-> what does it look and behave like) -order determines the shape of the concentration-time profile; the rate constant determines its slope -both must be determined experimentally -0, 1st, and 2nd most frequent in drug stability (2nd not as often) -concentration change is small (10-15%) so distinction between orders relatively unimportant and expiration dates are usually based on 0 or 1st order kinetics
how can we use pH to prevent a molecule from being oxidized
-increase the H by adding HCl -therefore drugs that we known are easily oxidized, we can put them into slightly acidic solutions to prevent oxidation
intradermal injections
-involve small volumes that are injected into the top layer of skin, -the usual site is the anterior surface of the forearm
What are the factors affecting dissolution?
-ionization -decreased particle size -amorphous particles -hydrate forms
What are the four requirements of parenteral drugs?
-isotonic -sterile -free from particulate matter -pyrogen free **must have these because it bypasses protective barriers
Colon's anatomical features and absorption
-lacks villi -limited drug absorption due: 1. Lack of large SA 2. Lack of blood flow 3. The more viscous and semisolid nature of the lumen contents
Where do we want the therapeutic range to be?
-less than the toxic range -to set the TR it has to be based on a pt population study -eventually we will hit a conc range where we won't see any more benefit -not every pt will respond, so you have to decide where you want to draw the line and determine the range
Photolysis
-light may provide energy (photon) for initiation of oxidative process -not always oxidative; conversion of ergosterol to ergocalciferol, degradation of nitroprusside; rearrangement of some steroids
Describe rectal delivery.
-local disorders and NPO for systemic -very abundant blood supply -Inferior and middle hemorrhoidal veins drain directly into inferior vena cava, therefore no first pass metabolism -superior hemorrhoidal vein drains into partial circulation and subjected to first pass
what is oxidation viewed as
-loss of electrons, loss of hydrogen or gain of oxygen CH3Ch2OH-> CH3CHO-> CH3COOH (ethanol-> acetaldehyde-> acetic acid)
What are some disadvantages of rectal administration?
-low patient compliance -local site reactions -high variability
What are the characteristics of Class II in the Biopharmaceutics Classification System?
-low solubility -high permeability -solubility limits absorption flux
What are the characteristics of Class IV in the Biopharmaceutics Classification System?
-low solubility -low permeability -no in vitro
Gels-
-made using substances called gelling agents that increase the viscosity (thickness) of the medium in which they are placed. -the agents form an interlacing three-dimensional network of particles that restricts the movement of the solvent.
Stabilization strategies
-many for: 1) hydrolysis 2) oxidation -also use: temp, complex formation, formulation
addition of antioxidants
-materials which are more easily oxidized than the product or free radical inhibitors (i.e. they will be oxidized first before drug itself, buying time) -inclusion of a chelating agent such as EDTA to consume trance amounts of metal ions which can function as catalysts may also be useful -selection is important as some may react with product components or there may be physiological issues (i.e. cannot put in antioxidants if being put into nervous system)
solvent effects
-may be necessary to incorporate water miscible solvents into formulation to solubilize the drug -range of solvents which can be used is somewhat limited and most common are alcohol (95%), propylene glycol, glycerol, and polymeric alcohol (e.g. PEG) -solvent effects on stability are very significant but may be quite complex and difficult to predict
are formation of complexes useful for stability
-may be of value -ie benzocaine-caffeine and drug-cyclodextrins -but some may accelerate decomp and some may alter solubility and bioavailability
Rectal administration
-may be used to achieve a variety of systemic effects -absorption from rectal administration is erratic and unpredictable -most common forms are suppositories, solutions, and ointments
formulation as suspension and its affects on stability
-may be useful since drug will probably degrade through apparent 0 order kinectics
Ethanol is completely ___ with water, which allows it to do what?
-miscible -easily cross cell membranes and is efficiently absorbed from the stomach
What factors affect the deposition of drug in the lungs?
-mode of inhalation (inhaled volume, flow rate, breath holding pause maintained at end inspiration) -aerosol properties (aerodynamic diameter > 2 um = deposition in the oropharynx)
Passive diffusion
-molecules diffuse randomly in all directions -has conc gradient -net diffusion from high to low conc
dermal formulations
-most dosage forms are used for local (topical) effects on or within the skin. -used to treat minor skin infections, itching, burns, diaper rash, insect things and bites, athletes foot, corns, calluses, warts, dandruff, acne, psoriasis, and eczema. -the minor disadvantage of this route of administration is that the amount of drugs that can be absorbed will be limited to about 2mg/hour
should you freeze the product
-no, unless shown to have no deleterious effect (may be harmful to emulsions, protein drugs, and drugs like ampicillin)
Describe oral elixirs.
-not as viscous or sweet as syrups -do not effectively mask taste of API -4-20% alcohol
what does water act as during a hydrolysis reaction
-nucleophilic agent-> attacks the electrophilic sites of drug molecule
subcutaneous dosage forms
-solutions -suspensions -emulsions -implants
stabilization against
-number of factors can affect the rate of hydrolysis -by modifying these variables some control over rate of hydrolysis can be achieved -drug must be in solution for hydrolysis to occur so exclusion of water will slow reaction (can do this by freeze drying it) -may be achieved by formulating product as solid dose form such a tab or cap -total exclusion of water is not usually possible -lower water activity with cosolvent; manage pH through salts or buffers; store at reduced temp
local effect
-occurs when the drug activity is at the site of administration
systemic effect
-occurs when the drug is introduced into the circulatory system and carried to the site of activity
oxidation
-often mediated through atmospheric oxygen -most are free-radical and occur spontaneously under ordinary conditions; referred to as "auto oxidative" -products of oxidation usually electronically more conjugated therefore colour and aroma changes -may cause product to be unfit even though only small amount degraded
parental administration
-often preferred when oral administration causes drug degradation or when a rapid drug response is desired (etc, emergency solution). -requiring a needle are intravenous, intramuscular, intradermal, and subcutaneous -the solutions must be sterile (bacteria free), have a appropriate pH and limited in volume
what can affect the stability of the carboxyl group?
-other functional groups on the molecule, due to inductive, resonance, steric or H-bonding effects
what states can oxidation occur
-oxidation can occur in aqueous and non-aqueous solution and in solid state
How are drugs absorbed through the alimentary canal and list examples of types?
-passive diffusion -sublingual, buccal, GI, and rectal absorption
Sublingual administration
-placed under the tongue -generally fast dissolving uncoated tablets, contain highly water soluble drugs -quickly absorbed into the circulatory system
Describe film strips route of administration.
-placed under tongue for rapid dissolution and then swallow the solution/suspension -combines convince, stability, and dose accuracy of a solid and ease of swallowing and bioavailability of solution/suspension -can be used for oral, buccal, or sublingual use
zero order calculations
-plot of concentration vs time is linear with slope of Ko (don't have to do any transformation of data) -shelf life t90= 0.1[D]o/ko - units for rate constant= conc/time -loss of drug independent of concentration and constant with respect to time [D]= - kot + [D]o
first order
-plot of log[D] vs time gives a straight line with slope -k1/2.303 -shelf life by t90= 0.105/k1 -units for first = t-1 or 1/time -loss of drug directly proportional to the concentration remaining with respect to time (t1/2 is constant) -graph is curved log[D] = (-k1t)/(2.303) + log[D]o ie tinidazole degradation (slide 28,29)
polymorphism
-polymorphs differ in crystal structure and crystal energies which results in solubility differences -may result in unusable product, e.g. conversion of soluble polymorph of cortisone acetate to stable polymorph results in caking of product when formulated as injectable suspension
Enteric coated tablets
-prevent the tablet from disintegrating until it reaches the higher pHs of the intestine
intranasal formulation
-primarily used for their decongestant activity on the nasal mucosa, the cellular lining of the nose -the drugs are typically used are decongestants, antihistamines, and corticosteroids
What is the purpose of binders?
-promote adhesion of the powder particle of the formulation, enabling a granulation to be prepared, and the adhesion of the granules into tablets -may increase disintegration time -generally have no impact on dissolution of water-soluble drugs but will adversely affect dissolution of water-insoluble drugs
Describe ODTs and films.
-quickly dissolve when placed in mouth vis saliva (no water needed), this leads to faster absorption -absorbed through oral, stomach, and intestinal mucosa -good for patients with difficulty swallowing -Ideal for small dose drugs because of large amount of excipients
what is activation energy of most drug decompositions
-range from 12-24Kcal/mol -once it hits this Ea, will go down to a lower energy level -often times to get to this activation, must be in just the right formation, or connect with other reactant at right force, etc (slide 34)
pH effects
-reaction rates in aqueous solutions often dependant on the pH of the solution -study of pH effects on reaction rates can give insight into the mechanism and provide practical info regarding the stability of the drug (i.e. how lowering the pH of an oxidizable molecule can prevent oxidation) -rate constant determined at a variety of pH values with variables such a temp, ionic strength, and solvent composition help constant -these data presented as plots where rate constant is a function of pH (log k vs pH for first order and k vs pH for zero order0 -referred to as pH-rate profiles and several characteristic curve shapes can be identified
oxidation/reduction reactions
-redoxy -electron transfer processes where oxidation is loss of e -electron transfer accompanied by change in structure and transfer of protons
what temperature usually benefits storing stability
-reduced temps increase stability
Describe ophthalmic delivery.
-require to be sterile -topically applied or as an injection particle size is generally < 10um
route of administration
-routes are classified as enteral and parental.
sigmoid shaped curve
-seen when drug molecule can undergo acid/base dissociation so this is the typical curve for an ionizable substrate (slide 40)
V shaped curve
-seen with non-ionizable substrate subject to hydrolysis -the higher the y value, the faster the reaction (slide 39)
subcutaneous injections
-sites include back of the upper arm, front of the thigh, the lower portion of the abs and the upper back. -the route can be used for both short term and long term therapies -the most common drug is insulin
what are our 3 areas of biggest concern when it comes to drug stability?
1) Chemical 2) Physical 3) Microbilogical *important for patient to understand how to store to maintain the product as long as possible
✰✰✰ (IMPORTANT) Polymorphic transition can lead to forming a slower dissolving form of a drug. What are 2 examples?
1) Corticosteroids 2) Chloramphenicol palmitate
USP monographs include guidelines for dissolution testing. Name all 4 types of guidelines.
1) Dissolution medium 2) Volume of dissolution medium 3) pH of medium 4) Rotational speed of the paddle or basket
What are 4 other names for the Stokes Radius?
1) Effective hydrated radius 2) Solvated radius 3) Hydrodynamic radius 4) Stokes-Einstein radius
How much of Alcohol USP should be added to a syrup for the unpreserved (free water) water?
1) Find the volume (mL) of sucrose used in the syrup. (use equivalent factor 0.63 mL/g) 2) Find the volume of water Preserved by the sugar. (use equivalent factor 0.54 mL/g) 3) Calculate the amount of free water. (subtract answers from 1 and 2 from the total amount of syrup) 4) Find the amount of alcohol necessary to preserve to remaining free water. (multiply the answer from 3 by 18%)
What 2 properties are Permeability dependent on?
1) K and D (properties of solute) 2) h (properties of membrane)
The release of drug from controlled release (CR) systems does NOT occur only by zero-order process. The release is DIFFERENT due to what 2 things?
1) Lag-time Effect (time needed to saturate membrane) 2) Burst Effect (initial rapid release of drug from pre-saturated membranes)
What are the factors affecting Dissolution?
1) Physicochemical properties of the drug 2) Formulation factors of dosage form 3) Physiological factors of the human
What are 2 basic Diffusional Release Systems?
1) Reservoir Systems 2) Matrix Systems
✰✰✰ (IMPORTANT) What are the 3 factors that influence dissolution of a drug in SUSPENSIONS?
1) Settling 2) Aggregation 3) Change in crystal form upon aging
What are the 4 types of Transcellular Pathways?
1) Simple Diffusion 2) Facititated Diffusion 3) Active Transport 4) Transcytosis
What 3 things does the Diffusion Coefficient (D) depend on?
1) Size (molecular weight) 2) Diffusional barrier 3) Temperature
What are the 2 Pharmaceutical Transport System?
1) Solute transport 2) Solvent transport
In these 3 dosage forms, the particle size of the drug DECREASES as the drug dissolves, changing the effective surface area?
1) Tablets 2) Capsules 3) Suspensions
What are the 2 Fundamental physical concepts involved in Drug Transport Across a Region?
1) Thermodynamics 2) Kinetics
functional groups (and common drug they are on) that are subject to hydrolysis
1) amide- acetaminophen 2) lactam- penicillin 3) ester- atropine 4) lactone- warfarin 5) acetal- erythromycin 6) imine- diazapam
types of chemical degradation
1) hydrolysis 2) oxidation 3) photolysis 4) dehyrdration 5) racemization 6) micellaneous (hydration, decarboxylation, additions, and stiff's base formation)
what may happen when electromagnetic radiation is absorbed by a molecule
1) molecule decomposes with release of free radical 2) energy retained- chemical change 3) energy converted to heat and no reaction occurs 4) absorbing molecules emit light of different wavelength (fluorescence)
functional groups (and drug examples) that are subject to oxidaton
1) phenols-> steroids 2) catechol-> isoproterenol 3) ether-> PEG 4) thiols-> methimazole 5) thioether-> chlorpromazine 6) aldehyde-> paraldehyde
Some physical degradation reactions
1) polymorphism 2) vaporization 3) aging 4) adsorption
how to stabilize products against oxidation
1) protect from light 2) exclusion of oxygen 3) addition of antioxidants 4) control of pH
factors affecting reaction rate
1) temp 2) catalysis 3) ph effects 4) solvent effects 5) solubility effects
absorption of light energy depends on what 2 things?
1) the length of the light path through the solution 2) the concentration of the colored compound
what was the aim of both experiments?
1) to find the wavelength max for Bromophenol Blue and Methyl Orange by plotting an absorbance spectrum (400nm to 700nm) 2) to calculate the absorption coefficient (E) for each by the use of a standard curve
Types of solid state
1)Crystalline rearrangement- Definite pattern which keeps repeating. Have a definite geometric shape and boiling point. Called ANISOTROPIC (LONG RANGE) which means they have different properties (like heat capacity and refractive index) in different directions of the crystal. 2)Amorphous solids- Pattern breaks after a short range, random structure. Dont have a sharp boiling point. Irregular arrangement of atoms. Same properties in all direction. Are called ISOTROPIC which means they have same properties in all directions. Don't have a specific geometric shape and will flow due to their own weight. CRYSTALLINE solids are TRUE solids AMORPHOUS solids are PSEUDOsolids. ISOTROPIC and ANISOTROPIC is determined by X-ray spectroscopy. Examples:Rubber,glass, plastics 3)Polymorphs - Same as crystalline solids, but they have different patterns at different P and T conditions
Packing pattern
1)Cubic closed packing 2)Hexagonal closed packing 3)Square closed packing 4)body center closed placking
Characteristics of solid state
1)Definite mass shape and volume 2)Intermolecular distances are short 3)Intermoleculr forces are strong 4)The constituent particles are fixed and can only oscillate about mean position 5)incompressible and rigid
State of a substance is defined by balance between these 2 opposing forces
1)Intermolecular forces 2)Thermal energy
Supersaturated Solution
Contains a larger amount of solute than the solvent can normally accommodate at that temperature and pressure
Classification of crystalline solids based on intermolecular forces
1)Molecular solids (i)Non-polar molecular solids: They comprise of either atoms, like Ar and He or the molecules formed by non-polar covalent bonds example I₂,H₂,Cl₂,CCl₄. The atoms or molecules are held by weak dispersion forces or London forces. The solids are SOFT and NON-CONDUCTORS of electricity. They have LOW MP and are usualy in liquid or gaseous state at room T and P. (ii)Polar molecular solids: The molecules of substances like HCl, SO₂, etc which are formed by polar covalent bonds. These solids are held together by relatively stronger dipole-dipole interactions. They have HIGHER MP than non-polar molecular solids and are also SOFT and NON-CONDUCTORS of electricity. Most of them are gases or liquids under room temperature and pressure. Example solid SO₂ and solid NH₃ (iii)Hydrogen bonded molecular solids: Molecules contain polar covalent bonds between H and F,O or N atoms. Strong H bonding binds the molecules of solids like H₂O (ice). They are non-conductors of electricity. Generally they are non-volatile liquids or soft solids under room T and P. 2)Ionic solids: Ions are constituent particles of ionic solids. Such solids are formed by 3D arrangement of cations and anions bound by strong Coulombic (electrostatic) forces of attraction. They have HIGH MP and BP and are HARD and BRITTLE. Since the ions are not free to move, they are INSULATORS in solid state but conductors in molten or dissolved state. eg:NaCl, MgO, ZnS, CaF₂ 3)Metallic solids: Metals are orderly collection of positive ions surrounded by and held together by a sea of free electrons. These electrons are mobile and are evenly spread out throughout the crystal. Each metal contributes one or more electrons towards the sea of mobile electrons. High thermal and electrical conductivity both due to free electrons (when E field is applied the electrons move through network of positive ions and when heat is supplied thermal energy is spread uniformly throughout bu free electrons) Are LUSTROUS and have specific colours due to free electrons. They are highly malleable and ductile. 4)Covalent/Network solids: These are also called GIANT molecules. Covalent bonds are strong and directional therefore particles are held strongly in their positions. Such solids are very hard and brittle. They have extremely high MP and may even decompose before melting. They are insulators and do not conduct electricity. Diamond and SiC (silicon carbide) are typical examples of such solids. Although graphite also belongs to this class of crystals, but it is soft and also conducts electricity. These exceptional properties are due to its structure. Carbon atoms are arranged in different layers and each atom is covalently bonded to three of it neighbouring atoms in the same layer. The fourth valence electron of each atom is present between different layers and is free to move about. Different layers can slide over each other which makes graphite a soft solid and a good lubricant Eg SiO₂, SiC, C, AlN, Graphite
Coordination numbers
1)SCC-6,(12,8) 2)BCC-8,(6,12,8) 3)FCC,CCP,HCP-12,(6,12,8) 4)ECC-4
Stacking pattern (2D)
1)Square closed packing 2)Hexagonal closed packing
Imperfections/Defects in solids
1)Stoichiometric defect 2)Non-stoichiometric defect 3)Impurity
Types of voids
1)Triangular void 2)Tetrahedral void 3)octahedral void 4)Cubic void
In the USP Test for Enteric Coated (EC) tablets, the tablet does NOT disintegrate for ______ hour in gastric fluid and _________% dissolves in the intestinal fluid within 45 minutes.
1, 75%
How to study permeation at GI track?
1- In vitro cell layer permeation: Caco-2 monolayer model 2- In vitro tissue permeation 3- In situ perfusion In vitro (Animal or human)
Describe phase 4 of fasted state
1. 0-5min 2. irregular contractions 3. medium descending amplitude
Describe phase 2 of fasted state
1. 20-40 minutes 2. irregular contractions 3. medium amplitude 4. bile secretion begins 5. onset of gastric discharge of administered fluid of small volume usually occurs before particle discharge 6. onset of mucus and particle discharge
Describe phase 1 of fasted state
1. 30-60 min 2. quiescence (nothing happened)
Describe phase 3 of fasted state
1. 5-15 minutes 2. regular contractions (4-5/min) with high amplitude 3. mucus discharge continues 4. particle discharge continues
Higuchi Module/Equations may predict:
1. Homogenous Matrix 2. Granular Matrix: + Porosity & Tortuosity 3. Soluble drugs in topical vehicles & matrices
Hydrolysis is catalyzed by what 3 components?
1. Hydrogen ions [H+] 2. Hydroxyl ions [OH-] 3. Buffers
Different drug release profiles
1. Immediate Release 2. Modified Release Extended Release Delayed Release 3. Repeat Action (Pulsatile Release)
Buffer Capacity depends on what 3 things?
1. Ka 2. [H+] 3. Molar Concentration
Describe class II of biopharmaceutical classification system
1. Low solubility 2. high permeability 3. bioavailability is controlled by the dosage form and rate of release of the drug substance (Ibuprofen, Naproxen)
Describe class IV of biopharmaceutical classification system
1. Low solubility 2. low permeability 3. Difficulty in formulating a drug product that will deliver consistent drug bioavaibility 4. an alternate route of administration may be needed (Amphotericin B, Neomycin)
Classification of modified-release delivery systems --- by formulation design & strategies
1. Matrix system (Monolithic) 2. Coating or membrane-controlling 3. Others
Describe zero order absorption
1. NOT common 2. drug is absorbed by a saturable process 3. controlled-release delivery formulation is used: dDb/dt = k0-kDb
Describe fed state
1. ONLY one phase 2. as long as food is present 3. regular frequent contractions 4. amplitude is lower than phase III 5. 4-5 contractions/ min
If there is a sufficient resource of a compound, what 2 types of co-solvents should be used?
1. PEG 400 and Propylene glycol 2. Oils and surfactants
Common routes of drug administration
1. Parenteral Routes: Intravenous bolus (IV), Intravenous infusion (IV inf), Subcutaneous injection (SC), Intradermal injection, Intrathecal injection, Intramuscular injection (IM) 2. Enteral Routes: Buccaneer, Sublingual (SL), Rectal (PR), Oral (PO) 3. Transdermal 4. Inhalation and intranasal
What are 2 advantages of using Fourier Transform Infrared Spectroscopy (FTIR)?
1. Rapid 2. Qualitative and Quantitative
Bioavailability of Intramuscular injection
1. Rapid from aqueous, slow from oil solutions 2. slower but more sustained blood levels than IV
What are some ⚠️Precautions⚠️ for stabilization against oxidation?
1. Replace Oxygen in the container with Nitrogen or inert gases (CO2) 2. Use containers NOT made of heavy metals 3. Use antioxidants 4. Use reducing agents
Example of Monotrophs:
1. Stearate 2. Chloramphenicol palmitate
4 Primary Tastes
1. Sweet 2. Bitter 3. Sour 4. Salty
Prefilled syringes
Contains sterile liquid medication that is ready to administer without further preparation.
What is the gamma camera used for in gamma scintigraphy(1) and what is being measured simultaneously(2)?
1. The image of the capsule breaking up in the stomach or the GI tract 2. Drug levels in blood and urine
What is pharmacokinetics?
1. The study of drug movement into, around, and out of the body 2. study of time course of drug concentration in body compartments 3. Drug at the site of action is the most important but rarely measured; measure plasma concentration with the assumption that change in plasma concentration will be proportional to change at site of action
What are the advantages to using Thermal Methods such as DSC, TGA, and TMA?
1. Thermodynamic parameter can be evaluated. 2. Heat of Transition from one polymorph to another can be measured. 3. Melting point can be determined
How do you protect a drug from photochemical decomposition?
1. Using colored glass containers (amber glass) 2. Store drug in the dark
What are the 3 Solute-Solvent interactions?
1. Van der Waals Forces 2. Hydrogen Bonds 3. Electrostatic Force
If there is a limited resource of a compound, what 4 co-solvents should be used?
1. Water 2. Saline 3. 0.1M HCl 4. 0.1M NaOH
Bioavailability of oral
1. absorption may vary 2. usually slower rate than IV or IM
Bioavailability of Rectal
1. absorption varies in suppositories 2. solutions more reliable
Advantages of SL
1. avoid 1st pass effects 2. available as prolonged action (mucoadhesives)
Advantages of IV inf
1. better control of plasma drug levels 2. may use irritating drugs or with poor lipid solubility 3. large volumes
GI drug transport is often (1)____ Whether the transporter causes absorption or exsorption depends on (2)____
1. bidirectional 2. which direction the flux dominates
Describe GI drug transport
1. bidirectional 2. whether the transporter causes absorption/exsorption depends on which direction the flux dominates 3. enterocytes: intestinal epithelial absorptive cells that express transporters
Describe overall oral drug absorption
1. bioavailability factor F = fraction of the dose that reaches the plasma intact 2. effective dose = F * dose given
Describe gamma scintigraphy
1. commonly used to track drug dosage form MOVEMENT from 1 region of the GI tract to another 2. Non absorbable gamma emitting radionuclide added as a marker to dosage form 3. the image is monitored using gamma camera 4. simultaneously, drug levels in blood and urine are measured
Bioavailability of Intravenous infusion (IV inf)
1. complete absorption 2. Rate of absorption controlled by infusion rate
Grapefruit juice
1. contains flavonoids that inhibit CYP450 2. increases bioavailability of drugs that are CYP450 substrates 3. can block drug efflux by inhibiting P-gp 4. doubled Cmax and increased AUC of talinolol
Purpose of gamma scintigraphy
1. correlate residence time of the drug in a given region after capsule break up to drug absorption 2. study drug absorption mechanisms in different regions of the GI tract before a drug is formulated for extended release
Enteric coats effect on: 1. Ka 2. tmax 3. AUC
1. decrease 2. increase 3. decrease to no effect
Sustained-release agents effect on: 1. Ka 2. tmax 3. AUC
1. decrease 2. increase 3. decrease to no effect
Describe gastric emptying
1. delayed by high fat meals, cold beverages, anticholinergic drugs -> slow the rate of drug absorption because it delays drug reaching the duodenum 2. liquids and small particles (<1mm) NOT retained in the stomach -> empty due to higher basal pressure in the stomach over the duodenum 3. different constituents of a meal empty from the stomach at different rates 4. liquids are generally emptied faster than digested solids from the stomach 5. large particles (tablets, capsules) are delayed for 3-6 hours by the presence of food in the stomach 6. indigestible solids empty slowly, mainly during interdigestive phase when food is not present and the stomach is less motile but periodically empties its content due to housekeeper wave contraction
Describe transcellular transport
1. determined by the easy of drug permeability across lipid membranes 2. best for small lipophilic drugs
Describe drug distribution into blood
1. drug distributes rapidly into a large volume after entering the blood 2. concentration of drug in the blood is low relative to the concentration at the site of drug absorption
Ph partition hypothesis when pH on one side of the barrier differs
1. drug will ionize to different degrees on either side 2. total drug concentration on the 2 sides will be unequal 3. the side where the drug is more ionized will contain greater portion of the drug
Advantages of transdermal
1. easy to use 2. good for lipid soluble drugs with low MW
Disadvantage of oral
1. erratic absorption 2. GI instability 3. 1st pass metabolism
Disadvantage of Rectal
1. erratic absorption 2. absorption from lower rectum avoids portal vein, from upper rectum still susceptible to 1st pass metabolism
Describe an atomic absorption window
1. exist for efficient absorption 2. drugs should be released from dosage form completely during this window
Factors affecting transit time of drug
1. formulation 2. fasted vs fed time for a drug to pass through the stomach and SI 3. fasted: 4-8h 4. fed: 8-12h
GI transit time of the drugs is affected by what factors?
1. formulation 2. fasted/fed: 4-8 hr for drug to pass through the stomach and SI in fasted state vs. 8-12 hrs in the fed state
1. Bioavailability factor F= 2. Effective dose=
1. fraction of the dose that reaches plasma intact 2. F x dose given
HYGROscopic is the same as HYDROscopic. (T/F)
FALSE! - They are completely different
Describe class I of biopharmaceutical classification system
1. high solubility 2. high permeability 3. bioavailability problem is NOT expected for immediate-release drug products (Acetaminophen)
Describe class III of biopharmaceutical classification system
1. high solubility 2. low permeability 3. bioavailability may be incomplete if drug is NOT released and dissolved within absorption window (Atenolol, Penicillins)
Describe the effect of Fick's Law
1. higher A favors absorption 2. drugs that are more lipid soluble -> higher K -> favor absorption
What drug NOT pass through cell membranes
1. highly charged molecules 2. large molecules
Describe intestinal permeability
1. in vivo studies of drug absorption and permeability are costly and technically challenging 2. Caco-2 human colon adenocarcinoma cells display properties of the epithelial lining in human SI 3. Caco-2 cultures are used to study permeability of PASSIVELY transported drugs 4. In some cases, the drug permeability may appear to be low due to efflux of drugs via membrane transporters
Disintegrants effect on: 1. Ka 2. tmax 3. AUC
1. increase 2. decrease 3. increase to no effect
Water effect on absorption
1. increase water volume -> increase bioavailability of erythromycin in fasted patient 2. large volume increase solubility 3. unabsorbed antibiotic influence the GI flora
Drug absorption may be affected by any disease that causes:
1. intestinal blood flow 2. gastrointestinal motility 3. stomach emptying time 4. gastric and intestinal pH 5. permeability of the gut wall 6. bile secretion 7. digestive enzyme secretion 8. alteration of normal GI flora
In gastrointestinal perfusion where is the tube inserted (1) and what is the typical choice (2)?
1. into a specific GI section 2. Jejunum is the typical choice because of lower peristaltic activity than duodenum --> duodenum, ileum, colon can be used too
Why is the colon has limited drug absorption?
1. lack villi 2. lack of large surface area 3. blood flow 4. more viscous and semisolid nature of the lumen contents
Describe P-gp
1. located in membranes -> protect body from undesirable compound 2. important in drug efflux and drug resistance 3. found in jejunum, colon, rectum, brain 4. could cause multiple drug resistance cancer because pumping out drugs from the cell
Describe gastrointestinal perfusion
1. method to study absorption and permeability of a drug in various segments of the GI tract 2. Tube is inserted into a specific GI section 3. Jejunum is the typical choice because of lower peristaltic activity than duodenum
Rules for drug molecules that would improve the chance for oral absorption
1. molecular weight < 500Da 2. NOT more than 5 H-bond donors 3. NOT more than 10 H bond acceptors 4. Octanol-water partition coefficient, log P <5
Water effect on absorption
1. most drugs should be taken with water 2. larger volume increases solubility 3. unabsorbed antibiotics influence the GI flora
Describe diffusion
1. no external energy 2. molecules diffuse randomly in all directions 3. Net diffusion from the high concentration side to the low concentration side -> concentration gradient
Disadvantage of inhalation and intranasal
1. particle size controls site of deposition in respiratory tract 2. may stimulate cough reflex 3. some drug may be swallowed
Physiological changes during pregnancy
1. plasma volume expansion 2. increased extracellular fluid space 3. increased total body water 4. decreased albumin plasma conc 5. increased cardiac input (30-50% above normal) 6. blood flow to the skin is increased to dissipate heat production by the fetus 7. increased renal blood flow and glomerular filtration 8. changes in hepatic drug metabolizing enzymes 9. changes in GI function
Bioavailability of inhalation and intranasal
1. rapid absorption 2. total dose absorbed is variable
1. dQ/dt 2. D 3. P 4. K
1. rate of diffusion 2. constant for each drug (cm^2/sec) 3. permeability coefficient 4. lipid-water partition coefficient of drug
Describe flux
1. rate of transfer (mass/unit area; mg/cm2)
Describe active (carrier-mediated) transport
1. require input of energy 2. transport against concentration gradient 3. important in GI absorption, renal, and biliary secretion of drug metabolites 4. a fixed number of carrier molecules are available 5. all the binding sites on the carrier may become saturated if the drug concentration get very high -> limited drug absorption 6. The rate of drug absorption increase with drug concentration until the carrier molecules are completely saturated 7. at higher drug concentration, the rate of drug absorption remains constant or zero order 8. The carrier molecules may be highly selective for the drug molecule (if the drug structurally resembles a natural substrate that is actively transported, then it is likely to be actively transported by the same carrier mechanism) -> drug of similar structure may compete for sites of absorption on the carrier
Advantages of oral
1. safest and easiest route 2. immediate and modified-release available
Disadvantage of IV inf
1. skilled practitioner needed 2. tissue damage at site of injection
Why most drugs optimum site of absorption after oral administration is upper portion of the small intestine (ie. duodenum region)?
1. slight acidic 2. optimal for enzymatic breakdown (pH 6-6.5 -> optimal for digestion of proteins and carbohydrates with pancreatic enzymes) 3. immense surface area for the drug to diffuse passively because of an atomic features such as villi and microvilli and villi are less abundant in other area of the GI 4. highly perfumed with a. network of capillaries and lymphatic vessels -> maintain a concentration gradient between the intestinal lumen and plasma circulation -> drive drug absortion 5. small intestine transit time: 3-4hour
Bioavailability of transdermal
1. slow absorption, variable rates 2. occlusive dressing increase absorption
Disadvantage of SL
1. some drugs may be swallowed 2. only for small doses
What influence the transmembrane movement of drugs?
1. the composition and structure of the plasma membranes 2. cell membranes are composed of phospholipid bilayers interspersed with carbohydrates and protein groups 3. Cell membrane consists of globular proteins embeded in a dynamic fluid, lipid bilayer matrix; the proteins provide a pathway for the selective transfer of polar molecules and charged ions through the lipid bilayer
Describe paracellular transport
1. through the water-filled junctions between cells 2. junctions are very tight in the GI - very minor role in drug absorption
Describe markers to study transit time
1. tools to study mechanism of drug absorption 2. mannitol added to a dosage form reduces uptake of drugs absorbed exclusively from SI 3. codeine slows GI transit by decrease stool water content and decrease drug absorption 4. lactulose accelerates GI transit by increase stool water content and increase drug absorption
Limitations of gamma scintigraphy
1. track 2 different things 2. voluntary patient
Disadvantage of transdermal
1. variable skin permeability 2. irritation
Describe intestinal epithelial transporters
1. various carrier-mediated systems (transporters) are present at the intestinal brush border and basolateral membrane for the absorption of specific ions and nutrients essential for the body 2. both influx and efflux transporters are present 3. influx: increase drug absorption 4. efflux: drug outflow 5. many transporters can move drugs in both directions 6. many drugs are absorbed by carrier system because of similar structure to natural substrates
What can pass through the cell membranes?
1. water 2. selected molecules 3. lipid-soluble molecules -highly charged molecules and large molecules do not
What drug pass through cell membranes
1. water 2. selected small molecules 3. lipid-soluble molecules
Advantages of rectal
1. when patient unable to swallow 2. local and systemic effects
Diamond covalent C-C bond length
1.54A value for C-C single bond
In the following graph for a co-solvent system: - What is the SOLUBILITY of Phenobarbital at Glycerin 40% and Alcohol 22%?
1.5g/100mL
Shelf life of a drug is the time it takes for _______% for a drug to degrade and ________% is still active at Room Temperature.
10%, 90%
In the following graph for a co-solvent system: - What is the percentage of WATER in Alcohol 0% and Glycerin 0% in Phenobarbital?
100% Water
The rate of most degradation reactions increases 2-3 times with each ________°C rise in temperature.
10°C
In a co-solvent system: The highest solubility is when the ratio is ______:_______
1:1
lititz pharmacopoeia
1st american pharmacopoeia in 1778
What order is extravascular absorption?
1st order
**On Exam Electrostatic Force occurs between _________ ions as the results of induced dipoles.
2
ALWAYS choose Buffers within range where pH is _______ units more or less than pKa.
2
If shelf life (t90%) is known at a warmer temperature and to be estimated at a cooler temperature, use Q10 value _________.
2
generally an increase in temperature by 10 degrees will cause an increase in rate by ___-____ fold
2-3
NaCl and H2O form a eutectic mixture with a eutectic point of -21.2°C and _________% salt by mass.
23.3%
Room Temperature is at ________°C.
25°C
What % of cardiac output is increased after meals?
28%
Step 3: At the Mucus layer
30 - 100 µm in thickness Considerable viscosity: impact on diffusion Complexation with mucin: streptomycin
In the following graph for a co-solvent system: - What is the percentage of WATER in Alcohol 22% and Glycerin 40% in Phenobarbital?
38% Water
ZnS type or AB type
4:4 CN compound r⁺/r⁻=0.3 S forms FCC lattice Zn occupies alternate(non-adjacent) tetrahedral voids. effective number of formula unit cell Z=4 r⁺+r⁻=½(√3 a/2) CN of Zn=4 CN of S =4
Mean mouth-to-rectum transit time
53.3 hr (35 hr for colon transit time) (the window of opportunity in the duodenum is relatively short)
Mean mouth to rectum transit time
53.3h (35h for colon transit time)
Packing fraction BCC
68%
NaCl type structure or rock salt structure
6:6 C.N. compounds r⁺/r⁻ =0.51 Cl⁻ ions in FCC lattice Na⁺ ions occupy all octahedral voids Therefore effective formula unit Z=4 CN of Na=6 CN of Cl=6 Edge length of unit cell=2(r⁺+r⁻)
the normal volume if tears in the eye is
7 microliters
CsCl type structure
8:8 CN compound r⁺/r⁻=0.93 Cl forms simple cubic structure Cs occupies body center void/cubic void Effective no of formula unit = 1 (mistake in NCERT) CN of Cs=8 CN of Cl=8
how much can cohesive packing energies differ by
8kJ/mol significant but not emormous
Shelf Life means _______% is still intact and ________% is expired/degraded.
90%, 10%
How much Molar Mass of HCl is used to stimulate gastric fluid in USP Equipment and Procedure?
900mL of 0.1M HCl
MEMORIZE the following Biopharmaceutical Classification System
:)
THE FOLLOWING ARE QUESTIONS FROM EASYGENERATOR
:)
The following Transport Mechanisms are on EXAM!
:)
shelf life
=t90 -time when the initial concentration of active has decreased by 10% (drops to 90% of its original value) -plot on a graph-> use linear; then using the 95% lower confidence and 90% specification limit to calculate
Rapidly dissolving
> 85% of labeled amount of drug substance dissolves within 30 minutes
Dehydrated Alcohol USP
>99.2 % w/w or >99.5% v/v
Second Order Kinetics A + B → C rate = k units: Half-life:
A + B → C rate = dc/dt = k[A][B] k units: 1/(concentration * time) Half-life: 1/k[Ao]
Hypothetical Reaction for Zero-Order and First-Order Reactions
A ----> P
See if we can switch to ER/DR maybe 2x daily so effect will work longer and overnight.
A 65 year old patient came to refill her Ditropan IR (oxybutynin IR) 5mg PO TID prescription for her overactive bladder. She thinks that her medication is helping very little. Because she still needs to wake up couple of times during night for voiding. How can you help this patient for effective medication therapy in collaborating with the physician?
Buffering Agent
A compound or mixture of compounds that when present in a solution, resists changed in the pH of the solution when small quantities of acid or base are added to the solution - Examples: Citric acid, Lactic acid, Phosphoric acid, Potassium Citrate, Potassium Phosphate, Succinic acid
What is the Basket method Dissolution Apparatus?
A drug is dipped in and out of a dissolution medium in order to simulate bio-dissolution
What is the Paddle method Dissolution Apparatus?
A drug is placed inside a test tube and a paddle is spun to simulate bio-dissolution
Drug Product
A finished dosage form ( i.e. tablet, capsule, or solution) that contains the Drug Substance (API) and one or more Inactive Ingredients (EXCIPIENTS)
Microencapsulation
A means of applying relatively thin coating to small particles of solid or droplets of liquids and dispersion; A rapidly expanding technique as a process
ER can't be crushed because it affects its release
A nurse practitioner called in a RX for metoprolol ER 50 mg for hypertension. Direction: Take ½ tablet by mouth twice daily. How would you consult this RX?
Normal to see capsule shell in stool because it's nonerodible
A patient with ADHD on Concerta 36 mg PO daily complains of drug induced hallucination as the patient is seeing capsule shells in stools. How would you consult this patient??
ER can't be crushed because it affects its release
A resident called in RX Metformin ER 500 mg (OSMO). Take 1 ½ Tablet by mouth once daily. What is wrong with is RX?
syrup
A thick, sweet, sticky liquid, consisting of a sugar base, natural or artificial flavorings, and water.
Mannitol marker does what?
Added to dosage form to reduce uptake of drugs absorbed exclusively from the small intestine
Fluctuation; Frequent; Convenience; Compliance; Reduced
Advantages of EXTENDED Release: -Less ____ in drug blood levels -Less ____ dosing -Enhanced ____ and ____ -____ adverse effects
Extended
Advantages of ____ Release: -Less fluctuation in drug blood levels -Less frequent dosing -Enhanced convenience and compliance -Reduced adverse effects
What route does the drug take to get into the bloodstream if it is administered IM?
After IM injection, drug diffuses from muscle into surrounding tissue, and then into blood
What shows both frenkel defect and schottky defect
AgBr
ccp hcp and fcc
All have same density In fact, CCP and FCC are same HCP is different
Example of polymerized molecules:
Amino-penicillins (i.e. ampicillin sodium)
(Amorphous/Crystalline) form is MORE soluble and requires LESS energy to break crystal lattices?
Amorphous
Why is the duodenum an ideal place for drugs to diffuse passively?
Anatomy provides an immense SA
As a pharmacist, what advice would you give to patients taking photosensitive drugs?
Apply at night (topical products) Use sunscreen Avoid sun Store away from light Don't take with other drugs that also cause sun sensitivity
When are oxidation reactions most likely to occur?
Aqueous environments Exposed to oxygen (ROS) exposed to light (photoinduced oxidation) catalyzed by trace amounts of metals at high pH
Prefilled cartridge
Are actually small vials with a needle attached. They fit into a metal or plastic holder and eject one unit-dose of a sterile drug in liquid form.
Transdermal patches or pads
Are adhesive bandages placed on the skin. They hold a drug form that is slowly absorbed into the circulation over a period ranging from hours to several days
Metered-dose inhaled
Are aerosol device with two parts; a canister under pressure and a mouthpiece. The canister contains multiple drug doses in either a liquid form or a micro fine powder or crystal. The mouthpiece fits on the container, and finger pressure on the mouthpiece opens a valve on the canister that discharges one dose. *the physician's or healthcare provider's order states the number of inhalations or puffs to be taken. More on page 68
Lozenges or pastilles
Are disklike solids that slowly dissolve in the mouth. (Cough drops) some drugs are prepared in a gun and are released by chewing (nicotine) may be packaged in unit dose as well as multi dose containers.
Industrial Pharmacy
Arm of pharmaceutics that involves the applications of physical pharmacy and pharmaceutics in the manufacturing of a dosage form.
Dependence of the rate constant of a chemical reaction on the absolute temperature
Arrhenius equation
Example Problem: - Aspirin has an Ea of 14,000 cal.mol-1 - Ascorbic Acid has an Ea of 23,000 cal.mol-1 - Which one has a LOWER degradation rate?
Ascorbic Acid has a LOWER degradation rate because it has higher Ea.
Why is drug dissolution the rate limiting step?
Because it is often the slowest of the various stages involved in drug release because of drugs lipophilic qualities
Why is the rate of drug dissolution important to know?
Because it is the rate limiting step
Why are drugs so difficult to put into solution through dissolution?
Because most drugs are lipophilic to enhance absorption
Why does a drug need to undergo dissolution?
Because only a drug in solution can be absorbed, distributed metabolized, excreted, or even exert pharmacological actions.
Preparation and variable storage may lead to physical, chemical and/or microbiological instability
Beyond-Use-Date
Which date is placed on a prescription bottle by a pharmacy?
Beyond-use-date
Food stimulates the production of what?
Bile acids, which increase solubility of fat-soluble drugs
Matrix systems (biodegradable)
Biodegradable particulate systems
Caco-2 cultures are used to classify what?
Biopharmaceutics Classification System (BCS) classes of drugs
Flavor High-MW Salts
Bitter
Increases
Blood pressure meds = Nifedipine for example ____ the risk of stroke if crushed
What equation describes the influence of ionic strength (√μ) on the degradation rate constant (k)?
Bronsted-Bjerrum equation
Advantages of Buccal and Sublingual Routes
Buccal: Oral mucosa allows rapid absorption of LIPOPHILLIC drugs Sublingual: Blood vessels under the tongue induce rapid onset of systemic drug action (2-5 mins) and AVOIDS First-Pass effect
Which of the following drug has a FASTER Diffusion?
Caffeine (smaller size = faster diffusion)
What compound loses its water of crystallization in the process of efflorescence?
Caffeine hydrate
Signs of instability in powders:
Caking Discoloration Release of pressure upon opening the container (may indicate bacterial or other degradation)
What compound is an exception to dissolution because it is exothermic?
Calcium Hydroxide Ca(OH)₂
Preparation of Buffer System: STEP 2
Calculate C from Buffer Capacity Equation, when β is in the range of 0.01 to 0.1
Preparation of Buffer System: STEP 4
Calculate INDIVIDUAL CONCENTRATIONS of S/A or B/S, using C and RATIO from above steps.
Preparation of Buffer System: STEP 3
Calculate the RATIO of [S] and [A] OR [B] and [S] for βmax from Henderson Hasselbach Equation.
How fast is disintegration and dissolution in the body?
Can vary, but usually very fast
In the Diffusion Layer Model: What is the concentration of the drug in bulk medium?
Cb
In Cell Diffusion: C₁ is the drug concentration that interacts with (Cd/Cr)
Cd
Step 2: Food & Drug Interactions (Changes in pre-systemic metabolism)
Certain food induce CYP3A while some inhibit CYP3A: e.g. Grapefruit Juice
Sustained
Characteristics of drug for formulation as ____ release dosage form: 1. Drug should exhibit neither very fast rate of absorption nor excretion 2. Drug should be uniformly absorbed throughout the GI tract 3. They should require relatively small doses 4. Should have a good margin of safety (i.e. that their therapeutic index should be relative range) 5. Should not show any cumulative action/ undesired side effect as in case of dose dumping it might produce toxicity
Absorption; Excretion; Uniformly; Small; Safety; Side
Characteristics of drug for formulation as sustained release dosage form: 1. Drug should exhibit neither very fast rate of ____ nor ____ 2. Drug should be ____ absorbed throughout the GI tract 3. They should require relatively ____ doses 4. Should have a good margin of ____ (i.e. that their therapeutic index should be relative range) 5. Should not show any cumulative action/ undesired ____ effect as in case of dose dumping it might produce toxicity
Preparation of Buffer System: STEP 1
Choose WEAK ACID/BASE and its CONJUGATE PAIR whose pKa is CLOSE to pH for MAXIMUM β.
What are some examples of additives?
Citrates, glucose, sorbitol, etc.
In BCS: Which classes have HIGH PERMEABILITY?
Class I and Class II
In BCS: Which classes have HIGH SOLUBILITY?
Class I and Class III
If we only enhance the dissolution process, which class will be impacted the most?
Class II
In BCS: Which classes have LOW SOLUBILITY?
Class II and Class IV
In BCS: Which classes have LOW PERMEABILITY?
Class III and Class IV
Bioavailability of Intrathecal injection
Complete absorption
Bioavailability of Intravenous bolus (IV)
Complete systemic drug absorption
Mechanical protection (packaging)
Compression - damage to outer packaging problematic for saleability Impact - breakage of dosage units can occur Vibration - segregation of powders - abrasion of tablets There are different types of mechanical stresses that can be placed on drugs during transport. The packaging will be tested to ensure that it suitably protects against these different stresses.
What are enteric-coated tablets?
Ones that have delayed release b/c they do not dissolve in the stomach
Impurity defects in covalent solids
Covalent network of atoms like Si,Ge,C is disrupted by a foreign atom. few atoms of silicon are replaced by atoms from group 14 or group 15 eg (B,Al,Ga) or (N,P,As) This increases electrical conductivity by formation of holes(group13) or free electrons(group 15) This is also called doping. Group 13 forms p-type semiconductors. Group 15 forms n-type semiconductors.
_____________ is a phenomenon where a solid dissolves and saturates a thin film of water on its surface.
Deliquescence
What is the net movement of molecules or atoms from a higher concentration to a lower concentration?
Diffusion
What is D in the dissolution rate equation?
Diffusion coefficient of solute in solution
Coating or membrane-controlling
Diffusion controlled Dissolution controlled Chemical or Bio-degradable
Matrix system (Monolithic)
Diffusion controlled Dissolution controlled Chemical or Bio-degradable
____________ _____________ is the medium in which the diffusants migrate.
Diffusional barrier
Failure; Dumping; Wash-Out; Conversion; Education
Disadvantages of EXTENDED Release: -System ____ and dose ____ -Long ____ period for dose termination -Dose ____ -Patient ____
In-vivo; In-vitro
Disadvantages of SUSTAINED release forms: Poor ____, ____ correlation
Dose Dumping
Disadvantages of SUSTAINED release forms: Possibility of ____ ____ due to food, physiologic or formulation variable or chewing or grinding of oral formulation by the patient and thus increased risk of toxicity
Normal; Accommodated
Disadvantages of SUSTAINED release forms: Sustained release forms are designed for the ____ population (i.e. on the basis of average drug biologic half-life's). Consequently disease states that alter drug disposition, significant patient variation and so forth are not ____
Decreased Systemic Availability
Disadvantages of SUSTAINED release forms: ____ ____ ____ in comparison to immediate release conventional dosage forms; this may be due to incomplete release, increased first-pass metabolism, increased instability, insufficient residence time for complete release, site specific absorption, pH dependent solubility, etc.
Retrieval; Difficult
Disadvantages of SUSTAINED release forms: ____ of drug is ____ in case of toxicity, poisoning or hypersensitivity action
Less Flexibility; Design
Disadvantages of SUSTAINED release forms: The physician has ____ ____ in adjusting dosage regimens. This is fixed by the dosage form ____
Extended
Disadvantages of ____ Release: -System failure and dose dumping -Long wash-out period for dose termination -Dose conversion -Patient education
Sustained
Disadvantages of ____ release forms: 1. Decreased systemic availability in comparison to immediate release conventional dosage forms 2. Poor in-vivo, in-vitro correlation 3. Possibility of dose dumping 4. Retrieval of drug is difficult in case of toxicity/poisoning/hypersensitivity reaction 5. The physician has less flexibility in adjusting dosage regimens 6. More costly processes and equipment 7. Sustained release forms are designed for the normal population. So significant patient variation and so forth are not accommodated
(Absorption/Dissolution) rate is limiting if dissolution < absorption.
Dissolution
What is the rate limiting step in SUSPENSIONS?
Dissolution
__________ is a process by which a SOLID solute with LOW solubility enters into a solution in the presence of a solvent.
Dissolution
What happens to dissolution and absorption rates as a drug becomes more lipophilic?
Dissolution decreases, but absorption increases
Solid ➞ _____?____ ➞ Solution ➞ _____?_____ ➞ Blood
Dissolution in GI Tract, Absorption
Channeling agent
Dissolution in the GI fluids: NaCl, sugars
What are susceptible groups to oxidation?
Double bonds
Extent to which a dosage form retains the same properties and characteristics that is possessed at the time of its manufacture
Drug Product Stability
The same technique as gamma scintigraphy is used to study what?
Drug absorption mechanisms in different regions of the GI tract before a drug is formulated for ER
PE; PVAc
Drug can be granulated with inert plastic (____, ____) and compressed into tablets
Beads; Pellets; Granules
Drug can be put on ____, ____ or ____ usually by spray method.
Spray
Drug can be put on beads, pellets or granules usually by ____ method.
Step 1: Drug dissolution & ionization in the Lumen (Stomach or Intestinal)
Drug ionization pH varies significantly throughout GI tract Influence of pH on dissociation/ionization & drug dissolution in GI fluids
Delayed Release (DR)
Drug is released at a time other than immediately following administration.
Distribution
Drug molecules carried by blood to site of action
Troughs
Drug release by osmosis: Methylphenidate (CONCERTA) in ADHD treatment: Controlled release of methylphenidate in the morning hours helps avoid the ____ seen with immediate-release products
Higher
Drug release by osmosis: Methylphenidate (CONCERTA) in ADHD treatment: ____ concentration of methylphenidate released in the early afternoon provides a smooth effect through the early evening hours
Rapid; 1; 2
Drug release by osmosis: Methylphenidate (CONCERTA) in ADHD treatment: Immediate-release overcoat provides a ____ onset of action (____-____ hours)
Ear drugs are labeled
Otic or auric or for the ear
Absorption; Excretion; Large; Uniformly; Small; Safety; Large; Chronic; Acute
Drugs suitable for Oral Extended release: 1. Neither very slow nor very fast rates of ____ and ____, respectively 2. Half-life is not too short (____ dose needed) 3. ____ absorbed from the gastrointestinal tract 4. Administered in ____ doses 5. Good margin of ____ (____ therapeutic index) 6. Treatment of ____ rather than ____ conditions
Small
Drugs suitable for Oral Extended release: Administered in ____ doses
Short; Large
Drugs suitable for Oral Extended release: Half-life is NOT too ____ (____ dose needed)
Slow; Fast
Drugs suitable for Oral Extended release: Neither very ____ nor very ____ rates of absorption and excretion, respectively
Chronic; Acute
Drugs suitable for Oral Extended release: Treatment of ____ rather than ____ conditions
Oral Extended
Drugs suitable for ____ ____ release: 1. Neither very slow nor very fast rates of absorption and excretion, respectively 2. Half-life is not too short (Large dose needed) 3. Uniformly absorbed from the gastrointestinal tract 4. Administered in small doses 5. Good margin of safety (large therapeutic index) 6. Treatment of chronic rather than acute conditions
Poorly; Unpredictable
Drugs that are absorbed ____ and at an ____ rate are not good candidates for SUSTAINED release dosage forms because their release rate and absorption are depending on the position of drug in the GI tract and rate movement of the drug (ex. Riboflovin is not absorbed in GI tract)
Larger
Drugs with a slow rate of absorption and elimination (ex. short half life less than 2 hrs) are difficult to formulate as system requires a ____ unit dose size and may contribute to patient complains problem and also difficult to control the release rate of drug
Magnetic Properties of solids
Each electron behaves like a tiny magnet. Its magnetic moment originates from its (i)Orbital motion around nucleus (ii)Spin around its own axis It can be considered as a small loop of current. Thus each electron has a PERMANANT SPIN and an ORBITAL MAGNETIC MOMENT associated with it. Magnitude of that moment is very small and measured in a unit called BOHR MAGNETON. It is equal to 9.27 x 10⁻²⁷ Am² CLASSIFICATION 1)Diamagnetism: Weakly repelled by magnetic field Weakly magnetised in opposite direction in magnetic field Shown in substances with all paired electrons Pairing cancels magnetic moment and they lose their mgentic character Eg H₂O, NaCl,C₆H₆ 2)Paramagnetism Weakly attracted by magnetic field Magnetism is lost in absence of magnetic field Due to the presence of one or more unpaired electrons which are attracted by the magnetic field O₂,Cu²⁺,Fe³⁺,Cr³⁺ 3)Ferromagnetism A few substances like Fe, Co, Ni ,Gd (gadolinium) and CrO₂ are attracted very strongly by a magnetic field. These substances can be permanantly magnetised In these in solid state, the metal ions of ferromagnetic substances are grouped together in domains. Thus each domain acts as a tiny magnet. In an unmagnetised piece the domains are randomly oriented and magnetic properties get cancelled. In magnetic field, all the domains get oriented in the same direction as the field and a strong magnetic effect is produced. This ordering of t he domains persists even after the external field is removed, thus these substances are used to make permanant magnets. 4)Antiferromagnetism Such substances also have domains but the are oriented opposite to each other and thus cancel each others properties. Example MnO 5)Ferrimagnetism Thus happens when the domains are arrange in parallel and antiparallel directions in unequal numbers, thus there is some residue magnetic properties. They are weakly attracted to magnetic field as compared to ferromagnets Examples Fe₃O₄, MgFe₂O₄ and ZnFe₂O₄ (Ferrites) These substances lose ferrimagnetism on heating and become paramagnetic.
Anatomic absorption window exists for?
Efficient absorption -drugs should be released from dosage form completely during this window
This phenomenon is the OPPOSITE of deliquescence, which occurs when the crystal loses water of crystallization below a critical water vapor pressure.
Efflorescence
In some cases, the drug permeability may appear to be low due to what?
Efflux of drugs via membrane transporters
Drugs must cross intestinal epithelium by what?
Either going through or between the epithelium cells to reach the systemic circulation
Attractive force (F) is calculated for what solute-solvent interaction?
Electrostatic force
Question from lecture: The unit for the linear expansion coefficient is
Elongation in percentage over degree (Elongation %/ °C)
Action
Embedding drugs in eroding matrices: Mechanism of ____ is based on successive hydration of the cellulose polymer, gel formation, erosion, and drug release
Immediate
Embedding drugs in inert matrices: ____ release portion may be compressed onto the SURFACE of the tablet
Slowly; Diffusion
Embedding drugs in inert matrices: Drug ____ released from the matrix by ____
Coating-controlling Reservoir systems
Enteric coating Drug reservoir: tablet or pellet Membrane coating: membrane-forming polymer Acrylic polymers (PAA, Poly Acrylic Acid), cellulose acetate phthalate, Release-modifiers: PEG, propylene glycol, glycerol
Schottky defect
Equal number of cations and anions are mising from the crystal. Thus neutrality is maintained This compound happens in compounds with High coordination number and a small difference in cation and anion sizes Examples NaCl KCl CsCl KBr Schottky defect leads to 1)reduce in density 2)Increases electric conductance due to formation of holes. Ionic mechanism of electricity conduction 3)Presence of too many voids lowers lattice energy and thus crystal stability reduces
Date given by the manufacturer guaranteeing potency of drug
Expiration date
Solute carrier family transporters PepT1 (Peptide Transporter 1)
Expressed in human intestine (apical domain) Uptake of ion (H+) Uptake of di- and tri-peptides Cephalosporin and ACE inhibitors
OATP (organic anion-transporting polypeptide)
Expressed in intestine (lateral) Uptake of fexofenadin
P-glycoprotein (P-gp)
Expressed in intestine, hepatocytes, and capillary endothelial cells comprising the blood-brain barrier (apical domain) Paclitaxel, tacrolimus, doxorubicin, vinblastin
Multidrug resistant protein 1 (MRP1)
Expressed in intestines (basolateral domain -- absorptive) Saquinavir (MRP)
Breast cancer-resistance proteins (BCRP)
Expressed in lungs, intestine, brain (apical domain) Mitoxantrone & anthracycline
XL
Extra Long
Drug is combined and made into granules with an excipient material that slowly erodes in body fluids and releases the drug for absorption.
How are drug embedded in slow eroding or hydrophilic matrix??
1- In vitro cell layer permeation: Caco-2 monolayer model
Human colon carcinoma cell line that spontaneously differentiate to form a monolayer of enterocytes: microvilli membrane transporters tight junctions intracellular enzymes
Tampering protection (packaging)
Human tampering can damage products and product packaging should be designed to show intentional tampering - plastic seals around boxes - blister packs for tablets and capsules
What drug types are released from the different types of ointment bases?
Hydrocarbon - neither lipophilic nor hydrophilic Absorption - hydrophilic not lipophilic Water-Removal - both hydrophilic and lipophilic Water-Soluble - both hydrophilic and lipophilic
What drugs from lecture are light sensitive?
Hydrocortisone, prednisone, riboflavin, ascorbic acid, folic acid, etc.
Chemical interaction with water, most commonly occurs in chemicals with labile carbonyl groups (esters, lactones, lactams, substituted amides)
Hydrolysis
_______________ is the ability of a substance to attract and hold water molecules from the surrounding environment.
Hygroscopy
Which route of drug administration has no absorption phase?
IV
Advantages of IV
Immediate drug effect
What dosage forms can you crush?
Immediate release tablets, film coated tablets, chewable tablets (dividing okay), sublingual tablets (dividing okay)
Suppositories
In foil or plastic wrappers are molded forms that can be inserted into the rectum or vagina. They hold medication in a substance that melts at body temperature and releases the drug. They may be used for unconscious patients or those unable to swallow.
How are dissolution studies carried out?
In large vessels with 500 to 1000mL of dissolution medium
On what level does drug absorption occur, in vitro or in vivo?
In vivo
additives
Inactive ingredients added to medications serving as fillers, flavorings, colorings, binding agents, or bulk agents
In pregnancy what may cause an increase in pulmonary drug absorption?
Increased CO and tidal volume
In pregnancy drug absorption from IM is enhanced due to what?
Increased tissue perfusion
A dimensionless number that describes how light propagates through that material.
Index of Refraction (R.I. or n)
Half-life is the time required for half of the ______________ ______________ reactants to form products.
Initial Concentration
Radical Chain Mechanism: Free radicals formed by heat or light
Initiation
Enterocytes are?
Intestinal epithelial absorptive cells that express transporters
Step 4. Across GI Membrane
Intra cellular pathway 1 Passive diffusion 2&3 Carrier mediated transport -2 Active transport, Na, Ca, -3 facilitated transport 4 Trans (para) cellular pathway 5 Efflux 6 Pre-systemic Metabolism -hepatic metabolism-gut wall metabolism 7 Endocytosis -pinocytosis (fluid phase) -Transcytosis, Phagocytosis (engulf > 500nm)
What are the involved Proteins in Facilitated Diffusion?
Ion channels
4 types of crystals
Ionic, Metallic, Covalent and organic molecular
Describe the GI contractions?
Irregular contractions followed by regular high amplitude contractions in the fasted state (controls the emptying and movement through the stomach)
cream
Is a dosage form of a medication that is a semisolid preparation, usually applied externally to soothe, lubricate, or protect.
An ampule
Is a glass container that holds a single sterile dose of drug-either liquid, powder, or crystal. The container has a narrow neck that much be broken to reach the drug. Then the nurse uses a sterile syringe and needle to withdraw the medication. Once the glass is broken the drug can not be kept sterile so nurse must discard any leftover portion of the drug.
A vial
Is a glass or plastic container with a sealed rubber top. Medication in the container can be kept sterile. The container may have a sterile liquid or a sterile powder that the nurse must reconstitute with a sterile diluent. Nurse must discard any remaining medication.
A conversion of drug into its optical and geometric isomers (a form of degradation), resulting in serious loss of therapeutic activity is defined as?
Isomerization (degradation product)
________ is the First-Order rate constant with units of time-1
K
In the Arrhenius Equation, Temperature needs to be in ______.
K (Temperature + 273K)
We want the (lower/higher) value of degradation half-life constant.
LOWER
Tell patient that combining IR and ER helps void the troughs seen with IR alone. ER will provide smoother effects throughout the eveining
MK is a 23 year old college student who has been diagnosed with adult ADHD. MK has been on immediate release methylphenidate 20 mg by mouth twice daily for 2 months. Today, you have noticed that MK dropped two prescriptions: 1. Methylphenidate 20 mg. 1 tablet by mouth every morning 2. Methylphenidate ER 36 mg (Concerta 36 mg). 1 tablet by mouth every morning. You verified with the doctor office and the nurse confirmed that the prescriber want the patient to have both drugs. How would you apply your professional knowledge educating this prescriber and the patient.
Types of Excipients: Lubricant
Magnesium Stearate
A method to suppress or minimize degradation:
Make drug less soluble OR add additives
matrix former
Matrix remains intact during drug release hydrophobic component; solid at room temperature and not melt at body temperature E.g. hydrogenated vegetable oils, carnauba wax, cottonseed hydrogenated oil amount used influence drug release: too much vs too little
Disadvantage of Intradermal injection
Max volume 0.1mL (diagnostic, desensitization, or immunization agents)
Ancillary component
May come into contact with a tertiary packaging component during the distribution, storage, and/or transportation of the packaged article ( i.e. pallets, skids, and shrink wrap)
Flexible plastic bags or glass vials
May hold sterile medication for intravenous use. The nurse administers the fluid via IV tubing connected to a needle or catheter placed in the patients blood vessel.
Adding ___________ prevent polymerization reactions.
Methanol (or similar organic solvents)
Gastrointestinal perfusion
Method to study absorptin and permeability of a drug in various segments of the GI tract
In the GI there is what during the interdigestive (fasted) state
Migrating motor complex
MEC
Minimum effective conc -the conc above which we want to be above to get therapeutic effect
What is the Caco-2 cell line model?
Model used to test specifically for permeability of a drug
How could storing drugs in the bathroom affect the rate of degradation?
Moisture (high relative humidity) Temperature Light
absorb certain wavelengths of light
Molecules in a solution have the ability to do what?
Per oral administration
Most commonly used delivery route
Some important terms related to crystal structure and lattices
Motif/basis : the basic structural unit Space lattice/Crystal lattice: pattern of points representing the locations of these motifs (scaffolding) Lattice point/ Lattice site: A point on the space/crystal lattice Crystal structure: formed by placing motifs on lattice points Each motif should have the same structure and spacial orientation to form a crystal. The environment of each motif is the same, except on the surface Unit cell: small part of the crystal used to spacify the complete crystal Normally that unit cell is chosen which has PERPENDICULAR SIDES OF SHORTEST LENGTH. The whole crystal can then be generated simply by translating the unit cell.
Methylphenidate ER 20mg
Mrs. Smith is dropping a prescription for her 10 year old son, who has recently been diagnosed with ADHD . The Rx was written for Methylphenidate ER 20 mg. While you are entering the RX, you found that methylphenidate comes in: -Methylphenidate Immediate Release (IR) -Methylphenidate Extended Release (Methylin ER, Concerta) -Methylphenidate Sustained Release (Ritalin SR) -Methylphenidate Long Action (Ritalin LA) -Methylphenidate Controlled Release (Metadate® CD) Which one you should choose for correct drug entry?
For the parenteral route with multi dose packaging
Multi dose vials contain either a sterile liquid or a powder to be reconstituted using sterile techniques. The nurse must write the date and time of the preparation on the label and must note the expiration date and storage.
Immediate; Hydrophilic; Extended
Multilayer tablets can be made: -One layer containing the drug for ____ release -The other layers containing the drug embedded in the ____ matrix for ____ release
Cation anion formulae for different unit cells
NaCl r⁺+r⁻=½(d) CaF₂ and Na₂O and ZnS r⁺+r⁻=((√3)/4)d CsCl r⁺+r⁻=((√3)/2)d Where d is edge length of unit cell
Why we study dissolution in vitro?
New product development Quality control Determination of bioequivalence Regulation of post-approval changes Possible substitution of clinical studies in some cases
Stoichiometric defects
No difference in formula of crystal. Examples 1)Schottky Defect 2)Frenkel Defect
Can a drug undergo dissolution without being in a solution?
No, a solution is needed
Does increasing the amount dissolved increase the solubility?
No, it just manipulates it
Do drugs in liquid form undergo dissolution?
No, once fully dissolved in a liquid, cannot undergo any more dissolution
Body centered cell (BCC)
No. of atoms per unit cell: 2 a=unit cells edge r= radius of atom Taking body diagonal, √3a=4r r=(√3)a/4 d=distance between nearest atoms d=2r=(√3)a/2
Face centered cell (FCC)
No. of atoms per unit cell: 4 a=unit cells edge r= radius of atom Taking face diagonal, √2a=4r r=a/(2√2) d=distance between nearest atoms d=2r=a/√2
Two different kinds of organic molecular crystals
Non ionised and ionised (salts and zwitterions)
What kind of dosage forms are zero-order releasing mechanisms? Examples?
Non-disintegrating forms; Topicals, implantables, and oral controlled-release
**On Exam What solvents have low or little dipolar character and immiscible with water?
Non-polar Solvents
In gamma scintigraphy what is added as a marker to the dosage form?
Nonabsorbable gamma emitting radionuclide
Intact; Stool
Nonerodible plastic matrix shells and tablets remain ____ in the ____
Drugs for nasal administration are labeled
Nose drops.
Coordination number
Octahedral void - 6 Tetrahedral void -4 Triangular void - 3 Cubic void - 8
Repeat Action
One dosage form contains multiple doses. A first dose is released immediately after administration, a second or third dose, released at intermittent intervals
Saturated Solution
One in which drug molecules in solution are in equilibrium with an excess of solute in a solution.
The change from ER to IR shouldn't be done without the consideration of any remaining blood level concentrations (check blood levels first)
Patient discharged from hospital 7 days ago with metoprolol ER 50 mg PO daily. Today, PCP ordered metoprolol tartrate 25 mg (IR) PO twice daily. What would be your counseling points for this patient/caregiver??
Modified
Patients should be advised that ____-release TABLETS and CAPSULES should not be crushed or chewed
Crushed; Chewed
Patients should be advised that modified-release tablets and capsules should not be ____ or ____
Immediate; Concentrations
Patients stabilized on a modified-release product should NOT be changed to an ____-release product without consideration of any remaining drug blood level ____
Dissolution
Pellets, beads granules are coated in ways to change ____ rate
Coated
Pellets, beads granules are ____ in ways to change dissolution rate
Relative Humidity (φ) is expressed as a _______ (unit)..
Percentage (%)
Bio-pharmaceutics research
Permeability Assay
The _________ __________ represents the inherent permeability of a membrane.
Permeability coefficient (P)
Step 5: Hepatic Pre-systemic Metabolism
Phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation
Photo _______: Immunological response Light causes a drug to act as a hapten, triggering a hypersensitivity Relatively rare NOT dose dependent
Photoallergy
Primary _________ reactions occur when the wavelength of incident light is within the wavelength range of absorption of drug.
Photochemical
Usually indicated by a change in COLOR of drug or solution
Photodegredation
Polymorph
Polymorphs are different 3D packing arrangements of the same object ie different crystal structures eg carbon different allotropes
Polycrystalline
Possibility that amorphous compounds are aggregates of very small crystalline particles which are too small for crystallinity to be apparent to the naked eye
Drug release
Process by which drug leaves a dosage form being subjected to ADME, and eventually becoming available for pharmacologic action.
Radical Chain Mechanism: reaction of radical with non-radical, forming new radicals
Propagation
Caco-2 human colon adenocarcinoma cells display what?
Properties of the epithelial lining in human small intestine
Step 5: Hepatic Pre-systemic Metabolism (examples)
Proporanolol Estradiol Lidocaine Cyclosporin
Light - Resistant Container
Protects the contents from the effects of light by virtue of the specific properties of the material which it is composed, including any coating applied to it
________________ Order: rate dependent on 2 reactants but the concentration of 1 reactant is very large or doesn't change.
Pseudo-First
____________ Order: rate is dependent on 1 reactants but that concentration is very large or does not change.
Pseudo-Zero
When solvent molecules get incorporated into crystal lattice of solid solvates, these solvates exist in a different crystal form called ______________.
Pseudopolymorphs (Phenomenon is called pseudopolymorphism)
Quartz and Quartz glass
Quartz is a crystalline solid. Quartz glass is amorphous and does not have a fixed structure. Its structure is similar to LIQUIDS (Like all amorphous solids) Amorphous solids are often regarded as extremely viscous liquids. They are called super cooled liquids or pseudosolids.
Equation of Solubility and Particle Size
R = (8.314 x 10^7)
Equation for Drug Solubility in an Ideal Solution
R = 1.987
What is therapeutic range?
Range of plasma concentration that are associated with optimum response and minimal toxicity in most patients
Therapeutic range
Range of plasma concentrations that are associated with optimum response and minimal toxicity in most patients -can vary significantly
Expresses the relationship between rate of reaction and concentration of reactants
Rate Law
What is drug release rate?
Rate a drug that is in liquid form interacts with the body
Pseudo-Zero Order
Rate depends on 1 reactant but that concentration is very large or doesn't change.
Pseudo-First Order
Rate depends on 2 reactants but the concentration of 1 reactant is very large or doesn't change.
Second Order
Rate depends on concentrations of 2 reactants.
First Order
Rate depends on initial concentration of reactant.
Zero Order
Rate is NOT dependent on concentration of reactant.
Peaks; Valleys
Rationale for Extended Release: Conventional immediate release forms cause sequential therapeutic blood level ____ and ____
Short; Multiple
Rationale for Extended Release: Many drugs are inherently ____-lasting and require ____ daily dosing
Inconvenient
Rationale for Extended Release: Multiple daily dosing is ____ for the patient (missed, made-up doses)
Zero-Order Kinetics: Reaction: rate = rate = Zero-Order Integrated Rate Law:
Reaction: A → B rate = -d[A]/dt rate = -slope Zero-Order Integrated Rate Law: [A]t = [A]0 - kt
What are some methods to prevent hydrolysis?
Reduce or eliminate water from formulation Protect solid dosage forms from humidity Refrigerate to slow rate of hydrolysis pH adjustment
How can you increase S in the dissolution equation?
Reducing the particle size (breaking it up)
Beer-Lambert Law
Relates the absorption of light to the concentration of a solution
What relationship does the Antoine Equation describe?
Relationship between vapor pressure and temperature
Immediate; Delayed
Repeat action systems usually contain two single doses of medication, one for ____ release and the second for ____ release (i.e. initial dose, then, 4-6 h later, second dose)
What was the only HIV drug in 1998?
Ritonavir
The grey area under the Eutectic Point in the following Binary Eutectic Phase Diagram includes (solids/liquids) ONLY.
SOLIDS
**On Exam What solvents exhibit strong dipolar bonds but NOT strong hydrogen bond property?
Semipolar Solvents
The time which drug is expected to remain in greater than 90% concentration (t90%)
Shelf-Life
Impurity defects in ionic solids
Similar to metal deficiency defect. An extra cation of some other type is added. So on adding Sr⁺² to NaCl, 2 Na⁺ ions are replaced by one Sr²⁺ ion. Examples NaCl+SrCl₂ AgCl+CdCl₂
Disadvantages of Transdermal Route
Skin's barrier function constrains the absolute amount of a drug that can be absorbed across a reasonable area of skin during a dosing period: reserved for delivering POTENT molecules
Most hydrolytic reactions have a pH where rate is ______ due to a lack of acid-base catalysis
Slowest
Codeine marker does what?
Slows GI transit, decreases stool water content, and decreases drug absorption
Neutralisations are usually carried out in a solvent other than water, why?
So the salt precipiates out (ethanol)
What is Cs in the dissolution rate equation?
Solubility of the solid (at the surface of the solid)
Transporters (Influx)
Solute carrier family transporters PepT1 (Peptide Transporter 1) OATP (organic anion-transporting polypeptide
What is C in the dissolution rate equation?
Solute concentration in the bulk solution
what is happening at 1
Solution not saturated dissolution will occur
Oleaginous Solutions
Solutions of fat soluble vitamins (Vitamin A, E0, or other fat soluble substances in vegetable oils or mineral oil.
Cqiseuilin
Some drugs do not have any clear advantage for sustained release dosage forms, an example is??
Double peak phenomenon
Some drugs exhibit two maxima on blood conc curves -usually in fasted patients
Larger
Some drugs, like sulfonamides, require ____ dose for therapeutic activity so this kind of drugs are difficult to form in SUSTAINED-release drug forms as unit dose increases to an extent where it is difficult to swallow by patient
What shape does a particle take undergoing dissolution?
Sphere
What method is used to predict stability of a drug at Room Temperature?
Stability Studies using the Arrhenius Equation.
Oral absorption process
Step 1: Drug dissolution & ionization in Lumen the stomach or intestinal Step 2: interact with food and other contents Step 3: attach to the mucosa Step 4: permeate through the epithelium membrane Step 5: get in to blood first pass hepatic metabolism!
Some basic drugs with limited aqueous solubility benefit from the presence of food in the stomach because it does what?
Stimulates hydrochloric acid secretion, which lowers the pH, causing more rapid dissolution of the drug and better abosorption
For oral route in multi dose packaging
Stock bottles contain liquid or solid form such as tablets, capsules, or powders. Large stock bottles hold medication that is dispensed over a period of days. When reconstituting the powders, the nurse must write the date and time of the preparation on the container's label and must carefully note storage directions and expiration date. Caution; powders, once dissolved , begin losing potency.
What are some other ways to inhibit oxidation
Storage in inert gas Add antioxidants Add a chelating agent to bind metals Buffer the system if base-catalyzed Protect from light if photoinduced
Surfactant
Substances are dispersed in the bulk of liquids and those with part of their molecule lipophilic and part hydrophilic move on their own to the surface of interfaces of the liquid (at very low conc.), where they lower the surface or interfacial tension - LOWER interfacial tension (between 2 immiscible liquids): emulsion formation - Adsorption of the INsoluble particles: insoluble particle dispersion in suspension - Adsorption of the SOLID particles: Solubilization - Incorporation of water insoluble compounds in water: Micelle formation (clear solution)
aerosol
Suspension of small solid droplets or particles in gas or vapor (liquid under pressure).
Insoluble; Non-toxic Anion; Cation
Sustained delivery of ionizing acidic and basic drugs can be obtained by complexing them with ____ ____ ____ exchanger and ____ exchanger resin respectively
Flavor Polyhydroxyl cmpds, polyhalogenated compounds, and alpha amino acids.
Sweet
C is the _________ concentration of a buffer system.
TOTAL
T/F: A temperature decrease will decrease the rate of dissolution.
TRUE
T/F: Buccal tablets are designed to stick to buccal mucosa.
TRUE
T/F: Injectable doses can be modified to be sustained release.
TRUE: they can be modified by using viscous, oil based vehicle, using suspension, making a saturated drug solution, using microspheres for API release
Process of Dissolution in the GI tract: Tablet ➞ DISINTEGRATION ➞ ________ ➞ DEAGGREGATION ➞ _________ ➞ DISSOLUTION ➞ Drug in solution ➞ AbsorptionDME (ADME)
Tablet ➞ DISINTEGRATION ➞ Granules ➞ DEAGGREGATION ➞ Powder ➞ DISSOLUTION ➞ Drug in solution ➞ Absorption (A) ➞ Systemic Circulation (DME)
vaginal
Tablets and suppositories inserted vaginally and used to treat vaginal yeast infections and other irritations.
Isolating; Concentrating
Targeted release systems are directed toward ____ or ____ a drug in a body region, tissue, or site for absorption or for drug action
Factors that affect the Rate of Degradation
Temperature pH and Hydrolysis Oxidation Ionic strength Solvent Isomerization Photochemical Decomposition Polymerization
Boiling Point
Temperature at which the vapor pressure of a liquid equals the atmospheric pressure.
Equilibrium Condition
The condition when the rate of transfer or a solid into the solvent and the rate of deposition of solute molecule from the solvent onto the solid crystal become equal.
Hermetic container
The container is impermeable to air under normal handling, shipment, storage, and distribution.
Question from lecture: Thermodilatometry (TD) is a special type of ThermomechanicalAnalysis (TMA). In the TD measurement:
The external force acting on the sample can be considered as zero.
Parenteral route with unit dose packaging
These drugs (which may come in powder or liquid form) are given by injection, via the route specified in the order (ex, IM Sub-Q IVPG)
Example: 10mL solution of drug A (10%w/v) and drug B (25%w/v) are stores in two identical test tubes under identical storage conditions at 37C for 3 months. If BOTH drugs DEGRADE by FIRST-ORDER, which drug will retain the HIGHEST % of Initial Concentration (Ao)?
They will be THE SAME
What is h of the dissolution rate equation?
Thickness of diffusion layer
Criteria for Acceptable Levels of Stability
Throughout the shelf life of the drug product: -Chemical stability: Each active ingredient retains its chemical integrity and labeled potency, within the specific limits -Physical stability: The original physical properties, including appearance, palatability, uniformity, dissolution, and suspendability, are retained -Microbiological stability: Sterility or resistance to microbial growth is retained according to the specific requirements. Antimicrobial agents that are present retain effectiveness within the specific limits -Therapeutic stability: The therapeutic effect remains unchanged -Toxicological stability: No significant increase in toxicity occurs
TR
Time Release
Guidelines on using multi dose containers for topical medication.
To avoid contamination of medicated creams, ointments, and pastes in jars, always use a sterile tongue blade or sterile glove to remove the medication. When using dropper bottles for eyes, ears, or nose medication, prevent cross contamination by labelling each container with the patients name and using the container only for that patient. The nurse must be care to not touch mucous membrane with the dropper.
Serial dilutions
To ensure that the dilutions are accurate, what type of dilutions will be used?
What are the involved Proteins in Active Transport?
Transporter proteins
A hygroscopic compound retain water by bulk or surface adsorption, capillary condensation, chemical reaction, and deliquescence. (T/F)
True
Ionization depends on pH. (T/F)
True
Like dissolves like. (T/F)
True
Question from lecture: Amorphous solids have greater solubility. (T/F)
True
Question from lecture: Asparagine is sweet. (T/F)
True
Question from lecture: Assume that a drug molecule is a hard sphere and all conditions are ideal and identical. Is the following statement (T/F)? - The smaller the MW, the faster the molecule diffuse.
True
T or F: Matrix systems drugs release does not follow zero-order
True
Can in vitro test and physical model predict in vivo dissolution, absorption and bioavailabity?
Would be great! Very difficult! Clinical trials are still often needed. Some drugs are predictable ... IVIVC: in vitro in vivo correlation (and prediction)
Diffraction at work
X-rays impinge on a single crystal sample, x-rays are diffracted by planes in the crystal, diffracted x-rays are collected and analysed by computer, shape and size of unit cell and position of atoms dtermined, 3D geometry of molecular and crystal structure
What happens if you increase the viscosity of the dissolution medium?
You decrease the dissolution rate (solution moves slower)
Physiological
____ Factors: 1. Dosage Size 2. Partition Coefficient and molecular size 3. Aqueous Solubility 4. Drug Stability 5. Protein Binding 6. pKa
Targeted Release
____ ___ systems are directed toward isolating or concentrating a drug in a body region, tissue, or site for absorption or for drug action
Pain Killers
____ ____ = Crushing Morphine for example could lead to a faster release that is potentially fatal
Immediate release
allow fast release no intention of prolonging dissolution or absorption by design
Electrical properties
Types of solids Conductors :- 10⁴-10⁷ Ω⁻¹m⁻¹ Insulators :- 10⁻²⁰-10⁻¹⁰ Ω⁻¹m⁻¹ Semiconductors :- 10⁻⁶-10⁴ Ω⁻¹m⁻¹ BAND THEORY: Electricty can be conducted due to movement of ions like in electrolytes, or movement of free electrons like in metals Metals conduct electrons in bpth solid and molten state. The conductivity depends on the number of valence electrons available per atom. Atomic orbitals of metals which are close in energy overlap to form a valence band . If this band is partially filled or it overlaps with a higher energy unoccupied conduction band, then electrons can flow easily under an applied electric field. If the gap between then is large, then the electrons cannot jump and the solid is an insulator Semi conductors have a small gap between the bands. The conductivity of electrons thus increases with rise in temperature. Example Si, Ge, etc are INTRINSIC SEMICONDUCTORS Their conductivity is low and they thus need to be doped There are 2 types of extrinsic semiconductors (1)P type (2)N type (Same as physics) APPLICATIONS:- 1)Diodes 2)Transisters Large number of solids have been prepared by group 13-15 combinations Some combinations are InSb AlP GaAs (very fast response, revolutionalised the design of semiconductors) There can also be 12-16 groups which are not completely covalent and have ionic character ZnS CdS CdSe HgTe Transition metal oxides show marked differences in electrical properties like TiO, CrO₂ and ReO₃ behave like metals ReO₃ is like metallic copper in its conductivity and appearance Others like VO, VO₂, VO₃, TiO₃ show metallic or insulating properties depending on temperature.
✰✰✰ (IMPORTANT) - Moderately WEAK ACIDS (pKa 2.5 - 7.5) are UNIONIZED in the ________ pH, IONIZED in the __________ pH, therefore better ABSORBED in the ___________.
UNIONIZED in the Gastric pH ➞ Better ABSORBED from stomach IONIZED in the Intestinal pH
(USP/UPS) monographs provide description of dissolution testing procedure for pharmaceutical products.
USP
Tretinoin (for acne) is converted to isotretinoin through which type of reaction?
UV radiation > isomerization of tretinoin Tretinoin degrades to 9 isomers Isotretinoin is also known as Accutane
What happens on either side of the membrane if the pH is different?
Unequal conc of ionizable drugs on either side
How is therapeutic range determined?
Usually be studying drug effects in large pt population and noting plasma conc's at which pt's: 1. experience therapeutic effects 2. experience side effects
What are some examples of second-order phase transitions?
Vaporization, sublimation, absorption, adsorption, desorption.
Double peak phenomenon is caused by?
Variability of stomach emptying and intestinal motility, food, or failure of dosage form
Polymorphism is explained by which scientist?
Walter C. McCrone
**On Exam Example of a Polar solvent:
Water
In a co-solvent system: There is NO DMI on the Solubility side, only ________.
Water
What co-solvent has the HIGHEST dielectric constant (ε) and is the MOST polar?
Water
What are some common dissolution mediums?
Water 0.1 N HCl Buffer Solutions Biorelevant media
How can you protect solid dosage forms from humidity?
Water-proof coating Package with desiccant
the concentration of an unknown
What can we solve for with a plot of absorbance vs. concentration?
absorbance measurements
What does A mean in the Beer-Lambert Law?
molar absorptivity/ how intensely a solution absorbs a specific wavelength of light
What does a or e mean in the Beer-Lambert Law?
path length (usually 1 cm)
What does b mean in the Beer-Lambert Law?
concentration
What does c mean in the Beer-Lambert Law?
a wavelength of light is absorbed and can be measured
What does the color mean on the graph?
a complimentary color to appear
What does the color the object absorbs cause?
spectrophotometer or a colorimeter
What does visible light spectroscopy uses?
Your absorbance is no longer accurate so you should re-adjust your concentrations so that you can get an accurate reading
What happens when your absorbance is higher than one or under .2?
Colorimeter
What is the name of an instrument used to measure the absorbance of a colored compound in solution?
When does photodegredation occur?
When drug is removed from manufacturing packaging and placed in new environment
When would you have to take into account C?
When it is greater than 20% of Cs
If doctor is willing on 3x daily, give the IR form. If doctor is willing to change, ask if we can give ER 1x daily for better patient compliance
While you were working in a retail pharmacy after-hour, a resident doctor called in a prescription for an adult female with a recent diagnosis of seizure. Depakote 250 mg by mouth three times daily with food. Later, you realized that that Depakote (Divalproex Sodium) is available in three dosage forms including (a) immediate release, (b) delayed release, and c) extended release. You called the resident back. The resident answered that he didn't know the difference and the supervising physician could not be reached. How you should handle the situation to dispense the RX??
the molecules will absorb and reflect different wavelengths of light
Why do solutions appear certain colors?
to ensure the best fit of the line
Why do the dilutions need to be made accurately?
It can cause an error reading and the absorbance is higher because it is blocking the light path from coming through, so you cannot transmit as much light as you should
Why does the path of light need to be clear
atomic polymorphs are known as
allotropes
Controlled Release
____ ____systems include a component that can be engineered to regulate essential characteristic (e.g., rate or duration of release) and have a duration of action longer than a day
Beads
____ have coats of different compositions to control release or same coating with different thickness
Extended
____ release should not be crushed because they may cause an increased risk of adverse effects or potentially deliver a toxic dose of the active ingredient. (this also goes with the other abbreviated formulations above)
Multilayer
____ tablets can be made: -One layer containing the drug for immediate release -The other layers containing the drug embedded in the hydrophilic matrix for extended release
Enteric-Coated
____ tablets that are crushed can released the drug too early and may be destroyed by stomach acid or irritate the stomach lining
sterile
a condition which is free of all microorganisms
contraceptive
a device or formulation designed to prevent pregnancy
nasal inhaler
a device which contains a drug that is vaporized by inhalation
granules
a dosage form larger than powders that are formed by adding very small amounts of liquid to powders
when the length is constant, what type of relationship must exist between absorbance and concentration?
a linear relationship
A solvent is...
a liquid that can dissolve another substance to form a solution
solvent
a liquid that dissolves another substance in it
gargle
a medicated solution used for gargling and rinsing the mouth & throat
transdermal
a method of administering medication through the unbroken skin via patch or ointment
douche
a method used to cleanse the vagina and sometimes mistakenly thought to serve as a contraceptive, disinfect or removal of debris
emulsion
a mixture of two liquids that do not mix with each other in which one liquid is spread through the other by mixing and use of a stabilizer
hydroalcoholic
a mixture of water and alcohol, a Non-aqueous solution with water, including elixirs & tinctures
toxic shock syndrome
a rare and potentially fatal disease that results from a severe bacterial infection of the blood
vial
a small bottle that contains a drug (especially a sealed sterile container for injection by needle)
ampoule
a small bottle that contains a drug (especially a sealed sterile container for injection by needle) & iv bag
suppository
a small cone shaped solid drug/ medication designed for insertion into the rectum or vagina where it melts
pellet
a small, rounded or spherical body, as of food or medicine. implantation beneath the skin example: testosterone.
diluent
a solvent that dissolves a freeze dried powder or dilutes a solution
liquid
a substance in the fluid state of matter having no fixed shape but a fixed volume
elixir
a sweet flavored liquid (usually containing a small amount of alcohol) used in compounding medicines to be taken by mouth in order to mask an unpleasant taste
Cubic System (Bravias Lattice)
a=b=c α=β=γ=90° 1)Primitive 2)Face centred 3)Body centred
Rhombohedral/Trigonal system (Bravias Lattice)
a=b=c α=β=γ≠90° 1)Primitive
Hexagonal System (Bravais lattice)
a=b≠c α=β=90° γ=120° 1)Primitive
Tetragonal System (Bravias Lattice)
a=b≠c α=β=γ=90° 1)Primitive 2)Body centred
diluents
add bulk
preservatives
added to a compound to prevent microbial growth contamination must be compatible with active drug or other ingredients
unit dose topical administration: transdermal patches or pads
adhesive bandages placed on the skin. they hold a drug form that's slowly absorbed into the circulation over a period ranging from hours to several days
effervescent
adj. giving off gas bubbles; showing high spirits or excitement example: alka-seltzer
Another way to define Absorption is the movement of UNCHANGED drug from the site of ____________ to the site of ____________.
administration, measurement
Absorption is the movement of UNCHANGED drug from the site of ___________ to __________ circulation.
administration, systemic
multidose packaging: topical administration - MDI
aerosol devices with 2 parts: canister under pressure and mouthpiece. canister contains multiple drugs in either liquid form or microfine powder or crystals. mouthpiece fits canister and finger pressure on mouthpiece opens a valve on the canister that discharges 1 dose. provider states the number of inhalations to be taken. medication for inhalation also may be packaged as liquids in vials or bottles or as capsules containing powder for use with either a HHN, intermitten positive pressure breathing appartus
Tinctures
alcoholic or hydroalcoholic solutions prepared from vegetable or chemical substances by maceration or percolation - Alcohol concentation varies 15-80% - Non aqueous solution containing alcohol
susceptible groups to photochemical decomposition
alkenes, carbonyls, sulfides, aryl halides
light and moisture testing: samples irradiated at ____ and subject to various amounts of _________
all wavelengths humidity
Vapor pressure (or equilibrium vapor pressure) is the pressure exerted by a vapor in thermodynamic equilibrium with its ___________ phases at a given temperature in a ___________ system.
condensed, closed
What is a nasal inhalant?
consist of drug or combination of drugs that by virtue of their high vapor pressure can be carried by an air current into nasal passage where they exert effect
Diffracted beams arise due to
constructive interferece betweeen X-rays reflected by planes which satisfy Braggs law at given scattering angle
Bragg X-ray diffraction arises from
constructive interference of x-ray radiation reflected from crystal planes which satisfy braggs law
Non - Aqueous Solutions
contain solvents other than water, alone or in addition to water. Alcohol or a binary mixture containing alcohol is the most commonly used non-aqueous solvent
Pharmacist Responsibility: Dispense in proper __________ with proper _________ Educate patients on proper ______, _________ and __________
container and closure storage, handling and disposal
The pharmaceutical pack is as important as the packaged medicine. The pack provides
containment, protection, presentation, identification, information, and convenience, and aids with patient adherence. In some cases, the pack is essential for the medicine's administration.
Syrup USP
contains 850 g sucrose and ~ 450 mL (453 mL exactly) of water in each liter of syrup - NOT saturated - Since 1 g sucrose completely dissolves in 0.5 mL water, 435 mL water needed to dissolve 850 g sucrose - slight excess of water enhances the syrup's stability and indicates high degree of hydration - Syrups have a lower solvent power than water and "salting out" may be a problem
unit dose parenteral route: prefilled syringes
contains sterile liquid medication that's ready to administer without further preparation. although expensive, it's very useful in an emergency
Saturated Solution
contains the maximum amount of solute than the solvent will accommodate at room temperature and pressure
Alimentary canal characteristics
covered mucus and mucous membranes and highly perfused
In the Ritonavir Story, there was a recall of the Abbott Laboratories' HIV drug due to "undesirable" ____________ formation. Solution: Reformulation to Soft gelatin capsules.
crystal
Physical Properties depend on
crystal structure
Solubility (Cs) depends on
crystal structure
which state is more thermodynamically favourable
crystalline state
AI form organic molecular crystals
crystals comprised of organic moleculs - molecules comprising covalently bound atoms pack together via non-covalent interactions
The 7 crystal systems
cubic, rhombohedral, tetragonal,hexagonal,orthorhombic, monoclinic, triclinic
DSC and M.P. determination are only useful when the substance is heated through phase transition ____________.
decomposition
Lubricating agents (increase/decrease) the dissolution rate by forming a hydrophobic layer on the particles.
decrease
Parameters affecting dissolution: surface area (A)
decrease in particle size; increase in are Surfactants (stomach & bile) in GI fluids increase particle wettability Decrease particle size (micronization) Prevent aggregation
Inhibitors of CYP3A ______ CYP3A activity, _______ drug metabolsim and ______ bioavailabilty.
decrease, decrease and increases
In Thermogravimetric Analysis (TGA), as temperature increases, mass ____________.
decreases
In the Hixson-Crowell Cube Root Plot, Particle Size (increases/ decreases) over time.
decreases
In the following Reaction for Reaction Rates: Concentration of Reactant (A) always _____________ with time and amount of Product (P) always _____________ with time.
decreases, increases
Viscosity (fluid resistance to flow) of EMULSIONS and SUSPENSIONS decreases the diffusion coefficient (D), (increasing/decreasing) the dissolution rate.
decreasing
✰✰✰ (IMPORTANT) In Fasting & Nonfasting: - The presence of food in stomach increases viscocity, therefore (increasing/decreasing) the dissolution rate.
decreasing
using the meta stable form
decreasing stability and increasing solubility
Hygroscopicity is the ___________ to which a substance is hygroscopic.
degree
What dosage forms can you not crush?
delayed release, extended release, enteric coated, biphosphates
drug dissolves in excess water
deliquescent
What is the purpose of the Noyes-Whitney Equation?
describes the process of dissolution dC/dt = KS(Cs-C) K = D/hV D = k'T/n Dissolution rate may be increased by an increase in T and/or decrease in n in extreme cases of Cs, S may not be significant
Packaging must be
designed for the safe use of medicines.
X-rasy relfected by other planes which do not satufy braggs law at a value of 2theta being measured will produce
destructive interference so no braggs diffraction observed
Powder X-ray diffraction
detect many bragg diffraction peaks simultaneously across a range of 2theta
Single crystal x-ray diffraction
determine unit cell dimensions and determine 3D position of atoms in a crystal
atomizer
device used to convert liquid to a spray
Advantages of intradermal injection
diagnostic, immunization
Matrix systems (lipid matrix/inert matrix)
diffusion controlled drug particles are dissolved in an insoluble matrix Drug is released through diffusion after fluids enter the matrix and dissolve the drug
Aqueous Acids
dilute aqueous solutions of acids (usually < 10%)
unit dose topical administration: lozenges, troches, and pastilles
disklike solids that slowly dissolve in the mouth (e.g. cough drops). some drugs are prepared in a gum and released by chewing (e.g. nicotine)
Matrix systems (Hydrophilic matrix)
dissolution controlled drug is dispersed in a soluble matrix that swells and dissolves in contact with fluids
What is the disintegration step of capsules?
dissolution of the capsule, therefore the bioavailability may be better than compressed tablet
bioavailability may depend on
dissolution rate
Obtaining crytsals from solution
dissolve solid in solvent, remove excess solid from saturated solution, allow solution to cool or evaporate solvent, ss solution, nucleation and growth
The RATE of Zero-Order Reactions (depends/does not depend) on CONCENTRATION.
does not depend
multidose packaging: topical administration - dropper bottle
dropper bottles for eyes, ears or nose mediaction. prevent cross contamination by labeling each container w/patient's name and using the container for only that patient. must be careful to not touch mucous membrane to avoid contaimination. dropper comes in 2 forms: monodrop containers which are squeezed to release mediaction; containers with removable droppers which have a packaged dropper
pharmakon
drug
In passive diffusion what will happen after the drug enters the blood?
drug distributes rapidly into a large volume
What is the mechanism/pathway of sublingual absorption?
drug enters venous blood from sublingual regions, drains into internal jugular vein, subclavian vein, and brachiocephalic vein, directly into superior vena cava and enters systemic circulation
dosage form
drug formulation, the way it is to be administered
Controlled (constant) release profile
drug is released over an extended period of time at a controlled rate (plasma concentration remains invariant) - zero order (an ideal goal
transcorneal transplant
drug transfer into the eye
transcorneal transport
drug transfer into the eye
Making salts of active ingredients (b)
drug with basic centre
inhabition
drugs administered by inhalation enter through the mouth into the lungs. example asthma, lung disease, systemic disease
unit dose topical administration
drugs applied to skin or mucous layer can achieve a local effect. can also have systemic effect because they can be absorbed into the circulation
How does drug absorbed?
drugs may be absorbed by PASSIVE DIFFUSION through all parts of the alimentary canal including sublingual, buccal, GI, and rectal absorption
Duodenal area of the SI shows the most rapid drug absorption why?
due to such anatomic features such as microvilli and villi--> provide a large SA
When identifying polymorphs
during prodcution of raw materials , maufacture of final product and storage of raw material and final product
prone to losing water to evaporation
efflorescent
N-H atoms
electron deficient H-bond donor
Tensile strength in metallic crystals
electron delocalisation increases cohesive force
what do xrays interact wuth
electron orbitals of atoms of molecules
Cl- ion
electron rich H bond acceptor
Oxidation involves the ADDITION of an (electronegative/electropositive) atom, radical, or electron.
electronegative
Oxidation involves the REMOVAL of an (electronegative/electropositive) atom, radical, or electron.
electropositive
Gastric emptying and small intestine motility reduced in pregnancy due to?
elevated progesterone
which layer of skin contains the stratum corneum
epidermis
What are the drawbacks of parenteral drug delivery?
establish IV, difficulty to remove drugs from body, difficult formations
what's a common functional group to make a prodrug?
ester
how does ethanol absorbed?
ethanol is completely miscible with water and easily crosses cell membranes and is efficiently absorbed from the stomach
what are non-aqueous vehicles that solvolysis can occur in?
ethanol, polyethylene glycol
larger particles formed when cycling between increased and decreased temperatures
excursions
why are BUD and expiration dates almost always different?
expiration: overall stability in a specific container and under specified storage conditions BUD: preparation and variable storage may lead to instability
XR
extended release
modified release tablets might be called
extended release, prolonged action, long acting
Highly permeable
extent of absorption in humans is determined to be ≥ 90% of administered dose, based on mass balance determination or compared to intravenous reference dose.
