Dosage Forms I
What are some common routes of protein degradation?
Aparagine deamidation Peptide bond hydrolysis ("clipping") Methionine oxidation Disulfide bond scrambling Aggregation
What is the breakdown of the increase in surface area in the small intestine?
Area of cylinder = 1 Folds of Kerckring x 3 Villi x 30 Microvilli x 600
Asparagine deamidation can turn an asparagine into ___________.
Aspartate
What can we say about the plateau Cp value, Cpf?
At Cpf, input and output rates are equal
For a stable salt: pK(conjugate acid) < pK(conjugate base) with a minimum difference of _______ units.
At least 2-3
What is Steady State?
At steady state, the rate going into the body must equal the disposition (the rate distributing early and being metabolized, and/or being excreted from the body throughout).
What are the two major types of oxidation?
Auto-oxidation and Chain oxidation
What is the class definition of a cocrystal?
a homogeneous crystalline phase of fixed stoichiometry containing two or more components (solid at room temperature).
IV bolus definition
a loading dose to increase blood levels quickly
What is a prodrug?
a pharmacologically inactive chemical derivative of a drug. Prodrugs are often created to improve the drug's solubility or absorption. In the body, the prodrug is converted to the active "parent" drug chemically or enzymatically.
What is a pH-rate profile?
a plot of the observed reaction rate as a function of pH. The y-axis, showing the rate constant, is usually plotted on a log scale (base 10). Must be measured experimentally.
What is super saturation?
a solution concentration of drug higher than the equilibrium concentration
Of the 60 million women who are at reproductive age, how many of them become pregnant annually?
about 10%
What is the gastric emptying half time?
about 30 minutes
Efflux and metabolism can affect the net __________ absorption of drug.
absorption
Which cell type makes up the villus region?
absorptive enterocytes
A base is a proton __________.
acceptor
On a pH rate profile a slope of -1 in the acidic region is consistent with specific ______ catalysis.
acid
When permeability of PAMPA<<Caco-2, __________ is indicated.
active or paracellular transport
Continuous infusion definition
administered over a period of days at a constant rate
Intermittent infusion definition
administered over short periods (e.g. 20-60 min)
Biologics can __________ which can lead to increased or decreased potency and increased potential for adverse immune response (allergy).
aggregate
e.g. for aspirin overdose, _______ of urine results in ionization of drug and enhanced renal clearance
alkalinization
Asparagine deamidation causes the loss of an amine group as __________.
ammonia
In "pseudo" first-order reactions, the ____________ depends on on concentration (e.g. ester hydrolysis).
apparent rate
For a series of polymorphs, at a given temperature, the most stable crystal form is the _____ energy state that a given chemical entity can reside in.
lowest
What is transdermal drug delivery?
medication is administered through the skin to reach the systemic circulation
What is topical drug delivery?
medication is administered to the skin to treat a local skin condition
What are biologics?
medications derived from or produced by living organisms. Also called "biotech drugs" or "biopharmaceuticals"
All living cells are enclosed by one or more __________, which define the cell as the living unit.
membranes
What is the largest sector of biotech drugs according to 2010 sales?
monoclonal antibodies
Biologics tend to be _______ (more or less?) fragile than small molecule drugs.
more
In general, amides tend to degrade __________ slowly than esters.
more
Route of administration examples
oral, transdermal, intravenous and rectal
Solubility of weak acids/bases is ________ dependent.
pH
The mechanism of amide and lactam hydrolysis depends on _________.
pH
The mechanism of ester and lactone hydrolysis depends on ________.
pH
What is the first factor to be considered when determining solubility?
pH
What is the importance of pKa values in salt selection?
pKa values determine whether salt formation occurs and measure the stability of the resulting salt.
When permeability of PAMPA and Caco-2 correlate, then _____________ is indicated.
passive diffusion
Cellular lipid composition is ________ and intracellular membrane lipids are different than extracellular lipids.
polarized
The case of Ritonavir highlights the importance of __________.
polymorph screening
What kind of cells is the stomach comprised of?
predominantly epithelial cells, mixed with other cell types like mucus producing goblet cells and parietal (acid-secreting) and enterochromaffin-like (histamine secreting) cells.
What is nucleation?
process where a new phase is spontaneously formed from an existing phase
For first-order reactions, the rate of drug degradation is _________ to drug concentration.
proportional
Rate of decrease in concentration is _________ to concentration.
proportional
Amides and lactams are found in many drugs, notably ________ and _______________________.
proteins; beta-lactam antibiotics
What kind of epithelium is the trachea composed of?
pseudostratified squamous
A ______ enantiomer is preferred over the racemate in many marketed dosage forms from a safety and efficacy point of view.
pure
What is process performance measured for?
quality
What is product performance analyzed for?
quality
In "true" first-order reactions, the _______ depends on the concentration of one species.
rate
Solubility is a controlling factor on the ________ of dissolution.
rate (and extent)
What is Termination?
re-combination of free radicals to form stable products
What is Propagation?
reaction of free radicals with oxygen or other species, with generation of new free radicals
Some types of biologics include:
recombinant proteins, vaccines, stem cells, and gene therapy
What is relative bioavailability (Knipp's definition)?
refers to the AUC of a given dosage form compared to an arbitrary reference standard
What is bioavailability (Knipp's definition)?
refers to the rate and extent of drug absorption
Disposition drives ________ and ________; there is a need for consideration of distribution, metabolism and elimination in the system-BDDCS.
safety; efficacy
Approximately 50% of all drugs are administered as ______.
salts
The cell membrane is a ___________ membrane, permitting the rapid passage of some chemicals, while retarding or preventing the passage of others.
semi-permeable
What kind of epithelium is the sublingual part of the oral cavity composed of?
simple squamous
Auto-oxidation is generally _________ than chain oxidation.
slower
Where do enteric coated tablets dissolve?
small intestine, higher pH
Urine pH can be deliberately altered e.g. by administration of ___________ in order to enhance or retard clearance
sodium bicarbonate
Complexation is used for increasing _________.
solubility
The amorphous form is theoretically more _______ and has faster ___________.
soluble; dissolution
pH also often influences chemical __________.
stability
Weak acids should be absorbed in the __________.
stomach
what kind of epithelium is the esophagus composed of?
stratified squamous
What kind of epithelium is the buccal part of the oral cavity comprised of?
stratified squamous epithelium
What is the spring and parachute effect?
super saturation
What is an amorphous solid?
supercooled liquid in which the molecules are arranged in a somewhat random manner; often reffered to as glasses.
What is the equation for the half-life of a first-order drug degradation?
t 1/2 = 0.693/k (k is the rate constant)
Physical form examples
tablet, suspension, solution and patch
Solid dosage form examples
tablets, capsules, patches, powders, implants, suppositories, nanoparticles, microparticles, and rapidly dissolving tablets
What is absolute bioavailability (Knipp's definition)?
the AUC of a given dosage form compared with the AUC of the same dose injected intravenously
A cold chain is necessary when:
the drug is not stable at ambient temperature.
Expiration date definition
the end of the shelf-life. FDA requires expiration dating of all drug products.
Diffusion definition
the movement of molecules in space driven by a gradient in concentration
Convection definition
the movement of molecules in space driven by a gradient in pressure
What is a coformer?
the other molecule in a cocrystal that is not the API
Shelf-life definition
the period of time that a drug product maintains its properties (e.g. potency) within specified limits
In the crystalline state, the different enantiomers have _____ bioavailability. However, enantiomers can have ______ biological activity.
the same; differing
Shelf-life is often based upon the t90, which is:
the time for the drug concentration to decrease to 90% of its initial value
What is the Half-life?
the time required for the drug concentration to decrease to one-half of its initial value
What is auto-oxidation?
the uncatalyzed oxidation of a drug by molecular oxygen, O2. It may serve as the initiation step in chain oxidation.
Opposite enantiomers often differ in _______ and _______ properties.
toxicological; pharmacokinetic
What is often (not always) the target shelf-life?
two years
Only ______ drugs will pass through the GI membrane.
unionized
Different polymorphs are more susceptible to the _________ which can impact both chemical and physical stability.
uptake of moisture
For an amide hydrolysis mechanism during acidic conditions, the first step is nucleophilic attack of __________ on amide carbonyl group.
water
In a hydrate the API has already intimately interacted with _______.
water
The hydrolysis mechanism for carboxylic acid esters during acidic conditions begins with a nucleophilic attack of ______ on ester carbonyl group.
water
For ________ order kinetics, the half-life depends on the initial concentration.
zero
What is the fed pH in the stomach?
5-7
What is the pH of the colon?
6.6-7
What is the pH of the small intestine?
6.8
What are some details about ATP-Binding Cassetes (ABC)?
7 subfamilies 50 members presently identified Generally efflux-multidrug resistant transporters P-glycoprotein, MRPs
What is the fasted pH of the stomach in normal, healthy adults?
<3
What is disulfide scrambing?
A common route of covalent aggregation of proteins. In solution, the reactive species is the thiolate anion (RS-). There are also oxidation pathways that give the same products.
What is a crystalline hydrate?
A crystalline solid containing water as a participant in the crystal lattice
What is the definition of a generic drug?
A drug product that is comparable to a brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use. Pharmaceutic and bioequivalent.
What is therapeutic equivalence?
A generic product judged therapeutically equivalent to the reference drug will have the same identity, strength, quality, safety, and efficacy.
What is a protein?
A linear chain of amino acids Linked together by peptide bonds That folds to produce particular structures The structure is stabilized by disulfide bonds, hydrogen bonds and ionic interactions May be glycosylated Can be a drug
What is a chiral molecule?
A molecule that has a mirror image that cannot be superimposed on itself
Lactams hydrolyze by mechanisms like those for amides. The product is:
A ring-opened compound with carboxylic acid and amine groups, aka an amino acid
What is propolol?
A short acting hypnotic emulsion used in anesthesia. Note the milky appearance of the emulsion.
What are excipients?
A substance (as gum Arabic or starch) that forms a vehicle (as for a drug)
What are some details about Solute Carriers (SLC)?
43 subfamilies >300 members identified Generally influx or secretory efflux transporters PepT1, OATs, OATPs
Medical Device definition
"...an instrument, apparatus, implement, machine, contrivance...which does not achieve its primary intended purposes through chemical action within or on the body...and which is not dependent upon being metabolized..."
pH rate profiles often have a _____ or ____ shape, though other shapes are possible.
"U"; "V"
What common saying concerning solubility is half truth, half myth?
"like dissolves like"
What is the simplest second-order equation?
(1/CA) = (1/CA0) + kt
What is the equation for finding the half-life of a zero-order reaction?
0.5CA0 = CA0 - k(t1/2)
What is the pH of the stomach?
1-1.5
What is the residence time of the jejunum?
1-2 hours
What is the physiological pH range?
1-8.5
What are the three categories of cell based permeability assay variations?
1. Cell culture methods/techniques 2. Transport Experiments 3. Data analysis
List some functions of dosage forms.
1. Provide an accurate dose 2. Promote drug dissolution 3. Promote delivery to the site of action 4. Ensure drug stability 5. Protect the patient from the drug 6. Protect the drug from the patient 7. Control drug delivery to the body 8. Determine dosing interval 9. Manufactured by drug companies and CMOs 10. The most important component of the drug product 11. Regulated by the FDA and other agencies 12. Dispensed by pharmacists
What is the risk process?
1. Risk assessment: identify, analyze, evaluate 2. Risk control: reduction, acceptance 3. Risk communication: saying out loud what the risk is 4. Risk review: acceptance
What are some reasons for enteric coating?
1. To protect acid-sensitive drugs from gastric fluid 2. To prevent gastric distress due to irritation from drug 3. To deliver drugs intended for local action in the intestines 4. To deliver drugs that are optimally absorbed in the small intestine to their primary absorption site in their most concentrated form 5. To provide a delayed release
Know and employ basic definitions related to dosage forms
1. the physical form in which a drug is produced and dispensed, such as a tablet, a capsule, or an injectable 2. the physical form of a dose of a chemical compound used as a drug or medication intended for administration or consumption
What is the half-life equation for second-order reactions?
1/0.5CA0 = (1/CA0) + k(t1/2)
What is the residence time of the colon?
15-48 hours
Which early USA regulation required safety and efficacy demonstration for FDA approval and marketing?
1962 Kefauver-Harris Drug Amendments
Cells from the crypt migrate to the villus tip and are extruded-sloughed off at the time-enterocyte lifetime is _________, entire lining of the GI tract turns over every ___________.
2-3 days; 4 days
Rule of thumb: for every 10 degree Celcius increase in temperature, expect the rate to increase by at least _________.
2-3 fold
What is the residence time of the ileum?
2-3 hours
What is the bile salt content in the jejunum?
2.88 + or - 1.8
Approximately what fraction of total drugs are ionizable?
2/3
What percentage of approved drugs have pediatric labeling?
20-30%
What is the mouth to anus transit time?
24-32 hours
About ________% of cardiac output goes to the GI tract.
25-30%
What is the buffer capacity in the jejunum?
3.23 + or - 1.26
2885 patients receiving phenytoin, carbamazepine or valproic acid were queried. What percentage of the respondents reported an issue with a switch to a generic product?
30%
What is the pH range of urine?
4.5-8
What is the pKa range for weak acids and weak bases?
4.5-9.5
Fasted emptying cycles though __ phases culminating with a _______ Wave.
4; "Housekeeper"
What are some factors involved in mini-tablet platform formulation?
Ability to incorporate BCS Class I and III: less effect of formulation; likely more beneficial for testing of medications already on the market Easy translation to market formulation: pediatric compliance; flexible dosing; protected from degradation of vehicle or stomach Minimal excipients: single filler, disintegrant, lubricant with functional coatings Same or similar manufacturing conditions: size is constant, number can fluctuate Fractional factorial DOE approach: many process and formulation variables
What is the small intestine transit time?
About 3 hours
What are some physiological factors affecting absorption?
Absorbing surface area Residence time at absorption site pH changes in lumen Permeability/perfusion: functional and molecular characteristics of transporters and metabolism Dietary fluctuations/effects Complexation/protein binding Biliary uptake and clearance
Drugs need to be in solution fluids form for:
Absorption Distribution Reaching the site of action Elimination
What does ADME stand for?
Absorption, Distribution, Metabolism, and Excretion or Elimination
What kind of transporters transfer substrates into the systemic blood circulation?
Absorptive transporters
What are the goals of quality?
Achieve product realization Establish and maintain a state of control Facilitate continuous movement
What are the carrier-mediated (saturable) intestinal transport mechanisms?
Active (energy dependent) Facilitated diffusion (energy independent)
Why is aggregation a big problem in proteins?
Activity can increase or decrease Aggregates have greater potential for adverse immune response Low levels of aggregates and pre-aggregates are difficult to detect Increased demand for high concentration protein formulations
What are some factors involved in facilitative/active transcellular permeation?
Affinity capacity Concentration dependent saturation Expression level Function Excipients like surfactants can limit the effects of efflux by Pgp or BCRP
What are some challenges which remain with pediatric pharmacology?
Age based dosage form selection Need for descriptive pharmacology (especially for new drugs) in pediatric patients Children are not "miniature adults": dosing based on scaling needs to better incorporate age based ontogenic changes Animal models need to be refined for prediction Enable clinical studies in children by tackling some of the ethical and financial hurdles Better means of drug administration are needed
What are some functional groups subject to oxidation?
Alkenes Aromatic groups Ethers Thioethers Amines Carboxylic acids Nitrites Aldehydes
What are peptide bonds?
Amide groups which link together amino acids in proteins
What kind of solid state is isotropic and has no definite melting point?
Amorphous solids
What is gentamicin?
An aminoglycoside antibiotic solution, used to treat bacterial infections, particularly gram negative. It has no oral bioavailability.
What is ganciclovir?
An antibiotic lyo powder used to treat cytomegalovirus infection. It is administered IV following reconstitution and is often unstable in solution.
What are the aspects of preformulation?
Analytical: mass spec, purity Physical: X-Ray, Melting point Pharmaceutical: Excipients, ADME Physiochemical: Log P, pH, solvent, pKa
A pharmaceutical-quality salt must:
Be crystalline, be soluble, be stable, and be non-hygroscopic
Why is pH important in drug stability?
Because many degradation reactions are pH sensitive Because drug products are often formulated at optimal pH Because changes in product pH may accelerate degradation
Why are dosage forms important?
Because that's what patients take.
Why is temperature important in drug stability?
Because the rates of most chemical reactions increase with temperature. Because the pharmaceutical industry conducts "accelerated stability testing" to approve drug products. Because some drug products need to be refrigerated to remain stable ("cold chain").
What are penicillins?
Beta-lactam antibiotics. There are several different kinds of penicillins with different R groups.
What are some common methods for excipient compatibility testing?
Binary or formulation blends Binary or formulation blends with 10-20% w/w water Suspension or solution of excipients and drug Mechanical stress by milling or co-milling drug Using amorphous drug Compacts of prototype formulation by direct compression Tablets processed by wet granulation Calorimetry
What are some general classes of excipients?
Binders, disintegrants, fillers, lubricants, compression aids, colors, sweeteners, preservatives, flavors, film formers, etc.
Excipient examples (general types from Dr. Topp)
Binders, fillers, buffers, solvents, stabilizers, etc.
What are some common reasons for salt formation?
Bioavailability, developability, purification, and intellectual propery
What are some challenges with pediatrics?
Biological challenges: Ontogenic changes; compositional changes Clinical challenges: clinical trials; caregiver requirements Formulation challenges: dosage form selection; flexibility in dosing; excipient selection; taste masking
____________ depends on solubility and permeability.
Biovailabiliy
What are some issues with drug solubility?
Bodily fluids are predominantly aqueous environments The majority of drugs are hydrophobic Many drugs are difficult to solubilize
What are some factors influencing drug solubility? ******multiple choice question on final******
Buffer capacity Bile salts Regional fluids Other drugs Potential issues from endogenous substrates
What are synthons?
Building blocks consisting of two or more molecules held together by intermolecular interactions
How are dosage forms described and classified?
By physical form and route of administration
What is the equation for zero-order kinetics?
CA = CA0 - kt
What can be learned from the Noyes-Whitney equation?
Can move from change in mass to change in concentration by dividing by volume. Dissolution rate is proportional to D. Dissolution rate is proportional to tablet/particle surface area. Dissolution rate is proportional to the difference in the concentration gradient. Dissolution rate is inversely proportional to h (thickness of the stationary layer).
What was the first angiotensin converting enzyme (ACE) inhibitor developed?
Captopril
Fetal imprinting has been linked to:
Cardiovascular diseas-Barker Hypothesis Neurological disorders Obesity/diabetes, as well as others Very difficult to predict human effects based on: Many factors involved aside from genetics, e.g., diet Many exposure studies done in animals
What are some common excipients?
Cellulose based (MCC, HPC, methylcellulose) Sugars (sucrose, lactose, mannitol) Starch (sodium starch glycolate) Synthetic polymers (Polyvinyl pyrrolidone aka PVP) Inorganic (silicon dioxide)
What is permeability limited?
Characteristic of the API itself similar to solubility limited Dissolution is fast with sub-saturated fluids Increasing the amount of drug increases absorption Increasing Cd by increasing the amount of drug Increases dM/dt which is absorption in this case
How do protein drugs degrade?
Chemical degradation: Breaks the "correct" covalent bonds and/or forms "incorrect" ones Hydrolytic reactions Oxidation reactions Physical degradation: Changes in protein structure, usually without breaking covalent bonds Unfolding Aggregation
Descriptive pharmacology (especially for new drugs) in pediatric patients is often lacking because:
Children are not "miniature adults"; dosing based on scaling (by body weight or body surface area) not always predictable for a given drug Animal studies not always predictive Clinical studies in children fraught with ethical and financial hurdles Administration of drug can also be problematic
What are some new challenges based on the paradigm shift?
Children are not miniature adults Pediatric patients need to be age classified Pediatric patients require age appropriate formulations that used to be primarily made through compounding First in child safety and efficacy preclinical models are lacking
What are some laboratory studies required for abuse deterrent products?
Chopping Heating Alcohol treatment
What are the main ways to "break" oxycontin?
Chopping Heating Alcohol treatment
Our joint NICHD-FDA Task Force tentatively proposed the following BCS classification:
Class 1: (pediatric, volume = 25ml): rapid dissolution (t50 = 15min.) for immediate release Class 2: (Subclasses a,b,c for acidic, basic and neutral drugs); dissolution criteria are critically needed BCS Class 3: very rapid dissolution BCS Class 4: Same as BCS Class 2
What are some examples of traditional controlled release formulations?
Coated beads, granules, or microspheres Multitablet system Microencapsulated Drug embedding in a slowly eroding or hydrophilic matrix
How long is each respective part of the colon?
Colon is 125cm long from cecum to anus, with transport being much slower than in small intestine. Ascending colon 20cm long Transverse colon 45cm long Descending colon 30cm long- rest is sigmoid
What is the function of the colon?
Colon is responsive for water and electrolyte absorption (cecum, ascending colon)-prevents dehydration and leads to formation of solid fecal matter.
What is the primary method for purification of the API during manufacturing?
Crystallization
What is process design?
Crystallization, formulation, method, contols i.e. how we make it
What is sustained release?
Describes a pharmaceutical dosage form formulated to slow the release of a therapeutic agent such that its appearance in the systemic circulation is delayed and/or prolonged and its plasma profile is sustained in duration. In other words: the onset of pharmacologic action is delayed, but its therapeutic effect has a sustained duration.
What are some universal tests for specifications for drug substance and drug product?
Description: state, color Identification: IR, or combo of chromatography HPLC-MS Assay: Stability indicating procedure to determine the potency of the new drug substance Impurities
What is the importance of API pKa?
Determines solubility as a function of pH and determines salt forming ability
In making a solution, what factor controlling solubility is involved with "melting"/crystallinity?
Difficulty of dislodging solute molecules from the crystal
How is permeability different from dissolution?
Diffusion across a barrier (cell membrane) instead of across an unstirred layer. Need to include Partition Coefficient (K) to account for the changes in environment between inside and outside of barrier. Can remove Ca if we assume sink conditions.
What is the rate of dissolution dependent on?
Diffusion coefficient Surface area of tablet/granules available to donate drug to solution Thickness of the stationary layer Concentration of drug in the donor Concentration of drug in bulk solution
What are some ingredients which affect bioavailability, stability, and marketing considerations?
Disintegrants: enhance rate of disintegration/dissolution Coatings: control release Flavors/Sweeteners: mask drug taste Colors: Recognition Miscellaneous: ingredients
What are some aspects of rates of drug release from the dosage form?
Disintegration, dissolution, deaggregation, erosion of coatings, osmotic pumps, etc.
The stronger the crystal, the more difficult for the solute molecules to ________.
Dislodge
What is the Common Ion Effect?
Dissociation of salt will be suppressed in the presence of an external counterion. For example, for a HCl salt, the dissociation of the salt will be suppressed in the stomach by the presence of Cl- ions.
Disposition is comprised of _______ and ________.
Distribution and Elimination
Non-hygroscopic definition
Does not absorb moisture
What are factors to consider in mimicking clinical conditions?
Dosage form design requires consideration of patient related variables. Patient related variables are not accurately assessed during development and scale up. "Absorption windows" are defined more based on physical chemical properties and not physiology. Better in vitro and in vivo testing models are required for optimizing dosage form design and scale-up.
Who said, "Children are therapeutic orphans" ?
Dr. Shirkey, 1962
What's in a dosage form?
Drug (API) and excipients
What is dissolution limited?
Drug is unable to dissolve into the solution from the dosage form in sub-saturated fluid Dissolution time is greater than the time for absorption in the intestines Often due to poor formulation/manufacturing Need to have a tablet that can dissolve but also stand up to shipping and handling
What are some processes required for oral absorption of monolithic dosage forms?
Drug molecules at the surface dissolve to form a saturated solution. Dissolved drug molecules pass throughout the dissolving fluid form the area of high concentration to low concentration. Drug molecules diffuse through the bulk solution to the absorbing mucosa and are absorbed. Replenishment of drug molecules in the diffusion layer is achieved by further dissolution.
What are the processes required for oral absorption of monolithic dosage forms? *****may be a multiple choice question on final****
Drug molecules at the surface dissolve to form a saturated solution. Dissolved drug molecules pass throughout the dissolving fluid (diffuse) from the area of high concentration to low concentration Drug molecules diffuse through the bulk solution to the absorbing mucosa and are absorbed Replenishment of drug molecules in the diffusion layer is achieved by further dissolution
What are some factors to consider in oral delivery?
Drug performance is controlled by the interplay of excipients (formulation), the physiocochemical properties of the drug, and the physiological barriers between the GI tract and the site of action. Oral formulations can control the absorption rate, which then has to be optimized with respect to disposition to yield a safe and efficacious response. Dosage form design is dynamic and is unpredictable, so patient habits have to be considered for dosing regimens. Patients will vary in response, so this needs to be considered. Generic formulations are not the innovator, and thus can cause some problems with performance.
Solubility limited: drugs with very poor solubility are often limited as ________________.
Druggable candidates
The higher the _____, the more sensitive the reaction is to temperature.
Ea
For diseases, the duration of the drug's plasma concentration in the therapeutic window, as indicated by the Cmax and Tmax, and the duration of the chronic therapy all influence _______ and ______.
Efficacy and safety
What kind of transporters pump substrates out of cells?
Efflux transporters
Definition of enteral
Enteral = "by way of the intestines"
List salt formation methods
Evaporation, cooling, temperature oscillation, antisolvent addition, solvent/antisolvent distillation, solvent diffusion, slurry Drug + HCl + evaporate = salt
What are some characteristics of drugs best suited for oral controlled release formulation?
Exhibit neither slow or fast rates of absorption and excretion Uniformly absorbed from the gastrointestinal tract Administered in relatively small doses Have good safety/therapeutic window Chronic therapies better suited than acute
Toxicity is a result of _________.
Exposure
What can oxidation be promoted by?
Exposure to oxygen, metal ions, light or heat
Which legislative incentives/mandates were put in place to promote pediatric development?
FDA: Pediatric Plan, BPCA, PREA EU: Pediatric Investigation Plan (PIP) WHO: Make Medicines Child Size
True or false: Biologics retain their activity if they unfold.
False
True or false? Bioequivalent means that the therapeutic effect of two dosage forms are equivalent.
False
True or false? Ionized compounds are reabsorbed in the distal tubule.
False
True or false? Weak bases will be absorbed from the stomach.
False
True or false? When you reduce the particle size to the nanoparticle domain, the solubility actually increases.
False
True or false? Excipients are inert substances.
False; excipients are not inert!
True or False? Solubility is the only parameter controlling dissolution rate.
False; it is important but not the only parameter.
True or false? the fed state has 3 defined phases.
False; the fed state has no defined cycle.
True or false? There is no issue in the interchangeability of generic products and the Reference Listed Drug (RLD).
False; there is definitely an issue in the interchangeability of these products.
True or false: There is no variation of intra-individual small intestinal transit times using the same batch of non-disintegrating pellets.
False; there was significant variation shown in this particular study.
How has the FDA encouraged pediatric studies?
Financial incentive to conduct studies (orphan and off-patent drugs--no incentive to do studies) Increased studies resulted in new labeling for 40 drugs For approval of selective number of new drugs pediatric studies have been required
What is the molecule with the most structurally characterized API polymorphs?
Flufenamic acid, which is octamorphic.
What is Fick's First Law used for?
Flux of diffusing particles. It determines how solute moves from high to low concentration in a solvent. The rate of concentration change is dependent on the rate of diffusion.
What are ionic interactions?
Formed between anions (negative) and cations (positive); held together by electrostatic interaction
In transdermal drug delivery, drug moves...
From the reservoir to the patch Through the barrier layer Through the stratum corneum Through the viable epidermis and the lower layers of the skin Through the blood vessel wall and into the bloodstream
What are some strategies to overcome the effects of the pH partition hypothesis?
Functionalize the compound-change of pKa Prodrug strategy Salt selection Drug Delivery System
What are the three parts of the stomach and their functions?
Fundus-contains gas and produces contractions to move stomach contents Body-reservoir for ingested food and fluids Antrum-lowest part of the stomach, funnel shaped, contains the pyloric region and controls flow into the small intestine
In this study, the Bravo pH capsule was administered 30 minutes before a standard breakfast and 4 hours before a standard lunch. What are the main points of interest gained from this study?
Gastric pH and residence changes occur even when the formulation is taken before meals. Also, this is another study where the fed state pH did not go up to 5.
In this study, the plasma levels of 4-amino-salicylic acid were measured in two different patients after ingestion of an enteric coated capsule. What can be noted from the results?
Gastric residence differs dramatically Gastric emptying controls colonic absorption, where greater GI residence leads to higher absorption. Patient 2 had significantly faster GI transit-capsule voided in <6 hours! Illness?
What kind of factors can impact the fetus during the 9 month gestation period?
Genetics, diet, environment, etc.
What is controlled release?
Goes beyond sustained release and implies a reproductability and predictability in the drug release kinetics. Therefore the kinetics from one dosage unit is reproducible and predictable from one unit to another. Allows us to maintain a narrow drug plasma concentration-Steady State
What are some techniques for innovation?
Group A techniques: involve incremental tweaking of existing products--change tablet shape Group B techniques based on analogy Group C techniques: wild ideas Brainstorming, storyboarding, mind mapping, excursion method, product improvement method, Osborn checklist, scenario planning
What are some advantages to using cocrystals in pharmaceutical manufacturing?
High bioavailability Relatively easy to develop Especially useful for poorly soluble compounds IP on crystal forms can be developed after successful Investigational New Drug trial Improve physiochemical properties without altering biological function of the drug
BCS Class I has ______ permeability, _______ solubility.
High, high. Those compounds are well absorbed and their absorption rate is usually higher than excretion. Example: metorpolol
BCS Class II has _______ permeability, _______ solubility.
High, low. The bioavailability of these products is limited by their solvation rate. A correlation between the in vivo bioavailability and in vitro solvation can be found. Examples: gibenclamide, bicalutamide, ezetimibe, phenytoin
What are some characteristics of the rectum?
Highly folded High drug absorption There are a number of high potency drugs that may be delivered rectally Preferred administration in rectum for patients with gag reflex problems with pills Low residence time
What are some other pediatric pharmacology issues?
Historical cases with drugs like thalidomide in the 1950's induced in utero malformations. Exposure to xenobiotics are poorly understood. For example, endocrine disrupting chemicals led to in utero programing of cancer in adolescence. Animal models have differing sensitivity to xenobiotic exposure than humans. Human data is sparse, but xenobiotic exposure can lead to changes in developmental PK/PD. The target moves even further due to the environment!
What are the two types of synthons?
Homosynthons and Heterosynthons
Initially cocrystals were studied in order to learn about _______ in the solid state.
Hydrogen bonding
What are some factors involved in passive paracellular permeation?
Hydrophilicity Molecular size and shape pKa of the ionizable groups Linear increase in permeability with increasing concentration Adjuvants can open tight junctions and increase transport
What product is formed by hydrolysis of a lactone?
Hydroxy acid (hydroxyl group on one end and carbonyl group on the other end)
When is a drug considered low solubility?
If more than 250mL of water is required to dissolve the largest dose at any pH at 37 degrees C
When is a drug considered highly soluble?
If the largest human dose is soluble in 250 mL or less of water in normal pH
What limits food flow from the ileum into the cecum and vice versa?
Ileocecal valve
What is the importance of tight junctions?
Important for the function of the confluent epi-/endothelia Restrict solute movement between the cells (paracellular) Polarize cells into apical (luminal-blood facing) and basolateral (abluminal-brain facing) areas Allow for differing functions between the two membranes TJs can involve up to 50 proteins
What is a solid?
In a solid the atoms, ions or molecules are held together at a short distance through different type of intermolecular interactions.
Where does colon drug absorption mainly occur?
In the ascending region nearest to the SI
Where does most absorption occur?
In the small intestine
What is used to determine bioequivalence besides in vivo measurement of active moieties in biologic fluids?
In vivo pharmacodynamics comparison In vivo limited clinical comparison In vitro comparison
Testing drugs in children presents considerable scientific, clinical, ethical, technical, and logistical challenges. Several practical challenges have discouraged the testing of drugs in pediatric populations including lack of:
Incentives for companies to study drugs in neonates, infants, and children Technology to monitor patients and assay very small amounts of blood Suitable pediatric clinical infrastructure for drug trials Is 6 months of exclusivity worth the risk? After 6 months, is it cost effective to drop pediatric programs?
Drugs can be given transdermally to avoid hepatic first-pass metabolism. In transdermal drug delivery, bioavailability can be reduced by:
Incomplete absorption Chemical degradation in the skin Enzymatic degradation in the skin
In oral administration, bioavailability can be reduced by...
Incomplete dissolution Chemical degradation of the drug in the GI tract Enzymatic degradation of the drug in the GI tract Poor absorption across the GI mucosa Efflux transporters "First-pass metabolism" in the liver
What does uptake of moisture do to amorphous dispersions?
Increases molecular mobility Increases rate of crystallization Reduces bioavailability of drug product
What are the routes of permeability involved in absorption?
Influx transporter mediated Passive transcellular Passive transcellular and efflux Passive paracellular Metabolism Efflux of the metabolite(s)
What kind of transporters transfer substrates into cells?
Influx transporters
What are the three concurrent types of reactions involved in chain oxidation?
Initiation, Propagation and Termination
What is a crystalline salt?
Ionic interactions between chemical entities present in the crystal lattice
What are the three types of interactions found between molecules in the solid state and what are their ranks in strength of intermolecular interaction?
Ionic, Hydrogen bonding, and Van der Waals Ionic > hydrogen bonding > van der waals
Median small intestine transit times in the fasted, fed and pre-fed states showed no difference in the fasted and fed states. What happens when the drug is taken 30 minutes post feeding and not with a meal directly?
It accelerates transit time.
Why is first-order kinetics important?
It is frequently used to describe drug degradation kinetics
What is an IV piggyback used for?
It's often used to administer drugs and IV fluids by infusion, by gravity feed or infusion pump
What are the two cardinal rules of GMP?
Know what you have and make the same thing every time.
What are pharmaceutical equivalents (Knipp's definition)?
Same active ingredient(s); same dosage form; same route of administration; identical in strength or concentration; and may differ in characteristics such as shape, excipients, color...
The relevance of animal models (differences in the developmental timing of anatomical, physiological, biochemical and physicochemical events) can limit extrapolation to humans due to what factors?
Length of gestation and timing of events Relative organ function maturity at birth Significant species differences exist in some transport proteins and regulatory machinery
__________ often (but not always) causes oxidative degradation and can serve as an initiator in chain oxidation.
Light
What are some factors involved in Passive Transcellular Permeation?
Lipophilicity: hydrogen bonding potential; hydrophobicity Molecular size and shape pKa of the ionizable groups linear increase in permeability with increasing concentration Dissolution/solubility limited with high lipophilicity
BCS Class III has _______ permeability, _______ solubility.
Low, high. The absorption is limited by the permeation rate but the drug is solvated very fast. If the formulation does not change the permeability or gastro-intestinal duration time, then class I criteria can be applied. Example: cimetidine
BCS Class IV has _________ permeability, ________ solubility.
Low, low. These compounds have a poor bioavailability. Usually they are not well absorbed over the intestinal mucosa and a high variability is expected.
What besides blood supply exists in the villi?
Lymphatic drainage
What are some different polymers for coating?
Matrix and coated beads Matrix: drug embedded in polymer matrix Coated beads: sugar sphere is coated in drug and then dried Nonenteric: HPMC, Methylhydroxyethylcellulose, HPC Enteric Polymers: Acrylate polymers, CAP, HPMCP, PVAP
What is the residence time for tablets in the stomach (fasted)?
Median time (hr): 0.5 Typical range: 0.25-4
What is the residence time for tablets in the stomach (fed)?
Median: 2-3 hr Typical range: 0.75-10
What is the residence time for tablets in the small intestine?
Median: 3 hr Typical range: 2-4
What is the residence time for tablets in the colon?
Median: 32 hr Typical range: 4-96
Elimination describes the removal of the drug from the body and includes both:
Metabolism and Excretion
Contrast the blood levels and other parameters for concerta and metadate.
Metadate CD has peak exposure during critical learning hours.
Methionine can oxidize into:
Methionine Sulfoxide or Methionine Sulfone
What are some different types of ADHD drugs?
Methylphenidate IR, Methylphenidate ER, Ritalin SR, Metadate ER, Metadate CD, Concerta, Ritilin LA, and Daytrana are all methylphenidate drugs. Intuniv is a nonstimulant drug. Adderall is an amphetamine based drug.
What does MEC stand for?
Minimum Effective Concentration
Solubility depends on:
Molecular structure Physical state Composition of solvents Measurement methods
Plasma concentration decreases _________ with time.
Monotonically
What fraction of marketed drugs are chiral?
More than 1/2
What are some characteristics of different parts of the intestines?
Most transporters are located in the SI. Upper SI = mixing Lower SI = electrolyte Colon = fluid and electrolyte absorption
What are some aspects controlling residence time at absorption site?
Mucoadhesives, coatings, etc.
What are the three layers on the colonic mucosa?
Muscularis mucosae Lamina propria Epithelium
Does cholesterol only have harmful effect on membranes?
No, it provides fluidity at lower levels. Actually, when it exceeds a certain level in a membrane, the membrane undergoes a phase transition and forms a liquid crystalline state. We call this hardening atherosclerosis when it occurs in the vasculature.
What factors govern regulation of transporter expression and activity during growth and development?
Nuclear receptor regulation Endocrine changes Do genetic variations add to age-related variation in drug transporter expression and function? What is the impact of disease, drug-gene interactions, drug-drug interactions, food-drug interactions, and exposure to environmental chemicals on the expression and function of drug transport proteins?
What kinds of cosolvents have the best solubilizing effect?
Ones that match the drug in polarity; "like dissolves like" at work here
What are some critical factors in excipient selection?
Origin, source and availability Functional category Quality and purity Impurity levels and extent of characterization Batch-to-batch consistency Stability in the pure form and in formulation Compatibility with active and packaging material Toxicological considerations Cost, regulatory or compendial status Biological activity, if any Patent status
What are sink conditions?
Outside concentration is at least 90% of what the overall concentration is
What is the mechanism of the reactivity of captopril?
Oxidation is catalyzed by metal ions. It also undergoes amide hydrolysis, but this is quite slow.
What are the strategies currently used for abuse deterrent products?
OxyContin included material that made the tablet hard and formed a gel to reduce syringeability Embeda is formulated as capsules of ER morphine pellets that contain a sequestered core of the opioid antagonist naltrexone (Once you crush it, the antagonist is released and it loses its use) Hysingla ER now incorporates excipients that form a viscous gel when the capsules are crushed and dissolved. Targiniq ER (Purdue), and opioid agonist/antagonist combination containing ER oxycodone and naloxone
What are the most abused prescription drugs?
Oxycotin and hydrocodones
What determines the strength of a crystalline material?
Packing motifs
What are the passive (non-saturable) intestinal transport mechanisms?
Paracellular (between cells) Transcellular (through cells)
Routes of administration that do not go through the intestines are called...?
Parenteral (par = "to one side of, beside")
Patients don't take drugs...
Patients take dosage forms.
What does "clipping" refer to?
Peptide bond hydrolysis; cleaving peptide bonds through the addition of a water molecule.
What are the different types of van der Waals forces?
Permanent dipole, Keesom forces, Debye forces and London forces
When permeability of PAMPA>>Caco-2, _________ is indicated.
Pgp efflux
What is bioequivalence (Knipp's definition)?
Pharmaceutical equivalents whose rate and extent of absorption are not statistically different when administered to humans at the same molar dose under similar experimental conditions
Formulation design requires a consideration of:
Physicochemical properties of the drug Physicochemical properties and composition of the formulation Biological factors that influence performance (ADME and Toxicity; ADMET) For a dosage form to reach the clinic, these must be properly balanced.
What are the factors governing drug performance in the clinic?
Physiochemical properties of the API Physicochemical properties of the composition of the formulation Physiological barriers that influence the "targeted bioavailability" of the drug
Many pregnant women are on meds for treating pre-existing conditions. Why is the PK of drugs in pregnancy complex?
Physiological changes alter ADME of drugs Toxicity is a significant concern
Understand matrix tablets and their compositions.
Polymer with holes that is soaked in drug and the drug goes in the holes.
___________ of a drug can cause urinary tract stones and other conditions.
Precipitation
What kind of cells are the small and large intestines composed of?
Predominantly columnar epithelial cells which are also mixed with many different cell types
What are some quality issues with tablets?
Process design, process performance, product performance, product design, process controls, process parameters, product quality attributes, product specifications, process understanding, product knowledge and continuous improvement
How can degradation of protein drugs be prevented?
Protect from heat Protect from light Protect from moisture Protect from oxygen Protect from transition metals AVOID SHAKING (may cause aggregation)
How can hydrolysis of amides and lactams be prevented?
Protect from moisture Protect from heat Control pH in solution formulations
How can hydrolysis of esters and lactones be prevented?
Protect from moisture Protect from heat Control pH in solution formulations
How can oxidation and photolysis be prevented?
Protect from oxygen (nitrogen fill) Protect from heat Protect from light (colored glass bottles) Include anti-oxidants such as ascorbic acid, but these can sometimes act as pro-oxidants Include metal chelators such as EDTA
Which factors cause variability in oral absorption?
R distribution pH/bile distribution Permeability distribution Enzyme distribution Blood flow distribution Transporter distribution
What is zero-order kinetics?
Rate of drug degradation is constant, independent of concentration.
What is first-order kinetics?
Rate of drug degradation is proportional to concentration OR rate of change of drug concentration with time is proportional to concentration.
What is the partition coefficient?
Ratio of concentration in two immiscible solvents. It is only valid when referring to permeability through a lipid membrane.
What kind of dosage forms are absorbed in the distal colon?
Rectal administration, e.g. suppositories
What kind of cells are in the rectum?
Rectum has an upper (simple columnar) and lower (stratified squamous non-keratinized region transitioning to stratified squamous keratinized region near the anal sphincter) half.
What is the Arrhenius equation used for?
Relates reaction rate (k) to activation energy (Ea), ideal gas constant (R) and absolute temperature (T). If obeyed, a plot of ln(k) vs. (1/T) is linear with slope (-Ea/R).
What is solubility of a solute determined by?
S = f (crystal packing energy + cavitation energy + solvation energy)
The solubility of weak electrolytes is _________ dependent on pH.
STRONGLY
What kind of transporters transfer their substrates from the blood circulation into bile, urine, and/or GI lumen?
Secretory transporters
What is the structure of the colon?
Serosa-squamous epithelium covered with adipose tissue Muscularis Externa-inner circular muscle layer and incomplete outer longitudinal layer Submucosa and mucosa
What are the organoleptic senses to consider when coating/binding treatments?
Sight: size, shape, color, marking, pkg Smell: odor of dosage form Sound: tablet/pellet inside a capsule does not rattle Taste: mask any unique taste Touch: coatings, isotonicity, viscosity
What are the different types of epithials cells?
Simple squamous: lines most blood vessels-placenta, endothelial cells Simple columnar: usually found in the GI tract Transitional: comprised of several layers with different shapes-usually required to stretch Stratified squamous: multiple layers of squamous cells that cover areas subject to wear and tear-skin is one type that the barrier function comes from keratinization.
Protein drugs differ from small molecule drugs in....
Size and structure Routes of administration Types of formulation Common instabilities Manufacturing methods Regulatory environment
What are some aspects of dosage form design?
Size, excipient compositions, manufacturing parameters, etc.
What is the most common physical dosage form?
Solid dosage forms
What are the physiochemical properties of the drug that affect absorption?
Solubility Drug stability in solution Lipophilicity Molecular size and shape pKa of the ionizable groups Physical state of the drug
The BCS has been widely used to expedite generic and drug repurposing formulations for industry. Classification is based on three factors that influence the drug's bioavailability from a peroral formulation:
Solubility (in vitro, biorelevancy?) Intestinal permeation across the intestinal barrier (in vitro vs. in vivo, regional?) Dissolution rate (in vitro, biorelevancy?)
Why do we care about hydrates?
Solubility, Processability and Physical Stability
What are 3 factors that can limit the ability of a drug to absorb after oral administration?
Solubility: Can't get enough drug into solution Dissolution: Can't get drug out of tablet Permeability: Can't get drug across GI cell membrane
Even if the solute mixes well with the solvent, a strong, stable crystal will make it more difficult to ________.
Solubilize
What are some types of IV dosage forms?
Solutions Emulsions (e.g. total parenteral nutrition, TPN) Powders for reconstitution
What is second-order kinetics?
Squared dependence on concentration, for binary reactions. They depend on concentration to the second power (squared).
What is hydroquinone used in?
Sunscreens Topical medications for skin whitening
List some types of oral dosage forms.
Tablets, capsules, caplets, lozenges, orally dissolving tablets, sublingual tablets, buccal tablets, films, thin films, solutions, suspensions, and elixirs
What is performance?
The ability of the drug to elicit a therapeutic response The ability of the drug to stay in a safe therapeutic range during the dosing regimens A lack of toxic or non-efficacious response
What is Ka?
The acidity or dissociation constant
What is the Ea?
The activation energy (Ea) is a measure of how sensitive the degradation reaction is to temperature. High (Ea) (e.g. 100 kcal/mol) = very sensitive to temperature changes. Low Ea (e.g. 20 kcal per mol or less) = less sensitive to temperature changes
What is the rate of dissolution?
The change in the amount of mass that appears in solution over time
What is the blood brain barrier?
The endothelial cells that make up the capillary walls which are tightly attached to one another
Bioavailability definition
The fraction of an administered dose of a drug that reaches the systemic circulation intact
First-pass effect definition
The metabolism of orally administered drugs by gastrointestinal and hepatic enzymes, resulting in a significant reduction of the amount of unmetabolized drug reaching the systemic circulation
What is oxidation?
The net loss of electrons; always accompanied by reduction (redox)
What is the stratum corneum?
The outermost layer of the epidermis, comprised of dead cells (corneocytes) without nuclei. It is a barrier to water loss, infection, and chemical insult and is often the major barrier to transdermal drug delivery.
Which part of the colon do enteric coated formulations target by oral administration?
The proximal colon
How are different sized lactams categorized and named?
The size of the ring is indicated by a greek-letter prefix. Beta lactam: 2 carbon atoms outside the carbonyl Gamma lactam: 3 carbons outside the carbonyl Delta lactam: 4 carbons outside the carbonyl Epsilon lactam: 5 carbons outside the carbonyl
Why as pharmacists should we care about the solid form of an API?
The solid form you choose affects the physicochemical properties of your material
Pharmacokinetics definition
The study of the time course of drug absorption, distribution, metabolism and excretion. More specifically, it's the study of the time course of drug concentration in blood (or plasma) following the administration of a dose.
How do dosage forms work?
They control the "A" in ADME.
What is the significance of nanoparticles compared to micro particles?
They increase surface area but do not really help too much for diffusion.
Where are endothelial cells found?
They line the inside surfaces of body cavities, blood vessels and lymph and have simple squamous morphology.
Why are abuse deterrent products important?
They result in fewer overdose deaths and they generally prevent abuse.
What is the disruptive innovation story related to insulin pens?
Thick gel-like substance cannot go through an insulin pen. They tried to spend money and make a human insulin, but the pre-existing, pork insulin worked well enough and was cheaper.
How is Cp0 related to the dose?
Through the volume of distribution, Vd. Dose = Cp0 x Vd
What is the role of the stomach?
To digest food and control the flow of its contents into the intestine Acts as a food reservoir Processes food into fluid chime for nutrient absorption Regulates food delivery to intestine pH protects against most bacteria, allows pepsin to function
_________ is a limiting factor in cocrystals as drug forms for development.
Toxicity
What are some types of transdermal dosage forms?
Transdermal patches, transdermal patches with penetration enhancers, ointments, creams, and lotions. The last three are more common for topical delivery.
What are some challenges to assumptions made with GI physiology-clinical considerations? ********question on exam********
Transporters and enzymes vary along the GI tract. Variability is enormous in GI fluid composition. Diet and chemical exposure varies. Pharmacogenetics and genomics are huge issues. Interindividual variation is also significant. Drug-nutrient and drug-drug interactions are common. So much more.... Bottom line: One Size formulations do not fit all.
True or False? Different extracellular and the intracellular pHs can affect drug transport.
True
True or false: all aspects of protein structure can be important in the therapeutic effect.
True
True or false? Columnar epithelial cells form a single continuous layer of absorptive cells covering each villus.
True
True or false? Drug performance can be a moving target.
True
True or false? GI fluid volumes do not correspond with dissolution bath volumes.
True
True or false? There is an urgent need to expedite the development of pediatric formulations.
True
True or false? fasted and fed state GI transit times show some differences in gastric emptying and cecal arrival time.
True
True or false? increased stir rates lead to increased dissolution rate.
True
Which drugs can be delivered transdermally? What kind of qualities do they have?
Typically these drugs have low dose and high diffusion coefficient in the skin. Usually, this means relatively small molecular weight. They often also have high hepatic first-pass metabolism and/or short dosing interval by the oral route.
What role does intestinal disposition play?
Under debate: effect of transporters and drug metabolizing enzymes in influencing BCS class. Intestinal transport and metabolism can be misrepresented by simple screening studies. Cell line variability can dramatically influence expression levels of transporters and drug metabolizing enzymes. Phase II metabolism is not always completed in absence or sufficient conjugate concentrations in buffer.
What is accelerated stability testing used for?
Used by the pharmaceutical industry to estimate shelf-life and set expiration dates. Typically involves: Storing the product at high temperature Measure degradation kinetics and rate constant Estimating degradation rate at the desired storage temperature assuming Arrhenius behavior Estimating the time for 2-5% degradation at storage temperature to set shelf-life
The stomach emptying rates and colonic retention of the contents appear to correlate quite well over fairly extended time periods. What does this tell us about the retention in the small intestinal regions?
Usually does not change significantly with light or heavy meals
How thick is the colon?
Varies in thickness from 2.5cm in the sigmoid region to 8.5cm in the cecum
Volume of distribution definition
Vd is the theoretical volume that the total amount of administered drug would have to occupy ( if it were uniformly distributed) to provide the same concentration as in blood plasma.
What is product design?
What is dispensed, dosage form, polymorph
What are the big questions for preformulation?
What is the structure of the compound? What is the likely dose? What is the route of administration and desired dosage form? What is the indication? How soluble is the compound/formulation? How well is the compound absorbed? What is the toxicology of the compound? What doses should be used for Phase 2 clinical trial? What are its solid state properties? How chemically stable is the compound? How well will the powder flow? Is moisture an issue? What is the design, composition, and manufacturing procedure of the formulation?
Under what circumstances can zero-order kinetics be observed?
When the drug concentration in solution is constant, as in a suspension In the solid-state
Know Intuniv and its release profile
Works in 20% of cases It is a nonstimulant Formulation: Guanfacine hydrochloride in polymer matrix Granfacine base is insoluble Fumeric acid acidifies matrix and prevents guanfacine base from precipitating Without fumaric acid, guanfacine precipitates at pH 6.8 and does not fully dissolve
Is half-life concentration dependent for second-order kinetics?
Yes
The AUC for two dosage forms are equal even though their blood level vs. time graphs are different. Are they bioavailable? Are they therapeutically equivalent?
Yes; no
Carboxylic acid esters undergo hydrolysis to produce:
a carboxylic acid and an alcohol
Amides undergo hydrolysis to produce ________ and ______.
a carboxylic acid and an amine
What is a crystal?
a highly ordered solid phase. The atoms, ions or molecules pack into an infinite repetitive 3D structure.
The columnar epithelia is separated from the lamina propria by ________ comprised of glycoproteins and penetrable by lymphocytes.
basal lamina
On a pH rate profile a slope of +1 in the basic region is consistent with specific _____ catalysis.
base
Second-order kinetics is sometimes needed to describe __________ reactions.
binary or bimolecular; for protein degradation or in thiol-disulfide exchange for example
Pharmaceutical companies will not risk using a metastable polymorph unless it can be proven that over the shelf life of a drug product the ________ and ______ is not compromised.
bioavailability and efficacy
The slowest rates on a pH rate profile are usually shown toward the ________.
bottom
How is a salt formed?
by acid-base reaction involving either proton donation or proton acceptance
How is a supercooled liquid prepared?
by rapid cooling of a melt below melting point such that molecules do not have time to rearrange into a crystalline lattice
What is the function of coatings?
can be applied to control diffusion rates and modify the release properties of the drug from the interior protection of agent from air and/or humidity mask taste provide special drug release aesthetics prevent inadvertent contact with drug
What is the function of disintegrants?
can be used to control regions of release based on physicochemical properties
What is the function of internal excipients? ***** may be question on final*****
can be used to modify the release rates as well swellable matrices non-swelling matrices inert plastics
What is the function of lubricants?
can slow dissolution based on properties
Hydroquinone is a suspected ______________.
carcinogen
Mechanisms of oxidation are much more __________ than hydrolysis.
complex
In zero-order kinetics, drug concentration decreases at a ___________ rate.
constant
What is a cold chain?
continuous and uninterrupted refrigeration of the drug product, from the manufacturer to the patient.
It is often _____ to resolve a racemic mixture into its pure enantiomers.
costly
The _______ region is composed of 3x more crypt than villi, comprised of undifferentiated cells that proliferate
crypt
What are lactams?
cyclic amides
What are lactones?
cyclic esters
Free drug concentration ________ as API crystallizes.
decreases
Polymorphism definition
different crystal structures of the same chemical entity
In making a solution, what factor controlling solubility is involved with "mixing"/hydrophobicity?
difficulty of solvating dislodged molecules
IV push definition
direct injection into a vein
What are amorphous dispersions?
dispersion of a solute in an amorphous solvent
When the "brick dust" part is the limitation (we hit the "brick wall") it becomes necessary to:
disrupt the orderly crystal structure
An acid is a proton _________.
donor
What is photolysis?
drug degradation caused by exposure to light
Small Vd definition
drug primarily in the vasculature
What is the absorption rate defined by?
drug properties, the excipient/drug composition of the formulation, and the physiological barriers between the GI tract and systemic circulation
How is the shelf-life for a drug set?
during drug development, in negotiation between the FDA and the manufacturer
The stronger the intermolecular interactions between molecules in the crystal lattice the greater the _________ required to overcome them
energy
What is the importance of amorphous solids in dosage forms?
enhanced bioavailability, solubility and dissolution rate but less physical stability
The pH-rate profile must be measured ________ and can give information on reaction mechanisms.
experimentally
Cosolvents increase solubility ___________.
exponentially
For first-order reactions, drug concentration decreases ________ with time.
exponentially
Large Vd definition
extensive distribution and/or binding in extravascular tissues
Penicillin contains an amide group as well as a lactam. Hydrolysis of the lactam is usually ________ (faster or slower?) than that of the amide, presumably due to ring strain.
faster
Biologics are one of the ________ growing sectors of the pharmaceutical industry.
fastest
What do aqueous film coatings generally contain? ******may be question on final*****
film-forming polymer plasticizer to produce flexibility and elasticity of coating colorant and opafier vehicle
Non-aqueous film coatings generally contain:
film-forming polymer-produce smooth films alloying substance to provide water solubility or permeability to the film plasticizer to produce flexibility and elasticity of coating surfactants enhance film coat spreading colorant and opafier improve appearance sweeteners, flavors, and/or aromas glossant providing luster volatile solvent allows spreading and evaporation
What is the most common order kinetics?
first-order and pseudo first-order
What is crystalluria?
formation of crystals in the urine
Paradigm shift for industry: Traditional views over the last couple of decades have been to protect children ______ clinical research. However, the current regulatory paradigm shift is to now protect children ________ clinical research.
from; through
What does initiation of chain oxidation involve?
generation of free radicals by: Auto-oxidation Exposure to heat Exposure to light Exposure to metal ions
The solubility of a hydrate in solvent or a solvate in water will almost always be ______ than that of the anhydrous/unsolvated form.
greater
Low clearance rates are associated with ______ toxicity. Dose lowering adjustments and higher hydration rates should be required in children carrying these phenotypes.
higher
What is a hydrogen bond?
highly directional intermolecular bond formed between certain polarized functional groups (N-H, O-H, O, N, Cl, F); they are a special case of Van der Waals forces.
For an amide hydrolysis mechanism during basic conditions, the first step is nucleophilic attack of ____________ on amide carbonyl group.
hydroxide anion
The hydrolysis mechanism for carboxylic acid esters during basic conditions begins with a nucleophilic attack of _______ on ester carbonyl group.
hydroxide anion
What is captopril used to treat?
hypertension and congestive heart failure (CHF)
When is a drug product considered bioequivalent (statistics related)?
if the 90% confidence interval of the ratios of the test to reference log-transformed mean values for AUC and Cmax are within 80-125%. [both Cmax (111-126%) and AUC (97-108%) from the Meyer study]. Differences in Cmax and Tmax were due to faster dissolution of the generic products comparative to the RLD.
Andydrous crystalline forms may convert to a hydrated form _________.
in-vivo
Amorphous solids have no crystal packing to disrupt, intermolecular interactions are weaker. No energy barrier to overcome = _________ in solubility
increase
For an acidic compound, solubility _________ exponentially as pH increases.
increases
Strong intermolecular interaction __________ stability.
increases
For an acidic compound, if pH <<pKa, solubility is nearly __________ of pH.
independent
Rate of clearance can be impacted by urine pH due to variation in _______ state of drug
ionization
Solubility of weak acids/bases varies with pH---- higher for the __________ form.
ionized
At any pH the solubility is the sum of the concentration of the _________ and ________ forms.
ionized and unionized
At any pH the solubility is the sum of the concentration of the _______ and ______ forms.
ionized; unionized
In the simplest case, degradation is _____________.
irreversible
On a pH rate profile a flat minimum can indicate ____________.
k0 contribution
Solid state phase transitions are _________ processes.
kinetic
Rates of drug degradation can be affected by pH. These effects can be _______.
large
The magnitude of the temperature effect can be very _______.
large
Biologics are _____ than small molecules, so there are _____ bonds that can break.
larger; more
Energy released upon dissolution and further interaction with water is ______ for the hydrate.
less
The solubility of a solvate in solvent will almost always be _____ that that of an unsolvated form.
less
The solubility of water will always be _____ than that of an anhydrous form.
less
Less common physical forms; may be very important in some settings (e.g. hospitals)
liquids (solutions and suspensions) and gases (aerosols and gases)
