PHAR 6708 Final

Freedom from Pyrogens

"Pyrogens" or bacterial endotoxins are: dead microorganisms and metabolic products of living microorganisms the most potent when produced by gram-negative microorganisms lipopolysaccharides

The activity of solute in a solution, a2, may be thought as....

"effective concentration"

Activity

"effective concentration" or "escaping tendency of molecule from a phase (crystal or solution)

operator p =

- log ( )

deltaTf =

-(RTf^2/deltaHf)*X2 X2 = mole fraction

Weak acid reaction rates, Ka

--------------kf HA + H20 ======= A- + H3O+ --------------kr Rate of forward reaction (Rf) = kf[HA][H20] Rate of reverse reaction (Rr) = kr[A-][H3O+]

Solution of dextrose (MW 180) made up to be 0.56 M. What is it in g/L?

0.56 moles/1 L x 180 g/mol = 100 g/L

Eye can tolerate tonicity values equivalent to

0.6 to 2% NaCl

Formula for 1 L of an elixir contains 0.25 mL of peppermint oil. What is % (v/v) of flavoring oil in elixir?

1 L = 1000 mL 0.25 mL/1000 mL = x mL/100 mL x = (0.25 mL/1000 mL)x 100 mL = 0.025 % v/v peppermint oil in elixir

How many grams of Na2SO4 (MW 142 g/mol) are required to make 1.2 liters of 0.5 N solution?

1 M = 2 N 142 g Na2SO4/mol x (1 mole/L)/2N x 0.5N x 1.2 L = 42.6 g Na2SO4

198 dextrose added to 1000 mL water, % (w/w) strength of solution?

1 mL = 1 g 1000 mL = 1000 g 198 g + 1000 g = 1198 g (198 g dextrose/1198 g) x 100 g solution = 16.5 % (w/w)

1 mg/L = ? mcg/mL

1 mg/L x 1000 mcg/mg x 1 L/1000 mL = 1 mcg/mL

Roles in drug-drug interaction

1) Drug A: Single drug = 5% unbound. 2 drugs = 10 % unbound = 100% change 2) Drug B: Single drug = 50% unbound. 2 drugs = 55% unbound = 10% change

Common Pharmaceutical Solutes

1) Drugs 2) Flavors and sweeteners 3) Colorants 4) Preservatives 5) Stabilizers

Joule-Thomson effect

1) Energy is invested to overcome attractive forces between molecules 2) Potential energy increases with expansion 3) Thermal energy decreases (conservation of energy) 4) Thus, temperature decreases

Examples of conjugate acid-base pairs cocrystals

1) Nicotinamide: semi-salt= 2 Nicotinamide molecules and one HCl 2) Naproxen: semi-salt= 2 Naproxen molecules and one Na+

1.6 ng/mL = ? mg/L

1.6 ng/mL x 1 ng/1 x 10^6 mg x 1000 mL/1 L = 0.0016 mg/L

Maximum pH effect on solubility of weak acid or weak base may result in as high as ______ fold change of intrinsic solubility of undissociated drug

10^4, this corresponds to change of pH by 4 pH units above pKa of weak acid or below pKa of weak base----where 99.9 % drug is ionized

120 lb =

120lb x 1 kg/2.2 lb = 55 kg

Consider a Scatchard plot, a straight line that intercepts the x-axis at 2 suggest the number of protein binding sites is

2

How many phases does a mixture of sugar and sand have?

2

How many phases does ice water have?

2

Mixture of theophylline crystals and ice: theophylline & H2O = ? components

2

What are the F, C and P of a suspension of theophyilline monohydrate in water?

2 components 2 phases 2 degrees of freedom F = C - P + 2

Binary solution

2 components/constituents

2 polymorphs can be as different in properties as

2 different compounds

2 g API in 250 mL solution, ratio strength is 1: _____ (w/v)

2 g API/250 mL = 1 g/x mL x mL = (250 mL x 1 g)/2 g Ratio strength = 1: 125 API

2 mg API in 2 mL solution, ratio strength is 1: _____ (w/v)

2 mg API x 1 g/1000 mg = 0.002 g 0.002 g/2 mL = 1 g/x mL x mL = (2 mL x 1 g)/0.002 g = 1000 Ratio strength = 1:1000 w/v API

Solubility ratio between 2 polymorphs may be as high as

23:1

25 lb =

25 lb x 1 kg/2.2 lb = 11.4 kg

What are the F, C and P of a mixture of sand, sugar and NaCl?

3 components 3 phases 2 degrees of freedom F = C - P + 2

330 lb =

330 lb x 1 kg/2.2 lb = 150 kg

Urine pH varies from ________ and can have profound effect on excretion of _________ and _________, through effects on reabsorption

4.5 to 7.5 (average 6.3), weak acids, bases

More than _________% drugs used in hospitals given in form of injection

40

1 lb, 5.2 oz =

5.2 oz x 1 lb/16 oz = 0.325 lb + 1 lb = 1.325 lb x 1 kg/2.2 lb x 1000/1 kg = 602 g

An injection contains 50 mg phenobarbital sodium in each mL solution. What is % strength (w/v) of solution?

50 mg phenobarbital/1 mL solution x 1 g/1000 mg x 100 mL solution = 5% w/v phenobarbital

How many grams of a drug are needed to prepare 400 mL of 5% w/v solution?

5g/100 mL = x g/400 mL (5g/100 mL)x 400 mL = 20 grams

7.5 lb =

7.5 lb x 1 kg/2.2 lb = 3.4 kg

A total of _____ polymorphs have been observed and characterized

9

93 lb =

93 lb x 1 kg/2.2 lb = 42 kg

Effect of pH on ionization (base)

A base, B, takes up hydrogen ions from water to form a conjugate acid, BH+ The protonated base, BH+, is a weak acid B + H20 ====== BH+ + OH- base 1 acid 2----acid 1 base 2 BH+ ===== B + H+ Ka = ([B][H+])/[BH+] pH = pKa + log ([B]/[BH+] B = base BH+ = weak acid

What is a plasma concentration-time profile?

A patient takes a dose of drug Blood samples are taken from patient at various times after dose is taken Blood is analyzed for drug content (drug concentration in plasma) Plasma concentrations can be plotted as function of time

Osmotic pressure includes

A semi-permeable membrane allows small solvent molecules to diffuse across, but NOT large solute molecules

What is a phase?

Any part of system that is homogenous in both chemical composition & physical state & is separated from rest of system by definite boundaries

High pH

Apparent distribution coefficient is much smaller than actual partition coefficient, for acids

Change in boiling point can be computed using

Clausius-Clapeyron equation

When pKa = pH....

Compound is 50% ionized

How is choice of dosage form made?1

Condition of patient Age Elderly may have difficulty with: swallowing large tablets or capsules seeing well enough to accurately measure out liquid or injection taking many pills Children may have difficulty with: bad tasting medicine swallowing anything they don't want to swallow Is the patient: Unconscious? Vomiting? Uncooperative?

Tinctures are alcoholic or hydroalcoholic solutions made from vegetable materials or chemical substances

Contain 15 to 80% alcohol This alcohol content needed to keep medicinal agents in solution But don't need a preservative Generally can't mix with other aqueous solution because the medicinal agents will precipitate out Co-solvents like glycerin may also be used Not used much except for paregoric or tincture of opium

pH shift in formulations examples

Container effect: glasses contain metal oxides and sodium hydroxide CO2: forms carbonic acid when dissolved in water

Mass balance:

Cw^o = Cw + Vo/Vw x Co Cw^o = original concentration of HA in water phase, will distribute into both phases Cw = final equilibrium concentration of HA and A- in water phase (= [HA]w + [A-]w) Co = final concentration of HA in oil phase = [HA]o = K of o/w[HA]w

As size of molecule increases

D decreases, and rate of absorption decreases rate of absorption = ((DSK of o/w) x Cout)/h

At 25C, a sodium salt of a drug (Na+D-) has solubility of 0.02 M in water. What is the concentration of the drug ion (D-) in 0.1 M of NaCl aqueous solution at 25C? (Assuming the salts completely dissociate in water and the solution is in equilibrium with Na+D- crystals)

D- = 0.02 M Na = 0.02 M Ksp = [Na][D] = 0.02 x 0.02 = 4 x 10^-4 M^2 [Na][D] = 4 x 10^-4 M^2 NaCl = 0.1 M [Na + X][X] = 4 x 10^-4 M^2 [0.1 M + X][X] = 4 x 10^-4 M^2 X^2 + 0.1X - 4 x 10^-4 M^2 = 0 Quadratic formula: (-0.1 + ( 0.1^2 - 4 x 1 x - 4 x 10^-4)^1/2)/2 x 1 = 0.0039 M

Many factors influence therapeutic response to drugs

Biological characteristics of patients Pharmacokinetics Dosage regimens Routes of administration Types of dosage form These factors manifest themselves through the plasma (blood) concentration-time profiles

Physiological pH ranges

Blood pH = 7.4 Muscle pH = 6.60 to 7.08 Tear pH = 6.5 to 7.6 (average = 7.0)

D, Diffusion coefficient

Influenced by size of molecule, fluidity of membrane

Any other examples of tincture?

Iodine

Why does FDA require that the dye FD & C Yellow No. 5 be specifically named on drug products that contain it?

It can cause an allergic reaction in patients with aspirin allergies

What controls [A-]?

It is pH dependent

Apparent distribution coefficient for bases

K' weak base = K of o/w/(1 + 10^(pKa - pH)) Low pH ==== apparent distribution coefficient is much smaller than the true partition coefficient

Kw =

Ka x Kb = 1 x 10^-14

Relationship between Ka and Kb of conjugate acid-base pair

KaKb = Kw

USP Bacterial Endotoxins Test

Limulus ambebocyte lysate (LAL) test as stest for bacterial endotoxins Use of blood cells of horseshoe crab Cells clot in presence of endotoxins in 60 min Appears more sensitive than rabbit test for endotoxins FDA now accepts this as replacement for rabbit test

Things that affect the rate of membrane transport via Fick's Law have direct effect on pharmacokinetic profile of drug:

Lipophilicity, ionization (pH partition) Diffusivity Membrane thickness (skin vs lung vs GI) Concentration at site of admin (inside GI tract or renal tubules) Surface Area

Condensed matter

Liquid Solid

When solid is dissolved in liquid

Liquid is considered the solvent, regardless of relative amount in mixture

Boiling

Liquid to gas

Stronger acid =

Lower pKa, weak conjugate base

Deep Eutectic Solvents (DES)

DES - Eutectic systems with very low Teu Green solvents: Easy to prepare in pure state Chemically stable Non-volatile Many are biodegradable Well characterized toxicological properties Good solvents for a wide range of materials Inexpensive

Biological Significance of Particulate matter

Development of lung emboli in patients, particularly those: Receiving large volumes of infusion fluids Who are recumbent and have sluggish pulmonary circulations Are receiving concomitant coritosteroid therapy or other tissue repsonse-modifying agents

Interactions between Neutral Molecules (van der Waals Forces)

Dipole-Dipole (Keesom Force) Dipole-Induced Dipole (Debye Force) Induced Dipole-Induced Dipole (London or Dispersion Force)

Solutions

Dispersions at molecular level (miscible systems)

Distribution into an organ

Distribution half-life (t1/2, d) describes the time it takes the tissue concentration to reach half its equilibrium concentration

Dosing regimen will affect concentration-time profile:

Dosing interval (how often)

Salting-out definition

Ions STRENGTHEN solvent structure to make it more difficult to insert drug molecules

Considering 2 completely miscible non-volatile liquids in a container at room temperature and 1 atm pressure, the number of components (C), the number of phases (P), and the number of degrees of freedom are:

F = C - P + 2 With temp and pressure given, # 2 is no longer there C = 2 P = 1 F = 1

Considering a mixture of nitrogen gas and water vapor in a sealed container: if the relative humidity is 60% at 23 degrees C, it remains at 60% at 30 degrees C since the compositions of the mixture do not change with temperature

False

Presence of another gas above a liquid reduces the equilibrium vapor pressure due to a dilution effect

False

A solution of sodium chloride in water has 3 components: Na+, Cl- and water

False, Na+ and Cl- are not independent---count as one component

Rate of reabsorption: Fick's Law

Fick's law has direct effect on renal clearance profile of reabsorbed drug: Lipophilicity, ionization Diffusivity Membrane thickness (thicker than GI) Concentration in renal tubule Surface Area

Barrier to absorption in small intestine is

GI epithelium

Distribution of Acids

Generally, only Cw (not [HA]) can be experimentally measured Also uses ionized forms

Paracellular

Going through the spaces between cells Controlled by fluid flow (convection)

Molecules

Group of 2 or more atoms linked together by sharing electrons in a chemical bond

Throat sprays

Halitosis, sore throat, laryngitis Contain antiseptics, deodorants, flavorants

Factors affecting Blood Flow: Vessel radius

Heat exposure Alcohol Some antidepressants (amitriptyline) Antihypertensive drugs (calcium channel blockers, ACE inhibitors) Nitrates Bacterial infections Nerve damage Atherosclerotic plaque build-up

Heat of solution =

Heat of mixing----amount of heat evolved in process

Osmotic pressure of solution of urea (MW 60) with 0.3 g of drug in 50 mL of water at 20 degrees C.? (Use Van't Hoff eq)

II = [Csolutes]RT 0.3 g urea x 1 mole urea/60 g urea = 0.005 mole urea/0.05 L water = 0.1 mole/L urea 50 mL water x 1 L/1000 mL = 0.05 L water 20 degrees C + 273 = 293 K II = 0.1 mole urea/L urea x 0.08205746 (L x atm)/(mol x K) x 293 K = 2.4 atm

How is the choice of dosage form made?

Identify the disease, a drug that can treat it, what the concentration at the active site will need to be, and how long duration of use is The desired shape of the plasma concentration-time profile Therapeutic response to drug can be controlled by altering the onset and duration of pharmacological effect Can be modified by changing the shape of the plasma concentration-time profile

Glass transition temperature (Tg)

If T > Tg = dramatic increase in molecular mobility Propensity to crystallize is increased Chemical reactivity is increased Temp decreases = elasticity decreases

Forced diuresis in clinical practice

If drug is highly reabsorbed, its excretion is dependent on urine flow rate Forced diuresis is often used in overdose cases Changes pH and increases urine flow Give agent to change pH such that maximum proportion of drug is ionized

Under what situation is high alcohol content necessary?

Improve drug solubility

What factors are important in defining blood flow?

Poiseuille's Law Q = (pi x r^4)/8n x [delta P/L] Q = Volumetric flow rate (mL/min) r = vessel radius (larger radius = larger flow rate) n = blood viscosity delta P = pressure drop L = length (longer length = smaller flow rate)

Examples of cosolvents

Propylene glycol, ethyl alcohol, alcohol, glycerin

Pharmaceutical relevance of solubility

Protein drugs ----lyophilized (freeze dried) products, typically buffered to ensure stability

What is the concentration of oxygen in 2L of water when the water is saturated with a mixture of oxygen and nitrogen at 25C when the partial pressure of oxygen is 0.5 atm and total pressure is 1 atm? (kO2 = 43400 atm O2/mole fraction and kN2 = 85700 atm N2/mole fraction at 25C, express answer in mole fraction)

Psolute = k(solute) 0.5 atm = 43400 atm x mole fraction O2 0.5 atm/43400 atm = mole fraction O2 1.15 x 10^-5 = mole fraction O2

Biological actions of pyrogens

Pyrogenic reaction manifested by fevers and chills Following injection, latent period of 45 to 90 minutes Then rapid rise in body temp, followed by chills, headache and malaise (Chills last 10 to 20 min) Reaction reaches peak in 2nd or 3rd hour Can control by use of antipyretics Very serious for very ill patients

A 2 L cylinder is loaded with N2O gas (MW 44.02) to pressure of 3.5 atm at 30 degrees C. What is the mass of N2O in the cylinder at that pressure and temp? Assume gas behaves ideally

R = 0.0821 L x atm/(mol x K) PV = nRT 3.5 atm x 2L = n x 0.0821 L x atm/(mol/K) x 303 K n = PV/RT n = ((3.5 atm)(2L)/((0.0821 L x atm/mol x K) x 303 K) = 0.281 mol Mass = n x M = 0.281 mol N2O x 44.02 g/mol N2O = 12.4 g

If the association constant, K, between a drug and a protein is 381074 at 23 degrees C, the standard Gibbs free energy (cal/mol) of protein binding is:

R = 1.987 cal/Kmol T = 23 +273 = 296 K deltaG = -RT(lnK) -1.987 cal/Kmol x 296 K x (ln 381074) = -7558 cal/mol = delta G

Ethanol (MW 46.1) has boiling point of 78.3 degrees C at 1 atm and latent heat of vaporization of 204 cal/g. Calculate the vapor pressure of ethanol at 25 degrees C.

R = 1.9872 cal/molK 273 + 78.3 = 351.3 K ln(P2/P1) = (deltaHv/R) x (1/T1 - 1/T2) ln(P2/1 atm) = (204 cal/g)/(1.9872 cal/molK) x (1/351.3 K - 1/298 K) x 46.1 g/mol Raise both sides to e^(each side) P2/1 atm = 0.0899015 P2 = 0.09 atm

Mole fraction definition

Ratio of the moles of one constituent (ex: the solute) of solution to the total moles of all constituents (solute and solvent)

Cmax

Maximum concentration

Entropy (delta S)

Measure of disorder of system Negative deltaS = more ordered or fewer degrees of freedom Positive delta S = more disordered or more degrees of freedom

Theobroma oil polymorphs

Melting temps: Alpha = 22 degrees C Beta = 34.5 degrees C = stable form Beta prime = 28 degrees C Gamma = 18 degrees C

What happens when you microwave ice?

Melts, because microwave radiation interacts with dipole and increases molecular motion = increase in temperature

Extravascular administration

Membranes involved: Oral Topical (skin, nasal, throat) Opthalmic Nasal

Why can't opthalmic solutions be used for systemic effects?

Membranes not very easy to permeate through eyes into blood

What solvent is not used for preparing an oral solution for drug delivery?

Methanol

The concentration of MgCl2 solution with 0.009 ionic strength is:

Mg2+ Cl 2 ions ionic strength = 1/2(sum)(cizi^2) ci = concentration zi= number of ions 0.009 = 1/2((ci) x 2^2 + 2(ci) x 1^2) 0.009 = 1/2( 4ci + 2 ci) 0.009/3 = 1/2(6ci) = 3 ci/3 = 0.003 M

The anatomical feature that most enhances surface area?

Microvilli

What happens when you microwave dry ice?

Microwave radiation excites the dipole, but dry ice has no dipole---so dry ice will not change

What happens to equilibrium when pH increases?

More drug dissolves to keep equilibrium constant between HA (solid) and HA (solution)

Example of weak base---Ammonia (NH3)

NH3 + H20 ===== NH4+ + OH- The protonated base, NH4+, is a weak acid NH4+ ===== NH3 + H+ Ka = ([NH3][H+])/(NH4+] pH = pKa + log ([NH3]/[NH4+])

Most pharmaceutical solutions are...

NOT saturated with drug---use other excipients to make more soluble

Salting-in:

Needs less energy Solubility increases Increase in salt content

In a weak acid reaction, are concentrations of reactants and products equal?

No

Typical properties of amorphous solids

No long range order No sharp melting point X-ray diffraction shows diffuse pattern (halo) Higher free energy, solubility, and chemical reactivity than crystalline counterparts

Does the concentration unit matter?

No, because it is a ratio

Is water a good propellant?

No, because it needs to stay at boiling point to remain stable at room temp

Purified Water, USP/NF

Obtained by distillation, reverse osmosis, ion-exchange treatment Prepared with water meeting EPA standards for drinking water

Monotropic polymorphs

One polymorph is always stable

Ideal gas law

PV = nRT

Membrane Pathways

Passive: Transcellular & Paracellular

Polymorphs of carbon

Same molecular structure, different internal structure (crystal packing)

pH solubility profile of weak acid

See slide 7, Nov 3 HA(solid) ===== HA (solution) ==== H+ + A- Cs = Co + [A-] Higher pH ==== equation moves to right, total amount of drug in solution increases Graph goes up from left to right

Interconverison between states of matter: Heat energy taken from environment

See slide 9 on Gases Ice melts, leads to liquid Liquid evaporates, leads to vapor OR Ice sublimates to vapor

Oral solutions can be

Simple solutions (in water or other solvents) Syrups Elixirs Tinctures

Understanding whisker growing tablets (solid-vapor)

Slide 11 Phase Equilibria 1 Possible causes: Capillary condensation of vapor Temperature fluctuation

Negative deviation (activity coefficient < 1)

Slow down evaporation

Melting

Solid to liquid

Solute types

Solid, liquid or gas

Solvent types

Solid, liquid or gas

Heat of solution (delta H solution) =

Solid-----solution Heat of solution = Heat of fusion (solid to liquid at melting point) + Heat of mixing (heat generated when mixing 2 liquids)

Drug crystal + solvent =

Solution dosage form

Can liquid crystals be a solvent?

Yes

Does size of dose given influence the Cmax?

Yes, larger the dose = larger Cmax

Calculate the pH of a 0.01 M solution of procaine (Kb = 7 x 10^-6 at 25C)

[OH-] = (Kb x Cb)^1/2 = (7 x 10^-6 x 0.01)^1/2 = 0.000264575131 = OH- concentration - log (0.000264575131) = pOH = 3.58 pH = 14 - 3.58 pOH = 10.42 pH

Mass Law Relationship

[P] + [Df] ===== [PD] [P] = protein [Df] = free drug [PD] = protein/drug complex or concentration of drug associated with protein Association constant, K = [PD]/([P][Df]) ==== [PD] = k[P][Df] Total protein concentration = [Pt] = [P] + [PD] [Pt] = [P] + k[P][Df]

The activity, a (ion) of any ion is:

a (ion) = yi x C (ion) activity coefficient (yi) calculated by: log (yi) = -Azi^2 x (Ionic strength)^1/2 A= constant zi = charge on ion

Citric acid, anhydrous and sodium citrate dihydrate together are for

a buffer to stabilize pH of solution

Alcohol is

a disinfectant = will kill the bacteria

Solid-Liquid Phase diagrams: Nature of Eutetic Phase diagram

Sugar in water See slide 4 Phase Equlibiria 2

Description of morphology

Tabular Platy Prismatic Acicular: elongated prism Bladed: flattened acicular crystals See slide 7 Solids

Generally how many mL of solution in teaspoon? Tablespoon?

Teaspoon = 5 mL Tablespoon = 15 mL

Applications in preparing orally disintegrating dosage forms

Techniques for making orally disintegrating tablets Freeze drying or lyophilization Compressed tablets Molding Oral thin-film pharmaceuticals/neutraceuticals

What is the same between the solubility of a drug in water and the solubility of same drug in ethanol?

The activity of the solute and ideal solubility

Preservation of Oil-in-Water emulsions

The addition of preservatives is common in Pharmacy to preserve drug solutions from growth of microorganisms in water phase 1) Soluble salts of benzoic acid (HA) are often used 2) Only neutral benzoic acid can penetrate bacterial membranes, causing lysis (destruction of cell membrane followed by cell disintegration)

Bioavailablity (F) and AUC (exposure)

The area under the plasma concentration vs time curve (AUC) is used to measure extent of absorption AUC from 0 to infinity = antiderivative from 0 to infinity Cdt = (F x D)/CL F = Bioavailability D = Dose CL = Drug clearance

Solubility of a gas definition

The concentration of the gas in a liquid that is in equilibrium with the pure gas (above it)

Ionic equilibrium definition

The condition in which the rate of dissociation of neutral molecules is equal to the rate of combination of the ions

Tonicity

The osmotic pressure of solution (can be adjusted by controlling concentration of solutes)

pH = pKa + log (Cs/Co -1)

This equation is basis for determining pKa of acidic drug from the solubility measurements at different pHs

Onset

Time it takes for plasma concentration to reach MEC

tmax

Time where concentration is highest

Influence of perfusion

Tissue perfusion varies widely in body From 10/mL/min/min (lung)=== high flow rate, small volume, to 0.03 mL/min/mL (fat)====low flow rate, high volume?

Dosage regimen will affect concentration-time profile:1

Type of dosage form

Hildebrand Equation

V2 = partial molar volume of solute O1 = volume fraction of solvent (approx = 1), where O1 = (V1X1)/(V1X1 + V2X2) lower case delta = solubility parameter in (cal/mL)^1/2

Intermolecular forces: Ionic interactions

Very strong Distance dependence is 1/r

Intermolecular forces: Covalent interactions

Very strong Distance dependence is complex

Variability in patient characteristics will affect the concentration-time profile

What can be done to optimize therapy for patient with cirrhosis? Extend dosage intervals, lower dose

What is a metabolite? Are metabolites always inactive?

What the drug becomes after it is metabolized in liver. No they're not always inactive. Sometimes an inactive drug has active metabolites

Why do salts affect the solubility of caffeine?

When add salt to medium, dissolves into cation & anion----then reacts with solvent and changes the solvent This changes the activity coefficient of the drug

Changes in pH...

affect stability of drug product

Ion

atom or molecule with a net positive or negative electrical charges Total number of electrons does not equal number of protons

A crystal =

atoms/ions/molecules arranged in periodic fashion in 3 dimensions

According to the Biopharmaceutical Classification System, to which class does a drug with low solubility and high permeability belong? a) I b) II c) III d) IV e) V

b) II

Rate at which gas goes into liquid phase and vice versa is

balanced

r is the ratio of moles of ______ to moles of _______

bound drug, protein

Protein binding limits

brain penetration Slide 23 intravascular Admin

Molecules with highest energies

break away from the surface of liquid (evaporation)

Apparent solubility ____ be changed

can, by changing pH---adding solubilizing agents, etc

Intrinsic solubility _____ be changed

cannot

Ionic strength of solution

ci = molar concentration of i ion present in solution zi = charge number of ion i Summation is to include all ions present in solution

Ionic strength of solution practice problem

ci = molar concentration of i ion present in solution zi = charge number of ion i Summation is to include all ions present in solution What is the ionic strength of following solutions? a) 0.01 M KCl 1 K- ion, 1 Cl- ion Ionic strength = 1/2 (0.01 x 1^2 + 0.01 x 1^2) = 0.01 b) 0.01 M BaSO4 Ba(2+), SO4(2-) charges Ionic strength = 1/2(0.01 x 2^2 + 0.01 x 2^2) = 0.04 c) 0.01 M Na2SO4 2 Na ions, SO4(2-) charge Ionic strength: 1/2(0.02 x 1^2 + 0.01 x 2^2) = 0.03

Elimination processes quantitatively described by

clearance

SD alcohol 38B

co-solvent

alcohol

co-solvent

glycerin

co-solvent

polyethylene glycol

co-solvent

propylene glycol

co-solvent

PVP (polyvinalpyrorolidone)

co-solvent and inhibitor of crystallization

The release rates of some drugs need to be

controlled

Topical solutions may require

cosolvents for solubility reasons

Chronic disease

could have slower absorption rate

The concentration of HA in water phase is

critical to its effectiveness

Internal structure of solid can be

crystalline or amorphous

A solid can also be

crystalline solid

For a base, as pH increases, % ionization....

decreases

Elimination

defined as irreversible loss from site of measurement

System

defined region of space

greater than 90% RH

deliquensce = solution

Lipid-like character is given to a drug by

its chemical structure

Activity of solid is quantified by...

its solubility in an ideal solution

Maximum solubility of drug in ionic form is limited by ______, which significantly changes the max pH effect

its solubility product, Ksp

The solubility of the electrolyte is determined by...

its solubility product, Ksp

States of Matter are

determined by how molecules are arranged in space See slide 2 on Gases

For partially miscible systems, solubility may be...

determined from phase diagram

The unionized form of drug is more

lipophilic than ionized

Most drugs are non-polar----

difficult to dissolve in water (polar) "Like dissolves like"

Humidity causes ______ in glass transition temperature = _________

drop, change in formulation

Pharmacokinetics is the study of the time course of

drug absorption, distribution, metabolism and excretion in the body (ADME)

In pharmacy...

drug considered solute and other component(s) as solvent---most drugs not very soluble

Distribution is reversible process of transfer of

drug to and from blood, site of meausrement

Urine pH can be altered by:

drugs, diet and clinical status of patient

Gases are released by

effervescent tablets for treating heartburn

Ionic equilibrium pertains to ____ only

electrolytes

PEG-40 hydrogenated castor oil

emollient

w22 definition

energy involved in interaction between solute and molecules

w11 definition

energy involved in interaction between solvent and molecules

w12 definition

energy involved in interaction between solvent and solute

For dilute aqueous solutions (including drug solutions), molarity and molality are...

essentially equivalent

Freezing point depression may be treated as

eutectic melting deltaTf = Kfm2 = Kf x ((1000*w2)/(w1*M2))

Surroundings (or universe)

everything not in the system

Systemic

exposing whole body to drug ex: injecting drug into vein

Boiling point depends on

external presssure

Cherry syrup

flavoring

Most materials occur in

gas, liquid or solid phase

Strength of acid/base is measured by the tendency to _____ ____ or ____ ____ protons

give up, take on

Solubility curve goes up when temperature is _____

higher = higher solubility

Protein binding will limit

how much drug can be filtered at Glomerulus of kidney

GI epithelium is one of the most _________ in the body

important barriers

Amorphous solids provide

improved drug delivery

At triple point, all 3 phases are

in equlibrium

Some drugs need to be injected directly into blood

in order to get pharmacological effect

Cyclodextrin can _______ in drugs with ______

increase solubility, low solubilty

Cosolvent(s) may be added to _____ solubility of drugs with _____ aqueous solubility

increase, poor

Solid----liquid----gas transitions occur with

increasing entropy (decreasing order)

Some drugs need to be

inhaled

All colligative properties are

interrelated

If 2 species feel an attractive force towards each other and the force decreases with an increase in temperature, the 2 species are likely to be:

ion/dipole

If 2 species feel a strong repulsive force towards each other, and the potential energy if proportional to 1/4, the 2 species are likely to be:

ion/ion

Activity depends on ______ of solution

ionic strength

Salting-in definition

ions WEAKEN solvent structure to make it easier to insert drug molecules

Amorphous matter

is between a liquid and a solid in composition

1.9% w/w solution of boric acid is ______ but not ________

isosmotic with blood, isotonic to blood

Solution with osmotic pressure the same as that of body fluid is called

isotonic

Gas has

low density low order high molecular mobility/freedom

Low free drug concentration =

low r

Higher melting point =

lower activity, because hard to break molecules up

Higher affinity for drug at

lower temperatures

Molality symbol(s)

m or mole/kg

Dosage regimen is defined as

manner in which drug is taken Ex: 20 mg po bid Size of dose Type of dosage form Route of Administration How often (dosing interval) How long

One drug can have

many dosage forms

The unionized form of drug is

more lipid-soluble than ionized form

Solid will melt at

normal freezing point---freezing point must be depressed to maintain equilibrium with the solution

Metastable

not at lowest free energy

Dissociated salts (ex: Na+ + Cl-) are

not independent and therefore count as one component

Positive deltaG =

not sponteneous (endergonic)

Charged compounds don't go well into

oil, or membranes---not well absorbed

Surface area considerations may

overcome issues of ionization

A dilute solution containing a nonvolatile solute may be considered as an ideal solution such that p2 goes to 0 (for the solute) and:

p = p1 = p1^o x X1 Since X1 + X2 = 1, and therefore X1 = (1 - X2) such that: p = p1 = p1^o x X1 = p1^o x (1 - X2) p1 - p1^o = delta(p1) = -p1^o x X2

As consequence of Henderson-Hasselbach relationship, absorption depends on

pKa of drug and pH of body fluid

pH + pOH @ 25C =

pKw = 14

Pharmacologically active drug plus the pharmaceutical ingredient is a

pharmaceutical dosage form (also called a formulation)

Protein binding affects ______ and _________ of drug

pharmacokinetics and pharmacodynamics

The way a dosage form is designed has a direct relationship to

pharmacological effect that is needed

By reducing temperature (or pressure) in a miscible system....

phase separation occurs

Crystalline solids that are a single entity can have

polymorphs

Crystalline solids with a stoichiometric compound can also have

polymorphs

The slope of the sublimation line is always

positive

States of matter are differentiated by:

pressure, temp, and intermolecular forces

Rate of condensation is

proportional to vapor pressure

Amorphous materials are widespread

proteins peptides polymers sugars

What cannot be removed with the use of a membrane filter with a pore size of less than 22 mcm?

pyrogens

If n binding sites from the same class:

r = (nK[Df])/(1 + K[Df])

Colligative properties depend on...

relative numbers of solvent and solute molecules (mole fraction)

Can ignore gas volumes

relative to container volume

IMPORTANT: If reabsorption increases

renal excretion decreases

Hydrophobic

repelled by water

Actual chemicals used as drugs are

seldom delivered to patient alone

Although most nasal delivery used for local effects on nasal mucosa,

several large molecules like peptides and polypeptides delivered for systemic effects

Gases

shape determined by container, expands to container volume

Liquids

shape determined by container, stable volume

Volume of distribution has influence on

shape of concentration-time profile

Most transmembrane movement of drugs occurs by

simple diffusion When more concentration on one side of cell, concentration will redistribute into other side until a uniform concentration on both sides exists

Crystalline solids can be

single entity or molecular complex

Miscible systems:

single phase (layer), variable concentration

Some drugs need to be admin to patient by topical (local) route of admin

skin, ear, nose, eye rectum, vagina

Phase diagram of water

slope of line between solid and liquid (ice to water) = negative Slope between liquid and vapor (water to vapor) is positive See slide 8 Phase equilibria 1

When freeing a molecule from the solute (step one in regular solution theory)...

solute-solute attraction is very strong----very difficult to remove molecules from solid = high w22

When creating a hole for solvent (step 2 in regular solution theory)...

solute-solvent attraction is very strong---easy to remove molecules from solid = high w12

Purified water

solvent

Gibbs Free Energy is a measure of

spontaneity

Negative deltaG =

spontaneous (exergonic)

Need to deliver sprays with

spray bottles, atomizers, pumps, etc

Topical solutions may be delivered as

sprays

pH shift can cause issues with ____ and ______!

stability, solubility

Solids

stable shape and volume

Opthalmic solutions are

sterile solutions, essentially free from foreign particles, suitably compounded and packaged for instillation into the eye

What is NOT a characteristic of Water for Injection, USP?

sterility

Amorphous =

structureless

Molality may be used to avoid _____ effect

temperature

Vapor pressure of propellant inside a container depends on

temperature

Miscibility is a function of

temperature and composition

Phase separation depends on both ____ and _____

temperature and composition

Ion-dipole interaction

tends to stabilize ions in water Ex: NaCl is soluble in water, because dipoles interact with the Na+

The chemical potential of the solute is related to

the chemical potential of water

Extent and rate of distribution of drug in the body is NOT affected by:

the clearance of drug from the body

The driving force for passive diffusion is

the concentration gradient Fick's First Law of diffusion

Boiling is

the condition of free vaporization throughout the liquid (not just at surface)

Buffers can undergo changes during....

the crystallization process

The boiling point of a liquid is the temperature at which vapor pressure of liquid is equal to

the external (ex: atmospheric) pressure delta(p1)/p^o = - X2

Lowering of the vapor pressure for dilute solution depends only on

the mole fraction of the solute delta(p1)/p1^o = - X2 Relative vapor pressure lowering of the solution is equal to the mole fraction of the solute

The more oil you put in an emulsion

the more drug you can dissolve

There are no charges in

the oil phase, because is non-polar

For two compounds whose unionized forms have equal lipophilicity (K of o/w)

the one with the higher percentage of unionized at given pH should be more rapidly absorbed

As lipophilicity increases (increase in K of o/w)

the percent absorbed increases

Osmotic pressure is

the pressure that must be applied to the side of the concentrated solution to prevent the flow of the pure solvent into the solution

If the deltaG for a reaction is negative, you know that

the reaction is spontaneous

Electric Polarizability is

the relative tendency of a charge distribution to be distorted from its normal shape by an external electric field

When at equilibrium, chemical potential is

the same throughout the system

At freezing point of pure solvent, the vapor pressure of the solution is obviously lower than that of

the solid phase and the system exhibits a free energy that favors the liquid phase

The change of the vapor pressure for the solution consists of the lowering of the vapor pressure by

the solute addition and then the temperature change d(ln P)solute = -dXb d(ln P)temp = deltaHvap/(RTf^2) x dTf At equilibrium: d(ln P)sub = d(ln P)solute + d(lnP)temp

The concept of solubility is not applicable for miscible liquids since...

there is only a single phase

P-T phase diagram shows regions of pressure & temperature at which various phases of substance are

thermodynamically stable

For drugs to get from site of admin to site of action

they must cross biological barriers, generally cell membranes, to reach systemic circulation

Purified water, USP/NF meant for use in preparation of dosage forms, except

those intended for injection

t1/2, d is dependent on

tissue perfusion

Sodium Chloride 0.9%

tonicity-adjusting agent, solvent, isotonic

When pH changes...

total concentration changes

When molecule crosses thru cell, considered to go through the ____________ route across barrier

transcellular

Local

treatment of specific area of body ex: putting lotion on arm with eczema

5 to 80% RH

trihydrate is stable

Because water ionizes only to a small extent, concentration of _____ water is approximately _____

unionized, constant

p1^o and p2^o are the

vapor pressures of the pure solvents (no solute)

Stability of anhydrate/hydrate is controlled by

water activity

For equilibrium processes (chemical reactions)

we are interested in spontaneity

Conjugate base of a strong acid is a _____ base

weak

As pH decreases, ionization decreases

weak acid

Rectal temperatures

approx 1 degree F > oral temp

Two drugs with solubilities of 0.001 mg/mL vs. 10 mg/mL. Which one's bioavailability is likely to be dissolution-limited?

0.001 mg/mL solubility drug---takes a long time for drug to get into solution, and then for drug to pass through membrane and be delivered throughout the body

pH Observed Solubility (M) 1 0.0015 2 0.00151 3 0.00152 4 0.0017 5 0.003 6 0.017 7 0.152 8 1.5 The table shows solubility data for a drug. What is the intrinsic solubility of the drug (in M)?

0.0015

How many mg benzalkonium chloride present in 30 mL container of opthalmic product preserved with 0.007% bezaolkonium chloride?

0.007 g benzalkonium chloride/100 mL solution x 1000 mg/g x 30 mL = 2.1 mg benzalkonium chloride

Electrons are

1/1840 of the mass of a neutron

Ionic (Coulomb) interaction

1/r Always attractive Valence

Antibiotic cream contains 10 mg tocophenol/kg. Ratio strength (w/w) is 1:_____

10 mg tocophenol/kg x 1 g/1000 mg x 1 kg/1000 g = 1 x 10^-5 g tocophenol/1 g product x 100 g product = 0.001 g tocophenol/100 g product = 1 g tocophenol/x g product x = (100 g product x 1 g tocophenol)/0.001 g tocophenol = 100,000 Ratio strength = 1:100,000 w/w tocophenol

pKw =

14

Calculate pHp for 0.5% w/v solution cocaine hydrochloride (base). Molecular weight of salt = 339.8 and molar solubility of base = 5.16 x 10^-3 M. PKb of cocaine = 5.59

14- 5.59 =8.41 pka 0.5 g/100 mL x 1000 mL/L x 1 mole/339.3 g = 1.47 x 10^-2 M = Cs pH = pKa - log (Cs/Co -1) pH = 8.41 - log(1.47 x 10^-2/(5.6 x 10^-3 -1)) pHp = 8.2

What is the concentration (% w/v) of solution containing 15 g of drug in 500 mL?

15 g/500 mL x 100% = 3% w/v of drug in 500 mL solution OR 15 g/500 mL = x g/100 mL x = (15 g x 100 mL)/500 mL = 3 g = 3% w/v of drug in 500 mL solution

Higher solute concentration =

more freezing point depression

For bases, lower pH =

more ionization

Electronegativity

Ability of atom in molecule to attract shared electrons (valence electrons in outer shell) to itself in a covalent bond

Polymorphism

Ability of substance to exist as 2 or more crystalline phases that have different arrangements and/or conformations of the molecules in crystal lattice

Factors affecting Blood Flow: Cardiac Output

Abnormal heart rhythms Heart muscle damage or malfunction Heart valve disorders Pulmonary embolism

Urinary pH and reabsorption: Agents that increase urine pH

Acetazolamide (carbonic anhydrase inhibitor) Sodium bicarbonate Low protein diet

Activity =

Activity coefficient x mole fraction

Different modes of interaction with cyclodextrin

Alpha Beta Gamma

Dipole-Dipole (Keesom) interaction

Always attractive 1/r^6 Dipole moment Temperature increase = energy decreases

Urinary pH and reabsorption: Agents that decrease urine pH

Ascorbic acid (Vitamin C) Ammonium chloride Mandelic acid Hippuric acid Methionine

Solute = Liquid, Solvent = Liquid

Example: Antiseptic alcohol solution

Solute = Solid, Solvent = Gas

Example: Iodine vapor in air

Solute = Solid, Solvent = Solid (both at ambient conditions)

Example: Metal alloy, gem stones, solid-state diffusion

Solute = Liquid, Solvent = Gas

Example: Water in air (humidity)

Raoult's law region

Bulk solvent dominates

For the conjugate acid of a base, pKa =

pKa = pKw - pKb = 14 - pKb

What does the "E" in ADME stand for?

Excretion

Renal Clearance

Excretion of unmetabolized parent drug in urine

Intermolecular forces: Ion-dipole interactions

Strong Distance dependence is 1/r^2

Diseases related to solubility, Hydroxyapaptite crystal deposition disease

Caused deposition of hydroxyapaptite crystals near or in joints Localized pain, swelling and tenderness about the affected joint

If both pressure and temp are fixed, then

F = C - P

Gibb's Phase Rule

F = C - P + 2 2 is related to temp and pressure P = number of coexisting phases in system C = number of components in system F = number of degrees of freedom (independently specifiable P, T, concentration of components)

Polymorphs of carbon differ in

Thermal properties Conductivity Hardness Color Density Stability

If the 2 species feel an attractive force towards each other and the force is independent of temperature, the 2 species are likely to be

Either induced dipole-induced dipole OR dipole-induced dipole

Weak acid at low pH

Less drug is ionized

The pKb of pilocarpine (a weak base) is 7.2 at 25C. Find the percentage of free base at pH of 7.4 (25C)

Step 1) Acid or base? Base Step 2) Which equation to use? Step 3) pH and pKa pKa = 14 - 7.2 pKb = 6.8 %I = 100%/(1 + 10^(pH -pKa)) = 100%/(1 + 10^(7.4-6.8)) = 20.076 Free base = unionized 100-20.076 = 79.92% free base

Drawing the ionization (titration) curve

Step 1) Find 50% ionization, when pH = pKa Step 2) determine direction of titration curve (with increasing pH, % ionization INCREASES for weak acid and DECREASES for weak base) Step 3) pH 1 unit above and below pKa----for base (9.1%, 90.9%) Step 4) pH 2 units above and below pKa-----for base (1% , 99%) Step 4) pH 3 units above and below pKa-----for base (0.1% and 99.9%)

IMPORTANT Characteristics of Parenteral Dosage Forms

Sterility Freedom from particulate matter Freedom from pyrogens

pH in GI tract varies widely

Stomach = pH < 2, proximal jejunum = pH 5 to 6.5, transverse colon = pH 6.6

What is NOT true with respect to perfusion-rate limited distribution?

The time it takes for the drug to reach equilibrium between the tissue and the blood depends on diffusion through the membrane

2nd Law of Thermodynamics

The total entropy of a system and its surroundings always increases

Effect on suppository drug delivery

Theobroma oil (cacao butter), a matrix for suppository drug delivery

Why are containers for parenteral injections overfilled?

To permit ease of withdrawl and admin of labeled volumes

Lewis classification of acids/bases

Too broad (electron pair criteria) If molecule can donate/accept electrons = acid/base

Arrhenius classification of acids/bases

Too restrictive (H+ and OH- criteria) Dissociates and gives H+ = acid Dissociates and gives OH- = base

1st Law of Thermodynamics

Total energy of system and its surroundings is constant (Conservation of Energy)

On the pressure-temperature phase diagram of any pure substance, the slope of at least 2 of the 3 boundary lines will always be positive according to the Clapeyron equation

True

Polymorphs of a drug molecule may have the same habit despite different internal structure (ex: unit cells)

True

What is NOT a characteristic of parental dosage forms?

Volumes of greater than 100 mL

Solution between liquid and water

Water considered the solvent

Kw (ionic product of water)

Water is capable of accepting or losing a proton (It is both a weak acid and a weak base----amphiprotic)

Solids can be _______ or ________ into a liquid

heated (melted) or compressed See slide 4 Liquids

Gas can also be

a supercritical fluid

Liquid can also be

a supercritical fluid or liquid crystal

Sodium Brequinar has a solubility product constant (Ksp) of 0.0355 M^2 at 25C in water. a) Calculate the molar solubility of this drug in water, assuming ideal solution b) What is the solubility of this drug in a 0.154 M NaCl solution?

a) 1:1 ratio 0.0355 M^2= Ksp (0.0355 M^2)^1/2 =0.1884 molar solubility b) 0.0355 = (0.154 + S) x S = S^2 + 0.154S - 0.0355 = 0 (-0.154 + (0.154^2 - 4 x 1 x -0.0355)^1/2)/2 x 1 = 1.27 molar solubiilty

Dipole moments (m)

add as vectors in molecules

Activity equations

a2 = X2ideal a2 =X2y2 X2 = non-ideal solution (in mole fraction) y2 = activity coefficient a2 = activity

See workshop problems Slides 21 to 25 on Phase Equilbria

and Written practice problems on Phase Equilibria

Acids/Bases can be _____, ______, or ______

anions (HSO4-, CH3COO-), cations (NH4+, H3O+) or neutral (HCl, NH3)

Sodium metabisulfite is for

anti-oxidant

Methylparaben

antimicrobial preservative

Propylparaben

antimicrobial preservative

Basic drugs will be less soluble in ______ solutions and more soluble in ______ solutions

basic, acidic because they will have more protons to react with

Partition coefficient says if drug is going to

be absorbed, if too small----not going to happen (0.001 to 10,000)

Lower free energy =

better stability

There are H-bonds in DNA and RNA

between stacked base pairs

Different polymorphs can have dramatically different

bioavailability

Electrolytes

dissociate in water---ionic solutions

Strong acid

dissociates completely in water HCl + H20 ------- H3O+ + Cl-

NOT all drugs...

dissolve easily

Kinetic energy is not

distributed evenly among all molecules in a liquid

The pH of solvent (does or does not) affect the solubility of ionizable drug (weak acid/weak base)

does

Activity (a2) (does or does not) change by solvent for a given solid

does NOT

Today's drug molecules are very potent, so

doses needed are very low Dose of aspirin is 325 mg Dose of ethinyl estradiol is 0.05 mg (1/6500 of aspirin dose)

Higher density (n/V) =

more collisions, leads to higher pressure

Air is a mixture of 21% oxygen and 79% nitrogen (all other gases are negligible). Air is in equilibrium with 1 L of water at a total pressure of 1 atm and temperature of 25C. What percentage of the gases dissolved in water is oxygen? (kO2 = 43400 atm O2/mole fraction and kN2 = 85700 atm N2/mole fraction)

kO2 = 43400 atm O2/mole fraction kN2 = 85700 atm N2/mole fraction Henry's Law: Pi = kiCi PO2 = kO2 x Concent O2 0.21 x 1 atm = 43400 x Concent O2 ConcentO2 = 4.84 x 10^-6 moles PN2 = kN2 x Concent N2 0.79 x 1 atm = 85700 x Concent N2 Concent N2= 9.22 x 10^-6 moles %O2 = Concent O2/(Concent O2 + Concent N2) = 4.84 x 10^-6/(4.84 x 10^-6 + 9.22 x 10^-6) x 100% = 34.4% Note that solution is more enriched in oxygen compared to air

Solutions should have same pH as

lacrimal fluid (7.4)

Activity is affected by....

melting point and heat of fusion

Consider a solvent and its corresponding solution to be

near the freezing point, Tf (solvent) and Tf (solution) at a total pressure of 1 atm

Before you use the Henderson-Hasselbach equation

need to know whether drug is weak acid or weak base How? Look at chemical structure (counterion) Na+ = weak acid Cl = weak base

Factor having greatest effect on blood flow through a vessel is:

radius of the vessel

Fick's Law

rate of absorption = (DSK of o/w x Cout)/h

Metastable forms will tend to

revert to stable form

Increasing concentration =

rising r, eventually reach plateau

Solubility of drug depends on both ______ and _______

salt concentration, type of salt

Chemical modifications of drug into _____ or _____ forms are frequently used to increase solubility

salt, ester

Polymorphs can have the

same habit

Solute

substance that is dissolved

Ionizable drugs

will ionize in water, because is a polar solvent

How much drug is needed (in grams) to make 5 L of 1:400 w/v solution?

x g/5000 mL = 1 g/400 mL x = (1g x 5000 mL)/400 mL = 12.5 g

If solute-solvent attraction > solute-solute attraction...

y2 < 1 y2 = activity coefficient

If solute-solute (in solid) attraction > solute-solvent attraction...

y2 > 1 y2 = activity coefficient

Percent by volume symbol

% v/v

Percent weight in volume symbol

% w/v

To make 5 L of 0.01 % (w/v) solution, I need to add ____ mg Red dye #40.

(0.01 g Red dye #40)/100 mL solution x 1000 mg/1 g x 5L x 1000 mL/1 L = 500 mg Red = 500 mg Red dye #40

Cw^o (Concentration of HA in water before distribution) =

(1 + 10^(pH - pKa) + K of o/w x (Vo/Vw)) x [HA]w [HA]w = concentration of HA in water after distribution

You are adding 1 mL of 0.01 M HCl to 100 mL of pure water (pH = 7). The volume of final solution = 101 mL. Calculate the pH of the final solution

0.01 moles HCl/1 L solution x 1 L/1000 mL = 1 x 10^-5 moles H+ added with when 1 ml of 0.01 M HCl added 1 x 10^-5 moles H+/(101 mL x 1L/1000 mL) = 9.9009901 x 10^-5 = concentration of H+ pH = - log (9.9009901 x 10^-5) = 4 = pH

Calculate the pH of precipitation of codeine with a salt concentration of 0.0295 M. The intrinsic solubility of weak base is 0.0279 M. The pKa is 8.21.

0.0295 M = Cs 0.0279 M = Co pH = pKa - log ((Cs -Co)/Co) pH = 8.21 - log ((0.0295 -0.0279)/0.0279) pH = 9.45

Nitrous Oxide (N2O) used for anestheisa. Use ideal gas equation and compute molecular weight of gas given that 1 L at O degrees C & 760 mmHg weighs 1.97 g

0.0821 Latm/molK = R 273 = T 760 mmHg = 1 atm PV = nRT n= PV/RT (1 atm x 1 L)/(0.0821 Latm/molK x 273 K) = 4.46163662 x 10^-2 mol 1.97 g N20/4.46163662 x 10^-2 mol = x g/1 mol N2O x = 44.15 g MW = 44.15 g/mol N2O

How many mL of liquid drug needed to make 1 pint of 0.1% v/v preparation (1 pt = 473 mL)?

0.1 mL/100 mL = x mL/473 mL (0.1 mL/100 mL) x 473 mL = 0.473 mL

Calculate amount (in grams) of NaCl (MW 58.5) required to make 250 mL of 0.5% w/v solution of Lidocaine HCl (MW 270.8) that is isotonic with blood. The E-value of Lidocaine HCl is 0.22

0.5% w/v = 0.5g/100 mL Osmotic equivalent of 0.5 g Lidocaine HCl in 100 mL solution = 0.5 x 22 = 0.11 g of NaCl Isotonic saline solution (0.9% NaCl) contains 0.9 g of NaCl in each 100 mL of solution Amount of NaCl needed to make 100 mL of Lidocaine HCl isotonic is: 0.9 - 0.11 = 0.79 g NaCl For 250 mL isotonic solution = 0.79 x 250/100 = 1.975 g of NaCl

Ethanol density

0.789 g/ml or 0.789 kg/L

1 mL water =

1 g =

Colloidal dispersion

1 to 500 nm (liposomes), solution or in gas phase

Steps for calculating tonicity adjusting agents

1) Calculate the total amount of NaCl required to make an isotonic solution 2) Calculate NaCl equivalent of existing components in the prescription 3) Calculate the amount of NaCl equivalent required to reach the total amount 4) Calculate the amount of adjusting agent that provides the missing amount of NaCl equivalent

Other colligative properties are determined experimentally to

1) Characterize solution 2) Relate back to osmotic pressure

Mass Transfer Processes

1) Convection: movement of fluid (or collection of molecules) due to pressure difference 2) Diffusion: random movement of solutes (single molecules) due to thermal motion a) membranes (absorption) b) fluid (dissolution)

Warfarin

1) Extensively bound 2) Weakly bound 3) Sensitive to being replaced (freed from binding protein) by many other drugs 4) Sudden increase of unbound warfarin leads to toxicity

When must drug molecules be in solution?

1) Intravascular Administration a) All processes take place in systemic circulation & organs it perfuses b) Drug molecules move by convection 2) Extravascular Administration a) Drug molecule must be in solution in order to cross membranes by diffusion

100 mg/dL = ? mg/mL

100 mg/dL x 1 dL/100 mL = 1 mg/mL

Topical solution contains 2% (w/v) erythromycin. Express concentration in mg/mL

2 g erythromycin/100 mL solution x 1000 mg/1 g = 20 mg erythromycin/1 mL solution

The solubility of ampicillin trihydrate is 6 mg/mL in water at 20C. The heat of solution is 5400 cal/mol. Calculate solubility at 40C

20 +273 = 293 K 40 + 273 = 313 K ln(C2/C1) = (-delta Hsolution/R) x ((1/T2) -(1/T1)) 1.987 cal/K x mol = R e^ln (C2/6 mg/mL) = -5400 cal/mol/1.987 cal/K x mol x ((1/313) - (1/293)) = e^0.59267 (C2/6 mg/mL)x 6 mg/mL = 1.8 x 6 mg/mL C2 = 10.8 mg/mL

6'4" =

6 ft x 12 in/foot = 72 in + 4 in = 76 in x 2.54 cm/1 in = 193 cm

60 mg/dL = ? g/L

60 mg/dL x 1 g/1000 mg x 10 dL/1 L = 0.6 g/L

How does [OH-] affect equilibrium? A- + H20 ===== HA + OH-

A- + H20 ==== HA + OH- Equation will move mostly to the left if OH- concentration is increased

Henderson-Hasselbalch Equation

A- = conjugate base of weak acid HA B = conjugate base of weak acid BH+ General form of ionization equations for acids and bases =

For a non-ideal (real) solution, A-A and B-B = _____ and activity coefficient = ____

A-B (ideal solution), 1

A pharmacologically active drug is also known as

Active Pharmacological Ingredient (API)

What are some factors that determine dosage regimen?

Activity Toxicity Pharmacokinetics Clinical state of patient Therapy Management

Non-ideal Solubility---Regular Solution Theory

Actual solubility = ln X2 = (- delta Hf/R) x ((1/T) - 1/Tm) - Hidebrand equation to the left------ Applicable to non-electrolytes and weak electrolytes!

Concentration gradient

After oral dose of drug, inside of GI tract would have high concentration (Cout) & inside intestinal cells would have low concentration (Cin)

Common Ion Effect example

AgCl (s) ====== Ag+ (aq) + Cl- (aq) Ksp = [Ag+][Cl-] How with the concentration of Ag+ be affected by adding NaCl to solution? It will decrease. When adding NaCl to water, it is also a strong electrolyte. So Cl- ion will increase because it is coming from both AgCl and NaCl----Ag+ will decrease in order to stay in equilibrium with AgCl (s)

Solvent

Agent used to dissolve another pharmaceutical substance or drug in the preparation of a solution

Calculating Ksp of multivalence electrolytes

Al(OH)3 ==== Al(3+) + 3OH Ksp = [Al(3+)][OH-]^3 How is [OH-] related to [Al(3+)]? For each Al(3+) there are 3 OH- ions How to express Ksp by [Al(3+)]? Ksp = [Al(3+)] x [3 xAl(3+)]^3 = 27 x [Al(3+)]^3 = 27 x [Al(3+)]^4 Ksp = y x (3y)^3 = y x 27y^3 = 27y^4

Pharmaceutical examples of solubility of liquid in liquid

Alcohol & water-----hydroalcoholic solution Volatile oils & water-----aromatic water Volatile oils & alcohol----spirits or elixirs

Examples of pharmaceutical solvents

Alcohol, USP (ethanol, ethyl alcohol) = 94.9 to 96% ethanol in water Dehydrated alcohol (99.5% ethanol or greater) Alcohol, rubbing, approximately 70% ethanol Glycerin, USP (glycerol) = miscible with both water and alcohol Propylene glycol, USP = miscible with both water and alcohol Oils Ex: Corn Oil NF, Olive Oil NF, Sesame Oil NF

Dipole-induced dipole (Debye) interaction

Always attractive Dipole moment Electric polarizability 1/r^6

Ion-dipole interaction1

Always attractive Dipole moment Valence 1/r^4 Temp increases = energy decreases

Dispersion (London) interaction

Always attractive Electric polarizability 1/r^6

Dipole-Induced (Debye) Dipole Interaction

Always attractive Independent of temperature 1/r^6 distance dependence

Dispersion Force

Always attractive Requires quantum-mechanical treatment Same distance dependence as Debye (both 1/r^6)

Dipole-Dipole (Keesom) Interaction

Always attractive Temperature Dependent Moderate fall off with distance

Pharmaceutical hydrates

Amoxicillin - anhydrous, trihydrate Lisinopril (ACE inhibitor) - dihydrate, anhydrous form NOT listed in USP Azithromycin - anhydrous, monohydrate, dihydrate Hydrocodone - anhydrous and hemipenta (2.5) hydrate----1 hydrocodone & 2.5 water molecules Caffeine - anhydrous and 0.8 hydrate

Aqueous acid-base reaction

An acid reacts with a base to form a new acid and new base through transfer of proton----also known as protolytic reaction or protolysis HA + H2O -------- A- + H3O+ acid 1 base 2------base 1 acid 2 Conjugate acid-base pairs: HA and A-, H20 and H3O+

Weak acid

An acid that INCOMPLETELY dissociates in water HA + H2O ======= A- + H3O+

Co-solvent definition

An organic solvent miscible with water Better interaction with drug molecule----increase solubility

Concentration-time profile

Anything that affects the performance of a dosage form will have a direct impact on whether the patient experiences a therapeutic (or toxic) effect

Cyclosporine is a fine white powder. Restasis appears as a white opaque to slightly translucent homogeneous emulsion. It has an osmolality of 230 to 320 mOsmol/kg and a pH of 6.5 to 8.0. Each mL of Restasis opthalmic emulsion contains: Active: cyclosporine 0.05% (500 mcg/mL). Inactives: glycerin, castor oil, polysorbate 80, carbomer copolymer type A, purified water, and sodium hydroxide to adjust pH. Aqueous solubility 27 mcg/mL. Cremophor XL 57 mg/g (polyoxylated castor oil). What is the estimated castor oil/water partition coefficient of cyclosporine? How much Cremophor is needed in the formulation to dissolve CyA at the desired concentration of 0.05%?

Aqueous solubility: 27 mcg/mL Cremophor XL 57 mg/g (polyoxylated castor oil) What is the estimated castor oil/water partition coefficient of cyclosporine? K of o/w = Oil solubility/Water solubility = 57,000 mcg/g = 2111 g/mL Can correct for density of Cremophor (1.05 g/mL), but this is an estimate. How much Cremophor is needed in the formulation to dissolve CyA at desired concentration of 0.05%? 1) Need 0.5 g/100mL or 0.5 mg/mL 2) Wo + Ww = 0.5 mg, where W is mass 3) CoVo + CwVw = 0.5 mg, C & V are conc. and vol. 4) (57 mg/mL x Vo) + (0.027 mg/mL x Vw) = 0.5 mg 5) Vo = (0.5 mg)/57 mg/mL) 6) Vo = 0.009 mL in 1 mL formulation How much oil would you add to 1 mL, so precipitation will not occur? A little over 0.009 mL

Patient was not getting relief from nausea and vomiting, even though she was taking an oral drug to treat these symptoms. What was the best thing you can do to help her?

Ask her physician to prescribe the drug in suppository form

Henry's law definition

At a constant temperature, the solubility of a gas in a dilute solution is proportional to the partial pressure of the gas 1) Applies to dilute solutions only 2) Gas does not react with the liquid

At equilibrium, does [HA] in solution change under given temperature and solvent? HA solid ===== HA solution ====== H+ + A-

At different pHs, it does not change as long as solid is in the solution---molecules in solid will try to dissolve to maintain equilibrium

Protein purification: Salting-out

At high concentration, the solubility of proteins DECREASES and precipitation may take place Dialysis can then be used to remove the salt

pH Observed Solubility (M) 1 0.0015 2 0.00151 3 0.00152 4 0.0017 5 0.003 6 0.017 7 0.152 8 1.5 The table shows solubility data for a drug. What is the pKa of drug?

At pH = pKa, Cs = 2 x Co 2 x 0.0015 M = 0.003 M pKa = 5

Cooking on a mountain

Atmospheric pressure decreases at high altitudes Boiling point is lowered

Same crystal structure can have different habits, and different crystal structures can have the same habit. Why?

Because you start with the same unit cell, doesn't mean you're fixed. Can use smaller legos to make the same structure or different legos to make same structure

Positive delta H

Binding is endothermic

Negative delta H

Binding is exothermic

Negative delta G

Binding is spontaenous

Factors affecting Blood Flow: Viscosity

Blood thinners (warfarin and heparin) Hematocrit

Normal body temperature is 98.6 degrees F. What is this temp in C?

C = (F - 32) x 5/9 F = (C x 9/5) + 32 C = (98.6 -32) x 5/9 = 37 degrees C

What is the dose for opthalmic solutions?

Can't put much into eye

pH-partition hypothesis

Central assumption Hypothesis: Only unionized non-polar drugs can penetrate membrane----charged form will not cross membrane

Solubilization strategies:

Changing intrinsic solubility (or activity) Changing apparent solubility Changing solvent environment (y)

What is the pHp of 2% w/v solution of sodium phenobarbital in hydroalcoholic solution containing 15% by volume of alcohol? Solubility of phenobarbital in 15% alcohol is 0.22 % w/v. PKa of phenobarbital (weak acid) in this solution is 7.6. Molecular weight of sodium phenobarbital is 254.22 g/mole & phenobarbital is 232.23 g/mole.

Co = 0.22g/100 mL x 1 mole/232.23 g = 0.00947336692 M = Co Cs = 2g/100 mL x 1000 mL/L x 1 mole/254.22 g = 0.0786720164 M = Cs pH = pKa + log ((Cs-Co)/Co) = 7.6 + log ((0.0786720164 - 0.00947336692)/0.00947336692) = 8.46 pHp

K of o/w =

Co/[HA]w

What type of flavoring is best used to mask a bitter tasting drug?

Cocoa

What type of flavoring is best used to mask a bitter-tasting drug?

Cocoa flavoring

Consider a strong electrolyte, AgCl, at a concentration above solubility limit:

Completely dissociates AgCl (s) ===== Ag+ (aq) + Cl- (aq) Equilibrium constant: Keq = ([Ag+][Cl-])/[AgCl] = products/reactants K eq x [AgCl] = Ksp = [Ag+][Cl-] Solubility of the electrolyte is determined by its solubility product, Ksp

Weak acid, pKa less than 2

Completely ionized at all pH Very little reabsorption, relatively high renal clearance Urine pH has little effect on renal clearance

Liquefaction of Gases by Cooling

Compressed air, cooled = gas expansion = cooler gas = liquid air

Distribution

Concentration and disposition of drug at target site is influenced by its distribution

Oral absorption

Concentration in GI >> Concentration in blood

Relationship among Partition Coefficients

Concentration of drug in Solvent 1 = Concentration of drug in Solvent 2 = Concentration of drug in Solvent 3 C1 = C2 = C3, and C1 = C3 C3/C1 = C3/C2 x C2/C1 K3/1 = K3/2 x K 2/1 See slide 6 Partitioning

Boiling temperature of water is 100 degrees C at 1 atm with latent heat of vaporization (deltaHv) of 9.72 kcal/mol. Calculate the boiling point elevation of water upon adding 0.155 M NaCl at 1 atm (R = 1.987 cal/mol x K)

Concentration of ions = 0.155 x 2 = 0.31 M X2 approx = (0.31 mol/L)/55.5 mol/L deltaTb = ((RTb^2)/deltaHvap) x X2 deltaTb = ((1.987 cal/(mol x K) x (100 + 273)^2 x K^2)/9720 cal/mol) x (0.31 mol/L)/55.5 mol/L = 0.159 K = 0.159 degrees C deltaTb approx = Kbm2 Kb = deltaTb/m2 = 0.159 degrees C/0.31 mol/kg = 0.51 degrees C x kg/mole

Solid-Liquid Phase diagram

Constant Pressure See slide 6 Phase Equilibria 2

Aerosol

Contains drug in carrier liquid and propellant mixture of proper vapor pressure---we use mixtures to control vapor pressure

What is the intravascular (within the blood circulation) mass transfer of molecules due to?

Convection Blood flow & perfusion

Drug pH buffered at 7.4 & ionic strength of 0.2

Could affect equilibrium binding, pH, ionic strength, temperature

Apparent solubility of HA

Cs Cs = Co + [A-] Co = intrinsic solubility of HA = constant [A-] = concentration of anion of drug

Important properties of liquids

Density Viscosity (blood thinner, aspirin, warfarin, plavix, etc) Heat capacity Vapor pressure Boiling point Heat of vaporization

Colligative properties

Depend mainly on the number (not size) of species (ions or molecules) in a solution

Additive properties

Depend mainly on total contribution of atoms/molecules that constitute the solution

Constitutive properties

Depend on the arrangement of atoms/molecules

Paracellular transport1

Dependent on convection

Clausius-Clapeyron Equation

Describes relationship between equilibrium vapor pressure and temperature

Ionization: Henderson-Hasselbach equation

Describes relationship between pKa of ionizable drug, the pH of its surroundings and the proportion of the drug that is in its ionized form pH = pKa + log (base/acid) for weak acid: HA ===== H+ + A-

How is the choice of dosage form made?2

Desired shape of concentration-time profile Therapeutic response to a drug can be controlled by altering onset and duration of pharmacological effect This can be modified by changing shape of plasma concentration-time profile

Clapeyron Equation

Determines slope of phase boundaries dP/dT = deltaH/TdeltaV (T is always positive)

Phase diagram

Diagram that describes equilibrium phase(s) under given conditions (ex: temp, pressure, concentration)

Effects of salt on solubility

Different from common ion effect, which must have shared ion

Solute = Liquid, Solvent = Solid

Example: Viscous polymer solution

Perfusion

Expressed as vol/time/vol tissue or flow rate/vol of tissue going into (ex: mL/min/mL tissue) Blood flow to a tissue or organ (Q) given as mL/min, so: perfusion = Q/Vt Q = flow rate Vt - volume of tissue (mL)

You see patient has oral temp of 39.6 degrees C. What is it in F?

F= (C x 9/5) + 32 F = (39.6 x 9/5) + 32 = 103.3 degrees F

According to the Henderson-Hasselbach equation, two different weak acids with an identical pKa of 4.5 should be expected to have the same aqueous stability in the same pH 3 buffer (temperature constant). True or False

False

At a constant temperature, equilibrium vapor pressure of a liquid is not affected by its surface area, but is affected by volume of head space

False

Name 3 types of information in USP monograph

First: Official name (generic or brand) Second: structural formula, empirical formula, molecular weight, established chemical names, and Chemical Abstracts Service number Third: Statement of drug's purity, cautionary statement that describes toxic nature of drug, packaging and storage information, chemical and physical tests, and prescribed method of assay to substantiate the ID and purity of drug

Oral solutions generally contain

Flavorants and colorants Stabilizers Preservatives (if needed)

pH solubility profile of weak bases

For weak base, B: ex: alkylamines, alkanolamines, pyridines, quinolines, piperidines, indoles, phnothiazines B solid ===== B solution ==== BH+ + OH- Cs = Co + [BH+] pH = pKa + log [OH-]/[BH+]

Types of matter:

Gas or Condensed matter

Deposition

Gas to solid

Normality definition

Gram equivalent weights of solute in 1 L of solution

Normality examples

Gram equivalent weights of solute in 1 L of solution 1 M of NaCl solution = 1 N 1 M of Na2CO3 solution = 2 N

Percent by weight definition

Grams of solute in 100 g of solution

Percent weight in volume definition

Grams of solute in 100 mL of solution

What are pH and pOH of 5 x 10^-8 M solution of HCl at 25C?

H+ in pure water = 1 x 10^-7-------contributes to total H+ in solution H2O ===== H+ + OH- ==== contribution to H+ by water dissociation is same as OH- Total H+ concentration = y H+ concentration from water dissociation = (y - 5 x 10^-8) This is also the concentration of OH- = y - 5 x 10^-8 At equilibrium, y x (OH-) = 1 x 10^-14 y(y- 5 x 10^-8) = 10^-14 = y^2 - 5 x 10^-8y -10^14 = 0 Quadratic equation: (-b + (b^2 -4ac)^1/2)/2a (5 x 10^-8 + ((-5 x 10^-8)^2 - 4 x 1 x (1 x 10^-14)^1/2)/2*1 = 1.28 x 10^-7 = H+ concentration pH = -log [H+] pH = - log [1.28 x 10^-7] = 6.89 pH 14-6.89 pH = 7.11 pOH

Autoprotolysis of water

H20 + H20 ===== H3O+ + OH-

Phosphate buffer

H2PO4- ===== H+ + HPO4(2-) H2PO4 will crystallize out with potassium phosphate buffer solution HPO4(2-) will crystallize out with sodium phosphate buffer solution

Ka (acidity constant)

HA + H20 ===== A- + H3O+

What is the ionic strength of 0.01 M solution of salicylic acid in water? Ka = 0.00106

HA + H2O =========A- + H3O+ [A-] = [H3O+] [H3O+] = (KaCa)^1/2 = 3.256 x 10^-3 M Ionic strength = 1/2(sum of(cizi^2) ci = concentration of i ions zi = charge on ions Summation of all molecules in solution 1/2(0.003256 x 1^2 + 0.003256 x 1^2) = 0.003256

General rules for reabsorption: Weak acids

HA ===== H+ + A- As pH increases, ionization increases, and lipophilicity decreases

Buffers

Happen when compound is 50% ionized, 50% unionized----stabilize compound within 0.5 pH points from pKa in both directions

Stronger base =

Higher pKa (of conjugate acid), weak conjugate acid

Pharmaceutical advantages of amorphous materials

Higher solubility and dissolution rate Enhanced bioavailability

Advantages of Solution dosage forms

Homogenous (all in one physical phase) Drug is immediately available for pharmacological effect Can be given by any route of administration Easy to adjust the dose

Absorption

How does a drug move from site of admin to site of action? Absorption is defined as process by which a drug proceeds from site of admin (intestine or muscle) to site of measurement in body (blood) For absorption to occur, drug must cross membrane to reach blood

Duration

How long drug concentration is above MEC

Rate and extent of distribution determined by:

How well each tissue is perfused with blood Binding (affinity) of drug to plasma proteins Permeability of tissue membranes to drug

Rate of injection: venous access

IMPORTANT: Venous access controls rate of infusion If need high rates (large veins) may need to obtain central venous access (pg 436 in Ansel) Cytotoxic drugs, need high blood flow for rapid dilution (minimize irritation and pain) Hyperalimentation, TPN Central venous access obtained under anesthesia (general or local) Catheter inserted into central vein through: Arm (cephalic vein) Neck (external jugular vein) Groin (saphenous vein) Catheter emerges through skin Increased care needed due to potential for infections

Intravenous administration

IV drugs MUST be in solution Generally aqueous solution IV drugs must stay in solution Insoluble particles will lodge in capillary beds (often pulmonary), causing blockage

Hypothetical weak acid R-COOH (pKa = 4.4)

In stomach pH = 2.4 Drug is 100/1 unionized (because 2 pH units lower than pKa) Would expect significant absorption from stomach In plasma pH = 7.4 Drug is highly ionized, so it's trapped in plasma 3 units above pKa = 1000 times more ionized Intestine pH = 5.4 Unionized is only 1/10 of that ionized (1 pH unit above pKa = 10 times more ionized) In theory, should be less absorption from intestine (but there is a larger surface area ==== higher absorption)

More forced diuresis

Increase fluid intake, IV or PO, to increase urine flow Dilutes urine and decreases drug concentration, decreasing driving force for reabsorption Flow is so high, decreased time drug is in tubules, so decreased reabsorption Outcome is increased clearance

Electronegativity trends

Increases moving left to right or up in the periodic table

Routes of administration influences the concentration-time profile

Intravascular IV, intra-arterial No absorption step req to enter blood Parenteral dosage forms Injectable dosage forms Bolus, infusions

Under what circumstance(s) would an elixir dosage form be inappropriate?

It is needed to be a very precise dose and only kitchen utensils (teaspoon, tablespoon) were available to measure it out. If patient was unable to understand who to measure the dose If patient uses an elixir containing alcohol, and is taking another medication with Antabuse-like activity could become violently ill Children, alcoholics

Between diamond and graphite, which one is more stable?

It matters at what temp/pressure Graphite is more stable at room temp/pressure Diamond is stable at high pressure/high temp

Is the equilibrium vapor pressure affected by surface area or volume of head space? Slide 7 Liquids

It will not be affected by SA, since surface area has been made smaller for both escape and recapture. It will also not be affected by volume, because it will reach equilibrium after enough time

A drug is distributed in 3 immiscible solvents. If K 2/1 = 100, K 3/1 = 20, what is K 3/2?

K 3/1 = K 3/2 x K 2/1 20/100 = (K 3/2 x 100)/100 K 3/2 = 0.2

Chemical reaction proceeds to completion at 50 degrees C. What is this in K?

K = 273.15 + C 273.15 + 50 = 323.15 K

Define equilibrium partition coefficient

K = [concentration of drug in membrane/concentration of drug in cytoplasm] at equilibrium

Calculate the solubility (S) of silver chromate (Ag2CrO4) in a) pure water, b) presence of 0.04 M silver nitrate or b) 0.04 M KCrO4. The ionic strength may be neglected, and Ksp = 2 x 10^-12

Ksp can be affected by ionic strength, activity of water is affected Ag2CrO4 ====== 2Ag+ + CrO4(2-) Ksp = 2 x 10^-12 a) Water: Ksp = [Ag+]^2[CrO4(2-)] = (2S)^2 x S = 4S^3 = 2 x 10^-12 S = (Ksp/4)^1/3 = 7..94 x 10^-5 M b) 0.04 M AgNo3: Ksp = (2S + 0.04)^2 x S = (2 x 7.94 x 10^-5 M + 0.04 M)^2 x S = 0.0016 X S = Ksp S= Ksp/0.0016 = 1.25 x 10^-9 M c) 0.04 M KCrO4: Ksp = (2S)^2 x (S x 0.04 M) = 4S^2 x (7.94 x 10^-5 + 0.04 M = 0.16 x S^2 = Ksp S = (Ksp/0.16)^1/2 = 3.54 x 10^-6

What determines solubility of salt?

Ksp is constant for given salt, if drug concentration changes----solubility changes

You have been asked to formulate an amoxicillin suspension containing 250 mg of amoxicillin (as the anhydrate) per teaspoonful (5 mL). In your pharmacy, you only have the trihydrate form of amoxicillin. How much of trihydrate will you use? Total volume of suspension is 100 mL

MW anhydrous amoxicillin = 365.4 MW amoxicillin trihydrate = 419.5 250 mg amoxicillin anhydrate/5 mL x 100 mL suspension = 5000 mg amoxicillin x 1 g/1000 mg = 5 g amoxicillin anhydrate needed 5 g/365.4 g/mol anhydrous amoxicillin = x/419.5 g/mol amoxicillin trihydrate x = 5.74 g amoxicillin trihydrate

You have been asked to prepare azithromycin tablets using the dihydrate form of the API. Each tablet should contain the equivalent of 250 mg of anhydrous azithromycin. What will be the azithromycin dihydrate content in each tablet? MW anhydrous azithromycin = 748.9

MW water = 18 g Dihydrate = 2 x 18g = 36 g water + 748.9 anhydrous azithromycin = 784.9 g azithromycin dihydrate MW 250 mg/748.9 g/mol anhydrous azithromycin = x mg/784.9 g/mol azithromycin dihydrate x = 262 mg azithromycin dihydrate

Scatchard Plot

Main purpose: linearizing protein binding data for convenient plotting. r/[Df] = nK - rK = straight line equation y = b - mx Slope is K x-intercept is n = number of binding sites y intercept is nK Plot r/[Df] vs r

In Practice:

Maintain sterility: Maintain aseptic procedures with sterile solutions When preparing solutions extemporaneously use appropriate sterilization technique Membrane filters/screen filters: 1 to 200 microm thickness Pore sizes available from 0.022 microm to 8 microm Pore sizes less than 0.22 microm are considered sterilizing

Milligram percent definition

Milligrams of solute in 100 mL of solution

Percent by volume definition

Milliliters of solute in 100 mL of solution

Weak acid, pKa greater than 8

Mostly unionized through normal urine pH range If drug is non-polar, increased reabsorption, very low renal clearnace Ex: Phenytoin

Steps in Oral Bioavailability

Mouth Gut Lumen Disintegration Dissolution Absorption Liver First Pass metabolism Systemic circulation

Convection

Movement from pressure 1) Blood flow 2) Stomach emptying 3) Paracellular movement of particles Fluid flow can change the rate at which drug reaches target

Distribution

Movement of drug throughout the body Rate = how quickly drug will go there Extent = how much of drug gets there Rate and extent of distribution of drug molecules are determined by: How well each tissue is perfused with blood Binding of drug to plasma proteins and tissue components Permeability of tissue membranes to the drug

IMPORTANT: pKa value itself will

NOT tell you whether drug is an acid or a base

Equivalent weight (g/Eq) for salts examples

NaCl (g/Eq) = 23 g (Na+) + 35.5 g (Cl-) = 58.5 g/1 = 58.5 g/Eq Na2C03 (g/Eq) = (2 x 23 + 60)/2 = 53 g/Eq KH2PO4 MW = 136 KH2PO4 (g/Eq) = 136 g/1 = 136 g/Eq if K+ used KH2PO4 (g/Eq) = 132 g/2 = 68 g/Eq if H+ used KH2PO4 (g/Eq) = 136/3 = 45.3 g/Eq if PO4^-3 is used Depends what species you are looking at to determine valence

Strong electrolytes

NaCl, HCl

Disadvantages of Parenteral Therapies

Need strict adherence to aseptic procedure Pain and/or tissue damage may occur upon injection Once administered, drug can't be removed Potential for needle sticks to cause Hepatitis B or HIV infections 200,000 needle stick injuries/year in US 18,000 hepatitis cases/year due to needle stick injuries (most from re-capping) Dosage forms more expensive than preparations for other routes Parenteral drugs must be prepared under carefully controlled conditions by specially trained personnel Parenteral products must be packaged in containers that meet standards and ensure sterility is maintained. Dosage forms must be admin by trained personnel, may need other specialized devices as well as infusion pumps

Enatiotropic polymorphs

One polymorph is stable over one temp range, another polymorph is stable over a different temp range See slide 21 Solids

Plasma protein binding LIMITS distribution

Only free (unbound) drug can reach site of action Only free drug is cleared by liver, kidney Clinical assay often measure total (bound + free) drug ===Typically only measure drug in blood, not tissue

Types of colligative properties

Osmotic pressure Vapor pressure lowering Freezing point depression Boiling point elevation

What is the most important colligative property?

Osmotic pressure, because it is related to the physiological compatibility of pharmaceutical solutions, but inconvenient to measure

If 0.5 g drug in vapor state occupies 100 mL at 120 degrees C & 1 atm, what is approximate MW?

PV = nRT n = PV/RT R = 0.0821 Latm/Kmol 100 mL x 1 L/1000 mL = 0.1 L 120 + 273 = 393 K (1 atm x 0.1 L)/(0.0821 atmL/Kmol x 393 K) = 3.09930483 x 10^ -3 M 0.5 g/3.00930483 x 10^-3 M = x g/1 mol x = 161 g MW = 161 g/mol

IV administration

Parenteral solutions

Raoult's law

Partial pressure of volatile constituent (solute) is equal to the vapor pressure of the pure constituent (Po) multiplied by its mole fraction (X) in the solution

Limits on extent of distribution

Perfusion is only thing that will limit how quickly drug gets into tissue How quickly organ fills up with blood is determined by how quickly blood can get to organ What limits drug's ability to cross from blood capillaries into the cells in the tissues? Some drugs are not water-soluble enough to be in the aqueous portion of the blood These drugs may be bound to proteins in the blood, which carry the molecules throughout the body

What limits movement of drug molecules from intravascular space into target tissues?

Perfusion rate-limited movement driven by convection Protein binding in blood (plasma)

What determines shape of concentration-time profile

Pharmacokinetics Dosage regimen Route of admin Patient characteristics Dosage form

Pharmaceutical disadvantages of amorphous materials

Physical instability (tends to crystallize) Chemical instability Stability is affected by moisture content & temp

Solid dispersions: Eutectic systems

Physical mixture of 2 crystalline components (immiscible in solid state) Melting point of both together is lower than what they are apart

Three categories of solvent

Polar, semipolar and nonpolar based on dipole moment, or dielectric constant Dielectric constant is for the solvent, dipole moment is for the molecule/drug

Parenteral solutions

Prepared in the same way as non-sterile forms with following additional considerations: Solvents used as vehicles must meet special purity standards Added substances such as buffers, antioxidants, and antimicrobial preservatives fall under specific guidelines and are used only where absolutely necessary

Combination of Attractive and Repulsive forces

Rapidly decreasing positive potential energy with separation

Pharmacokinetics

Rate ======= how fast? Extent ======== how much drug?

Tie line and Lever Rule

Relative amounts of each phase can be calculated for any point in the 2 phase region of phase diagram by drawing a tie line

Water activity

Relative humidity Vapor pressure of water Phase diagram

Hepatic Clearance

Removal of parent drug by conversion to metabolites May include biliary excretion of parent and metabolites

Bronsted-Lowry classification of acids/bases

Right balance (H+ criteria, most commonly adopted) Based on proton criteria only

Give one example of commercial medicated syrup and its use

Risperidone 1 mg/mL for schizophrenia

At equilibrium, Rf =

Rr

Application of Ternary Phase diagram

Salicylic acid forms needle shaped crystals when crystallized from ethanol Extremely poor flowability makes it difficult to process using direct compression Spherical agglomerates form when a suitable amount of chloroform was added This created better compress-ability, easier for powder flow

Ionization of salts

Salt of weak acid (ex: CH3COOH) and a strong base (ex: NaOH) NaA ----- NA+ + A- complete ionization The conjugate anion base, A-, reacts with water to form the neutral acid A- + H20 ==== HA + OH-

Partition Coefficient

Same activity, a, in both phases a1 = a2 activity of drug in phase 1 = activity of drug in phase 2 Partition coefficient = K, also known as distribution ratio or distribution coefficient K of 1/2 = C1/C2 Concentration of drug in phase 1/Concentration of drug in phase 2 For octanol/water systems, Koctanol/water = P P is commonly used for defining lipophilicity of compounds

What will be the concentration of tolbutamide in the water phase of an emulsion that contains 10 mg drug, 20 mL water and 2 mL peanut oil, if the oil/water partition coefficient is about 90?

Se approx = Sw x [1 + K of o/w *(Vo/Vw)] 10 mg/22 mL = Sw x [1 + 90 x (2 mL peanut oil/20 mL water)] 10mg/22 mL/(10) = Sw = 0.045 mg/mL

The solubility of a non-ionizable drug in water is 5 mcg/mL. To solubilize this drug, an emulsion was prepared by mixing 20 mL of an oil and 80 mL of water. The K of o/w is 1.2 x 10^4. What is the maximum concentration of drug that can be dissolved in this emulsion?

Se approx = Sw x [1 + K of o/w *(Vo/Vw)] Se = 5 mcg/mL x [1 + 1.2 x 10^4 x (20 mL oil/80 mL water)] = 15000 mcg/mL x 1 mg/1000 mcg = 15 mg/mL

Classification of solids

See slide 3 Solids Molecule has a Habit (external) and internal structure

phase diagram

See slide 9 Phase equilibria 1 T1 = temperature that hits bottom of line between vapor and solid, then top of line between liquid and solid With increase in pressure; vapor goes to solid (ice) and then liquid T2 = Hits top of line between vapor and liquid With increase in pressure; vapor goes changes into liquid T3 = is above all phase changes Above critical temperature; no phase transition. Liquid does not exist

Interconversion between states of matter: Heat energy released to environment

See slide 9 on Gases Vapor condenses, leads to liquid Liquid freezes, leads to ice OR Vapor undergoes deposition to Ice

Very sensitive API formulated as freeze dried powder. API exist in amorphus state in freeze dried powder. Powder packaged in sealed glass vial & reconstituted by solution before being admin by IV. What are your responsibilities in regard to storage/use of product?

Since is injectable product, find product is sealed and doesn't come into contact with ambient atmosphere. One concern is storage temp---should be stored below glass transition temp (Tg) to decrease risk of crystallization

Molecules can be joined by:

Single bond Double bond Triple bond

Dosage regimen will affect concentration-time profile:

Size of dose

See Workshop 11 b

Slide 22 Protein binding

Sublimation

Solid to gas

Solubility of liquid in liquid

Solubility may be determined from phase diagram

Supersaturated solution definition

Solution that contains a solute at concentration higher than that of a saturated solution---solute crystallizes out Can be made by heating a saturated solution and adding more solute, then when is cooled down the solute crystallizes out of the solution (becoming 2 phases: saturated solution and solid sugar) Is unstable, excess solute tends to leave the solution (ex: forming crystals, another layer of fluid, or bubbles)---can undergo phase separation

Unsaturated solution

Solution with concentration below equilibrium solubility Is a stable, single phase system---if temp kept constant, won't crystallize

At 25C, the binding constants of econazole with B-CD and HP-B-CD are K11 = 4.08 x 10^3 M^-1 and K11' = 3.9 x 10^3M^-1, respectively. Calculate the apparent solubility of econazole in an aq solutoin containing 0.1 M B-CD and 0.008 M HP-B-CD. Intrinsic solubility of econazole in water is 1.2 x 10^-5 M.

St = So + K11 x So x [B-CD] + K11' x So x [HP-B-CD] 1.2 x 10^-5 + 4080 x 1.2 x 10^-5 x 0.01 + 3900 x 1.2 x 10^-5 x 0.008 = 5.016 x 10^-4 + 3.744 x 10^-4 = 8.76 x 10^-4

B-CD is used to solubilize miconazole. What is the minimum concentration of B-CD required to prepare a 1 x 10^-5 M aq solution of miconazole? The intrinsic solubility of miconazole is 5.4 x 10^-7 M in water and the binding constant between miconazole and B-CD is 4.2 x 10^3 M^-1

St = So + K11 x So x [CD] 1 x 10^-5 M- 5.4 x 10^-7 M = 5.4 x 10^-7 M + 4.2 x 10^3 M x 5.4 x 10^-7 x [CD] - 5.4 x 10^-7 M (9.46 x 10^-6)/2.268 x 10^-3 = (2.268 x 10^-3 x [CD])/2.268 x 10^-3 = 0.0042 M

Different properties of polymorphs

Stability (chemical/physical) Apparent solubility Absorption (rate and extent) Melting point Density Mechanical properties Crystal habit Optical properties (color)

Hypothetical weak base R-NH2 (pKa = 10 for conjugate acid)

Stomach pH = 2 8 pH units under pKa = 10^8 times more ionized molecules than neutral Plasma pH = 7.4 2.6 pH units under pKa = 10^2.6 more ionized than neutral Intestine pH = 6 4 pH units under pKa = 10^4 more ionized molecules than neutral One would predict very poor absorption in both intestine and stomach because of high ionization at both sites

Characteristics of membrane: Surface Area

Stomach relatively unimportant for oral drug absorption Small intestine is most important absorptive organ for majority of drugs and dosage forms Why? Surface area of human small intestine is at least 100 m^2 (approximately size of football field) Surface area in small intestine is 10 x that of stomach Large surface area in intestine due to villi and microvilli Surface area of intestine 600 x greater than that present if intestine was a smooth tube

Syrups are concentrated aqueous preparations of a sugar or sugar-substitute with or without added flavoring agents and medicinal substances

Sugar, usually sucrose (60 to 80%) or sugar substitutes, for sweetness & viscosity Sugar may be substituted for by a polyol, such as sorbitol, or a mixture of polyols such as sorbitol and glycerin (for diabetic patients) Anti-microbial preservatives (not needed if sugar content is high) Bacteria needs water to grow, and with high sugar content, there isn't enough water for bacteria to grow Flavorants Colorants

Apparent solubility definition

Sum of all species of drug in solution---anions counted in this kind Total amount of drug (unionized/neutral) in solution

What is partitioning?

The distribution of a solute between 2 immiscible phases Preference of a solute for one phase over another Partitioning is an equilibrium process Activity (or effective concentration) of the solute is the same in both solvents

E value of dexamethasone sodium phosphate is 0.17 (at 1%)

The osmotic pressure of 1 g of dexNaPhos is equivalent to 0.17 g NaCl Because 0.9 g/100 mL of NaCl is isotonic with blood, then a 1% (1 g/100 mL) solution of DexNaPhos is hypotonic (it is "short" by 0.9 - 0.17 = 0.73 g of NaCl) How much NaCl should we add to 1% DexNaPhos to make it isotonic? 0.73 g

The amorphous material always has a higher free energy than their crystalline counterparts

True

Transcellular

Two pathways: 1) Diffusion through lipid bilayer---molecule must have "lipid-like" character 2) Carrier mediated transport

What means can be used to make dosage forms easier to use in elderly patients?

Use a liquid form Crush medicine & put in applesauce

Isotonic Solution Method (V-Values)

V value: volume of water needed to make 0.3 g of drug isotonic Some tables are for 1 g of drug For DexNaPhos, the V value is 18.9 mL To make 100 mL of 1% DexNaPhos solution, add 18.9 mL of water to 1 g drug and qs with an isotonic solution (ex: 0.9% NaCl)

When rate of condensation = rate of vaporization

Vapor becomes saturated The corresponding pressure is called equilibrium vapor pressure

Air bubble is blown by fish at bottom of aquarium tank & rises to surface. Volume increases as pressure in bubble decreases. Bubble has radius of 0.1 cm at bottom of tank where pressure is 1.3 atm & temp is 14 degreees C. At surface of tank, pressure is 750 torr and temp is 27 degrees C. What is the radius of the bubble at the surface?

Volume of sphere = 4/3 x pi x r^3 1 atm = 760 torr 750 torr x 1 atm/760 torr = 0.986842105 atm 273 + 14 = 287 K 273 + 27 = 300 K PV = nRT n & R constants P1V1/T1 = P2V2/V2 (1.3 atm x (4/3 x pi x (0.1 cm)^3)/287 K = (0.986842105 atm x (4/3 x pi x r^3))/300 K Multiply both sides by (300 K/0.986842105 atm) and cancel out 4/3 x pi on each side (1.37700348 x 10^-3)^1/3 = (r^3)^1/3 r = 0.111 cm

Protein binding sites in Plasma

When drug is bound to protein, chemical potential is reduced, so drug does not want to leave the protein and go into the tissue Albumin 60% of total serum protein Binds many drugs, especially weak acids alpha1-Acid Glycoprotein 0.4 to 1% of serum protein Concentration affected by disease, trauma Binds weak bases Lipoproteins (HDL, LDL, VLDL) Red Blood Cells (RBCs)

Methanol

Will blind you, then kill you if ingested

X2ideal(ideal solubility) =

X2y2 X2 = real solubility (in mole fraction) of solute y2 = activity coefficient

Can delta H of solution be a negative value?

Yes, because it is the slope

Does delta H of solution depend on solvent?

Yes, because of different interactions

Can supercritical fluid be a solvent?

Yes, but not used for pharmaceutical systems

Can a solid have a vapor pressure?

Yes, ex: ephedrine Used as a stimulant and for treating hypertension asssociated with anesthesia See slide 19 Colligative Properties Solutions

Is the solubility of a salt in water always higher than its parent drug?

Yes, in most cases. Ions tend to interact with water more strongly. Takes energy to take ions away from crystals of parent drugs.

At pH = pKa

[HA] = [A-] Cs = 2 Co log(Cs/Co - 1) = 0

Cw =

[HA]w + [A-]w

Non-ideal solubility (regular solutions) equation

a2 = X2ideal = X2 x y2 X2ideal = ideal solubility a2 = activity of solute X2= real/non-ideal solubility (in mole fraction) of solute y2 = activity coefficient of solute ( = 1 for ideal solution) y2 reflects intermolecular interactions in solution

Passive diffusion1

absorption rate directly proportional to concentration at absorption site

Membrane structure influences

absorption through interactions with drug molecule

Weak electrolytes

acetic acid----Ionic equilibria

Higher pH levels, for acids

acid is more ionized

Acidic drugs will be less soluble in _____ solutions and more soluble in _____ solutions

acidic, basic because their protons will react with anions more easily

Solutions must be free of chemicals or agents that cause

allergies or toxicities

Proteins and phospholipids each have hydrophilic and lipophilic characteristics. This is why they are known as

amiphatic molecules

X1 and X2

are their respective mole fractions

Parenteral medications

are used for systemic effects

acewulfame potassium

artificial sweetener

neotame

artificial sweetener

potassium acesulfame

artificial sweetener

saccharin sodium

artificial sweetener

Weak acid HA===== H+ + A-

as pH increases, ionization increases, lipophilicity decreases Greater transport rate at low pH, less transport rate at high pH

Pharmacological activity means

biochemical or physiological effect that is elicited by a drug molecule (Activity can be desired activity (lowering BP) or toxic one (dizziness))

At same pressure, for compounds,

boiling point and heat of vaporization (deltaHv) are indications of magnitude of attractive forces

Crystalline solids with a nonstoicioometric inclusion compound can be a

channel layer cage

Salt of a weak base B (ex: NH3) and a strong acid (ex: HCl)...

completely dissociates in water BHCl ------ BH+ + Cl- The conjugate acid, BH+, reacts with water to form the neutral base. BH+ + H20 ===== B + H3O+ Final solution is acidic

Non-electrolytes

compound that does not ionize when dissolved in solvent

Electrolyte

compound that ionizes when dissolved in a solvent

Gas can be _______ or ________ into a liquid

compressed or cooled See slide 4 Liquids

Minimum effective concentration (MEC)

concentration in the plasma that must be reached in order for pharmacological response to be achieved

Cb =

concentration of neutral molecule + concentration of ions

What are units of Ksp?

concentration units

Parenteral dosage regimens influence

concentration-time profile See slide 35 Intravascular Admin

Two drug characteristics that will decrease rate of absorption across membrane are

decrease in drug concentration outside membrane, increase in size of drug molecule

For an acid, as pH decreases, % ionization

decreases

Calculate the relative vapor pressure lowering at 20 degrees C for a solution containing 171.2 g sucrose in 100 g water. The molecular weight of sucrose is 342.3 and the molecular weight of water is 18.02 g (vapor pressure of water at 20 degrees C is 17.54 mmHg)

delta(p1) = - p1^o x X2 X2 = n2/(n2 + n1) = 171.2 g/(342.3 g/mol)/((171.2 g/342.3 g/mol) + 100 g/18.02 g/mol) X2 = 0.5/(0.5 +5.5) = 0.083 delta p1 = -17.54 mmHg x 0.083 = 1.46 mmHg Vapor pressure is lowered by 1.46 mmHg

Gibbs free energy equation

deltaG = deltaH - T x deltaS delta H = enthalpy (heat of system) deltaS = entropy (disorder of system) T = temp in K

deltaHsub =

deltaHf + deltaHvap

Considering the solubility of a crystalline drug in liquids, which of the following statements is false? a) the ideal solubility is independent of solvent b) the ideal solubility is affected by temperature c) the activity coefficient is affected by solvent d) the activity is not affected by solvent e) none of the above

e) none of the above

Some drug molecules are very sensitive to

environment and need to be protected Some drugs are sensitive to oxygen or humidity Some drugs very sensitive to acidic environment

At equilibrium, the concentration of unionized species is

equal on both sides of barrier Applies only to passive diffusion

Gas molecules are very far apart/close most of the time

far apart

Have a headache

fast absorption rate

Gas molecules move faster/slower at higher temperatures

faster

flavors

flavoring

General Solubility Equation

for nonelectrolytes in water at 25C MP = melting point (not applicable for liquid)----affected by lattice strength Kow = coefficient of drug interactions between oil and water---tells how well drug reacts in water Swsolid = solubility of solid in water Strong the lattice energy (crystals holding together), higher temperature it takes to melt

xanthan gum

for viscosity

Highly bound drug

fu < 0.1

Fraction of unbound in plasma (fu) or "free fraction"

fu = Cu/C Cu = concentration of unbound (free) drug C = concentration of total drug (bound & free) 0 < fu < 1 % unbound = fu x 100

Drug A has Cu of 0.04 mcg/mL and C of 20 mcg/mL Drug B has Cu of 0.04 mcg/mL and C of 0.1 mcg/mL Drug C has Cu of 0.1 mcg/mL and C of 0.1 mcg/mL Calculate the free fraction (both as fraction and as a %). Which drug would you expect to enter tissues to the greatest extent?

fu = Cu/C fu % = Cu/C x 100 0.04/20 = 0.002 x 100% = 0.2% for Drug A 0.04/0.1 = 0.4 x 100% = 40% for Drug B 0.1/0.1 = 1 x 100% = 100% for Drug C Since Drug C is not at all bound to protein in plasma, you would expect it to enter tissues to ther greatest extent

Weakly bound drug

fu > 0.8

Solid has

high density high order very low molecular mobility/freedom

Liquid has

high density medium order low molecular mobility/freedom

Ideal solubility in phase 1 must equal

ideal solubility in phase 2

Some solutions are considered

ideal solutions (ex: dilute solutions that contain non-volatile solute)

Polar molecules tend to line up

in the direction of the electric field

Parenteral dosage form regimens

influence concentration-time profile

Gases have an

inhalation propellant (drug delivery)

Can use gases to manufacture

injectable drug products (freeze drying)

Parenteral ("not by intestine") solutions are

injected through one or more layers of skin

Protein purification: Different proteins respond to change in solution _______ differently

ionic strength (different Ks)

Extent of ionization of weak acid at any given pH can be calculated from...

ionization constants (Ka or Kb) of acids and bases

Enthalpy (deltaH)

is measure of heat of system Negative deltaH = heat released from system = exothermic Positive deltaH = heat absorbed by system = endothermic

By focusing on the atomic structure of mater & understanding the attractive and repulsive forces between atoms & molecules & presence of thermal energy...

it is possible to explain nearly all the bulk properties of gases, liquids, and solids in terms of relatively simple models

The vapor pressure of water at 25 degrees C is 23.8 mmHg. Average heat of vaporization between 25 degrees C and 40 degrees C is 10,400 cal/mole. Using Clausius-Claperyon eq, calculate vapor pressure at 40 degrees C.

ln (P2/P1) = (deltaHv/R) x (1/T1 - 1/T2) R = 1.987 cal/molK 25 + 273 = 298 K 273 + 40 = 313 K 1 mole H2O = 18 g ln (P2/23.8 mmHg) = (10,400 cal/mol)/(1.9872 cal/molK) x (1/298 K - 1/313 K) Take e^(both sides) P2/23.8 mmHg = 2.3197794 P2 = 55.2 mmHg

The vapor pressure of water is 78 cmHg at 100 degrees C. The heat of vaporization of water is 9800 cal/mole. What is the approximate vapor pressure of water at 90 degrees C?

ln(P2/P1) = (deltaHv/R) x (1/T1 - 1/T2) R = 1.987 cal/Kmole T1 = 273 + 90 =363 K T2 = 273 + 100 = 373 K P2 = 78 cmHg Hvap = 9800 cal/mole ln(78 cmHg/P1) = (9800 cal/mole/1.987 cal/Kmole) x (1/363K - 1/373K) e^ln(78 cmHg/P1) = e^0.364261064 78 cmHg/P1(P1) = 1.43944995(P1) 78cmHg/1.43944995 = 1.43944995 x P1/1.34944995 = 54.2 cmHg

Opthalmic solutions are used for

local pharmacological effects

Setschenow's equation

log(S) = log(So) - Ksc So = solubility of drug in pure water Ks = salting constant (negative for salting in) C= molar salt concentration (mol/L) Ks is unitless

Activity coefficient (yi) =

log(yi) = - Azi^2 x (ionic strength)^1/2 A = constant zi = charge on ion

Thermal motion tends to

maintain disorder

Small intestine is usually

major site of drug absorption

Well perfused tissues take up drug

more rapidly than poorly perfused ones

Nasal solutions

most often used as decongestants Most are aqueous preparations

Large intestine has very irregular mucosa and

much lower surface area May only be important for drugs which are largely unabsorbed in small intestine

Cell type with leakiest tight junction

muscle

Hematocrit is defined as fraction of blood volume made up of cellular fraction (about 99% of cells are red blood cells) and is approximately 40% in adult humans. In people with polycysthemia, the hematocrit can rise to 60 to 70%. In these patients, the blood viscosity can increase to 0.1 poise. For the capillary in question above, what will blood flow rate be in patient with polycythemia?

n = 0.1 poise = 0.1 dyne x sec/cm^2 Q = (pi x r^4)/8n x [delta P/L) (pi x (0.0012 cm)^4 x 26662 dynes/cm^2)/(8 x 0.1 dyne x sec/cm^2 x 0.32 cm) Q = 6.77 x 10^-7 cm^3/sec x 60 sec/min = 4.07 x 10^-5 mL/min. With increased hematocrit in polycythemia, the blood flow through the capillary is decreased 40%.

Vapor pressure of pure CFC 11 (MW = 137.4) at 21C is p11^o = 13.4 psi and that of CFC 12 (MW = 120.9) is p11^o = 84.9 psi. For 50:50 mixture (by gram weight) of the 2 propellants, what is the partial pressure of CFCs 11 and 12? What is the total vapor pressure of this mixture?

n11 = 50g/137.4 g/mole = 0.364 mole n12 = 50g/120.9 g/mole = 0.414 mole n11 + n12 = 0.778 mole X11 = 0.364 mole/0.778 total moles = 0.468 mole fraction CFC 11 p11 = p11^o x X11 =13.4 psi x 0.468 =6.27 psi = partial pressure CFC 11 X12 = 0.414 mole/0.778 total moles = 0.532 mole fraction CFC 12 p12 = p12^o x X12 = 84.9 psi x 0.532 = 45.2 psi partial pressure CFC 12 P = p11 + p12 = 51.47 psi total vapor pressure of mixture

A liquid mixture of 2 compounds, pawlentol and frankenol, is known to phase separate at room temp, with the resulting phases consisting of 20% weight frankenol (phase A) and 90% weight frankenol (phase B). If one mixed up a batch of 50 g pawlentol and 50 g frankenol, what will be the weight of the frankenol-rich liquid (phase B) at equilibrium?

naIa = nblb or na/nb = Ib/Ia n = weights of different phases I = distances along horizontal tie line that cross point of interest Weight of phase A/Weight of phase B = length(Ib)/length(Ia) Phase A = 20% Phase B = 90% (90-50)/(50 - 20) = 4/3 4 parts A for every 3 parts of B 7 parts total 100 g total x 3/7 = 42.9 g

Laughing gas

nitrous oxide (N2O)

For ideal solution...

no heat is generated or consumed

If pressure is fixed (ex: 1 atm), then pressure is

no longer a degree of freedom, and F = C - P + 1 Same is true for temperature (if it is fixed, is no longer a degree of freedom)

Real solutions are...

non-ideal. y2 is used to account for difference y2 = activity coefficient a2 = X2y2 a2 = activity X2 = non-ideal solution (in mole fraction)

Common ions drive the equilibrium towards _______, thus resulting in substantial ______ in solubility of the salt.

non-ionization, decrease

Drug molecules are mixed with variety of

non-medical ingredients that serve various specialized functions These are called pharmaceutical ingredients or excipients

Fatty acid

non-polar portion of phospholipid

Crystalline solids that have a molecular complex can be

nonstoichiometric inclusion compounds or stoichiometric (solvates/hydrates/salts/cocrystals)

Crystal hydrates (ex: amoxicillin 3H2O) are

one component since amoxicillin and water are not independent (their concentrations are related)

Partially miscible systems

one or 2 layers depending on total compositions of the system

The vapor pressure of pure propellant A at 21 C is 13.4 psi & that of propellant B is 84.9 psi. What is the total vapor pressure of a mixture containing 8 moles of A and 2 moles of B?

p1 = po x X2 Mole fraction A = 8 moles A/(8 moles A + 2 moles B) = 0.8 mole fraction A x 13.4 psi = 10.72 partial pressure A Mole fraction B = 2 moles B/(8 moles A + 2 moles B) = 0.2 mole fraction B x 84.9 psi = 16.98 partial pressure B 10.72 partial pressure A + 16.98 partial pressure B = 27.7 psi total vapor pressure of mixture

If pH of solution of strong base is 8.75, what is the hydroxyl [OH-] ion concentration? What is the hydrogen [H+] ion concentration?

pH + pOH =pKw = 14 14 -8.75 pH = 5.25 pOH pOH = - log [OH-] 5.25 = - log [OH-] 10^-5.25 = 10^log [OH-] [OH-] = 5.62 x 10^-6 pH = - log [H+] 8.75 = - log [H+] 10^-8.75 = 10^log [H+] [H+] = 1.78 x 10^-9 or divide Kw (1 x 10^-14) by [OH-] 1 x 10^-14/5.62 x 10^-6 = [H+] = 1.78 x 10^-9 = [H+ concentration]

Convert pH = 2.54 to hydrogen ion concentration, [H+]

pH = - log [H+] 2.54 = - log [H+] 10^-2.54 = 10^log [H+] = 2.88 x 10^-3 = H+ concentration

For pure water @ 25C, pH =

pH = - log [H+] = - log [1 x 10^-7] = 7 log 10 = 7

Anhydrous citric acid

pH adjustment (NOT a buffer)

Citric acid, anhydrous is for

pH adjustment (NOT a buffer)

What determines ionization behavior?

pH and pKa

Ionization of weak acids

pH and pKa are known % Ionized = 1/(1 + 10^(pKa- pH)) x 100%

The crystallization of a buffer component during cooling leads to...

pH change

Ionization, K of o/w and reabsorption

pH hypothesis says that unionized form of drug is more lipophilic and more likely to cross membrane

Ionization depends on the

pH of the medium surrounding the drug, and the pKa of the drug

What determines the extent of this reaction? A- + H20 ===== HA + OH-

pH of the solution, can determine H+ [H+][OH-] = 10^-14

If put weakly acidic drug into water without a buffer...

pH would change and degree of ionization would change

Ionization of salicylic acid, pH = 3

pKa = 3 What is % ionization when pH = 3 (pH = pKa)? % I = 100%/(1 + 10^(pKa-pH)) = 100%/(1 + 10^0) = 50 %

When compound is 50% ionized...

pKa = pH

When molecule crosses between cells, considered to go through the _____________ route across barrier

paracellular

p1 and p2 are the

partial pressures of the solvent and the solute, respectively

For an ideal solution (that contains 2 species) the total vapor pressure is linearly related to the

partial vapor pressure and the mole fraction of the constituents (Raoult's Law) p1 = p1^o x X1 p2 = p2^o x X2 p = p1 + p2

Low dielectric constant of organic solvents limits

partitioning of A- into organic phase

Boric acid and some other agents (ex: urea, ammonium chloride, alcohol, glycerin) will

penetrate RBC's plasma membrane As a result, these compounds cannot be used for tonicity adjustment for IV injections Can still be used for preparing pharm solutions for nose and eye treatments (difficult membranes)

Typically deltaV melt is greater than 0 (solid is less dense than liquid), this the slope of the melting line is

positive Ice water is an exception, liquid water is more dense than ice

Phase behavior with changing temp at constant pressure can be

predicted from phase diagram

Drugs with a short shelf life in solution must be...

prepared from a powder on request (compounding)

Edetate disodium

preservative

Methylparaben is for

preservative

sodium benzoate

preservative (works best in acidic conditions, which may be one reason for citric acid in solution)

Many patients are sensitive to the

preservatives and antioxidants used in opthalmic solutions

Absorption

process by which drug proceeds from site of admin (intestine or muscle) to site of measurement in body (blood)

Because the freezing point depression depends only on the __________ and the ____________, then the freezing point depression is a ________ of solution

properties of the solvent, mole fraction of the solute, colligative property

Ionization of weak acids, Ka: Rate of reaction is ______ to the product of ______ of the participating molecules

proportional, concentrations

Boiling point elevation equations (Clapeyron Equation & Raoult's law)

remove the negative sign because vapor pressure of solution is increased at elevated temperature

At the freezing point

since 2 phases are in equilibrium, escaping tendency between liquid and solid is the same (ex: solid to liquid = liquid to solid)

Ideal solution behavior can be expected for components that are similar in _____ and _________

size, intermolecular reactions

If molecule has relatively low octonal to water partition coefficient, you could expect its passive diffusion across membrane to be

slow

Various tissues serve as depots of the drug for

slow elimination after final dose is taken

Diffusion is much

slower than convection

When drug molecules bound more tightly together, Ksp is....

smaller----lower solubilty

Components =

smallest number of independent chemical constituents by means of which composition of every possible phase can be expressed

Tonicity adjusters

sodium chloride, sodium nitrate, sodium sulfate, boric acid

Heat of fusion (delta Hf)

solid to liquid at melting point

As temp increases, sequence at 1 atm is usually

solid-----liquid-----gas

Suppositories must remain ______ at room temp & __________ at body temp

solids, melt

Solubility of a drug in water is NOT equal to...

solubility of drug in ethanol They have different activity coefficients

For completely immiscible systems...

solubility of one in another is negligible (ex: oil & water)

Biological fluids can contain a common ion and therefore the _______ of the drug and ______ can be reduced

solubility, pH effect

Molal solution or one molal solution

solution contains one mole of solute per 1000 g (1 kg) of solvent

Isotonic

solution has equal concentration to inside red blood cells

Hypertonic

solution has greater concentration than inside red blood cells

Hypotonic

solution has less concentration than inside red blood cells

Water for Injection is for

solvent

deionized water

solvent

purified water

solvent

pKa is affected by...

solvent Ex: phenobarbital: in water, pKa = 7.41 phenobarbital: in 30% v/v alcohol, pKa = 7.92

Strength of acid or base varies with _____

solvent (HCL in water vs. in glacial acetic acid)----HCl in water is a strong acid, but in glacial acetic acid is a weak acid

Osmosis is the

solvent migration across a semipermeable membrane that allows the solvent (but NOT the solute) molecules to pass through (measured as osmotic pressure)

Emollient is

something that smooths or softens

Molarity is ____ dependent because volume of solution is ____ at higher ______

temperature, larger, temperatures (thermal expansion)

Degrees of freedom are the number of variable factors, such as __________, which need to be fixed in order that the condition of a system at equilibrium may be defined

temperature, pressure and concentration

Provided molecules of gas take up only small fraction of container volume, the ideal gas law relates

temperature, pressure, volume and number of moles of gas

Kw is affected by ______

temperature----as temperature increases, so does Kw

The way a dosage form is designed has a direct relationship to

the pharmacological effect that is needed

For an ideal gas mixture, the total pressure of a gaseous mixture is equal to

the sum of the pressures of the constituent species (Dalton's Law)

Boiling point is

the temp at which saturated vapor pressure of liquid is equal to the surrounding atmospheric pressure

Crystalline solids are

unit cells

Topical tinctures

usually employ an alcoholic solvent

The most stable polymorph has the lowest Gibb's free energy, thus the lowest:

vapor pressure solubility chemical reactivity (reaction rate)

Cs = [HA] + [A-]

varies with pH

A salt may have _____ _______ properties than its parent drug

very diffferent

Mineral oil is...

very nonpolar

Water is...

very polar

Blood flow is most sensitive to changes in

vessel diameter (2 x r), since r is raised to 4th power

Extent of distribution measured by

volume of distribution

Molecules of vapor exert pressure on

walls of container (vapor pressure)

As pH increases, lipophilicity increases

weak base

Crystal Habit (Morphology)

what is seen in the crystal

Freedom from Particulate Matter

"particulate matter" defined as mobile, undissolved substances in parenteral products Extraneous material found in parenterals have included: cellulose and cotton fiber glass, rubber, metal, plastic, rust undissolved chemicals dandruff, etc

Ionization of weak bases

% Ionization = 100%/(1 + 10^(pH-pKa))----switched from acid equation

Percent by weight symbol

% w/w

H-H equation: [A-]w =

(10^(pH - pKa)) x [HA]w

Flow =

(diffusion coefficient/membrane thickness) x change in concentration (D/h) x deltaconc

Strong acid (in water) examples

(in descending strength) HI > HBr > HCl > H2SO4 > HNO3

Solutions should have equivalent tonicity of

0.9% NaCl

States of drug in blood

1) Free drug = pharmaceutically active and reach targets 2) Protein + drug = protein bound drug not active See slide 2 Protein Binding

Dissolution Enhancement Methods

1) Gentle heating----however, some drugs degrade at high temperature (lost potency and increased toxicity), change in composition by evaporation of volatile components (ex: alcohol) 2) Particle size reduction---smaller particles have larger surface area for given amount of drug 3) Use solubilizing agents 4) Using agitation

Processes affecting renal clearance

1) Glomerular filtration (hydrostatic pressure) 2) Tubular secretion (usually active) 3) Tubular reabsorption (usually passive) IMPORTANT 4) Urinary flow (convection) See slide 62 Extravascular Admin

Common drug anions

1) Hydrochloride-----48.2% 2) Sulfate-------7.5% 3) Bromide------6.6% 4) Citrate------3% 5) Tartrate-----3.5%

Drug protein interactions

1) Hydrophobic = dominates 2) Electrostatic 3) Chelation 4) Donor-Acceptor

Common drug cations

1) Sodium-----62% 2) Potassium-----10.8% 3) Calcium-----10.5% 4) Zinc------3%

Degree of ionization depends on:

1) pH 2) pKa

Theophylline monohydrate: theophylline & H2O = ? components

1, there is water in it at a defined ratio

To prepare 10 tablets (so that each tablet contains 100 mg of anhydrous amoxicillin, MW 365.4), how much amoxicillin trihydrate (MW 419.5) is needed?

100 mg anhydrous amoxicillin x 10 tablets = 1000 mg total needed 1000 mg anhdrous amoxicillin/365.4 mg/mmole = x mg amoxicillin trihydrate/419.5 mg/mmole 1000 mg anhydrous amoxicillin x 419.5 mg/mmol amoxicillin trihydrate = x mg amoxicillin trihydrate x 365.4 mg/mmol anhydrous amoxicillin (1000 mg anhydrous amoxicillin x 419.5 mg/mmol amoxicillin trihydrate)/365.4 mg/mmol anydrous amoxicillin = x mg amoxicillin trihydrate = 1148 mg amoxicillin trihydrate needed

MW of water

18

36"

36 in x 2.54 cm/1 in = 91 cm

Added substances for parenteral products

Antibacterial preservatives Benzyl alcohol Chlorobutanol Methyl or propyl parabens Adjustment and maintenance of appropriate pH Buffers (ex: citric acid/sodium citrate) and pH-adjusting agents (ex: hydrochloric acid or sodium bicarbonate)---added because product has specific pH range it must meet===not considered buffers Solubilizers, solvents, co-solvents Ethanol, glycerin, etc Antioxidants --presence is a clue that drug is sensitive to oxidation sodium metabisulfite sodium bisulfite ascorbic acid edetate sodium (EDTA) (chelating agent)

Characteristics of drug molecule: size of molecule (molecular radius)

As radius (r) of molecule increases, it becomes more difficult for the molecule to diffuse through membranes

Distribution of bases

BH+ ====== B + H+ Fraction unionized [B]/[B]total = 1/(1 + 10^(pKa-pH)) See slide 11 Partitioning

Solute = Gas, Solvent = Gas

Example = Air

One-component system Slide 6 Phase Equilibria Part 1

F = C - P + 2 C = 1 F = 3 - P P = 1 : Single phase (gas, liquid, or solid) F = 3 - 1 = 2 P = 2: Phase boundary F = 3 - 2 = 1 P = 3: Triple point F = 3 - 3 = 0

How many degrees of freedom are there in the 2 phase region of the phenol-water phase diagram (at 1 atm)?

F = C - P + 2 C = 2 P = 2 With pressure given, 2 becomes 1 F = 2 - 2 + 1 = 1

Weak acid, pKa 3 to 7.5 (range of pH values of urine)

Favorable equilibrium for reabsorption of unionized form Renal clearance is pH sensitive

What is a Hickman catheter used for?

For giving drugs by a central vein (superior vena cava), not implanted subdermally---usually at the abdomen, after catheter tunneled under abdomen and chest

Why do we need to make a salt?

For injection, etc

When must drug molecules be in solution?1

For intravascular routes of admin (IV, intra-arterial)

Sterilty

Freedom from all living organisms "Sterile" is an absolute term: no such thing as "partially" or "almost" sterile Sterility of parenteral assured by: Initially subjecting product to valid sterilization procedure Proper packaging Use of aseptic technique by clinicians during preparation and admin of product

Water phase next to oil phase

H+ + A- ===== HA ==== HA === (HA)n Cw = [HA]w + [A-]w Co = [HA]o + n[HA]n

Effect of pH on ionization (acid)

HA + H20 ====== H3O+ + A- acid 1 base 2---- acid 2 base 1 HA ====== H+ + A- Ka = ([H+][A-])/[HA] pH = pKa + log ([A-]/[HA]) HA = acid A- = base

Acid-Base equilibria examples

HA + H20 ======= A- + H3O+ acid 1 base 2--- base 1 acid 2 B + H20 ======== BH+ + OH- base 1 acid 2----acid 1 base 2

Solubility of solid in liquid

Heat of solution (delta H solution): solid-----solution Solid + solvent (dissolution)----liquid----solution Solid to liquid = fusion Liquid to solution = mixing Heat of solution = Heat of fusion + heat of mixing Heat of fusion (delta Hf): solid----liquid at melting point Heat of mixing (delta Hmix): heat generated when mixing 2 liquids

Should pH be high or low to keep a weak acid in solution?

High pH

Dipole induction

Increases with number of electrons in a molecule Decreases when electrons are tightly bound to nucleus Does not depend on temperature

Diseases related to solubility, Gout

Inflammation and pain in joints: caused by crystallization of uric acid in joints, tendons and surrounding tissues due to elevated levels of uric acid in blood

K of o/w, Octanol/water partition coefficient

Influenced by lipophilicity, ionization

S, Surface Area

Influenced by location in GI tract

Why do the boiling points of noble gases at 1 atm differ?

Intermolecular forces are broken to go from liquid to a gas Large molecules have more dispersion forces, and takes more energy to get them to boil

Cout, Concentration of drugs in GI lumen or renal tubule

Is solubility and dosage form dependent

How does ionization of drug molecule affect its binding with Cyclodextrin, CD?

It will not bind as strongly, because drug will now be polar

Single Crystal X-ray Diffraction

It's possible to determine the unit cell composition from the position and intensity of the spots

The solubility product of a calcium salt, CaA2 , of a drug, A, is 1 x 10^-9 (mol/L)^3 in water. The concentration of the drug ion, A-, in a saturated solution in water is:

Ksp = [Ca(2+)][A]^2 = 1 x 10^-9 M^3 2 A = 1 Ca S x (2S)^2 = 1 x 10^-9 M^3 ((4S^3)/4)^1/3 = (((1 x 10^-9 M^3)/4)^1/3) S = (6.2996 x 10^-4) = concentration of Ca x 2 = concentration of A- = 1.26 x 10^-3 M = concentration of A-

Unit cell parameters

Lengths (a, b, c) Directions (alpha, beta, and gamma angles)

Weak base at high pH

Less drug is ionized

Elixirs are clear, sweetened hydroalcoholic (contains water and alcohol) solutions intended for oral use; are usually flavored

Less sweet, less viscous than syrups Don't tastes as well as syrups Better able to solubilize medicinal agents than syrups (because of alcohol content) Contain 5 to 20% alcohol Sometimes use co-solvents, such as glycerin and propylene glycol Sometimes contain sweeteners like sorbitol or artificial sweeteners (due to high alcohol content) Colorants, flavorants If alcohol content is greater than 10 to 12%, don't need a preservative

Solubility in an emulsion

Let Se, Sw, So be solubilities in emulsion, water and oil phases, repspectively Volume balance: Ve = Vw + Vo Mass balance: mass emulsuion = mass water + mass oil Se = mass emulsion/Ve = (mass water + mass oil)/(Vw + Vo) Se approx = Sw x [1 + K of o/w *(Vo/Vw)]

Pharmacy example of eutectics

Lidocaine (Tm = 68 degrees C) & Prilocaine (Tm = 38 degrees C), both solids at room temp Put together, add emulsifier, surfactant water = eutectic temp = 16 degrees C (61 degrees F)

Pharmaceutical solutions

Liquid preparations that contain one or more chemical substances dissolved in a suitable solvent or mixture of mutually miscible solvents

Changing intrinsic solubility (or activity)

Lower solubility to Higher solubility 1) Salts 2) Particle size reduction---surface area is increased when particle size decreased 3) Polymorphs 4) Amorphous solid dispersions 5) Co-crystals

Molarity symbol(s)

M, c, or mole/L

In practice, source of particulates

Manipulations involved in preparation of product for administration Glass from opening ampul Rubber particles from piercing septum of vial with needle Avoid by filtering product During admin of product Sets, syringes, devices Avoid by using in-line filter

Dosage regimen will affect concentration-time profile

Many drugs are given on a chronic basis rather than as a single dose The manner in which the drug is given will affect concentration-time profile

Molality definition

Moles of solute in 1000g (or 1 kg) of solvent

Why are the boiling points of N-N, O-O, N-O and H2O different at 1 atm? N-N = 77 K O-O = 90 K N-O = 121 K H2O = 373 K

O2 is heavier than N2, that's why boiling point is higher N-O has a permanent dipole, raising boiling point H20 has hydrogen bonding, can bond with 4 hydrogens, raising boiling point

Calculating phase compositions

See slide 16 phase equilibria 2 One phase---2 phases----one phase Within the 2 phases: first phase is 11% phenol (89% water) second phase is 63% phenol (37% water)

Osmotic pressure (II) is given by:

Van't Hoff equation: II = RTc c = concentration in mol/L (molarity) 1) II depends on concentration, but not solute type 2) Valid for dilute solutions (or ideal solutions) Morse equation: II = RTm m = concentration in mol/1 kg of water (molality)

Can delta H of fusion be a negative value?

Yes, if the liquid solidifies

Cw^o = (again)

[HA]w + [A-]w + Vo/Vw x K of o/w[HA]w [HA]w + [A-] = water phase Vo/Vw x K of o/w[HA]/w = oil phase

A 0.5 L canister is filled with a propellant (compressed gas) that is used to spray out a nonvolatile drug solution as an aerosol through a nozzle. At room temp (25 degrees C) the pressure of propellant is 5.76 atm. The canister is known to only tolerate pressures up to 6.2 atm before significant chance of bursting. The propellant acts essentially as an ideal gas a) Assuming volume and strength of canister are unaffected by temp, what is the highest temp that is OK for storing canister? b) After repeated spraying of aerosol, 10% of propellant has been expelled from canister. Now, what is the pressure of the gas in the canister at room temp? c) What is the highest temp that is OK for storage when 10% of the propellant has been released?

a) PV = nRT V = 0.5 L T = 273 + 25 = 298 K 5.76 atm/298K = 6.2 atm/X K X = 321 K b) V, R, T = constant T = 298 K PV = nRT P = (nRT)/V 10% of propellant expelled = 90% left n2/n1 = 0.9 n2/n1 = P2/P1 = 0.9 P2 = 0.9 x 5.76 atm = 5.18 atm c) Constant = n, R, T P1V1 = n1RT1 P2V2 = n2RT2 T2/T1 = P2/P1 T2/298 K = 6.2 atm/5.18 atm T2 = (298 K x 6.2 atm)/5.18 atm = 357 K

Following solubility data was collected at various pH values for weak base. pH Solubility (M) 1-------- 13.7 2--------13.6 3--------12.8 4--------9.49 6--------0.0979 7.5------0.006 9--------0.003095 11--------0.003001 14--------0.003

a) What is the intrinsic solubility? 0.003 M b) what is the pKa? 7.5 c) Calculate solubility at pH = 5 For weak base, as pH increases the solubility approaches the intrinsic value Co = 0.003 M At pH = pKa, Cs = 2 x Co So for Cs = 2 x 0.003 = 0.006 M, the pKa is 7.5 pH = pka + log (Co/(Cs- Co)) 5= 7.5 + log (0.003/(Cs - 0.003)) log (0.003/(Cs - 0.0003)) = -2.5 (0.003/(Cs -0.003)) x (Cs -0.003) = 10^(-2.5) = 0.00316(Cs -0.003) (Cs -0.003) + 0.003 = 0.003/0.00316 = 0.949 + 0.003 Cs = 0.952 M

What is the solubility of electrolyte magnesium bromide a) in moles/L and b) in g/100 mL if solubility product is 1.4 x 10^-11 M^3? Molecular weight Mg(OH)2 is 58.34

a) molarity of solution: Mg(OH)(2)(s) ------- Mg(2+)(aq) + 2 (OH-) Ksp = [Mg(2+][OH-]^2 1.4 x 10^-11 M^3 = S x (2S)^2 ((1.4 x 10^-11 M^3)/4)^1/3 = ((4S^3)/4)^1/3 S = 1.52 x 10^04 mol/L b) 1.52 x 10^-4 moles Mg(OH)2/1L solution x 58.3 g Mg(OH)2/1 mole Mg(OH)2 x 1 L/1000 mL x 100 mL = 8.86 x 10^-4 g/100 mL

Nasal solutions need to use

antimicrobial preservatives

Oral temperatures

approx 1 degree F > axiillary temps

Spray is defined as:

aqueous or oleaginous (oil based) solution in the form of coarse droplets or as finely divided solids, to be applied topically

Once absorbed a drug is distributed to various tissues of body

by the blood

Attractive forces between molecules

can be ignored

Lactose is for

filler (or diluent) can be added to provide bulk

microcrystalline cellulose and carboxymethylcellulose sodium

for viscosity

Systems tend to move toward state of

minimum Gibbs Free Energy (deltaG)

MEC

minimum effective concentration

The slope of vaporization is always

positive

Subscript 1 is for _____ and subscript 2 is for _______

solvent, solute

Since actual solubility is affected by solvent...

y2 is affected by solvent

Amidopyrine, a weak base with Ka = 1x 10^-5, was dissolved in a pH 3 buffer. Calculate the percentage of ionized amidopyrine.

% Ionization for weak base = 100%/(1 + 10^(pH-pKa)) pKa = - log(1 x 10^-5) = 5 100%/(1 + 10^(3-5)) = 99%

What is the % ionization for a base, when pH is 2 units above pKa?

%I = 100%/(1 + 10^(pH - pKa)) = 100%/(1 + 10^2) = 1%

What is the % ionization for base, when pH is 2 units below pKa?

%[BH+] = 100%/(1 +10^(pH - pKa)) = 100%/(1 + 10^-2) = 100%/(1 + 0.01) = 100%/1.01 = 99%

Indomethacin, a weak acid with a pKa of 4.5, is a NSAID used in the treatment of RA. Will the proportion of the ionized drug be greater in stomach (pH = 2.4) or the intestine (pH = 5.5)? What is the percent unionized in each situation?

%ionized = 100%/(1 + 10^(pKa - pH)) Stomach= 100%/(1 + 10^ (4.5-2.4)) = 0.788 Intestine = 100%/(1 + 10^(4.5-5.5)) = 99.2 Proportion of ionized drug is greater in the intestine % unionized in stomach = 100 - 0.788 = 99.21% % unionized in intestine = 100 - 99.2 = 0.08%

What determines rate of passive diffusion (absorption)?

((DSK of o/w) x (Cout))/h All other factors in rate equation affecting the rate of absorption across a membrane are either a characteristic of the membrane or a characteristic of drug molecule

The ratio strength (w/v) of 250 mL aqueous solution containing 40 mg of NaCl is:

(40 mg NaCl x 1 g/1000 mg)/250 mL solution = 1.6 x 10^-4 g NaCl per mL solution 1.6 x 10^-4 g NaCl/1 mL solution = 1 g NaCl/x mL solution (1 mL solution x 1 g NaCl)/(1.6 x 10^-4 g NaCl) = x mL solution x = 6250 Ratio strength is 1:6250 NaCl

Calculate the pH of a 0.01M solution of salicylic acid (Ka = 1.06 x 10^-3 at 25C) using both the approximate and exact quadratic equations. Why are the 2 values different?

(Ka x Ca)^1/2 = [(1.06 X 10^-3) x (0.01 M)]^1/2 = H+ concentration = 0.00325576412 - log (0.00325576412) = pH = 2.49 (-Ka + (Ka^2 + 4 x Ka x Ca)^1/2)/2 = (-0.00106 + (0.0000011236 + 0.0000424)^1/2)/2 = H+ concentration = 0.00276862092 - log (0.00276862092) = pH = 2.56 The 2 values are different because Ca = 0.01 M is not much greater than [H3O+] = 0.00325 M

More disordered chains in phospholipid bilayer =

(more fluid) able to solubilize drugs better, diffuse across more quickly

In a study of binding of caffeine to bovine serum albumin by equilibrium dialysis method, 2.8 x 10^-4 M of albumen was allowed to equilibrate with 1 x 10^-4 M of caffeine. After equilibrium was established, 0.7 x 10^-4 M of caffeine was contained in dialysis bag & 0.3 x 10^-4 M of caffeine was found in external solution. Calculate r, ratio of bound to total protein. What is the fraction bound of caffeine?

0.7 x 10^-4 M total caffeine in dialysis bag - 0.3 x 10^-4 M free caffeine on both sides of membrane = 0.4 x 10^-4 M caffeine bound to albumen 0.4 x 10^-4 M bound protein/2.8 x 10^-4 M total protein = r = 0.14 0.4 x 10^-4 M bound caffeine/(1 x 10^-4 M total caffeine - 0.3 x 10^-4 M free caffeine (left to other side of membrane) OR 0.4 x 10^-4 M bound caffeine/0.7 x 10^-4 M total caffeine on dialysis side of membrane Both = bound fraction of caffeine = 0.571 Total free drug on both sides of membrane (0.3 x 10^-4 x 2) = 0.6 x 10^-4 free caffeine

Patient has 0.8 mg glucose in each mL in blood. Express glucose concentration in blood as mg %.

0.8 mg glucose/1 mL blood x 100% = 80 mg% glucose/1 mL blood

How many grams of NaCl (MW 58.5) are required to make 150 mL of 0.2% w/v solution of Lidocaine HCl (MW 270.8) isotonic with blood? Evalue Lidocaine HCl is 0.22

0.9 g NaCl/100 mL solution x 150 mL solution = 1.35 g total NaCl needed 0.2 g Lidocaine HCl/100 mL x 150 mL solution = 0.3 g Lidocaine HCl 0.22 g NaCl/1 g Lidocaine HCl x 0.3 g Lidocaine HCl = 0.066 g NaCl equivalents from Lidocaine HCl 1.35 g total NaCl needed - 0.066 g NaCl from Lidocaine HCl = 1.284 g NaCl needed

How many grams of sodium chloride should be used in preparing the solution? Dextrose, anhydrous 2.5% (E value 0.18), NaCl qs, sterile water for injection ad 1000 mL

0.9 g NaCl/100 mL x 1000 mL = 9 g sodium chloride needed 2.5 g dextrose/100 ml x 1000 mL = 25 g dextrose 0.18 g NaCl/1 g dextrose x 25 g dextrose = 4.5 g NaCl equivalents by dextrose 9 g - 4.5 g = 4.5 g of additional NaCl needed to make solution isotonic

How many grams of boric acid should be used in compounding this prescription? Tetracaine HCl 0.1 g (E value 0.18), Zinc sulfate 0.05 g (E value 0.15), boric acid qs (E value 0.5), purified water 30 mL, make isotonic

0.9 g NaCl/100 mL x 30 mL = 0.27 g NaCl 0.18 g NaCl/1 g tetracaine HCl x 0.1 gtetracaine HCl = 0.018 g NaCl equivalents 0.15 g NaCl/1 g zinc sulfate x 0.05 g zinc sulfate = 0.0075 g NaCl equivalents Need 0.27 g - 0.018 g - 0.0075 g = 0.2445 g NaCl 0.5 g NaCl/1 g boric acid x Y = 0.2445 g NaCl Y = 0.489 g boric acid

How many mg of boric acid (E value = 0.5) should be used in compounding this prescription? Zinc Sulfate 0.06 g (E value 0.15), Boric acid qs, purified water ad 30 mL, make isotonic solution)

0.9 g NaCl/100 mL x 30 mL = 0.27 g NaCl needed 0.15 g NaCl/1 g zinc sulfate x 0.06 g zinc sulfate = 0.009 g NaCl equivalents 0.27 g NaCl needed - 0.009 g NaCl equivalents = 0.261 g NaCl to make isotonic 0.5 g NaCl/1 g boric acid x Y = 0.261 g Y = 0.522 g boric acid

Solutions with ___________ are isotonic with bodily fluids

0.9% NaCl (or 5% dextrose)

Freezing point depression method

0.9% NaCl is isotonic (deltaTf = 0.52 degrees C) D value is freezing point depression (degrees C) for given drug concentration Ex: DexNaPhos has D value of 0.05 degree C/0.5% concentration

Preparations of Isotonic Solutions: Methods

0.9% NaCl is isotonic (deltaTf = 0.52 degrees C) Methods: 1) NaCl equivalent method (E-value) 2) Freezing Point depression method (D-value) 3) Isotonic Solution method (V-values) All methods depend on osmotic pressure being colligative property (change in osmotic pressure is additive) All methods require use of tables, because most pharmaceutical solutions are NOT ideal (II = cRT does not work)

1 fluid ounce (29.573 mL) solution contains 4.5 grains (291.6 mg) of silver nitrate (E = 0.33). How much sodium nitrate (E = 0.68) must be added to this solution to make isotonic nasal fluid (0.9% NaCl)?

0.9g NaCl/100 mL solution x 29.573 mL solution = 0.266157 g NaCl total needed 0.33 g NaCl/1 g silver nitrate x 0.2916 g silver nitrate = 0.096228 g NaCl equivalents 0.266157 g total NaCl - 0.096228 g NaCl equivalents = 0.169929 g NaCl needed 0.68 g NaCl/1 g sodium nitrate x Y = 0.169929 g NaCl equivalents needed Y = 0.2499 g sodium nitrate x 1000 mg/g = 250 mg sodium nitrate

If normal human plasma contains about 3 mEq/L of hydrogen phosphate ion HPO4^-2, how many mg/L of dibasic potassium phosphate K2HPO4 (MW 174), required to supply the needed HPO4^-2 for an electrolyte replacement in the hospital?

1 M = 2 N for HPO4^-2 1 Eq/L = 1 N 1 mEq/L = 1 mN 3 mEq/L = 3mN x 1 M/2N x 1 N/1000 mN = 0.0015 M x 1000 mmol/1 mol = 1.5 mmol 1.5 mmol x 174 mg/mmol = 261 mg/L OR 1 atoms of HPO4 x 2 valence = 2 mEq/L of HPO4 per 1 mmol K2HPO4 3mEq/L HPO4^-2 x 1mmol K2HPO4^-2/2 mEq/L x 174 mg K2HPO4^-2/1 mmol = 261 mg/L

What is the volume of 2 moles of ideal gas at 25 degrees C & 780 mmHg?

1 atm = 760 mmHg R = 0.821 Latm/Kmol 780 mmHg x 1 atm/760 mmHg = 1.02631579 atm 25 + 273 = 298K V = nRT/P V = (2 moles x 0.0821 Latm/Kmol x 298 K)/1.02631579 atm V = 47.6 mL

1:1000 w/v solution =

1 g of constituent in 1000 mL of solution

1:1000 w/w preparation (drug in solid or semi-solid, ex: ointment) =

1 g of the drug in 1000 g of the preparation

One gram of sucrose is dissolved in 100 mL of solution at 25 degrees C. What is the osmotic pressure of the solution? Would this solution be hypotonic, isotonic or hypertonic with respect to red blood cells?

1 g/0.1 L x mol/342.3 g = 0.0292 mol/L = 0.0292 M II - RTc = (0.0821 L x atm/K x mol) x (298K) x (0.0292 mol/L) = 0.71 atm A solution of "normal" saline is considered isotonic with red blood cells 0.9% = 0.9g/100 mL = 0.9 g/0.1 L x mol/58.44 g = 0.154 mol/L IIRTc = (0.0821 L x atm/K x mol) x (298K) x (0.308 mol/L) = 7.53 atm (since NaCl is almost completely dissociated into two ions, for the purposes of colligative properties, one needs to take account the 0.154 mol/L actually represents 0.308 mol/L (2 x 0.154)) The sucrose is hypotonic with respect to RBCs.

I L water =

1 kg =

1000 mL aq solution with 198 g dextrose, % strength (w/w) of solution?

1 mL = 1 g 1000 mL = 1000 g 198 g dextrose/1000 g x 100 g = 19.8 % (w/w)

1:1000 v/v solution =

1 mL of constituent in 1000 mL of solution

How many grams of sucrose must be added to 475 mL of water to make 65% (w/w) solution?

1 mL water = 1 g water 65 g sucrose/100 g water = x g sucrose/(475 g water + x g sucrose) 100 g solution * x g sucrose = 30875 g sucrose * g solution + 65x g sucrose (100 g solution * x g sucrose - 65x g sucrose)/100 g solution = 30875 g sucrose * g water/100 g solution x g sucrose/solution - 0.65x g sucrose/solution = 308.75 g sucrose 0.35x g sucrose/0.35 = 308.75 g sucrose/0.35 = 882.1 g sucrose to be added

Radius of capillaries in humans is approximately 1 to 10 micrometers. The viscosity of blood at 37 degrees C is about 0.04 dynes x sec/cm^2 (0.04 poise). The pressure drop over a 3.2 mm length in the capillary is 20 mmHg. If radius of given capillary is 0.0012 cm, what is the flow rate of blood in the capillary?

1 poise = 1 dyne x sec/cm^2 1 atm = 760 mmHg 0.987 atm - 10^6 dyne/cm^2 1 cm^3 = 1 mL L = 3.2 mm = 0.32 cm r = 0.0012 cm delta P = 20 mmHg n = 0.04 dyne x sec/cm^2 Convert delta P to dyne/cm^2 20 mmHg x 1 atm/760 mmHg x 10^6 dyne/cm^2/0.987 atm = 26662 dyne/cm^2 Q = (pi x r^4)/8n x [delta P/L] = (pi x (0.0012 cm)^4 x 26662 dynes/cm^2)/(8 x 0.04 dyne x sec/cm^2 x 0.32 cm) =1.7 x 10^-6 cm^3/sec = 1.7 x 10^-6 mL/sec x 60 sec/min = 1.02 x 10^-4 mL/min

The aorta has average length of 30 cm and radius of 1.25 cm. The pressure drop (difference between pressure at beginning of aorta and that at the end of aorta) along aorta is about 120 dynes/cm^2. The viscosity of blood is 1.5 cp. This gives an average cardiac output of 256 cm^3/s. If aorta radius were to decrease to 1.2 cm, how would the pressure drop change (assuming viscosity and cardiac output are same)?

1 poise = 1 dyne x sec/cm^2 1 atm = 760 mmHg 0.987 atm - 10^6 dyne/cm^2 1 cm^3 = 1 mL Q = (pi x r^4)/8n x [delta P/L] L = 30 cm, r = 1.25 cm delta P = 120 dynes/cm^2 n = 1.5 centipoise n = 1.5 cp x poise/100 cp = 0.015 poise = 0.015 dyne x sec/cm^2 Q = 256 cm^3/sec Delta P = (Q x 8n x L)/(pi x r^4) = (256 cm^3/sec x 8 x 0.015 dyne x sec/cm^2 x 30 cm)/(pi x (1.2 cm)^4) = 141.6 dyne/cm^2 So radius of vessel decreased by 4%, but pressure change along vessel increased by 18%

The pressure drop over a 3.2 mm length in certain capillary is 20 mmHg. If radius of capillary is 00012 cm, the blood flow will be 1.02 x 10^-4 mL/min. Viscosity of blood at 37 degrees C in patient with normal hematocrit is about 0.04 dyne x sec/cm^2 (0.04 poise). In people with certain types of anemia, the hematocrit can fall to 20%. In these patients, the blood viscosity will decrease to 0.025 poise. For the capillary in question, what will the blood flow rate be in a patient with anemia?

1 poise = 1 dyne x sec/cm^2 1 atm = 760 mmHg 0.987 atm = 10^6 dyne/cm^2 1 cm^3 = 1 mL normal human hematocrit = 0.4 (40%) Q = (pi x r^4)/(8n) x [delta P/L] r = 0.0012 cm, L = 3.2 mm delta P = 20 mmHg x 1 atm/760 mmHg x 10^6 dyne/cm^2/0.987 atm = 26,662 dyne/cm^2 Q = (pi x (0.0012 cm)^4/(8 x 0.025 dyne x sec/cm^2) x [26,662 dyne/cm^2/(3.2 m x 100 cm/1000 mm)) Q = (pi x 2.07 x 10^-12 cm^4)/0.2 dyne x sec/cm^2 x [26,662 dyne/cm^2/0.32 cm] Q = (pi x 5.5 x 10^-8 cm^2)/0.064 sec/cm = 2.7 x 10^-6 cm^3/sec x 60 sec/min = 1.62 x 10^-4 cm^3/min

For reabsorption, need at least ________% unionized, and ________ unionized form

1%, nonpolar

Precipitation of drugs upon administration

1) Acidic drugs precipitate out in stomach 2) Basic drugs precipitate out in intestine 3) Drugs in cosolvent precipitate out in blood

Drug binding proteins

1) Albumin = doesn't have a large binding property, but there is a lot of it 2) Apolipoprotein 3) Glycoprotein 4) alpha, beta and gamma globulins

Ion - dipole interaction

1) Always attractive (negative sign) 2) Increases with ion charge & dipole moment 3) Present at shorter distances (1/r^2) than coulombic energy between 2 ions (1/r) 4) In bulk, potential energy is inversely proportional with temp (kBT) d/t thermal randomization of permanent dipoles

Henry's law

1) Aromatic Water (Henry's law region) 2) Small amount of water in some organic solvents may correspond to high water activity Psolute = k x Csolute

Rates of Renal processes

1) Arterial blood flow rate (25% cardiac output) = 1250 mL/min 2) Glomerular filtration rate = 125 mL/min 3) Typical urine flow rate = 1 mL/min Drug excreted in urine has been highly concentrated Reabsorption occurs throughout kidney tubules

Mole fraction of drug, X2, in diluted aqueous solutions

1) At room temperature, solution density is approximately the same as that of pure water (1000 g/L or 1 g/ml) 2) Number of molecules >> number of drug molecules M2/(1000g*L^-1/18.02 g*mol^-1)= M2/55 mol/L = m2/55.5 mol/L

Building blocks of matter

1) Atoms Ex: He, C, H. O, N 2) Ions Ex: OH-, Na+, H+ 3) Molecules O2, H2O

Some common bases and their pKas

1) Benzocaine (2.5) 2) Diazepam (3.4) 3) Cytarabine (4.3) 4) Tropicamide (5.3) 5) Amiodarone (6.6) 6) Droperidol (7.6) 7) Loperamide (8.6) 8) Atenolol (9.6) 9) Naphazoline (10.9)

Evaluating Data

1) Calculate r = [Db]/[Pt] = (nK[Df])/(1 + K[Df]) If Df <<< 1, can get rid of Df (on bottom of equation), r = nK[Df] If Df >>>, can get rid of number 1, r = n 2) Plot r vs [Df]

Other Pharmaceutical Importances of Partitioning

1) Extraction of active ingredients (ex: from plants) 2) PASSIVE MEMBRANE PERMEATION (ex: into cells) = Rate of transport from place of administration to bloodstream 3) Chromatography (analytic and preparative) 4) Solubilization of drugs (ex: emulsions, liposomes) 5) Preservation of oil-water pharmaceutical preparations

Pharmaceutical Relevance of Crystal Size and Morphology

1) Filtration (depends on habit/morphology of crystals) 2) Powder flow (size of crystal is relative to how easily it flows through pipes, etc) 3) Tableting 4) Freeze-drying efficiency Annealing leads to larger ice crystals By controlling size and shape of ice crystals, one is able to control the size of resulting pores Larger pores will lead to more efficient sublimation process 5) Dissolution rate 6) Content uniformity (in order to be approved, needs to be repeatable product) 7) Crystal engineering (ex: spherical crystallization based on triangular phase diagram)---can control conditions under which crystal forms

When looking at interactions in non-ideal (real) solution of A & B:

1) If each component likes itself more than the 2 components like each other (A-A and B-B > A-B), the "effective molar fraction" of A or B is higher than that of ideal mixture. Also, partial pressures (and vapor pressures) will be higher than that predicted for ideal mixtures (positive deviation, activity coefficient > 1) 2) If A-A and B-B < A-B, there is a negative deviation (activity coefficient < 1)

Ideal solutions

1) Intermolecular bonding is equivalent (solute-solute = solvent-solvent = solute-solvent) 2) No heat evolved or absorbed when mixed 3) No change in volume when mixed 4) Vapor pressure is proportional to molar fraction (dilution effect)

Attractive intermolecular forces (electrostatic interactions)

1) Ion+ -- Ion- 2) Molecule -- Ion Ion -- Dipole Ion -- Induced dipole 3) Molecule -- Molecule Dipole -- Dipole Dipole -- Induced dipole Induced dipole -- Induced dipole Hydrogen bonding

Types of equilibria

1) Ionic equilibria 2) Self association in solution (form a dimer, trimer, etc----will not be able to participate in equilibrium with solute/solid) 3) Complexation with solvent or another compound----when molecule complexes with another molecule, it is not available to participate in equilibrium with the crystal

Determine true partition coefficient from K'

1) K' weak acid = K of o/w/(1 + 10^(pH -pKa) 2) Depressing ionization by keeping water phase at a low pH Adjust pH so A- goes to 0, then could find true partition coefficient See slide 10 on Partitioning

Calculate the vapor pressure lowering of a solution containing 50 g dextrose (MW = 180) in 1000 g of water. The vapor pressure of water is 23.77 mmHg at 25 degrees C

1) Known: 50 g dextrose (MW = 180) dissolved in 1000 g of water at 25 degrees C. p1^o = 23.77 mmHg 2) Calculate the vapor-pressure lowering, delta p1 3) What should you know? delta(p1) = - (m/(m + 55.5) x p1^o 4) To calculate delta(p1), you need to calculate m for dextrose 50 g dextrose x 1 mol dextrose/180 g dextrose = 0.278 mol/kg = m delta(p1) = - (0.278 mol dextrose/(0.278 mol dextrose + 55.5 mol water)) x 23.77 mmHg = -0.12 mmHg

Weak acid examples

1) Lactic acid 2) Acetic acid 3) Formic acid 4) Citric acid 5) Oxalic acid

Solubilization by Cyclodextrin (CD)

1) Large number of -OH groups----cyclodextrins are highly water soluble 2) Relatively apolar interior---host drug molecule (or part of drug molecule)

Changing solvent envirionment (y)

1) Lipid based systems----stabilize using surfactants 2) Co-solvents 3) Surfactants---form a micelle in water (hydrophillic heads and hydrophobic tails)

Determination of r

1) Mix known amount of drug and protein 2) Allow to reach equilibrium 3) SEPARATE free and bound drug & measure concentration (hard to do) 4) Find r for various drug concentrations

Oral absorption route

1) Mouth 2) GI tract 3) Liver 4) Right heart 5) Lung 6) Left heart 7) Brain 8) Skin 9) Kidney 10) Other body systems 11) Liver 12) GI tract

Mechanism of taste masking

1) Na2CO3 (water penetration layer) dissolved in water 2) HPMC (in salting out layer) precipitates surrounding drug core (salting out) 3) After all salt is dissolved, HPMC starts to dissolve 4) Delayed drug release by 5 minutes 5) Eliminate problem of bitter taste for orally disintegrating tablets Slide 9, Nov 7th

Some common acids and their pKas

1) Penicillin G (2.8) 2) Fluefamic acid (3.9) 3) Valproic acid (4.8) 4) Glipizide (5.9) 5) Nitrofurantoin (7.1) 6) Pentobarbital (8.1) 7) Indapamide (8.8) 8) Metolazone (9.7) 9) Estrone (10.8)

The vapor pressure of pure chlorfluorocarbon, CFC 11, (MW = 137.4) at 21 degrees C is P11^o = 13.4 lb/in^2 (psi) and that of CFC 12 (MW = 120.9) is P12 ^o = 84.9 psi. 1) What is the partial pressure of CFCs 11 and 12 in the 50:50 mixture? 2) What is the total vapor pressure of a 50:50 mixture by gram weight of the 2 propellants?

1) Pi = XiPi^o P11 = 0.5 mole fraction x 13.4 psi = 6.7 psi P12 = 0.5 mole fraction x 84.9 psi = 42.4 psi 2) Ptotal = P11 + P12 = 6.7 psi + 42.4 psi = 49.1 psi

Pharmaceutical Importance of Solubility

1) Preparing drug solutions 2) Synthesizing drugs (mostly in solution) 3) Affecting drug dissolution, and, therefore, its bioavailability 4) Taste masking (do not want drug to be soluble in saliva) 5) Related to disease mechanism (ex: kidney stone)

Common Pharmaceutical Solvents

1) Purified water 2) Alcohol 3) Dehydrated alcohol 4) Rubbing alcohol 5) Glycerin 6) Propylene glycol 7) Oils

Solubility intermolecular forces

1) Remove one drug molecule from crystal----takes energy to break bonds between molecule in crystal 2) Make a hole in water/other solvent----also takes energy 3) Insert drug molecule into hole in water/solvent----releases energy Balance between the 3 steps determines how high solubility will be

Acid-Base equilibria definition

1) Simultaneous forward and reverse reaction 2) Protons transferred from one substance to another 3) Acid-base reaction always involves interactions between 2 sets of conjugate acid-base pairs

Differences between parent drug and salt

1) Solubility 2) Bioavailability 3) Physical stability 4) Chemical stability 5) Mechanical properties 6) Ease of crystallization (process of purification) 7) Taste (can make "sweet" tasting salts) 8) Melting point (Ex: ibuprofen has very low melting point)

Effects related to ionic strength

1) Solubility (salting in/out) 2) Activity of ions: Ksp of salt, pH of solution, other ion properties Activity of any ion is: a (ion) = yi x C(ion) Activity coefficient (yi) calculated by: log(yi) = -Azi^2 x (Ionic strength)^1/2 zi = charge number on ion, i A= constant depending on solvent

Sources of particulates

1) Solution itself & chemicals comprising it Chemical reactions among components of solution & packaging material Degradation of solution itself 2) Process of manufacturing During prep and packaging, filling equipment and personnel 3) Packaging components Glass/plastic containers Rubber closures

What factors affect solubility?

1) Solvent (like dissolves like, ex: based on polarity) 2) Temperature (van't Hoff equation, ideal/regular solution solubility equations) 3) Particle size (important only when size < 100 nm) 4) Solid form (ex: polymorphs, salts) 5) Solution pH (important for ionizable drugs 6) Pressure (important for gases)

Information gained from Scatchard Plot

1) Straight line implies: a) Only 1 type of binding site with same binding constant (K) b) x-intercept = number of binding sites (r = n) r/[Df] = nK - rK Assuming only 1 type of binding site with same binding constant 2) Curvature implies greater than 1 type of interacting binding site a) Initial slope = -K b) y-intercept = nK

Why doesn't pH-partition hypothesis always work?

1) Surface area considerations may override pH-partition theory, even with small percent unionized, absorption may be better if there is a high surface area available for absorption 2) Limited time in stomach 3) Unionized drugs are absorbed better, but there may be some absorption of ions, perhaps by pore transport

Pharmaceutical Solutions

1) Syrups 2) Elixirs 3) Tinctures 4) Spirits 5) Aromatic Water 6) Injectibles 7) IV infusion 8) Oral drug solutions

Dipole moment (m)

1) Total charge on molecule is zero 2) Asymmetrical electron distribution 3) Due to differences in electronegativity

Lever rule

1) Two phases a and b that are in equilibrium 2) na and nb are the amounts of a and b, respectively 3) Let Ia and Ib represent distances along the horizontal tie line that cross point of interest na x Ia = nb x Ib OR na/nb = Ib/Ia See slide 18 phase equilibria 2

Changing apparent solubility

1) Use cyclodextrins 2) Adjust pH For weak base----reduce pH to increase solubility For weak acid-----increase pH to increase solubility

Colligative properties include:

1) Vapor pressure lowering 2) Boiling point elevation 3) Freezing point depression 4) Osmotic pressure

Dispersed systems classified as:

1) coarse dispersion 2) colloidal dispersion 3) solutions

Controlling water activity

1) dilute water with solutes (ex: organic solvents or salts) 2) Saturate NaCl aq solution water activity it 0.75 or 75% RH See slide 16 Phase equilibria 1

The solubility of most gases will DECREASE with....

1) increasing temperature 2) decreasing pressure

Solubility facts

1) requires at least 2 equilibrating phases----cannot be single phase 2) may be determined from phase diagram----area under curve = phase compositions

Therapeutic serum concentration range for phenytoin is 10 to 20 mg/L. Phenytoin's molecular weight is 252. Therapeutic range in micromol/L?

10 mg/L x 1 g/1000 mg x 1 mol/252 g x 1 x 10^6 micromol/1 mol = 40 micromol/L to 80 micromol/L 20 mg/L x 1 g/1000 mg x 1 mol/252 g x 1 x 10^6 micromol/1 mol = 80 micromol/L

Theophilline's therapeutic range is 10 to 20 mg/L. Molecular weight is 180. Therapeutic range in micromol/L?

10 mg/L x 1g/1000 mg x 1 mol/180 g x 1 x 10^6 micromol/1 mol = 55 micromol/L to 111 micromol/L 20 mg/L x 1 g/1000 mg x 1 mol/180 g x 1 x 10^6 micromol/1 mol = 111 mol/L

The plasma concentration of Drug XYZ was found to be 50 mg/L. The concentration of XYZ not bound to plasma proteins was 10 mg/L. What was the fraction of unbound Drug XYZ in the plasma?

10 mg/mL concentration of unbound Drug XYZ/50 mg/mL total plasma concentration of Drug XYZ = 0.2 fraction of unbound Drug XYZ in plasma

150 lb =

150 lb x 1 kg/2.2 lb = 68 kg

183 lb =

183 lb x 1 kg/2.2 lb = 83 kg

Sodium chloride in water: Na+, Cl- and H2O = ? components

2

Sugar dissolved in water: sucrose & H2O = ? components

2

2 ng/mL = ? mcg/L

2 ng/mL x 1 mcg/1000 ng x 1000 mL/L = 200 mcg/L

Immiscible systems

2 phases (layers), fixed compositions in each layer. Size of 2 layers depends on amounts of 2 components

20 pg/mL = ? ng/L

20 pg/mL x 1 ng/1000 pg x 1000 mL/1 L = 20 ng/L

How many grams of zinc oxide powder should be used to prepare 120 g of 20% w/w ointment?

20g/100 g = x g/120 g x = (20g/100g)x 120 g = 24 g

Length of duodenum

22 cm

Cardiac output in adult human is said to be 5 L/min. How does this number compare to the cardiac output given in problem 1? (256 cm^3/s)?

256 cm^3/sec = 256 mL/sec x 60 sec/min x 1 L/1000 mL = 15 L/min This is higher than 5 L/min, which is the resting cardiac output for an adult. But cardiac output can be as high as 30 L/min, so this is not unreasonable

What is the ratio concentration (by weight in volume) of 6000 mL of solution containing 3 g of a drug?

3 g/6000 mL = 1 g/x mL x = (1g x 6000 mL)/3g = 2000 mL 1:2000 = 1 g in 2000 mL

If drug has an fu value of 0.03, this means that

3% of drug in plasma is not bound to plasma proteins

4'6" =

4 ft x 12 in/foot = 48 in + 6 in = 54 in x 2.54 cm/1 in = 137 cm

3 lb, 4.5 oz =

4.5 oz x 1 lb/16 oz = 0.28125 lb + 3 lb = 3.28125 lb x 1 kg/2.2 lb x 1000g/1 kg = 1491 g

5'10" =

5 ft x 12 in/foot = 60 inches + 10 inches = 70 in x 2.54 cm/1 in = 178 cm

5'4" =

5 ft x 12 in/foot = 60 inches + 4 inches = 64 in x 2.54 cm/1 in = 163 cm

50 mcg/mL = ? mg/dL

5 mcg/mL x 1 mg/1000 mcg x 100 mL/1 dL = 5 mg/dL

5 nM = ? micromol/L

5 nM/1 L x 1 micromol/1000 nM = 0.005 micromol/L

How many grams of sucrose must be added to 500 mL of water to make a 20% w/w solution?

500 mL water = 500 g water 20 g sucrose/100 g solution = x g sucrose/(x g sucrose + 500 g solution) (0.2 g sucrose/g solution)(x g sucrose + 500 g solution) = x g sucrose (0.2x g sucrose + 100 g solution) - 0.2x g sucrose = x g sucrose - 0.2x g sucrose 0.8x g sucrose/0.8 g sucrose = 100 g solution/0.8 g sucrose = 125 g sucrose to be added

Molar solubility of sulfathaizole (weak acid) in H2O is 0.002 M, pKa is 7.12 and molecular weight is 304. What is the lowest pH allowable for 5% solution of the salt?

5g/100 mL = x g/1000 mL = 50 g/L x 1 mole/304 g = 0.1645 mole/L = Cs pH = pKa + log (Cs/Co -1) = 7.12 + log (0.1645 M/0.002 M - 1) = 9.03 pH

Range of acceptable pHs for solutions:

6.5 to 8.5 Buffers or pH-adjusters must be added Boric Acid Vehicle Sorenson's Modified Phosphate Buffer

Therapeutic range is 60 to 80 micromol/L. Molecular weight is 320. What is this is mg/L? micrograms/mL?

60 micromol/L x 1 mol/1 x 10^6 micromol x 320 g/1 mol x 1000 mg/g = 19.2 mg/L to 25.6 mg/L 80 micromol/1 L x 1 mol/1 x 10^6 micromol x 320 g/1 mol x 1000 mg/1 g = 25.6 mg/L 60 micromol/L x 1 mol/1 x 10^6 micromol x 320 g/1 mol x 1 L/1000 mL x 1 x 10^6 microgram/1 g = 19.2 microgram/mL to 25.6 microgram/mL 80 micromol/1 L x 1 mol/1 x 10^6 micromol x 320 g/1 mol x 1 L/1000 mL x 1 x 10^6 micrograms/1 g = 2.56 microgram/mL

Structures of ______ polymorphs have been solved

7

5 lb, 9 oz =

9 oz x 1 lb/16 oz = 0.5625 lb + 5 lb = 5.5625 x 1 kg/2.2 lb x 1000 g/1 kg = 2528 g

Solubility parameters

= ((delta Hv - RT)/Vm)^1/2 = Pi^1/2 delta Hv = heat of vaporization = energy required to vaporize drug to gas is proportional to removing one molecule from a solid= estimation of how tightly molecules hold onto each other in solid state Vm = molecular volume Pi = cohesive energy density or internal pressure (ex: w11 and w22)

Spirits are alcoholic or hydroalcoholic solutions of volatile substances

Alcoholic content usually greater than 60% Used generally as flavoring agents for other pharmaceutical preparations Peppermint spirit, compound orange spirit

Ion-induced dipole interaction

Always attractive Valence Electric polarizability 1/r^4

Pharmaceutical Example

Amiloride hydrochloride, Ksp = 2.1 x 10^-4 M^2 in water at 25C. What is its aqueous solubility at 25C? Ksp = [AmH+][Cl-] [AmH+] = [Cl-] Ksp = [AmH+]^2 [AmH+] = (Ksp)^1/2 =0.0145 M What is its solubility in 0.5 M NaCl solution at 25C? When solubility is much less than what is added, can ignore 2nd AmH+ term in equation, or do quadratic equation Ksp = [AmH+] x ([AmH+] + 0.5 M) = 2.1 x 10^-4 M 2.1 x 10^-4 M/0.5 M = 0.00042 M = [AmH+] [AmH+]^2 + 0.5[AmH+] - 0.00021 = 0 Quadratic equation: (-b + ((b^2 -4ac)^1/2)/2a (-0.5 + ((0.5^2 - 4 x 1 x -0.00021)^1/2)/2 x 1 = [AmH+] = 0.00042 M

Structure of an atom

Atom consists of nucleus, electron(s) Nucleus consists of protons (positively charged) and neutrons & makes up the bulk of the mass of an atom Electrons move at speeds near speed of light (approx 1%) in defined orbitals around nucleus to form electron clouds

Hydrogen bonding

Atom of hydrogen is attracted strongly by 2 atoms X-H- - -A (X and A are extremely electronegative, ex: N, O, F) Electrostatic in nature ex: strong dipole-dipole interacton Dependent on geometry (how atoms of different molecules line up)

Low dielectric constant of organic solvent limits partitioning of

BH+ into organic phase BH+ ===== B + H+ See slide 11 Partitioning

Kb (basicity constant)

BH+ is the conjugate acid of B

What is a weak base?

Base with weak tendency to accept a proton (ex: Cl- is a very weak base)

Is a solution of a sodium salt and a weak acid: basic or acidic?

Basic

Why is Bacteriostatic Water for Injection prohibited from use in neonates?

Because it contains benzyl alcohol as an anti-microbial agent, can be toxic to neonates because they cannot detoxify high cumulative amounts in the liver

Saturated oil and water systems

Because of presence of solid, the concentration in the water phase is at the saturation solubility Solid drug on bottom, water on bottom/middle, oil on top Solid is in equilibrium with the water, then solid must also be in equilibrium with the oil

Are the ionization behaviors of weak acid drug and its salts different?

Because water is buffered, pH does not change and ionization behaviors are the same

Many factors influence therapeutic response

Biological characteristics of patient Physiochemical properties of drug and dosage form

Circulatory system

Blood flow carries drug throughout the body Blood flow rate varies from tissue to tissue Cardiac output 5 L/min at rest, up to 30 L/min during exercise Cardiac output = heart rate x stroke volume

The total equilibrium vapor pressure of a liquid mixture containing 0.2 mole of CFC (Po = 13.4 psi) and 0.8 mole of CFC 12 (Po = 84.9 psi) is approximately: Assuming mixture is ideal solution

CFC 11 = P1 = Po x X1 = 13.4 psi x (0.2/(0.2 + 0.8)) = 2.6 psi CFC 12 = P2 = Po x X2 = 84.9 psi x (0.8/(0.8 + 0.2)) = 67.92 psi 67.92 psi + 2.6 psi = 70.52 psi

Strong electrolyte

COMPLETELY dissociates into ions (ex: salts)

Thermodynamic Considerations

Calculate the standard Gibb's free energy, enthalpy, and entropy changes associated with protein binding K = 381074 = initial slope deltaG^o at 20 degrees C = - RTlnK = -(1.987 cal/molK)(293 K)ln(381074) = -7482 cal/mol = spontaneous binding deltaG^o at 40 degrees C = -(1.987 cal/molK)(313 K)ln(381074) = -7522 cal/mol = spontaneous binding delta H^o = -ln(Kt1/Kt2) x R x (T1 - T2) (from ln(Kt1/Kt2) = -(deltaH^o/R)(1/T1 - 1/T2) = -6872 cal/mol = Exothermic deltaS^o = (deltaH^o - deltaG^o)/T (from deltaG^o = deltaH^o - T x deltaS^o) delta S^o = 2.08 cal/molK = entropy change is positive

What type of solution dosage form cannot be made from Purified Water, USP? Why?

Can't be used for injectable drugs Water needs to be sterile to use in injectable drugs Needs to be pyrogen free

To prepare drug layered beads for controlled release of theophylline, a batch of micronized theophyilline anhydrate was suspended in water for spraying trhough a nozzle during fluid bed coating (used for drug layering). Howerver, a few minutes after the coating process started, the worker found that the nozzle is clogged by many needle shaped crystals. What is likely the cause of the crystals? How can the problem be solved?

Cause = Change in solubility to theophylline monohydrate Solve = Put something in the water to help the theophylline be soluble until tablet is coated with solution

What is NOT true with respect to plasma protein binding?

Clinical assays often measure unbound drug in plasma

Intrinsic solubility of HA

Co = constant

Pharmacist may dispense oral solutions that are:

Commercially prepared Diluted from a concentration form (like making a pediatric dose from an adult solution) Reconstituted from a dry powder supplied by manufacturer Extemporaneously compounded from bulk components

Distribution (D in ADME)

Concentration and disposition of drug at the target site is influenced by its distribution Once absorbed, a drug is distributed to various tissues of the body by the blood Blood carrying absorbed drug to rest of body is referred to as systemic circulation Distribution is a reversible process of transfer of a drug to and from blood, the site of measurement

Structure of an emulsion

Consider a lipophilic solute 1) Low solubility in water 2) High solubility in oil 3) Oil dispersed in water can act as a depot

Cw^o =

Cw + Vo/Vw x Co

If benzoic acid is distributed between equal volumes of peanut oil and water, what must be the original concentration in the water phase in order that 0.25 mg/mL of undissociated acid remains in the aqueous phase buffered at a pH of 4.0? The partition coefficient, K of o/w = 5.33 and pKa = 4.19 for benzoic acid

Cw^o = [1 + 10^(pH - pKa) + K of o/w x (Vo/Vw)][HA]w Cw^o = [1 + 10^(4-4.19) + 5.33 x (Vo/Vw)] x 0.25 mg/mL = 1.74 mg/mL benzoic acid

Salting-out:

Decrease in salt content Solubility decreases Needs more energy

Effect of Cardiac Output on Drug Effect

Dexmedetomidine reduces cardiac output As blood concentration of DEX increases (see slide 8 Intravascular Admin) (treatments A & B), cardiac output decreases Lower blood flow means anesthetic takes longer to leave the brain 2 hours post-anesthesia, all of placebo patients (treatment C) are awake, but significant portion of A and B treatments are still sedated

Factors affecting Blood Flow: Volume

Diarrhea Diuretics (furosemide and hydrochlorothiazide) Excessive bleeding, sweating or urination

Influence of solubility on rate of injection1

Diazepam is also poorly H20 soluble (if injected rapidly, could precipitate in vein) Injectable is 40% propylene glycol, 10% ethanol When solution added to saline, preciptation occurs, can't be added to IV solutions Package insert says solution should be injected slowly, directly into vein "taking at least 1 minute for each 5 mg given," usual dose for anticonvulsant activity is 5 to 10 mg. If given slowly, significant local pain (solvent effects) Can give IM if IV is difficult but may lead to erratic and slow absorption

Dipole induction in Non-polar molecules

Dipole can be induced in a non-polar molecule by electric field Ex: (O=C=O)

pH-solubility profile of weak base

Direction of curve goes down from left to right, instead of up from left to right like acid pH-solubility profile

Formulation =

Disintegration and Dissolution

Importance to Pharmacy

Drug discovery---interactions with biological targets (efficacy and toxicity) Understanding Drug solubility (Most drugs being designed are non-soluble) Colligative properties of liquid dosage forms (why normal saline is 0.9%) Crystal forms of drugs Powder flow Tablet mechanical strength

Passive diffusion

Drug moves from region of high concetnration (outside of membrane) to a region of lower concentration (inside of membrane)

Drug + nH2O =

Drug*nH2O

NaCl Equivalent Method (E-value)

E-value of a drug: the weight of NaCl that produces the same osmotic pressure as 1 g of drug

What are key differences between enantiotropic and monotropic polymorph systems?

Enantiotropic: Well defined transition temp, one form is stable over a temp range, while second is stable over different range Monotropic: Hypothetical transition temp, only one form stable over entire temp range

Influence of solubility on rate of injection

Ex: Phenytoin: very alkaline pH, needs to be injected very slowly in small vein or a little faster in larger vein Must formulate with NaOH to form salt, solution pH is 12 Use IV push (50 mg/min) in larger vein Very irritating and painful Flush with NS afterwards Slower infusions cause precipitation in vein because of blood buffer capacity lowering pH IM administration is associated with erratic absorption Fosphenytoin is an IV water-soluble prodrug Can be infused or given IM

pH shift in manufacturing process

Ex: freeze drying/lyophilization (for protein drugs) Called pH swing Happens while deep freezing, causes precipitation of some of salt or base Solution is to use right buffer that does not precipitate out and has no pH swing

Molecular complexes

Ex: hydrates, salts & co-crystals Assay value-based on anhydrous form Dose calculation MW of anhydrous form (ex: Amoxicillin is 365.4) MW of alternate form (Amoxicillin trihydrate is 419.5) Ex: for a 100 mg tablet, 100 mg of anhydrate = how many mg of trihydrate? 100 mg/365.4g/mol = x/419.5 g/mol = 114.8 mg amoxicillin trihydrate Stability---must be aware of storage conditions (temp and RH)

Solute = Gas, Solvent = Liquid

Example = Carbonated drink, pH reduction of ocean

Solute = Gas, Solvent = Solid

Example: Hydrogen in metal and porous crystals

Solute = Solid, Solvent = Liquid

Example: Normal saline, dilute polymer solution, oral drug solution

Name an excipient (pharmaceutical ingredient) that is used as a flavorant in dosage forms. Name a sweetening agent

Excipient: Anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil, vanillin Sweetening agent: Aspartame, dextrose, mannitol, saccharin sodium, sorbitol, sucrose

Drug polymorphism is a phenomenon of crystalline solids. It is not a point of concern for solution dosage forms because no drug crystal is present in the solution

False

There are only 3 known states of matter: solid, liquid and gas

False

True or False: The strength of an acid or base is an intrinsic property of the molecule and does not vary with solvent

False

According to the phase diagram of pure water, its freezing temp is 0 degrees C at 1 atm. Thus, the degree of freedom is zero (F = 0) along the freezing/melting curve of water (phase boundary between liquid and solid phases)

False F = C - P + 2 Temp and pressure given, so no #2 Components = 1 Phases = 2 F = 1 - 2 = -1 ???

When applying the Gibbs Phase Rule to pure amoxicillin trihydrate crystal, there are 2 components because amoxicillin and water are chemically distinct molecules

False, amoxicillin trihydrate has water associated with it

Examples of other pharmaceutical ingredients used for solutions

Flavors and sweeteners To make product more palatable Colorants Enhance product appeal Preservatives Prevent microbial growth Stabilizers Anti-oxidants and chelating agents Added to prevent drug decomposition

Use and Advantages of Parenteral Dosage forms

Fluid, electrolyte, nutrient replacement Drugs requiring rapid effects, and predictable effects Used for solutions of irritating drugs because of rapid dilution with blood Many veins readily available Drug diluted throughout systemic circulation rather than pooled in a particular organ In most cases, bioavailability is 100% Can dose precisely and accurately

How much dextrose monohydrate (E value 0.16) will be needed to create 250 mL of isotonic Lidocaine HCl

For 250 mL of isotonic Lidocaine HCl solution using NaCl = 1.975 g NaCl will be needed For 250 mL of isotonic Lidocaine HCl solution using dextrose monohydrate (E value 0.16) 1.975 g/0.16 = 12.3 g of dextrose needed

Rate of absorption =

For absorption through membranes in body: Cout (GI lumen) >>>> Cin (blood) Rate of absorption = (DSK of o/w x (Cout))/h D = Diffusion coefficient S = Surface Area K of o/w = Octanol/water partition coefficient h = Membrane thickness Cout = concentration of drug in GI lumen

Common features in the ionization equations of weak acids and bases

For acids: pH = pKa + log ([A-]/[HA]) For bases: pH = pKa + log ([B]/[BH+]) (A-, HA) and (B, BH+) are Conjugate acid-base pairs

Diffusion through membranes

For membranes, must account for drug that has higher affinity for membrane than aqueous environment Account for phase change (discontinuity) Distribution of drug in membrane phase in relation to distribution of drug in aqueous solution phase C1 = concentration outside the membrane of cell C2 = concentration inside the cell (past the membrane) Cout = concentration outside the cell Cin = concentration inside the cell C1/Cout = C2/Cin = K

Characteristics of drug molecule: Concentration outside of membrane

For passive diffusion, the rate of absorption is directly proportional to the concentration at the absorption site This means that absorption will be a first-order process Graph is a straight line going up from left to right = greater the concentration in the GI lumen, greater the rate of absorption

What is the mole % free phenobarbital in solution at pH= 8 (pKa = 7.8)

Free = unionized drug molecules Weak acid %I = 100%/(1 + 10^(pKa-pH)) = 100%/(1 + 10^(7.8 - 8)) = 76.81% 100 - 76.81 ionized = 23.19% free phenobarbital

What is the mole % free cocaine in solution at pH = 8? (pKa of conjugate cation acid of cocaine is 8.41)

Free = unionized drug molecules Weak base %I = 100%/1 + 10^(pH-pKa) = 100%/(1 + 10^(8-8.41)) = 71.99% 100-71.99% ionized = 28 % free cocaine

Only free drug exits capillaries

Free drug diffuses across capillary walls Plasma proteins are too large to exit Protein bound drug also too large Plasma protein binding RESTRICTS distribution

Solubility of weak acids

HA = carboxylic acid, sulfonamides, imides, phenols HA solid ===== HA solution ====H+ + A- HA solid and HA solution are neutral/constant H+ + A- are total ion concentration If amount of HA in solution is too high, will precipitate out 2 equilibria going on at same time, if change one----other will change

Partition of ionizable drugs in oil/water

HA ====== A- + H+ K = C1/C2 = Valid only with concentration of the species common to both phases K = [HA]o/[HA]w [HA]o = non-ionized form in oil [HA]w = non-ionized form in water

How many liters of carbon dioxide will dissolve in 1 liter of water at 25C when the pressure of gas is 0.7 atm? k(CO2) = 1.64 x 10^3 atm/mole fraction CO2

Henry's law: Psolute = k x Concent solute k(CO2) = 1.64 x 10^3 atm/mole fraction CO2 PCO2 = 0.7 atm Concent CO2 = PCO2/k = 0.7/1640 = 4.27 x 10^-4 mole fraction Mole fraction = Concent CO2 = moles CO2/(moles CO2 + moles H2O) moles H20 = 1 L H20 = 1000 g H20 1000 g H20 x 1 mole H20/18.01 g = 55.56 moles 0.000427 moles CO2 (mole fraction) = x moles CO2/(x moles CO2 + 55.56 moles water) 0.023724 moles water*moles CO2 + 0.00427 moles CO2 - 0.00427 moles CO2 = x mole CO2 - 0.00427 moles CO2 0.023724 moles water*moles CO2/0.99573 moles CO2 = 0.99573 moles CO2/0.99573 moles CO2 moles CO2 = 0.0238 At 25C & 0.7 atm, volume of CO2 can be calculated from ideal gas law: PV = nRT V = nRT/P = (0.0238 moles x 0.0821 L x atm/K x mol x 298K)/0.7 atm = 83 L volume of CO2

Rate of administration

How quickly drug is injected depends on individual drug Specific guidelines for IV administration in Trissel's Handbook on Injectable Drugs If solution is injected too quickly, it may cause local pain and undesireable cardivascular or CNS effects Rate of injection may be influenced by how soluble drug is

Pharmacist may need to make opthalmic solutions if there are no available commercial products

However, must have ability to make sterile product that is free of particulate matter

Weak electrolyte

INCOMPLETELY dissocates (ex: carboxylic acids)

Advantages and Uses of Parenteral Therapies

Immediate physiological response Required for drugs that are ineffective orally Drugs can be given to nauseated, uncooperative or unconscious patients Clinician has direct control over therapy Serious disturbances of fluids and electrolyte balance can be corrected Can supply TPN by parenteral route when patient can't eat (NPO) Can supply drug directly to an organ

For a given substance, how does enthalpy change with temperature?

Increase in temp = increase in enthalpy. As temp added to system, it breaks the intermolecular forces

For a given substance, how does entropy change with temperature?

Increase in temp = increase in entropy In a solid, molecules are locked in, in a liquid there are more places for molecules to be, and in gas even more places

Higher density (n/V) is achieved by

Increasing number of molecules Decreasing volume of container

What does not correspond to a mechanism by which molecular dispersions increase the dissolution rate of drug?

Increasing particle size

Intravenous Administratoin

Injection Area: Veins make this a very accessible route Large or small volumes of solutions can be administered Flow rate may be restricted by size of vein Intravenous sub-divided further into: Continuous or constant-rate infusion Intermittent IV push or bolus

Elemental isotopes

Isotopes contain the same number of protons (which determines the atomic number of element) but different number of neutrons Hydrogen = (0 neutron, 1 proton) Deuterium (1 neutron, 1 proton) Tritium (2 neutrons, 1 proton)

Is the melting point of salt always higher than parent drug?

It depends on structure of solid---usually salt melting point is higher than parent drug

Why can't sprays be used for systemic effects?

It doesn't easily enter the bloodstream, because skin has a very good membrane and it is hard to penetrate

For hypothetical drug being infused into organ at constant concentration, it was found that the concentration of organ reached equilibrium at approximately 15 min, adn was 20 mcg/mL. What was the distribution half-life of this drug? At one distribution half-life, what was the concentration in organ? For patient with polycythemia, would you expect equilibrium in organ to be reached more quickly or more slowly than a patient with normal hematocrit? Why?

It takes about 5 distribution half-lives to reach equilibrium, so t1/2, d is approximately 3 min. At 3 min, the concentration of drug in organ would be 10 mcg/mL Since the blood flow is decreased in polycythemia, it will take longer for the organ to come to equilibrium

Characteristics of drug molecule: Lipophilicity (K of o/w)

K of o/w is measure of lipid solubility K of o/w = partition coefficient = (concentration of drug in octanol)/(concentration of drug in water)

Apparent distribution coefficient for acids

K' weak acid = K of o/w/(1 + 10^(pH - pKa))

Which of these interactions, taken together, constitute van der Waals interactions? Is this interaction always attractive?

Keesom, London, Debye Yes, always attractive

Conjugate acid-base pairs cocrystals

Key feature: Charge assisted short strong H-bonds Advantages: higher potency than normal salt, potential to improve pharmaceutical properties

Van der Waals Force

Keysom Debye Dispersion

Calculate the Kf for water (Tf = 273.2K, deltaHf = 1437 cal/mol, R = 1.987 cal*mol^-1*K^-1, MW = 18.02). Then, calculate the freezing point depression of a solution containing 50 g dextrose (MW = 180.2) in 1000 g of water.

Kf = (RTf^2/deltaHf) x (MW of solvent/1000 g) Kf = ((1.987 cal*mol^-1K^-1 x (273.2K)^2)/1437 cal/mol) s (18.02 g water/mole/1000 g) Kf = 1.86 K*kg/mol deltaTf = Kfm deltaTf = 1.86 K * kg/mol x 50 g dextrose/180.2 g/mole dextrose = -0.516 degrees C Always report freezing point depression as a negative value The addition of 50 g dextrose to 1 L of water will decrease the freezing point of the solution by 0.52 degrees C

Parenterals are subdivided into:

Large volume parenterals (single dose injections of greater than 100 mL) Small volume parenterals (less than 100 mL)

Applications of Ideal Gas Law PV = nRT

Lypohilization (freeze drying) Solid to gas under vacuum Increase shelf life (stability) Easier to ship/store Easy to reconstitute Aerosols (Liquid to gas) Easy to admin Rapid and reproducible delivery Controlled environment Withdrawing a drug solution from a vial

Consider six 0.0001 M aqueous solutions of aspirin, Nacl, MgCl2, dextrose, mannitol and MgSO4. Which solution has lowest vapor pressure?

MgCl2 because it has 3 atoms that can dissociate in water, increasing the molar fraction because however many moles are added have to be multiplied by 3.

Intermolecular forces: dipole-dipole

Moderate strength Distance dependence is 1/r^3

Mole percent definition

Mole fraction x 100

Types of additive properties

Molecular weight, mass of a solution, volume

Distance dependence of interactions

Molecule-Molecule = closest Ion-Molecule = next closest Ion-Ion = farthest away

Membranes made up of phospholipid bilayers

Molecules need to have some lipid-like characteristics to be able to cross membrane passively

Molarity definition

Moles (gram molecular weights) of solute in 1 liter of solution

In practice...

Monitor particulate matter Careful visual monitoring: product swirled and viewed against dark/light backgrounds of certain intensity particles greater than 50 microm can be seen by visual inspection Filtration: Either post prep or in-line to patient

Weak acid at high pH

More drug is ionized

Weak base at low pH

More drug is ionized

What happens after we vacuum off the gas molecules in system (slide 6 Liquids) and then leave it alone?

More liquid would enter the gas phase, to establish equilibrium

Normality symbol(s)

N

Which of the following would exert the highest osmotic pressure, if each was an ideal solution at a concentration of 1 mM? NaCl FeCl3 KCl Na2SO4 Na(x)Alginate (Alginate has 15 charged carboxylic acid groups, COO- on each molecule)

Na(x)Alginate, because for each of the 15 charged groups on Aliginate, there will be a corresponding Na. Thus there are 16 species involved, which means any molar amount exerting pressure would have to be multiplied by 16.

Nasal sprays

Nasal congestion, inflammation, infection Contain antihistamines, sympathomimetics (decongestants), antibiotics

How is the choice of dosage form made?

Nature of illness Treating acne or cancer? Manner in which illness is treated, ex: systemic vs. local

Solvents used for parenteral solutions

No preservatives, one time use Water for Injection, USP Meets same standards as Purified Water, USP Not sterile, but pyrogen free No added substances To be used to make injectable products that will be sterilized later Containers used must be sterile and pyrogen-free Sterile Water for Injection, USP Sterile & pyrogen free No antimicrobial agents or added substances To be used as a solvent for already sterilized and packaged injectable medications Bacteriostatic Water for Injection, USP Sterile water for injection to which has been added one or more microbial agents May not be packaged in containers greater than 30 mL in size Can only be admin in small volumes because of antimicrobial agent Beware of incompatibilities between drug and antimicrobial agents Must be labeled "Not for Use in Neonates" because of preservatives Sodium Chloride Injection, USP Sterile, isotonic Used as sterile vehicle for reconstituting medications for injection Contains 0.9% NaCl (154 mEq each of sodium and chloride ion) in Water for Injection Bacteriostatic Sodium Chloride Injection, USP Contains 0.9% NaCl (154 mEq each of sodium and chloride ion) in Water for Injection One or more antimicrobial agents present May not be packaged in containers greater than 30 mL in size Beware of incompatabilities between drug and antimicrobial agents Must be labeled "Not for Use in Neonates" Non-aqueous solvents Vegetable oils (corn oil, cottonseed oil, peanut oil, sesame oil) Glycerin Polyethylene glycol, propylene glycol, alcohol Not used for intravenous injection, IM or ID only

Are the colligative properties of a 0.1 M salt solution the same as those of sugar solution?

No, because they dissociate differently

Does delta Heat of fusion depend on solvent?

No, it has nothing to do with solvent

Does the presence of inert gas (ex: air) above the liquid affect equilibrium vapor pressure?

No, it will re-establish equilibrium vapor pressure, because water molecules escaping will equal water molecules being recaptured. Inert gas = no effect

Repulsive forces

Non-bonding electrons repel as atoms approach one another As atoms get closer, nuclei also start to repel Always positive, because repulsive

For what kind of drugs is precipitation a problem?

Non-polar drugs

What is the bioavailability for opthalmic solutions?

Not easy to permeate, so low

Aromatic Waters are clear, aqueous solutions saturated with volatile oils or aromatic oils

Not used now except for perfuming or flavoring Prepared from such things as orange flower oil, peppermint oil, rose oil, wintergreen oil

Use of pH-partition hypothesis in drug development

Omeprazole, weak base, pKa approximately 4 Dissolve well in acid environment & absorbed well in intestine Given as capsule of enteric coated beads Absorbed in intestine, where it is unionized Gets into blood as unionized compound Blood carries it to stomach where it crosses into gastric parietal cells Since pH is very low in stomach, omeprazol is concentrated there in ionized form It exerts activiity against the H+, K+-ATPase pump

If one takes a drug orally--what barriers must be overcome to get drug to site of action?

Once drug is in solution, molecules must: Cross membrane in GI epithelial cell Cross membrane in capillaries to reach blood Cross membrane in organ where receptors are Diffuse to receptors and exert activity Cell membranes constitute major barriers to drug absorption in body

Solid dispersions: molecular dispersions

One component in another Solid is amorphous, have intermediate melting temp Ex: dispersion of solid particles in semisolids to facilitate dissolution Accelerated drug dissolution rate by: Decreasing in particle size Decreasing aggregation and agglomeration Increasing wettability (changing surface tension) Increasing drug solubility

How many phases does a solid solution have?

One, homogenous throughout

Pharmaceutical Solids

Oral solid dosage forms (immediate release, controlled release)---tablet or capsule Suppositories Powders Suspensions (solid suspended in liquid) Ointments (solids dispersed in ointment base) Parenteral products (ex: proteins)

Is bioavailability of an oral solution better or worse than a tablet?

Oral solution is better, because it does not need to dissolve first before it's absorbed

Why are liquids of interest?

Oral solutions, eye drops Vehicle for suspensions (pediatric patients) Parenteral products (infusion, flu shot) Inhalation products Drug dissolution in GI tract Drug transport in plasma Media for crystallization

Taste masking

Orally disintegrating tablet---for delivery of bitter drug, takes advantage of salt out formation There is a drug core, surrounded by a salting out layer (not permeable in high salt concentrations), which is then surounded by a water penetration layer (water insoluble) See slide 8, Nov 7th

Lady Gaga was recently hospitalized for chest pains following CNN's announcement that Madonna was the most highly paid musician in the world in 2013. While in hospital, Ms. Gaga received 12 hour infusion of Tacky-Card to treat cardiac arrythmia. Her total dose was 1200 mg in 12 hour period. After about an hour into infusion, Gaga began to complain of severe headache & wooziness, which persisted until about an hour after infusion stopped. Blood levels were taken throughout the infusion, and found they exceeded the therapeutic range for drug (1 to 2.5 mg/L). See concentration-time profile on slide 50 Intravascular Admin. Gaga needs to be restarted on Tacky-Card---need to determine new & more appropriate infusion rate such that Gaga will receive daily total dose of 1200 mg, but her steady state concentration is maintained in therapeutic range. What would you suggest, and what would her new concentration-time profile look like?

Original infusion rate = 1200 mg/12 hours = 100 mg/hour. This infusion rate gave a steady state concentration of 3.75 mg/L. The steady state concentration needs to be between 1 and 2.5 mg/L. What is the infusion rate that will generate 1.25 mg/L? 100 mg/hr/3.75 mg/L x 1.25 mg/L = 33.3 mg/hr = new infusion rate Will this work? What is wanted is a 1200 mg daily dose, so at this rate, it will take 36 hours at 33.3 mg/hr to get daily dose. Infusion rate not high enough There are 24 hours in a day, so what infusion rate to get 1200 mg/day? 1200 mg/24 hours = 50 mg/hour Will Gaga be in therapeutic range? 3.75 mg/L/100 mg/hr x 50 mg/hr = 1.87 mg/L So continuous infusion of 50 mg/hr will keep Gaga in therapeutic range. See slide 50 Intravascular Admin

How can pyrogens be removed from parenteral solutions?

Oxidizing them to easily eliminated gases or to nonvolatile solids----easily separated from water by fractional distillation. Potassium permaganate as oxidizing agent and barium hydroxide to increase alkalinity and make nonvolatile barium salts of any acidic compound present---these 2 reagents added to water that has been distilled several times, then distillation repeated & chemical free distillate is collected under strict aseptic conditions

Thermodynamics

P + D === PD K = [PD]/([P][Df]) Thermodynamic equations related to this equilibrium: 1) deltaG^o = -RTlnK (Negative deltaG = binding is spontaneous---larger the K, the more negative the delta G is) 2) ln(KT1/KT2) = -deltaH^o/R x (1/T1 - 1/T2) (Negative delta H: binding is exothermic, positive delta H = binding is endothermic) 3) deltaG^o = deltaH^o - TdeltaS^o (Negative delta G = spontaneous binding, negative delta H = binding is exothermic, positive deltaH = binding is endothermic

0.193 mole sample confined in 7.35 L vessel at 295 K. Calculate pressure produced

PV = nRT P = nRT/V (0.193 mol x 0.0821 Latm/Kmol x 295 K)/7.35 L = 0.636 atm

In assay of ethyl nitrite spirit, nitric oxide gas liberated from definite quantity of spirit & collected in gas burrette occupies volume of 30 mL at temp 20 degrees C & pressure of 740 mmHg. Assuming gas is ideal, what is volume at 0 degrees C and 760 mmHg?

PV = nRT n & R are constants P1V1/T1 = P2V2/T2 T1= 293 K T2 = 273 K (740 mmHg x 30 mL)/293 K = (760 mmHg x V2)/273 K) (740 mmHg x 30 mL)/293 K x (273 K/760 mmHg) = V2 V2 = 27.2 mL

When pH = pKa, for acids

Partition coefficient is 1/2 that of distribution coefficient

What is a PCA and what is it used for?

Patient controlled analgesia---used to control pain associated with variety of surgical procedures, labor, sickle cell crisis, and cancer---allows greater degree of ambulation and independence. Includes syringe or chamber that contains analgesic drug & programmable electromechanical unit. Unit can be worn on belt or carried in pocket, controls delivery of drug by advancing a piston when patient presses a button. Deliver IV bolus injections for rapid analgesia or slower infusion for steady state concentrations for sustained pain control

Why is it a requirement that dye FD&C Yellow 5 specifically be named on products that contain it?

Patients could have allergic reaction

Dissolution of Metastable Phase

Peak concentration of anhydrous form is approximately 2 times that of hydrate At prolonged time point, concentration in solution is the same Slide 20 in phase equilibria 1 is typical dissolution profile of metastable solid phase

Ion-Dipole interaction

Permanent dipoles are preferentially aligned near ion (ordered), but are randomly aligned farther away (alignments are flipped for negative ion)

Biopharmaceutical Classification System

Permeability = how fast/easily drug can pass through membrane----very important for drug delivery About 80% of top 200 drugs (oral, IR tablet) are practically insoluble---require special treatment to become soluble in body

Two-component system

Phase Rule: F = C - P + 2 At given T & P, F = C - P See slide 13 Phase Equilibria 1

For each dosage form the pharmaceutical ingredients establish the primary features of pharmaceutical dosage form. They contribute to:

Physical form Texture Stability Taste Overall apperance

Henry's law equation

Pressure of solute = k x Concentration of solute (gas) in solution K = Henry's law constant---can vary, match k value units with C units

In practice, key to freedom from pyrogens is:

Prevention. Once you have them, they are very difficult to get rid of Filtering through sterilization filters will not eliminate them Moist heat will not destroy them In practice, don't do much testing, but rely on manufacturers' procedures However, when required, Limulus test might be appropriate

Osmosis

Process where small solvent molecules diffuse through a semi-permeable membrane from a more concentrated solution into less concentrated solution

Estimate boiling point of water in Denver, CO where air pressure is about 620 torr. deltaHv of water is 10,500 cal/mol & boiling point of water is 100 degrees C at 1 atm

R = 1.9872 cal/molK 1 atm = 760 torr T1 = 373 K ln(P2/P1) = (deltaHv/R) x (1/T1 - 1/T2) log (620 torr/760 torr) = (10, 500 cal/mol)/(1.9872 cal/molK) x (1/373 K - 1/T2) Divide left side of equation by first part of right side of equation, then subtract 1/373 K from both sides = - 1/T2 T2 = 367.7 K

General rules for reabsorption: Weak bases

R-NH3+ ==== R-NH2 + H+ As pH increases, unionized form increases, lipophilicity increases As pH increases, reabsorption increases, renal excretion decreases Very polar in ionized form: no reabsorption unless actively transported Urine pH has no effect Ex: aminoglycosides (gentamicin, tobramycin)===not given orally, because not absorbed----too polar to be absorbed from intestine or renal tubules

What determines how quickly drug is distributed?

Rate of distribution of drug in body is determined by: Perfusion Diffusion

deltaG = deltaH - T x deltaS If delta H is positive & delta S is negative, how does it effect deltaG (reaction spontaneity)?

Reaction both enthalpically and entropically opposed. It is unspontaneous (endergonic) at all temps

deltaG = deltaH - T x deltaS If deltaH is negative, and deltaS positive----how does it effect deltaG (reaction spontaneity)?

Reaction is both enthalpically favored (exothermic) and entropically favored. It is spontaneous at all temperatures

deltaG = deltaH - T x deltaS If both deltaH and deltaS are negative, how does it effect deltaG (reaction spontaneity)?

Reaction is enthalpically favored, but entropically opposed. It is spontaneous only at temperatures below T = deltaH/deltaS

deltaG = deltaH - T x deltaS If both deltaH and deltaS are positive, how does it effect deltaG (reaction spontaneity)?

Reaction is enthalpically opposed (endothermic), but entropically favored. It is spontaneous only at temperatures above T = deltaH/deltaS

Pediatric pt has rectal temp of 102.4 degrees F. Calculate oral temp in both F and C.

Rectal temp = 1 degree F > oral temp 102.4 degrees F - 1 degree F = 101.4 degree F oral temp C = (F -32) x 5/9 C = (101.4 -32) x 5/9 = 38.6 degrees C oral temp

A premature baby has axillary temp 99.6 degrees F. What would be equivalent (in F) if taken rectally?

Rectal temp = 2 degrees F greater than axillary temp 99.6 F + 2 F = 101.6 degrees F

Equivalent weight (g/Eq)

Required for calculating normality (N) of solution 1) For acids or bases: The weight of compound that supplies or reacts with one mole of H+ in an acid-base reaction 2) For salts: The molecular weight divided by the number of positive or negative electrical charges that result from dissolution of compund

Snowflakes

Same structure, different shapes Different environment in which growth of crystal occurs

Measuring protein binding

See slide 11 Protein binding Equilibrium dialysis %bound drug in plasma = 100% x [PD]/([PD] + [Df]) Drug equilibrates across the membrane, but protein can't because it's too big Free drug concentration on buffer side is the same as the free concentration on plasma side How do we determine [PD]? Separate drug and do analytical method. Measure how much drug put in, and subtract how much free drug = drug bound Other methods: Ultrafiltration, dynamic dialysis

Relationship between pH-solubility of an acid and solubility of its salts

See slide 13, Nov 3 pHp = if pH goes below this, has risk of precipitation, if ph is above---no risk of precipitation

Liquid-Liquid phase diagram

See slide 14 Phase Equilibria 1 F = C - P + 2 Constant presssure, F = 3 - P (because C = 2)

Hydration/dehydration of drugs

See slide 15 Phase Equilibria 1 Anhydrate crystal in high relative humidity (RH) in gas form can become hydrate crystal Anydrate crystal in liquid can become crystallized and become hydrate crystal

pH-solubility profile of zwitterionic drug

See slide 15, Nov 3 U shaped curve = 2 ionizable groups on molecule Area to left = pH solubility of base Middle bottom = intrinsic solubility Area to right = pH solubility of acid

Calculating Phase composition using lever rule

See slide 19 Phase Equilibria 2 At point d, system contains 24% phenol and 76% water Upper layer (A) = water rich Lower layer (B) = phenol rich (Weight of Phase A)/(Weight of Phase B) = (length dc)/(length bd) = (63-24)/(24-11) = 39/13 = 3/1

Hydrophobic intereactions

See slide 21 Protein Binding 1) Water molecules are ordered around protein and drug molecules 2) Hydrophobic sites of drug and protein molecules avoid water by coming close to each other 3) Water molecules are "squeezed out" === broken water cage d/t hydrophobic interactions between drug and protein 4) This process is usually endothermic (positive deltaH), but also increases entropy (positive deltaS)----is entropy driven 5) deltaG = deltaH - T x deltaS, the delta G is negative because T- deltaS is larger than deltaH

Vapor phase mediated redistribution of Drug in tablet

See slide 22 Colligative Properties Solutions Nitroglycerin: a vasodilator to treat heart conditions, such as angina and chronic heart failure To solve the problem, evaporation of nitroglycerin must be depressed by reducing its vapor pressure, by mixing it with PEG 400

Addition of nonvolatile solution

See slide 25 Colligative Properties Solutions 1) lowers the vapor pressure of the pure solvent, and therefore, 2) the solution must be heated to higher temperatures to boil (boiling point elevation)

Osmotic drug delivery systems

See slide 36 Colligative Properties Solutions Has an impermeable, but flexible inner membrane Semipermeable outer membrane Water flows in, causing drug to release, by making inner layer collapse and pushes drug out

Types of solid solution

See slide 8 Phase Equilibria 2 Small molecule crystals as solvent: Substitutional solid solution Interstitial crystalline solid solution (in between crystals) Polymers as solvent: In amorphous region of a polymer In crystalline regions of polymer

Improving drug delivery by solid dispersion

Slide 9 phase equilibira 2 Increasing solid dispersion of drug makes it more crystalline & has less of co-solvent, decreasing bioavailability

Henry's law region

Small amounts of solute in large amounts of solvent (very dilute solutions)

Relative humidity (RH) over a saturated NaCl solution is about 75% at 25 and 40 degrees C. However, RH over saturated potassium nitrate solution is 94% at 25 C and 89% at 40 C. Why does temperature affect RH of 2 salt solutions differently?

Solubility of NaCl does not change with increase in temp Solubility of KNO3 increases with increase in temp Vapor pressure goes down, holds onto KNO3 a little bit more because there is more in solution, lowers escape rate NaCl relative humidity stays at 75% and solubility does not change KNO3 starts out at 94% relative humidity & as temp increases from 25 C to 40 C, RH drops to 89% Gas phase molecule does not know what is in condition Change in relative humidity = what is going on in liquid phase Less water vapor escaping the surface = decrease in RH Saturated solution at 40 C has more KNO3 as temperature increases

Protein purification: Salting-in

Solubility of protein INCREASES in dilute salt solutions

Types of constitutive properties

Solubility, interfacial energy (surface tension)

Positive deviation (activity coefficient > 1)

Solute and solvent remain separate

Solid dispersions: solid solutions

Solute is molecularly dispersed Solvent is solid (partially miscible), forming mixed crystals

Different intermolecular interactions

Solute-solvent 1 (ex: water) Solute-solvent 2 (ex: organic solvent)

Why do nasal solutions need to use antimicrobial preservatives?

Solution is mostly water, so does not have a very good preservative effect

Solubization by Cyclodextrin (CD) equation

St = So + K11 x So x [CD] St = concentration of drug So= intrinsic solubility of drug K11 = binding constant between drug and cyclodextrin [CD] = cyclodextrin concentration

Disadvantages of Solution Dosage forms

Stability Solubility Taste Hard to handle Dosing accuracy difficult to assure

Required properties of opthalmic solution

Sterility and clarity Prepare using aspetic technique with sterile parenteral drug products OR Prepare using non-sterile, but high quality ingredients, then filter final solution with membrane filter In either case, solution must be packaged in sterile, particle free container

General rules of reabsorption: Strong bases

Strong base, pKa greater than or equal to 12. No reabsorption because drug is completely ionized Renal clearance is independent of pH, but will generally be high, because these compounds are often actively secreted Ex: Guanethidine

Pharmacokinetics and ADME

Study of the time course of drug Absorption, Distribution, Metabolism, and Excretion in body (ADME) How do we measure and describe the "time course?" By measuring: Rate =====how fast? Extent ===== how much?

Bronsted-Lowry Base

Substance capable of ACCEPTING a proton

Bronsted-Lowry Acid

Substance capable of DONATING a proton

Skin sprays

Sun burn, athlete's foot, fungal infections Contain local anesthetics, antiseptics, skin protectants (sunscreens), antipruitics (anti-itch agents), anti fungals

Disadvantages of Parenteral Dosage forms

Sustained blood levels difficult to achieve unelss give continuous infusion Always the hazard of thrombus (blood clot) formation d/t irritation of tissues by catheter or drug solution If thrombus breaks free & circulates in blood stream, is an embolus Embolism (obstruction) of blood flow, generally in pulmonary circulation Once drug is admin, no retreat Duration of use after IV injection determined by initial dose, volume of distribution, and t1/2 Have to increase dose to increase duration of effect, may reach toxic levels early on IV drugs must be in solution Generally aqueous solution Fat emulsions: Nutritional support, Propofol, o/w emulsion Suspensions can't be used: Insoluble particles will lodge in capillary beds (often pulmonary), causing blockage

Clearance (CL), AUC ("exposure")

The area under the plasma curve (AUC) is used to measure the body's ability to eliminate the drug (CL) CL = F x D/(AUC) D = Dose CL = Clearance F = Bioavailability (% of drug absorbed)

We had earlier observed several drugs exist as hydrates. You have to prepare solid dosage form of a drug available as either anhydrate or dihydrate. Anhydrate stable up to 15% humidity. Humidity greater than 15% = stable dihydrate. What will the basis for solution of physical form of API? Relative humidity at manufacturing plant is 40 to 50%

The major consideration will be conditions (esp. water vapor pressure) under which anhydrous or hydrate forms are stable. Since relative humidity during manufacturing and storage is usually higher than 15%, the dihydrate is preferred. If anhydrate was selected, change to dihydrate may occur

Calculate the vapor pressure depression of water in the presence of 0.155 M of NaCl at 20 degrees C?

The vapor pressure of pure water (p1^o) is 17.54 mmHg at 20 degrees C delta(p1) = - p1^o x X2 1) NaCl dissociates completely into Na+ and Cl- ions in water. As a result, for each mole of NaCl, there will be 2 moles of solute constituents. 2) molarity = 0.155 x 2 = 0.310 M 3) X2 = n2/(n1 + n2) approximately = n2/n1 = M2/(density of solute/molecular weight of solute) = (0.31 mol/L)/55.56 mol/L 4) delta(p1) = - p1^o x X2 = (17.54 mmHg) x ((0.31 mol/L)/55.56 mol/L) = 0.098 mmHg

How is equilibrium vapor pressure of water affected by adding a salt?

There will be a decrease in VP, because water will be affected by positive ions in salt

Would completely miscible systems have a different phase diagram than on slide 14 of phase equilibria 1?

There would be no line, because there's no change in phase

Would phase diagrams for non-miscible systems look like graph on slide 14 of phase equilibria 1?

There would be no line, because there's no change in phase

The entropy for the same substance always follows: gas > liquid > solid

True

Under the same temperature and pressure, the free energy of a metastable polymorph is always higher than that of the corresponding stable form

True

How to distinguish between polymorph forms?

Try to deform/break them See slides 15 and 16 Solids

Can 2 polymorphs coexist over range of temps? Assume we are dealing with system under atmospheric pressure

Under given temp & pressure, only one polymorphic form is stable. 2 polymorphs can coexist in stable equilibrium only at transition temp. Both cannot be in stable equilibrium over range of temps, otherwise phase rule is violated

Henderson-Hasselbach Equation

Useful for calculating: 1) pH of solution containing: a weak acid and its salt, a weak base and its salt 2) percentage of drug in solution in ionized (A- or BH+) or unionized (HA or B) form 3) Solubility of drug at given pH 4) pH a which a drug can precipitate out of a solution

Factors that affect reabsorption from renal tubule

Vast majority of reabsorbed drugs are reabsorbed by passive processes All considerations discussed with regard to membrane transport (for absorption) hold true for reabsorption Fick's Law! (Membrane diffusion) Urinary pH rate of reabsorption = ((DSK of o/w) x (Curine))/h Concenration of blood is much lower than in the urine, don't have to account for that term

Intermolecular forces: London Forces

Very weak Distance dependence is 1/r^6

Intermolecular forces: dipole-induced dipole

Very weak Distance dependence is 1/r^6

Factors affecting Blood Flow

Vessel Radius Viscosity Cardiac Output Volume

You have been asked to formulate a drug into solid oral dosage form. Drug product is for use by group of hikers who will b experiencing wide range of humidity (very low to very high) values. Do you prefer tablet or capsule formation?

Water content in capsule (made of gelatin) is carefully controlled. If gelatin absorbs water, integrity of capsule is at risk----if loses water can become brittle and damaged easily. Tablet dosage is preferred

Pyrogen sources

Water used to make solution Water for Injection (WFI) must be used Containers used during preparation packaging, storage or admin of solution Dry heat sterilization Rinsing with WFI Chemicals used in preparation of parenteral Especially those from natural sources or fermentation

Intermolecular forces: ion-induced dipole

Weak Distance dependence is 1/r^4

Predictions of pH-partition hypothesis don't always hold

Weak acids Phenytoin with pKa of 8.2, is 100% unionized in stomach (pH of 1) and 98.2 % unionized in small intestine (pH= 6.5), but still mostly absorbed in small intestine Aspirin with pKa of 3.5 is 100% unionized in stomach, and 0.1 % unionized in the small intestine, but still mostly absorbed in small intestine

Still more general rules for reabsorption: Weak bases

Weak base = pKa between 6 and 12 (pH range of urine 4.5 to 7.5) Renal clearance greatly influenced by pH Reabsorption can be negligible or complete, depending on urine pH Ex: amphetamines, phenylpropanolamine

More general rules for reabsorption: Weak bases

Weakly basic non-polar drug with pKa 6 is extensively reabsorbed at all urine pHs (pH = 4.5 to 7.5) because there is a large concentration of unionized drug Renal clearance may vary with urine pH, but will usually be low (especially if bound to proteins) Increased reabsorption, decreased renal clearance Ex: diazepam, propoxyphene

Calculating compositions of System using Lever rule

Weight of A/Weight of B = length of dc/Length of bc 1) 2 phases are present Liquid phase (a1) = 53% thymol in salol Pure solid thymol (b1) 2) Applying lever rule Weight ratio of a1/b1 = (b1 - x1)/(x1 - a1) = (100 - 60)/(60 - 53) = 40/7 = 5.71 : 1 5.71 parts thymol salol solution to 1 part solid thymol See slide 20 Phase equilbria 2

Onset

When drug first gets to minimum effective concentration (MEC)

Can we determine pKa from graph of pH-solubility of weak acid (Nov 3, slide 7)?

Yes. Find where 2 x Co is to find corresponding pH, and this will equal pKa

The solubility of HCl salt of the drug is impacted by ______ in gastric fluid

[Cl-]

pH of solution of weak acid

[H3O+] = (-Ka + (Ka^2 + 4KaCa)^1/2)/2 When the concentration of acid, Ca, is much higher than that of the hydrogen ion, [H3O+], can use this equation: [H3O+] = (Ka x Ca)^1/2 Then - log (H3O+) = pH

pH of solution of weak base

[OH-] = (-Kb + (Kb^2 + 4KbCb)^1/2)/2 When concentration of base, Cb, is much higher than [OH-] (at least 10 fold), then can use this equation: [OH-] = (Kb x Cb)^1/2 Then - log (OH-) = pOH 14 - pOH = pH

The pH of a 0.03 M solution of procaine (Kb = 7 x 10^-6 at 25C) is:

[OH-] = (Kb x Cb)^1/2 Then - log (OH-) = pOH 14 - pOH = pH (7 x 10^-6 x 0.03M)^1/2 = 4.58257569 x 10^-4 = [OH-] -log (4.58257569 x 10^-4) = 3.33889 = pOH 14 - 3.33889 = 10.66 = pH

The freezing of a SODIUM phosphate buffer solution results in....

a pH DROP Phosphate buffer: H2PO4 ===== H+ + HPO4(2-) Leads to crystallization of disodium phosphate (Na2HPO4) Means less HPO4(2-) in solution Will cause reaction to move more from left to right----creating more H+ ions

The freezing of a POTASSIUM phosphate buffer solution results in...

a pH INCREASE Phosphate buffer: H2PO4- ==== H+ HPO4(2-) Leads to crystallization of the monopotassium dihydrogen phosphate (KH2PO4) Will cause reaction to move from right to left---meaning less H+ ions ions in solution

When a solution is to be used in multiple doses for longer than 24 hours

a preservative must be added Benzalkonium chloride, chlorobutanol, phenylmercuric acetate, thimerosol

Using sodium chloride equivalent method, make following solutions isotonic with respect to the mucous lining of eye a) Tetracaine HCl (E = 0.18): 10 g, NaCl qs, sterile water qs ad 1000 mL b) Tetracaine HCl: 0.1g, boric acid (E = 0.5) qs, sterile water qs ad 10 mL

a) 0.9 g NaCl/100 mL solution x 1000 mL solution = 9 g NaCl needed total 0.18 g NaCl/1 g tetracaine HCl x 10 g tetracaine HCl = 1.8 g NaCl equivalents 9 g NaCl total -1.8 g NaCl from tetracaine HCl = 7.2 g NaCl needed b) 0.9 g NaCl/100 mL solution x 10 mL solution = 0.09 g NaCl needed total 0.18 g NaCl/1 g tetracaine HCl x 0.1 g tetracaine HCl = 0.018 g NaCl equivalents 0.5 g NaCl/1 g boric acid x Y = 0.072 g NaCl = 0.144 g boric acid needed

Isoflurane & holothane are non-flammable volatile liquids used for general anesthesia a) What is the vapor pressure of isoflurane at room temp, 25 degrees C? Heat of vap of isoflourane = 6782 cal/mol at its boiling point. Vapor pressure of isofluorane at normal boiling point of 48.5 degrees C is 1 atm.

a) 298 K = T1 T2 = 273 + 48.5 = 321.5 K R = 1.9872 cal/molK ln(P2/P1) = deltaHv/R x (1/T1 - 1/T2) ln(1 atm/P1) = (6782 cal/mol)/(1.9872 cal/molK) x (1/298 K - 1/321.5 K) Raise both sides e^(both sides) 1 atm/P1 = 2.30935316 P1 = 0.433 atm

Calculate the pH at which free phenobarbital (pKa = 7.6, Co = 1 g/1000 mL) will precipitate from a solution containing 1% w/v sodium phenobarbital. MW of free acid is 232.23. MW of sodium salt is 254.22. What is observed solubility at pH = 8.3?

a) Co = (1g/1000 mL) x (1000 mL/L) x (1 mol/232.23 g) Co = 0.0043 M Cs = (1g/100 mL x (1000 mL/L) x (1 mole/254.22 g) Cs = 0.0393 M pH = pKa + log ((Cs- Co/Co) pH = 7.6 + log ((0.0393 - 0.0043)/0.0043) pH = 8.51 b) pH = pka + log(Cs/Co - 1) 8.3 = 7.6 + log (Cs/0.0043 -1) Cs = 0.0259 M Cs = 0.0259 mol/L x 0.1 L/100 mL x 254.22 g/mol Cs = 0.658% w/v

What is the pH of precipitation of 6% w/v phenobarbital sodium in 30% v/v ethanol/water solution? The intrinsic solubility of phenobarbital is 0.65% w/v. MW of sodium salt is 254.22 g/mol and MW of phenobarbital is 232.23 g/mol. pKa of phenobarbital in this solvent is 7.9. What will be the pH of precipitation if 30% v/v alcohol replaced with water? (Co = 0.1% w/v, pKa of phenobarbital in water = 7.6)

a) Cs = 6 g/100 mL x 1000 mL/L x 1 mole/254.22 g Cs = 0.236 M In 30 % v/v ethanol Co = 0.65 g/100 mL pKa = 7.9 Co = 0.65 g/100 mL x 1000 mL/L x 1 mole/232.23 g Co = 0.028 M pH = pKa + log((Cs-Co)/Co) pH = 7.9 + log ((0.236- 0.028)/0.028) pH = 8.77 b) In water: Co = 0.1 g/100 mL, pKa = 7.6 Co = 0.1 g/100 mL x 1000 mL/L x 1 mole/232.23 g Co = 0.0043 M pH = pKa + log((Cs - Co)/Co) pH = 7.6 + log((0.236 -0.0043)/0.0043) pH = 9.33

The solubility of SMP in 10% (v/v) of dioxane (a liquid) and 90% (v/v) of water is 1.8 mg/mL at 25C. Calculate a) molarity, b) molality and c) mole fraction of saturated SMP solution. The density of dioxane is 1.0313 g/mL, of the solution is 1.0086 g/mL, of water is 0.9970 g/mL and of the solvent mixture is 1.0082 g/mL. MW of SMP is 280.32 g/mole, MW dioxane = 88.1 and MW of water is 18.015.

a) In 1 L of solution, there is 1.8 mg/mL x 1000 mL = 1.8 g of SMP. 1.8 g SMP x 1 mole SMP/280.32 g = 0.06421 mole SMP/1 L solution = 0.006421 M SMP b) Weight of 1 L solution = 1 L x 1000 mL/L x 1.0086 g/mL = 1008.6 g. Weight of the solvent is 1008.6 g - 1.8 g = 1006.8 g 0.006421 mole/1006.8 g solvent x 1000g/kg solvent = 0.006378 mole/kg solvent = 0.006378 m c) Volume of solvent mixture = 1006.8g/(1.0082 g/mL) = 998.61 mL Volume of dioxane = 998.61 x 10% = 99.861 mL. Weight of dioxane = 99.861 mL x 1.0313 g/mL = 102.987 g 102.987 g dioxane x 1 mole dioxane/88.1 g = 1.169 mole dioxane Volume of water = 998.61 mL x 90% = 898.749 mL Weight of water = 898.749 mL x 0.997 g/mL = 896.053 g water 896.053 g water x 1 mole water/18.015 g = 49.739 moles of water Since there is 0.006421 mole of SMP, 1.169 moles of dioxane, and 49.739 moles of water, the mole fraction of SMP in the solution is: 0.006421/(0.006421 + 1.169 + 49.739) = 0.000126

a) Compute freezing point depression of 1 g methylcellulose (MW = 26,000 g/mole) dissolved in 100 g water b) Using van't Hoff equation, compute osmotic pressure of this solution at 20 degrees C. Express results in cm of solution. Convert mmHg to mm of solution by mm solution = mmHg x density of Hg/density of solution. Density of mercury at 20 degrees C is 13.5462 g/mL. Density of solution is 1 g/mL c) Assume you have a thermometer which is able to accurately read 0.05 degrees C & estimate value to 0.005 degrees C. Can you use freezing point depression of methylcellulose solution to determine MW of polymer? Can you use osmotic pressure to obtain molecular weight?

a) deltaTf = kfm2 m = moles/kg solvent 1 g methylcellulose x 1 mole methylcellullose/26,000g methylcellulose = 3.846 x 10^-5 mole methylcellulose 100 g water x 1 kg/100g = 0.1 kg water 3.846 x 10^-5 mole methylcellulose/0.1 kg water = 3.846 x 10^-4 m deltaTf = 1.86 Kg x K/mol x 3.846 x 10^-4 moles/kg methylcellulose = 7.15 x 10^-4 degrees C b) 20 degrees C + 273 = 293 K Osmotic pressure = II = [Csolutes]RT II = 3.846 x 10^-5 mole methylcellulose/(100 mL x 1 L/1000mL) x 62.36367((L x mmHg)/(K x mol)) x 293 K = 7.0276 mmHg 7.0276 mmHg x ((13.5462 g/mL mmHg)/(1 g solution/mL)) = 95.1976 mm of solution x 1 cm/10 mm = 9.51976 cm of solution c) Freezing point depression is too small to read on most thermometers. Should use osmotic pressure to determine molecular weight of methylcellulose

Diameter of left anterior descending (LAD) coronary artery has been reported to be 3.3 mm and it length from 10 to 13 cm. Under normal cirumstances, the blood flow through the LAD has been reported to be 54 mL/min. a) What is the pressure drop over a 12 cm LAD under normal circumstances? b) If LAD becomes 70% occluded because of atherosclerosis, what will pressure drop be if blood flow through LAD is maintained at 54 mL/min

a) r = d/2 = 3.3 mm/2 = 1.65 mm x 100 cm/1000 mm = 0.165 cm Q = 54 mL/min = 54 cm^3/min x min/60 sec = 0.9 cm^3/sec Q = (pi x r^4)/(8n) x [delta P/L] delta P = (Q x 8n x L)/(pi x r^4) = (0.9 cm^3/sec x 8 x 004 dyne x sec/cm^2 x 12 cm)/(pi x (0.165 cm)^4) delta P = 3.46 dyne x cm^2/2.3 x 10^-3 cm^4 = 1504 dyne/cm^2 b) Assume that cross sectional ara of LAD is that of a circle A = pi x r^2 = p x (1.65 mm)^2 = 8.55 mm^2 If LAD is 70% occluded, only 30% of area is open to blood flow, so area of occluded LAD = 8.55 mm^2 x 0.3 = 2.56 mm^2. What is the radius of this occluded vessel? 2.56 mm^2 = pi x r^2 2.56 mm^2/pi = r^2 r = 0.9 mm delta P = (Q x 8n x L)/(pi x r^4) = (0.9 cm^3/sec x 8 x 0.04 dyne x sec/cm^2 x 12 cm)/(pi x (0.9mm x 100 cm/1000 mm)^4) delta P = 3.46 dyne x cm^2/2.1 x 10^-4 cm^4 = 16476 dyne/cm^2

A solution of sucrose (MW 342) is prepared by dissolving 0.5 g in 100 g of water. Compute a) weight percent b) molal concentration and c) mole fraction of sucrose and water in solution

a) weight percent = 0.5 g sucrose/100.5 g solution x 100% = 0.498% (w/w) b) molality = moles/kg solvent 0.5 g sucrose x 1 mole sucrose/342 g sucrose = 0.001462 moles sucrose 100 g water x 1 kg/1000g = 0.1 kg water 0.001462 moles sucrose/0.1 kg water = 0.01462 m sucrose c) mole fraction = n1/(n1 + n2) 1 mole water = 18.01 g 100 g water x 1 mole water/18.01 g water = 5.55 mole water 0.01462 moles sucrose/(0.01462 moles sucrose + 5.55 moles water) = 0.0002629 mole fraction sucrose 5.55 moles water/(0.01462 moles sucrose + 5.55 moles water) = 0.999737 mole fraction water

The chemical structure of cell membranes determine the

ability of molecules to cross the membranes Both the phospholipid backbone and the proteins in membrane have important contributions to membrane permeability of drugs-----Drive partition coefficient

As a consequence of Henderson-Hasselbach relationship:

absorption depends on pKa of drug and pH of body fluid

Solubility definition

amount of solute that can be dissolved in a unit volume of a solvent to form a saturated solution (under given temperature and pressure) Need to define temperature and pressure Temperature for liquid Pressure for gases

pH-partition hypothesis is useful, but it is only

an approximation of physiological reality

Sodium bisulfite

antioxidant

Solubility can be quantitatively expressed using...

any expression of concentration: molarity, molality, mole fraction, percentage and ratio

Clapeyron Equation applies to

any phase equilibrium of any pure substance

Weak base R-NH3+ =====R-NH2 + H+

as pH increases, unionized form increases, lipophilicity increases Greater transport at high pH, less transport rate at lower pH

Drugs must be carried to organs of elimination by

blood

citric acid, sodium citrate

buffer system

Nasal solutions need

buffers to maintain stability of drug To maintain pH in normal pH of nasal fluids (pH 5.5 to 6.5)

Nasal absorption

by-passes first-pass metabolism by liver

When a lipophillic drug is partitioning between lipid and water, which of the following statements is correct at equilibrium? a) solubility in the 2 phases is the same b) concentration in the 2 phases is the same c) activity in the 2 phases is the same d) both a and c

c) activity in the 2 phases is the same

pH shift in formulations

can increase over time

Different drug or different protein =

change in equilibrium constant

Using 2 or more drugs simultaneously may

change protein binding. Are competing for binding sites Most significant for highly protein-bound (>95%) and with low therapeutic index (ex: warfarin, 99% bound)

Change shape of the concentration-time curve by

changing rate of input (absorption) Slide 5 on Extravascular Admin

The chemical potential of one component cannot change without

changing the chemical potential of the other component

The normal freezing point is the temperature at which solid and liquid

coexist at equilibrium under 1 atm of pressure

Gas pressure is

collision of gas molecules with container wall

No net loss in energy or speed after

collisions between molecules or within container walls All collisions are elastic

FD&C Red # 40

color

Elimination affect the

concentration-time profile

Rate and extent of absorption influence

concentration-time profile

Drug concentration does not affect

constant

At boiling point, all absorbed heat is used to

convert liquid to vapor & temp does not rise until all liquid is vaporized

Drugs in solution must

cross membranes

When a solution freezes, typically solvent

crystallizes into a solid free from solute, hence, higher escaping tendency than the solution

The change in the vapor pressure of the solid (Clausius-Clapeyron equation) occurs via the heat of sublimation such that:

d(ln P)sub = (deltaHsub)/(RTf^2)x dTf Tf is freezing point of pure solvent

Which of the following is not a colligative property? a) Vapor pressure b) Freezing point c) Boiling point d) Density e) Osmotic pressure

d) Density

Cyclodextrins (CD) are often used to solubilize drugs through complexation in solution. Which of the following does not affect the binding constant? a) temperature b) type of cyclodextrin (ex: alpha vs beta CD) c) size of drug molecule d) concentration of drug e) ionization state of drug molecule

d) concentration of drug

Which of following properties is not a colligative property? a) freezing point b) boiling point c) osmotic pressure d) solubility e) vapor pressure

d) solubility

Adding an electrolyte, such as NaCl, to an aq solution of gas will _____ it solubility

decrease known as "salting out"

Ideal solubility implies...

delta Hmix = 0

Calculate the vapor pressure when 0.5 mole of sucrose (n2) is added to 1000 g of water at 20 degrees C. The vapor pressure of pure water is 17.54 mmHg.

delta p1 = - p1^o x X2 X2 = n2(n2 +n1) = 0.5 mol/(0.5 mol + 1000g/18.02 g/mol) = approximately 0.5/55.5 = 0.009 delta p1 = -17.54 mmHg x 0.009 = -0.16 mmHg Vapor pressure is lowered by 0.16 mmHg

What is the percentage vapor pressure depression when 0.5 mole of NaCl is dissolved in 100 mL water (MW = 18)?

delta(p) = - po x X2 NaCl completely dissociates in water so 0.5 mole needs to be multiplied x 2 = 1 mole NaCl 100 mL water = 100 g water 100 g water/18 g/mole water = 5.5 mole water 1 mole NaCl/(1 mole NaCl + 5.5 mole water) = 0.1538 x 100% = 15.38% vapor pressure depression

Thermodynamics of Interaction Types

deltaG^o = deltaH^o - T x deltaS^o Protein binding is favored if deltaG is negative

Clausius-Clapeyron equation

deltaHv = molar heat of vaporization = heat absorbed by 1 mole of liquid when it's vaporized

Clapeyron Equation

deltaTb = ((RTb^2)/deltaHv) x X2 delta Tb = elevation of boiling point

Raoult's law

deltaTb approximately = Kbm2 delta Tb = elevation of the boiling point m2 = molality of solution Kb = boiling point elevation constant

Freezing point depression equation

deltaTf = (RTf^2/deltaHf)(molecular weight of solute/1000 g of solvent)*m2 = Kf*m2 approximately = Kf* ((1000*w2)/(w1M2) Kf = freezing point depression constant

Liquids are ________ and more _______ than gas

denser, more ordered

Preservatives may be required for topical solutions,

depending on solvent

Kb is

different for different solvents

At any given time, at a given temp

different gas molecules move in different directions, at different speeds

For absorption to occur,

drug must cross a membrane to reach blood

Which of the following can be used to solubilize drugs? a) use of cosolvent b) use of different solid forms c) adjustment of pH d) use of nano-sized crystals e) all of the above

e) all of the above

Usual dose of solution is generally an

easily administered volume

Unbound drug in the plasma is

equal to concentration of drug in the cerebral spinal fluid

Intrinsic solubility definitiion

equilibrium solubility of drug molecule----concentration of neutral molecule in water, anions not counted in this kind RCOOH ==== RCOO- + H+ Determined by structure of solid and how it interacts with the solvent At a given temp, with constant pressure

Elimination made up of

excretion (loss of chemically unchanged drug) and metabolism (loss by chemical modification)

Saturated solution

fixed amount of saturation

Topical solutions

generally employ aqueous vehicle

Solvent

greater amount in solution

Coarse dispersion

greater than 500 nm (emulsions and suspensions), need to shake before use

Heat of mixing (delta Hmix)

heat generated when mixing 2 liquids

Ideal solubility is determined by ______ and ______ only

heat of fusion, melting point

80 to 90% RH

hemptahemi (7.5) hydrate is stable

Higher temp =

higher molecular velocity, leads to higher pressure

Stronger the lattice energy (crystals holding together)....

higher temperature it takes non-electrolytes to melt

Tie line

horizontal line crossing 2 phase region of phase diagram

Chloresterol can cause

increase in membrane viscosity

Two membrane characteristics that will increase rate of absorption of drugs across membrane are

increase in surface area (fluidity), decrease in membrane thickness (viscosity)

Increased urine concentration =

increased driving force due to concentration gradient, increased reabsorption Renal excretion goes down

For a base, as pH decreases, % ionization....

increases

For an acid, as pH increases, % ionization...

increases

Vapor pressure increases/decreases with rising temp

increases

Equilibrium vapor pressure increases/decreases with increasing temp

increases PV = nRT Higher kinetic energy of molecules More molecules approach "escape velocity"

Mole fraction and molality are both ______ of temperature

independent

Components are the smallest number of _____________ by means of which the composition of every possible phase can be expressed

independent chemical constituents

The 2 in the phase rule corresponds to _________ pressure and temperature

independently variable

Nasal solutions must be made

isotonic with nasal fluids Tonicity equivalent to 0.9% sodium chloride in water "normal saline"

Sodium chloride is for

isotonicity

When drug is better able to be dissolved

it has a better bioavailability

For an API to be therapetuically effecitve

it must reach site of activity in sufficient amounts, at sufficient rate

Sulfadiazine (2) is dissolved in 1-octanol (1) at 25C. Using the following data, calculate solubility using regular solution theory.

ldelta = lowercase delta ldelta2 = 12.5 (cal/cm^3)^1/2, ldelta1 = 10.3 (cal/cm^3)1/2, deltaHf2 = 97400 cal/mol, V1 = 157.7 cm^3/mol, Tm2 = 254C, V2 = 182 cm^3/mol Calculate ideal solubility: ln X2ideal = (-deltaHf2/R) x ((1/T) - (1/Tm)) ln X2ideal = (-9740/1.987) x ((1/298)- (1/527) X2ideal = 0.000787 Calculate acvitity coefficient: Assume solvent volume fraction O1 = 1 ln y2 = (ldelta1 - ldelta2)^2 x ((V2 x O1^2)/RT) ln y2 = (10.3 - 12.5)^2 x (182 x 1^2)/(1.987 x 298) ln y2 = 1.49 y2 = 4.44 Calculate real solubility: X2 = X2ideal/y2 X2 = 0.000787/4.44 = 0.000177 X1 = 1 - 0.000177 = 0.99982 Calculate volume fraction with this new solubility O1 = X1V1/(X1V1 + X2V2) O1 = (0.99982 x 157.7)/(0.99982 x 157.7 + 0.0001777 x 182) O1 = 0.999979 Since number is in agreement with initial guess (O1 = 1), we can stop here

Raise temperature =

leads to disorder & things want to separate more

Duration

length of time that plasma concentration stays above MEC

Liquids are ______ than solid

less ordered

K of o/w of metabolite is

less than that of drug so reabsorption decreases, have greater renal clearance of metabolite

Solute

lesser amount in solution

At and above triple point

liquid and vapor (gas) phases become identical

A crystalline solid can be

liquid crystal

Some molecules in gas phase return to

liquid state (condensation)

The state of a solvent for solution can be....

liquid, solid, gas, or super critical fluid

Van't Hoff equation

ln (C2/C1) = (-delta Hsolution/R) x ((1/T2) - (1/T1)) delta H of solution = amount of heat involved when solute dissolves

Ideal mole fraction solubility equation

ln X2ideal = (-delta Hf/R) x ((1/T) - (1/Tm))

The vapor pressure of ethyl alcohol is 23.6 torr at 10 degrees C, 78.8 torr (mmHg) at 30 degrees C. Calculate delta Hv using C & C equation

ln(P2/P1) = (deltaHv/R) x (1/T1 - 1/T2) T1 = 10 + 273 = 283 K T2 = 30 + 273 = 303 K P1 = 23.6 torr P2 = 78.8 torr R = 1.9872 cal/molK ln(78.8 torr/23.6 torr) = (deltaHv/1.9872 cal/molK) x (1/283 K - 1/303 K) delta Hv = 10274.15 cal/mol

The solubility of a solute in an ideal solution is given by:

lnX2(ideal) = (-deltaHf/R) x ((1/T) - (1/Tm)) X2 = mole fraction of soute/drug T = temperature of interest Delta Hf = heat of fustion Tm = melting point of drug/solute

Topical solutions and tinctures almost always used for

local pharmacological effects

A 1: 250 (v/v) solution of drug X is made of 1 ____ X in 250 ____ of water

mL, mL

Route of administration will affect shape and

magnitude of concentration-time profile

Lever rule can be derived based on principle of

mass balance

What is NOT a characteristic of Bacteriostatic Water for Injection, USP?

may be packaged in containers greater than 30 mL in size

h =

membrane thickness

Liver often

metabolizes drugs to more polar metabolites

EDTA =

metal chelation is enabled by ion-dipole interactions Treating mercury and led poisoning; stabilizer (ex: metal catalyzed oxidation reaction---prevents oxidation)

For non-ideal solutions, the pressure-composition diagram has either

minimum or maximum total vapor pressure curve See slide 14 Colligative Properties Solutions

MTC

minimum toxic concentration, lowest concentration where toxic effect is achieived

Polymorphs can be

modified to increase bioavailability

In terms of molality, the vapor pressure lowering delta(p1) can be re-written as a function of the

molal concentration of the solute as follows: delta(p1) = - (m/(m + 55.5)) x p1^o

Boiling point elevation is independent of all other properties of solute except

molar fraction in the solution = colligative property As result, boiling point of solution is related to that of pure solvent as follows: Tb(solution) = Tb(solvent) + deltaTb

For diluted aqueous solutions...

molarity (M) approximately = molality (m)

Increase temperature

molecules move

An aqueous solution of glycerin, 7% by weight, is prepared. The solution is found to have a density of 1.0149 g/cm^3 at 20C. The molecular weight of glycerin is 92.0473 g/mol and its density is 1.2609 g/cm^3 (or g/mL) at 20C. What are the molarity, molality, and percent by volume of this solution?

moles of solute/volume of solution (L) = molarity moles of solute/weight of solvent (kg) = molality solution density = 1.0149 g/mL glycerin density 1.2609 g /mL Aq solution of 7% gylcerin by weight MW glycerin = 92.0473 g/mol 7 g glycerin x 1 mole/92.0473 g = 0.07605 moles glycerin 100 g solution x 1 mL/1.0149 g x 1 L/1000 mL = 0.9853 L Molarity = n/V of solution = 0.07605 mol/0.09853 L = 0.7718 M Molality = n/w of solvent = 0.070605 mol/((100 g - 7 g glycerin)x (1 kg/1000g)) = 0.811 m % by volume = (7 g glycerin/1.2609 g/mL)/98.53 mL x 100% = 5.63 % v/v

0 to 5% RH

monohydrate is stable

Drug molecules with more lipid-like characteristics are

more likely to "dissolve" into membrane, and therefore absorption rate increases Increases partition coefficient

Mole fraction

n2/(n1 + n2) = X2 n1 or n2 : number of moles in the solution Subscript 1 usually the solvent Subscript 2 usually the solute X1 + X2 = 1

In vapor intermolecular interaction is...

negligible

Along each phase boundary

neighboring phases are in equlibrium

Boiling point elevation

occurs when add solute Slide 6 Colligative Properties Solutions

Freezing point depression

occurs when add solute Slide 6 Colligative Properties Solutions

Vapor pressure lowering

occurs when add solute Slide 6 Colligative Properties Solutions

Vapor pressure, PB^o, of pure butane is 2.3966 atm at 25 degrees C and that of n-pentane, Pp^o, is 0.6999 atm at 25 degrees C. Using Raoult's Law, calculate partial vapor pressure of n-butane (MW 58.12) and n-pentane (MW 72.15) in mixture of 50 g of each of 2 vapors at 25 degrees C in atom and pounds/in^2 (psi)

p1 = p1^o x X1 p2 = p2^o x X2 p = p1 + p2 mole fraction = n1/(n1 + n2) 1 atm = 14.7 psi 50 g butane x 1 mole butane/58.12 g butane = 0.8603 mole butane 50 g n-pentane x 1 mole n-pentane/72.15 g pentane = 0.693 mole n-pentane mole fraction butane = 0.8603 mole butane/(0.8603 mole butane + 0.693 mole pentane) = 0.5539 mole fraction butane mole fraction n-pentane = 0.693 mole n-pentane/(0.8603 mole butane + 0.693 mole n-pentane) = 0.4461 mole fraction n-pentane butane = p1 = 2.3966 atm x 0.5539 mole fraction butane = 1.3274 atm 1.3274 atm x 14.7 psi/1 atm = 19.514 psi = partial pressure of butane at 25 degree C n-pentane = p2 = 0.6999 atm x 0.4461 mole fraction n-pentane = 0.31226 atm 0.31226 atm x 14.7 psi/atm = 4.59 psi = partial pressure of n-pentane at 25 degree C

What is the pH of a 0.00379 M solution of HNO3? What is its pOH?

pH = - log (0.00379) = 2.42 pH pOH = 14 - 2.42 pH = 11.58 pOH

What is the pH of 7.93 x 10^-4 molar solution of strong acid?

pH = - log [H+] = - log [7.93 x 10^-4] pH = 3.1

Calculate the pH of solution when [H+] = 0.00915 M

pH = - log [H+] pH = 2.04

pH dependence of solubility for acids

pH = pKa + log (Cs/Co -1) or pH = pka + log((Cs-Co)/(Co))

Fenoprofen is non-steroidal anti-inflammatory which is used in treatment of RA. PKa is 4.5. Structure is R-COOH a) Will proportion of unionized drug be greater in stomach (pH 2.4) or intestine (pH 6.6)? What is % ionized in each situation? b) Do you think fenoprofen will be more rapidly absorbed from stomach or intestine? Why?

pH = pKa + log (base/acid) 2.4 = 4.5 + log (base/acid) -2.1 = log (base/acid) 10^-2.1 = base/acid 0.0079 = RCOO-/RCOOH % ionized in stomach = 0.0079/(1 + 0.0079) x 100% = 0.78% 6.6 = 4.5 + log (base/acid) 2.1 = log (base/acid) 10^2.1 = base/acid 125.9 = RCOO-/RCOOH % ionized in intestine = 125.9/(1 + 125.9) x 100% = 99.2% Even though there is higher % unionized fenoprofen in stomach, it is probably absorbed faster from intestine because of much higher surface area in intestine

Which of following 2 bases will be reabsrobed from kidney tubules (assume urine pH of 6.3) to greatest extent? Drug Y = pKa 8.2 Drug Z = pKa 7

pH = pKa + log (base/acid) For base, the "base" is unionized 6.3 = 8.2 + log (base/acid) -1.9 = log (base/acid) 10^-1.9 = base/acid 0.0126 = base/acid 0.0126/(1 + 0.0126) x 100% = 1.24% unionized 6.3 = 7 + log (base/acid) -0.7 = log (base/acid) 10^-0.7 = base/acid 0.2 = base/acid 0.2/(1 + 0.2) x 100% = 16.67% unionized Drug Z is more likely to be reabsorbed to greater extent because it is more unionized than Drug Y at pH of urine

Henderson-Hasselbach Equation for acid

pH = pKa + log([A-]/[HA]) OR [A-]/[HA] = 10^pH - pKa

Equations for pH dependence of solubility for bases

pH = pKa - log (Cs/Co - 1) or pH = pKa - log ((Cs - Co)/Co) or pH = pKa + log (Co/(Cs-Co))

Ioniziation of salicylic acid, pH 1

pKa = 3 What is the % ionization when pH = 1 (pH is 2 units below pKa)? %I = 100%/(1 + 10^(pKa- pH)) = 100%/(1 + 10^(3-1)) = 100%/101 = 1%

Ionization of salicylic acid, pH = 5

pKa = 3 What is the % ionization when pH = 5 (pH is 2 units above pKa) %I = 100%/(1 + 10^(pKa - pH)) = 100%/(1 + 10^(3-5)) = 100%/(1 + 10^-2) = 99%

B1 is a stronger base than B2, the pKa of their corresponding conjugate acids are pKa1 and pKa2, respectively. Which one of the following is correct? a) pKa1 > pKa2 b) pKa1 < pKa2 c) pKa1 = pKa2

pKa1 > pKa2

For pure water @ 25C, pKw =

pKw = - log Kw = - log (1 x 10^-14) pKw = 14

Relationship between pKb and pKa in water @ 25C

pKw = pKa + pKb

For pure water @ 25C, pOH =

pOH = - log [OH-] = - log [1 x 10^-7] = 7 log 10 = 7

Need to have dosage form big enough for

patient to pick up (or even to see it)

Gases can affect the

physical stability of drugs (loss of drug when vapor pressure is high or phase changes when exposed to changing RH conditions)

What would be the osmotic pressure generated by a 0.9% sodium chloride solution (MW 58.44 g/mol) at 300 K, if it's assumed to be ideal?

pi = RTc R = 0.0821 Latm/molK T = 300 K 0.9 g NaCl/100 mL x 1 mole NaCl/58.44 g x 1000 mL/1 L = 0.154 moles NaCl x 2 (since NaCl dissociates completely) = 0.308 moles NaCl = concentration 0.0821 Latm/molK x 300 K x 0.308 moles NaCl = 7.59 atm

What is the partial vapor pressure of ethylene chloride in a 50C solution with benzene? Mole fraction of benzene is 0.6, and vapor presssure of ethylene chloride at 50C is 236 mmHg

pi = pi^o x Xi 1-0.6 = 0.4 mole fraction ethylene chloride 236 mmHg x 0.4 = 94.4 mmHg

What is the partial vapor pressure of benzene in 50C solution with ethlyene chloride? Mole fraction of benzene, pB, is 0.6 and vapor pressure of pure benzene at 50C is 268 mmHg

pi = pi^o x Xi =268 mmHg x 0.6 = 160.8 mmHg

Ammonium sulfate is commonly used to:

precipitate proteins selectively 1) very soluble in water (needed for making a solution of high ionic strength) 2) does not cause irreversible denaturation of protein

Nucleation inhibitors (Polymers) may be used to prevent _______ of neutral drugs

precipitation

pH modifiers may be used to prevent ________ of weak acid or base drugs in forumulation

precipitation

Benzyl alcohol is for

preservative

Adding salt to water or ice

raises the boiling point or lowers the freezing point See slide 6 Colligative Properties Solutions

As membrane thickness increases

rate of absorption decreases

As concentration outside of membrane (Cout) increases

rate of absorption increases

As surface area increases

rate of absorption increases

As the % unionized of the molecule increases,

rate of absorption increases

As the lipophilicity (K of o/w) increases

rate of absorption increases

Urine concentration and reabsorption

rate of reabsorption = (DSK of o/w x Curine)/h As urine proceeds down tubule, water is reabsorbed As water is reabsorbed throughout tubules drug becomes more concentrated in urine

Lipid solubility (K of o/w) and reabsorption

rate of reabsorption = (DSK of o/w x Curine)/h In general, increased K of o/w = increased reabsorption, decreased renal excretion Partition coefficient of metabolite is smaller, has less absorption, is more renally excreted

Molecular size and reabsorption

rate of reabsorption = (DSK of o/w x Curine)/h Molecular weight or size of molecule (r) As r increases, D decreases, reabsorption rate decreases, renal excretion increases D = diffusion coefficient

Even if drug distributes into non-eliminating tissues, it must

re-enter blood, be carried to organs of elimination in order to be removed from body

Direct correlation between tissue perfusion and time required for drug to

reach equilibrium between blood and tissue

Cosolvents work by ______ H-bond density of water

reducing

Nearly half of all drug molecules are administered as ______

salts

Weak acids and weak bases are often made into ______ to enhance their solubility

salts

Electrolytes can change ionic strength of the ______, hence, the activity coefficient of the _____

solvent, solute (y)

Solutions must be physically and chemically

stable. Antioxidants may be required Sodium bisulfite and sodium metabisulfite Edetate sodium (EDTA)

Isotonicity

state where osmotic pressure of pharmaceutical solution is equal to that of physiological fluids Minimizes discomfort/irritation during drug administration via sensitive membranes of organs (ex: ophthalmic and nasal)

Anatomical structure increases ________ per unit length

surface area

Nasal mucosa has large

surface area for drug absorption If taken orally, would get digested by stomach

When volume of oil is less than volume of water

surfactants form = partitioning

Sorbitol 70% solution

sweetener

high fructose corn syrup

sweetener

soribitol

sweetening

Oral solutions are almost always used to generate

systemic pharmacological effect

Some drug molecules

taste bad

Solutions should be isotonic with

tears

Since the membrane is made up of mostly lipid

the more lipid soluble form of the drug (unionized form) will more quickly cross the membrane

Most drugs are

weak acids or weak bases