Preformulation review PB

visible spectrum

(violet)400-750(red) nanometers

What info does microscopy tell us?

1. Crystal structure 2. Particle Size 3. Particle Size Distribution 4. Particle shape

Microscopic Examinations

1. Light microscopy 2. Scanning Electron Microscopy (SEM) 3. Spectroscopy: Fourier Transform Infra Red Spectroscopy (FTIR), Raman Spectroscopy 4. Powder X-Ray diffractometry

polymorphism can affect

1. Strength of the material 2. Solubility, dissolution 3. Melting point 4. Stability

Translation Gap "Valley of Death" inlcudes which stages

1. Target Validation & lead selection 2. Pre-clinical (Lead) 3. Phase I 4. Phase II

Stages of drug development

1. Target Validation & lead selection 2. Pre-clinical (Lead) 3. Phase I 4. Phase II 5. Phase 3 6. Submission

Kw = [H3O+][OH-] = 1 x 10-14 moles/liter at _______

25C

How many phases in clinical trial?

3

Kw = 1 x 10^-14 moles/liter at 25C H3O ins = square root( 1 x 10^-14 = 1 x 10 ^-7 -log(1 x 10 ^-7

7

Aspirin has a pKa of 3.5. If aspirin is a weak acid, which of the following is true at a pH of 8.0 A) The drug is highly ionized B) The drug is 50% ionized C) The drug is practically unionized D) Cannot determine from above information

A

API

Active Pharmaceutical Ingredient

Solubility vs dissolution

Analogy is the Boston Marathon How many people "complete" the race is the solubility The people who care about the "time" is the dissolution

If ranitidine is a Class III drug, it is most likely to have a problem/s with: A) Solubility B) Membrane permeation C) Both Solubility and membrane permeation D) No expected problems.

B

dC / dt

C2-C1 /t2 -t1 Just dropped in the drug what is t1 and c1? 0 and 0 After 1 minute the concentration is

Ergs

CGS unit of energy

Dyne

CGS unit of force, CGS version of newtons

Major difference between clinical trials and preclinical trials?

Clinical trials involves humans Preclinical trials involves animals

Example question: Lag time, the lag-time of butyl paraben for diffusion across a 0.085 cm thick membrane is 47.5 minutes. Calculate D for butyl paraben tL = h^2 / 6D

D = h^2 / 6tL 47.5 mins x 60 sec/1min =2850 seconds = tL 6 x 2850 = 17100 = 6tL h^2 = 0.085^2 = 0.007225 .007225 / 17100 = 4.23 x 10-7 cm2/sec = D

Examples of biological barriers

GIT Nasal mucosa Ocular membranes Alveolar membranes Skin

GI Time

Gastrointestinal time

Rapid dissolution definition

Greater than 85% of labeled amount dissolves within 30 minutes

High permeability definition

Greater than 90% dose is absorbed in humans

k = [H3O+] [OH-] / [____]^2

H2O

pH = negative logarithm of _______ (or H+) ions

H3O

HB + H2O <-->

H3O+ + B-

H2O + H2O <-->

H3O+ + OH-

Class I biopharmaceutics

High permeability, High solubility

Class II biopharmaceutics

High permeability, Low solubility

Dissolution

How "fast" does the substance go into soltuion (look for time in the equation) Kinetic property

Partition coefficient

How drug partitions between a water and an octanol phase

Solubility

How much drug goes into solution with an infinite time Thermodynamic property measured at equilibrium

Transport through an aqueous "bridge"

Hydrophilic molecules do this better Transport is limited by size

IND

Investigational New Drug

Acid - base equilibria for weak electrolytes, ionization constant for an acid = K___

Ka

Ionization constant, K___, for any weak acid, HB

Ka

Acid - base equilibria for weak electrolytes, ionization constant for a weak base, K___

Kb

Acid - base equilibria for weak electrolytes, ionic product of water = K____

Kw

Class III biopharmaceutics

Low permeability, High solubility

Class IV biopharmaceutics

Low permeability, Low solubility

Membrane Permeability

Molecules have to cross biological membrane barriers to get absorbed

NDA

New Drug Application

NCE

New chemical entity

Example question: permeability and diffusion rate, A drug passing through a 1 mm thick membrane has a diffusion coefficient of 4.23 x 10-7 cm2/s, and an oil water partition coefficient is 2.03. The radius of the area exposed to the solution is 2 cm, and the concentration of the drug in the donor compartment is 0.5 mg/mL. Calculate the permeability of the drug.

P = DK / h P = 4.23 x 10-7 * 2.03/1 P = permeability, D = 4.23 x 10-7 K = partition coefficient 4.23 x 10-7 h= membrane thickness 1mm P = 8.46 * 10^-7

Permeability

P = DK/h P = permeability, K = partition coefficient h= membrane thickness D = diffusion coefficient

Particle size vs particle size distribution

Particle size is one value (statistical mean, mode, or median) Particle size distribution gives a better idea of size for all particles

branches of pharmaceutics

Physical Pharmacy Pharmakokinetics Bio-pharmaceutics Drug Delivery Formulation Preformulation

[OH-] =

Root(Kb * c

Particle size

Smaller particle will dissolve faster

Physical description

Solids, liquids, gases

Target validation & lead selection

Start out with 10,000 molecules

Solubility in relation to particle size is determined by

Surface area in relation to mass

Factors affecting dissolution

Surface area of solid material Solubility of the drug in the dissolution fluid Volume of the liquid Stirring, other forms of mechanical agitation

Factors affecting solubility

Temperature Particle size Polymorphism

Difference between taking a drug while eating a steak vs a salad

The Gastrointestinal time, Pharmaceutical companys want to eliminate this variable

Polymorphism

The existence of two or more forms of individuals within the same chemical makeup

Ka = [H3O+] [B-] / ________

[HB]

Excipients, Binders: Cause _______

adhesion (Sodium carboxymethyl cellulose, ethyl cellulose, gelatin)

lower melting point means

better dissolution

Excipients, Diluents/fillers: Increase ________ of formulation

bulk (Microcrystalline cellulose, starch, lactose, mannitol)

Excipients, enteric coating

cellulose acetate phthalate, shellac

Phase 1 - 3 and submission

clinical trials

Excipients, Antiadherents/ lubricants/ glidants: Reduce friction during ______________, improve flow

compression (Stearates "calcium, magnesium, zinc), talc)

Dissolution Equation

dC /dt = [(DS) / (Vh)] x (Cs - C) dC/dt = the dissolution rate of the drug. D = diffusion coefficient, S = surface area of the particles, V = volume of the liquid h = boundary layer CS = solubility of the drug, and C = concentration of the drug.

Question: A preparation of drug granules weighing 1.55 g and a total surface area of 2.8 103 cm2 is allowed to dissolve in 500 mL of water at 25°C. After the first minute, 0.76 g have passed into solution. What is the value of D/h for the drug? Solubility of the drug = 15 mg/mL at 25°C. 3.36 x 10-4 cm2/sec

dC /dt = [(DS) / (Vh)] x (Cs - C) dC/dt = the dissolution rate of the drug. dC = 0.76 dt= 60s D = diffusion coefficient, S = surface area of the particles, V = volume of the liquid h = boundary layer CS = solubility of the drug, and C = concentration of the drug.

Example question: permeability and diffusion rate, A drug passing through a 1 mm thick membrane has a diffusion coefficient of 4.23 x 10-7 cm2/s, and an oil water partition coefficient is 2.03. The radius of the area exposed to the solution is 2 cm, and the concentration of the drug in the donor compartment is 0.5 mg/mL. Calculate the diffusion rate of the drug.

dM / dt = PSCd Permeability(P) = 8.46 * 10^-7 S = surface area of the particles, C = concentration of the drug, 0.5 mg/mL

Excipients, Stabilizers (antioxidants, chelating agents): Prevent ______________

decomposition (Antioxidants, ascorbic acid/vitamin C, sodium ascorbate, sodium metabisulfite Chelating agents: edetic acid, edetate disodium)

Ka = ionization constant, ____________ constant, or acidity constant

disassociation

Excipients Vehicles: Dissolve or _________ drug, carrying agent

disperse (Syrups "sugar solutions", elixirs "hydroalcoholic")

Excipients, Surfactants: helps ______________

dispersion (Sodium Lauryl sulfate (SLS))

Excipients, solvents: __________ drugs

dissolve (Ex. Water, sterile water, alcohol, peanut oil, mineral oil)

Formulation is the process of taking a drug to the ___________

dosage form (ON TEST)

Excipients, Coating agents, taste masking, __________ coating

enteric (protection)

Excipients, film coating

ethyl cellulose, methyl cellulose

Value of LogP data

for for two, logX = 2 2 is the exponent, log is base 10, 10^2 = X meaning the proportions would look like 1/100 value of 6 on the chart would be 10^6 or 1/1000000

High solubility definition

highest dose is soluble in 250 mL in pH range of 1 - 7.5

Melting point

how strong are the bonds between the molecules, characteristic of crystalline materials, measure of purity

Excipients, Disintegrating agents: Help break tablet after _______________ in water

incubation (Microcrystalline cellulose, starch)

Kw = [H3O+][OH-]

ionic product of water

Ka for acetic acid HAc + H2O <--> H3O+ + Ac-

k = [H3O+] [Ac-] / [HAc] [H2O]

Excipients, sugar coating

liquid glucose, sucrose

Solubility vs particle size (assuming same crystal type)

log (S)/ (So) = 2yV / 2.303RTr S is the solubility of small particles S0 is the solubility of large particles y is the surface tension (dynes/cm) V is the molar volume (cm3) R is the gas constant (8.317 x 107 ergs.deg-1mole-1) T is the absolute temperature (273 + temp in degrees C) r is the radius of small particles

Excipients, Preservatives: prevent _____________ growth

microbial (antifungal: parabens, methyl, ethyl, butyl, benzoic acid, sodium benzoate Antimicrobial: benzalkonium chloride, chlorbutanol, phenol)

Higher melting point means

more stability

Solid forms, amorphous

no form, molecules randomly arranged

K (or P) is the concentration of drug in _____________

octanol/concentration of drug in water

Solid forms, crystalline

organized structure

Kb for morphine is 7.4 x 10-7. What is the pH of a 0.02 M solution of morphine?

pH = -log 8.22 x 10-11 = 10.08

The Ka of lactic acid is 1.387 x 10-4 at 24C. What is the pH of a 0.02 M solution of lactic acid?

pH = -log root(Ka*c Ka * c = 1.387 x 10-4 * 0.02 = 2.774 x 10-6 Root( 2.774 x 10-6 = 0.0016655329 -log(0.0016655329 = pH = 2.778

Calculating Ka for acetic acid HAc + H2O <--> H3O+ + Ac- HAc = c-x, molar conc. of HAc remaining H3O+ = x, amount dissociated Ac- = x, amount dissociated c = molar conc. of acetic acid in water

pH = -log[H3O+] = -log root(Ka*c

Excipients, flavors/sweeteners, make drugs ___________

palatable (flavors: peppermint, vanillin, cocoa, cinnamon oil Sweeteners: sucrose, mannitol, sorbitol, glycerin, dextrose)

Excipients, Ointment bases:

petrolatum, polyethylene glycol (PEG)

Traget validation & lead selection and preclinical are

preclinical

Entering coating

protects the tablet from the acidic portion of the stomach

compliance

readiness to yield; conformity in fulfilling requirements

Lag time

tL = h^2 / 6D tL = lag time Seconds* h = membrane thickness D = diffusion coefficient