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