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BME 6210 E1 TEST WITH
COMPLETE SOLUTION
FDA Shelf Life - ANSWER 90+% Potency from day drug is made Look and effect must remain the same since day made Measuring Drug Potency - ANSWER Adding stressors *Changing temperature *Changing humidity are the main ones Mechanical/Physical Stress Temperature Stress Range - ANSWER 4, 20,30, 37, 50, 75 C Humidity Stress Range - ANSWER 30, 45, 60, 75, 90% relative humidity Physical Stresses - ANSWER Mechanical Chemical Thermal Most common Degradation Reactions - ANSWER Hydrolysis Oxydation Photolysis Zero Order Reaction - ANSWER Constant reaction rate Rate Equations
[A] = [A]o-kot -d[A]/dt=ko 90% Life t90 = 0.1[A]o/ko Half-Life t50=[A]o/2ko Graph [A] v t, neg linear with k0 = slope Pseudo Zero Order - ANSWER Solid state of drug in liquid solution and it dissolves to replace degraded drug. [Drug] is same Degradation will plateau when SS drug dissolves First Order Reaction - ANSWER Rate Eqns -d[A]/dt=[A]k ln[A]=ln[A]o-k1t 90% Life t90 = 0.105/k Half Life 0.693/k Graph
the pH at which kobs is lowest. -If parabolic: k increases with [H+] increase then stable then k increases with [OH-] increase ([H+] decrease). High [H+] = acidic Low [H+] = Basic = High [OH-] pH effects on Formulation - ANSWER pH = -log[H+] -d[Compound]/dt = kobs[Compound][H2O] if pseudo first order [H2O] is constant kobs is dependant on pH kobs - ANSWER kobs = kH+[H+] + kOH-[OH-]+kH2O kH+[H+] = kacidic kOH-*[OH-] = kbasic kH2O is constant because there is an abundance Acidic Catalyzed Hydrolysis - ANSWER In a dipole moment H+ is attracted to the partial negative so e- are pulled This allows an attack on the compounds ester by H2O If only ACH, slope of pH rt curve is - Base Catalyzed Hydrolysis - ANSWER OH- flat out attacks ester If only BCH slope of pH rt curve is 1 Sigmoidal pH rt curve - ANSWER pH = pKa so there is 50% of 1 ionized of 1 species and 50% of counterpart.
In part with bump, the hydrolysis moves from attacking one ionized species and changing it to counterpart more to attacking counterpart. For example Protonated -> neutral until 50% the attacking neutral pKa - ANSWER Lower pKa = stronger acid How tightly is a proton held by acid? pKa is what the pH needs to be for chemical species to accept or donate a proton. Solid Structures in Pharmaceutics - ANSWER Crystalline Amorphous Why are solid state forms of drugs more popular in pharmacy? - ANSWER More stable as formulation has less contact with the environment Easier to handle Better/No taste as solids Unit Cell - ANSWER Define crystalline structures Defines by distance between molecules/atoms Crystalline Solids - ANSWER Defined by Unit cell Impurities wont form crystals Can get relatively pure product when done multiple times Crystal Categories - ANSWER Cubic Tetragonal Monoclinic
Rhombohedral - ANSWER 3 Equal axes, 3 oblique angles
Hexagonal - ANSWER 6-sided with 6 angles
Triclinic - ANSWER Unequal lengths, no perpendicular angles
4 Types of Structures - ANSWER Polymorph Solvate Hydrate Desolvate
Polymorph - ANSWER Same compound, different unit cells (Change crystallization process) 2 Types: Monotrope and Enantiotrope
Solvate - ANSWER Unit Cell with solvent in structure
Hydrate - ANSWER Solvate with water in Unit cell
Desolvate - ANSWER Solvant is extracted so there is a hole in Unit Cell
Rate of Dissolution - ANSWER Rate at which a substance dissolves Different structure = different rate of dissolution Affects Bioavailability
Different Structure = Different... - ANSWER Rate of dissolution Refractive Index /Color Vapor Pressure
Bioavailability - ANSWER The rate at and the extent to which a nutrient is absorbed and used How much do you take vs how much gets to blood
Monotrope - ANSWER Irreversible transition from higher energy state to lower energy state Graph: Gibbs vs T: Lines don't cross between states Lower energy state has a higher MP
Reflection - ANSWER Change in direction of waves as they bounce back from object
Defraction - ANSWER Change in direction when wave travels through object Measured in XRay Diffraction (theta)
Differential Scanning Calorimetry (DSC) - ANSWER Measures temperature and Heat Flow Gives melting temperature and enthalpy of melting Down = melting: endothermic Up = crystallization: exothermic
Solid State Chemistry Chemical Reactions - ANSWER Hydrolysis and Oxidation
Hydrolysis - ANSWER Water reacts with a compound and breaks covalent bonds Hard to control, but can use a desiccant
Oxydation - ANSWER Lose an e- to gain an O Catalyzed metal
Non-straightforward Control with Anti-oxidant or Chelators to remove metal ions
Oxidation Example - ANSWER Methionine->Methionine Sulfoxide->Methionine Sulfone
Drug Excipient Reactions - ANSWER Inactive Substance reacting with drug formulation May stabilize, reduce activity, be an anti-oxidant, flavoring, etc.
Amorphous - ANSWER No Unit cell High energy therefore high rate of dissolution (Fast drug effect) Cons: High E = less stable Formulation Duration Hydroscopic (absorbs water) Preparation
Amorphous Preparation - ANSWER Lyophilization (freeze dry) in solution then vacuum solution out as gas Dissolve and flash precipitate
Skin Irritation Interpatient flux variation
Stratum Corneum - ANSWER Rate limiting step Part of epidermis Keratin and Lipids (prevent dehydration, therefore drug needs mix of solubility in oil and both hydrophobicity/philicity
Dermis - ANSWER Nerves and Capillaries Infinite Sink conditions where drugs immediately get swept into blood therefore [Drug]~
Passive Systems - ANSWER Concentration gradient fundamentals Reservoir System Matrix
Reservoir - ANSWER Adhesive + Membrane as RLS + Drug reservoir in solution
Matrix - ANSWER Band-aid of polymer matrix with embedded drug RLS = Stratum Corneum
Ficks Law - ANSWER J = DK(delta)C/l J = Flux D = Diffusion COefficient K = Partition Coefficient deltaC = Conentration Gradient l = Thickness of RLS How much drug goes through an area how quickly ug/(cm^2*s)
Partition Coefficient - ANSWER How much does drug want in skin Concentration of drug in 1 phase compared to in another phase K = []1/[] Higher: drug wants to be in skin, J increases Lower: drug wants to be in matrix, J decreases
How to increase Flux of system where skin is RLS - ANSWER Perturb skin or formulation
Perturb Skin - ANSWER Occlusion-trap water in skin to skin swells Increases flux of hydrophobic and hydrophilic molecules because H
Drug has to be charged: aabb Effect of ionic strength: Salt shields drugs and drops flux No salt = Jmax
Electromigration - ANSWER Pushing ions out
Electroosmosis - ANSWER Flow of water caused by current
aabb - ANSWER Acid Above: Base Below pHacid>pKa pHbase<pKa
Microneedles - ANSWER Mini needles that penetrate stratum corneum Hollow -> Degradable -> Adsorbable (drug on needle surface)
Sonophoresis - ANSWER Ultrasound puts holes in skin Cavitation Heat
Cavitation - ANSWER Microbubbles in H2O formed via ultrasound, when they pop = pores
Heat - ANSWER Friction from ultrasound increases heat therefore increases partition coefficient therefore increasing flux
Electroporation - ANSWER High voltage to charge proteins in skin and the repulsion creates pores (think plasmids)
Deamination - ANSWER Opening structure with H2O to remove NH ACH and BCH Backbone flexibility Hydrophobicity (more hydrophob environment = slower) Neighboring AA (bulk)
Oxidation - ANSWER Moving e- in presence of O Catalyzed by metal
Main Chain Cleavage - ANSWER Side chain attacks backbone to remove NH Not common
