Won’t be affected because post-solubilizationTherapeutic – blood levels & whether it reaches high enough/too high of levelsoDoes matter because need solubilizationPolymorphic conversions occur during salt formation/purification, milling, granulation, drying, compression, etc.Milling (high impact grinding) causes crystal to change to amorphousoHigh impact & high speedoCan increase temperature to alter the drugBring in different techniques to ensure no temperature changeoOverall purpose: reduction of particle sizeCompression decreases forms as wellBrand-specific agents may have a specific polymorphic form that can’t be substitutedWhen doctors request a certain brand, it promises a patient a specific polymorphic form to get absolute blood levelsRitonavir randomly quit responding & it was assumed that patients developed resistance, but instead it was due to a different, more stable crystal form being created in a manufacturing plantFDA now requires updates about polymorphismsOVERALL: would prefer to have no polymorphs, but if there are some, you want distinct differences, so you can pick a certain oneoParticle size, particle morphology, surface areaoDensity & porosityoMelting pointoHygroscopicity – absorbs moisture from the atmosphereDeliquescent compound – rapidly picks up moisture to solubilizeDrop unless valuable if realize this early onoChemical stabilityBiopharmaceutics Classification System (BCS)Middle is 250 because that’s if you took with a glass of waterLog, log graph
Class I:-Easy to formulate-Give out biowaiversoMay not have to recreate clinical trials when switching from brand to genericIf company can prove that generic mimics brand, then get the biowaiverClass II:-Can manipulate the solubility so you have more control-Easier to formulate than class IIIClass III:-Unless molecule changes, permeability remains the same-Can use permeability enhancers, but still an absolute NO from the FDA because exposes the patient to many other issuesClass IV:-Always bad news-Has to be very valuable-Only option is to give this direct injectionBiopharmaceutical Principles-Main barriers to oral delivery:oPoor drug solubility & dissolutionoAbsorption barriersi.e. intestinal barrier, BBB, etc.Intestinal barrieroSize of molecules (larger molecule, lesser odds of absorption)oEnzymatic degradation (breakdown of drugs by enzymes of the gut)Pepcid is presentin the stomach &the first enzyme encounteredIf taken by mouth, have to worry about degradation by amylaseoPassive diffusion or transports?Passive preferable – with extra drug you get extra absorptionoEfflux transportersMany present in the GI tract & if the drug is a substrate for these, may need to change how its administeredoLocal metabolism within intestinal cell enterocytesMostly 3A4
Happens before absorptionOxidative changes due to phase I enzymes occur hereoPre-systemic metabolismHepatic barrier & first pass effectPhase I or Phase II changesoPhase I – oxidative; phase II – conjugative
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- Fall '09