溶出度方法学验证-3.ppt

generapharm DRUG ABSORPTION A dissolution scientists view In vivo versus in vitro The development of the dissolution test ended up in the hands of analytical chemists This is reflected in the concentration on physical parameters and chemical systems such as buffers The fact that we are actually dealing with drug absorption has been lost Factors related to absorption and activity Lipophilicity The distribution of a molecule between an aqueous and lipid environment Solubility Limits the concentration of the drug and affects the rate at which it can dissolve Permeability How quickly a drug molecule can cross membrane barriers The drug absorption path The simple approachWhat could go wrong? Dissolution followed by precipitation Very rare First pass metabolism A potential problem Non linear kinetics A regulatory rather than real problem Food effects Various media proposed Potential barriers to oral drug bioavailability Gastric emptying-fasting stomach Stage 1 Minimal contractions lasting 1hr Stage 2 Irregular proximal to distal constractions ? hr Stage 3 Intense peristaltic waves lasting 5-15 minutes [housekeeping wave] Stage 4 Decreasing activity pH in fed/fasted state Tmax and site of absorption 0.5 - 1 - 2hr 2 -5 - 7hr 7hr plus Ionizable molecules Henderson-Hasselbach pH effect on solubility Many pharmaceuticals are simple acids or bases and the more ionized, the more water soluble they are IBUPROFEN pKa=4.4 Sink conditions requirement The rate of solution will decrease as the concentration reaches saturation In most drug absorption the drug passing into the blood stream is diluted so that it acts as a sink This means that the drug is potentially absorbed as soon as it dissolves Weak acids and bases This would lead to the conclusion that weakly acidic drugs [NSAID’s] should be absorbed from the stomach [at low pH they are not ionized] and weak bases should be absorbed in the intestine. This is a good general rule for simple drugs but there are competing effects Ev