A THEORETICAL BASIS FOR A BIOPHARMACEUTIC DRUG CLASSIFICATION - THE CORRELATION OF IN-VITRO DRUG PRODUCT DISSOLUTION AND IN-VIVO BIOAVAILABILITY

A biopharmaceutics drug classification scheme for correlating in vitro drug product dissolution and in vivo bioavailability is proposed base d on recognizing that drug dissolution and gastrointestinal permeabili ty are the fundamental parameters controlling rate and extent of drug absorption. This analysis uses a transport model and human permeabilit y results for estimating in vivo drug absorption to illustrate the pri mary importance of solubility and permeability on drug absorption. The fundamental parameters which define oral drug absorption in humans re sulting from this analysis are discussed and used as a basis for this classification scheme. These Biopharmaceutic Drug Classes are defined as: Case 1. High solubility-high permeability drugs, Case 2. Low solub ility-high permeability drugs, Case 3. High solubility-low permeabilit y drugs, and Case 4. Low solubility-low permeability drugs. Based on t his classification scheme, suggestions are made for setting standards for in vitro drug dissolution testing methodology which will correlate with the in vivo process. This methodology must be based on the physi ological and physical chemical properties controlling drug absorption. This analysis points out conditions under which no in vitro-in vivo c orrelation may be expected e.g. rapidly dissolving low permeability dr ugs. Furthermore, it is suggested for example that for very rapidly di ssolving high solubility drugs, e.g. 85% dissolution in less than 15 m inutes, a simple one point dissolution test, is all that may be needed to insure bioavailability. For slowly dissolving drugs a dissolution profile is required with multiple time points in systems which would i nclude low pH, physiological pH, and surfactants and the in vitro cond itions should mimic the in vivo processes. This classification scheme provides a basis for establishing in vitro-in vivo correlations and fo r estimating the absorption of drugs based on the fundamental dissolut ion and permeability properties of physiologic importance.