The Biopharmaceutics Classification System: Subclasses for in vivo predictive dissolution (IPD) methodology and IVIVC

Abstract

The Biopharmaceutics Classification System (BCS) has found widespread utility in drug discovery, product development and drug product regulatory sciences. The classification scheme captures the two most significant factors influencing oral drug absorption; solubility and intestinal permeability and it has proven to be a very useful and a widely accepted starting point for drug product development and drug product regulation. The mechanistic base of the BCS approach has, no doubt, contributed to its wide spread acceptance and utility. Nevertheless, underneath the simplicity of BCS are many detailed complexities, both in vitro and in vivo which must be evaluated and investigated for any given drug and drug product. In this manuscript we propose a simple extension of the BCS classes to include subspecification of acid (a), base (b) and neutral (c) for classes II and IV. Sub-classification for Classes I and III (high solubility drugs as currently defined) is generally not needed except perhaps in border line solubility cases. It is well known that the , pKa physical property of a drug (API) has a significant impact on the aqueous solubility dissolution of drug from the drug product both in vitro and in vivo for BCS Class II and IV acids and bases, and is the basis, we propose for a sub-classification extension of the original BCS classification. This BCS sub-classification is particularly important for in vivo predictive dissolution methodology development due to the complex and variable in vivo environment in the gastrointestinal tract, with its changing pH, buffer capacity, luminal volume, surfactant luminal conditions, permeability profile along the gastrointestinal tract and variable transit and fasted and fed states. We believe this sub-classification is a step toward developing a more science-based mechanistic in vivo predictive dissolution (IPD) methodology. Such a dissolution methodology can be used by development scientists to assess the likelihood of a formulation and dosage form functioning as desired in humans, can be optimized along with parallel human pharmacokinetic studies to set a dissolution methodology for Quality by Design (QbD) and in vitro–in vivo correlations (IVIVC) and ultimately can be used as a basis for a dissolution standard that will ensure continued in vivo product performance.

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

“…Perhaps the most definitive outcome from the in silico modeling of intestinal transport has been the evolution of the aforementioned BCS, now being used to classify which generic drugs need to undergo in vivo bioequivalence studies and to provide accurate IVIVC predictions (Tsume et al, 2014). However, in spite of this achievement, as well as the various developments detailed above, it also needs to be noted that we are a long way from precise prediction of human bioavailability.…”

pH-Dependent Solubility and Dissolution Behavior of Carvedilol—Case Example of a Weakly Basic BCS Class II Drug

“…Carvedilol, a nonselective beta blocker/alpha-1 blocker, is indicated in the treatment of mild to severe congestive heart failure and high blood pressure. It has a log P value of 3.8 with a basic pK a of 7.8 (6) and an acidic pK a of 15.0 (calculated using ChemAxon software). Carvedilol exhibits pH-dependent solubility (7).…”

Advancing Product Quality: a Summary of the Inaugural FDA/PQRI Conference

“…Biopharmaceutics Classification System (BCS) subclasses, as proposed by Dr. Gordon Amidon and shown in Table I, can inform development of predictive dissolution tools (13,14). A structured five-step approach can be envisaged as starting with a quality risk assessment, followed by development of tests for critical quality attributes (CQAs), followed by testing for impact of CQAs in the clinic, and finally using the data to establish CQA limits for incorporation into subsequent QbD steps.…”