In silico prediction of drug dissolution and absorption with variation in intestinal pH for BCS class II weak acid drugs: ibuprofen and ketoprofen

Abstract

The FDA Biopharmaceutical Classification System guidance allows waivers for in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms only for BCS class I. Extensions of the in vivo biowaiver for a number of drugs in BCS Class III and BCS class II have been proposed, particularly, BCS class II weak acids. However, a discrepancy between the in vivo- BE results and in vitro- dissolution results for a BCS class II acids was recently observed. The objectives of this study were to determine the oral absorption of BCS class II weak acids via simulation software and to determine if the in vitro dissolution test with various dissolution media could be sufficient for in vitro bioequivalence studies of ibuprofen and ketoprofen as models of carboxylic acid drugs. The oral absorption of these BCS class II acids from the gastrointestinal tract was predicted by GastroPlus™. Ibuprofen did not satisfy the bioequivalence criteria at lower settings of intestinal pH=6.0. Further the experimental dissolution of ibuprofen tablets in the low concentration phosphate buffer at pH 6.0 (the average buffer capacity 2.2 mmol L-1/pH) was dramatically reduced compared to the dissolution in SIF (the average buffer capacity 12.6 mmol L -1/pH). Thus these predictions for oral absorption of BCS class II acids indicate that the absorption patterns largely depend on the intestinal pH and buffer strength and must be carefully considered for a bioequivalence test. Simulation software may be very useful tool to aid the selection of dissolution media that may be useful in setting an in vitro bioequivalence dissolution standard.

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

“…pH, ionic strength, and buffer capacity are three major characteristics of the GI fluids that can affect the rate of drug release (2,12). Typical pH values in the stomach in the fasted state are within the range of 1.4-2.1.…”

“…On the other hand, the pH values in the small intestine gradually rise between the duodenum and ileum to a range of 5.5-8.3, depending on the location and fed and fasted states (1,14,16). This increase in pH is due to the neutralization of acid coming from the stomach with bicarbonate ions secreted by the pancreas (1,12). The ionic strength of the intestinal fluid was found to be within the range of 0.070-0.166 mol/L (17).…”

Application of Absorption Modeling to Predict Bioequivalence Outcome of Two Batches of Etoricoxib Tablets

“…In a previous publication, Okumu et al (16) had discussed the development of an oral absorption model in GastroPlus as the basis of a biowaiver argument for etoricoxib formulation. Similar arguments have been made in the literature for other weak bases (8,12). However a detailed validation of the concept against experimental data for formulations with different dissolution rates has not been reported.…”

“…Tubic-Grozdanis et al used a PBPK-based approach using the GastroPlus software to demonstrate how rapid in vitro dissolution translates to bioequivalence assurance for weak bases and weak acids (8). Tsume et al utilized similar simulations to demonstrate the applicability of BCS biowaviers to ibuprofen and ketoprofen, two BCS IIa compounds (12). WHO has adopted this recommendation for BCS IIa compounds (13).…”

Meeting Report: International Workshop on Implementation of Biowaivers Based on the Biopharmaceutics Classification System (BCS)

“…He focused on the element of the risk equation related to the capacity of detection and reviewed the literature to identify whether the current set of experimental conditions recommended by BCS guidelines could anticipate the bioequivalence outcome for poorly soluble and highly absorbed drugs. Some issues related to the dynamic acidification of the thin diffusion layer in response to ionization of some weak acids, which in turn can affect the dissolution of the drug product itself, which do not seem to be captured by the high buffer capacity dissolution media were raised (8). This led to the conclusion that the current capacity of detection would need to be improved to allow a biowaiver for BCS Class 2 drugs.…”