Bioequivalence Dissolution Test Criteria for Formulation Development of High Solubility-Low Permeability Drugs

Abstract

The purpose of the present study was to provide the experimental and theoretical basis of bioequivalence (BE) dissolution test criteria for formulation development of high solubility-low permeability drugs. According to the biowaiver scheme based on the biopharmaceutics classification system (BCS), for BCS class III drugs, a test formulation and a reference formulation are predicted to be BE when 85% of the drug dissolves within 15 min (T 85% < 15 min) in the compendial dissolution test. However, previous theoretical simulation studies have suggested that this criterion may possibly be relaxed for use in practical formulation development. In the present study, the dissolution profiles of 14 famotidine formulations for which BE has been clinically confirmed were evaluated by the compendial dissolution test at pH 1.2 and 6.8. The plasma concentration-time profiles of famotidine formulations were simulated using the dissolution data. In addition, virtual simulations were performed to estimate the range of dissolution rates to be bioequivalent. The fastest and slowest dissolution rates among the famotidine formulations were T 85% 10 min and T 85% 60 min at pH 6.8, respectively. The virtual simulation BE study suggested that famotidine formulations can be bioequivalent when T 85% < 99 min. In the case of BCS III drugs, the rate-limiting step of oral drug absorption is the membrane permeation process rather than the dissolution process. Therefore, a difference in the dissolution process has less effect on BE. These results contribute to a better understanding of the biowaiver approach and would be of great help in the formulation development of BCS class III drugs.

Dissolution Profiles of Oral Disintegrating Tablet with Taste Masking Granule Polymer Coating in Biorelevant Bicarbonate Buffer

“…Although each company's decision differs, there are many cases in which companies take on the risk of proceeding to BE studies even when the dissolution profiles of the reference and the test formulation are not similar. 4,36) The results of this study have the potential to make a significant contribution to enhancing the accuracy of BE predictions by in vitro dissolution tests.…”