In this study, we systematically evaluated “bottom-up” physiologically based oral absorption modeling, focusing on free weak base drugs. The gastrointestinal unified theoretical framework (the GUT framework) was employed as a simple and transparent model. The oral absorption of poorly soluble free weak base drugs is affected by gastric pH. Alternation of bulk and solid surface pH by dissolving drug substances was considered in the model. Simple physicochemical properties such as pK_a, the intrinsic solubility, and the bile micelle partition coefficient were used as input parameters. The fraction of a dose absorbed (Fa) in vivo was obtained by reanalyzing the pharmacokinetic data in the literature (15 drugs, a total of 85 Fa data). The AUC ratio with/without a gastric acid-reducing agent (AUCr) was collected from the literature (22 data). When gastric dissolution was neglected, Fa was underestimated (absolute average fold error (AAFE) = 1.85, average fold error (AFE) = 0.64). By considering gastric dissolution, predictability was improved (AAFE = 1.40, AFE = 1.04). AUCr was also appropriately predicted (AAFE = 1.54, AFE = 1.04). The Fa values of several drugs were slightly overestimated (less than 1.7-fold), probably due to neglecting particle growth in the small intestine. This modeling strategy will be of great importance for drug discovery and development.

The purpose of the present study was to harmonize the protocol of equilibrium solubility measurements for poorly water-soluble drugs to lower inter-laboratory variance. The “mandatory” and “recommended” procedures for the shake-flask method were harmonized based on the knowledge and experiences of each company and information from the literature. The solubility of model drugs was measured by the harmonized protocol (HP) and the non-harmonized proprietary protocol of each company (nonHP). Albendazole, griseofulvin, dipyridamole, and glibenclamide were used as model drugs. When using the nonHP, the solubility values showed large inter-laboratory variance. In contrast, inter-laboratory variance was markedly reduced when using the HP.

The purpose of this study was to evaluate the biopharmaceutical drug properties suitable for orally disintegrating tablets (ODTs). The net charge at pH 7.4, log D6.5, the highest dose strength, solubility in water, dose number, and elimination t1/2 of 57 ODT drugs and 113 drugs of immediate-release (IR) formulations were compared. These drugs were classified according to the Biopharmaceutical Classification System (BCS). A lower dose strength and a longer elimination t1/2 have been observed as characteristic properties of ODTs. The proportion of basic drugs was higher in the ODTs than in the IR. A significant difference was not observed between the ODT and the IR formulation for log D6.5, solubility in water, and dose number. The distributions of the ODT and IR formulations among each BCS class were similar, suggesting that an ODT can be developed regardless of the BCS class of a drug.

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 (T85% < 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 T85% = 10 min and T85% = 60 min at pH 6.8, respectively. The virtual simulation BE study suggested that famotidine formulations can be bioequivalent when T85% < 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.