(M0930-08-45) Use of Predictive Dissolution to Guide Formulation Development - A Case Study of a Weak Base Drug in Conventional and Enabled Oral Formulations

Purpose: Compound A, a weak base molecule, is a BCS class 2 drug with highly pH dependent solubility. The free base of compound A is very soluble in gastric pH but has extremely low solubility in the intestinal  pH causing a rapid precipitation. Multiple formulation strategies, such as on-site suspension, direct compressed tablets, and amorphous solid dispersion, were developed to tackle the drug delivery and enhance the bioavailability of Compound A. The significant pH solubility difference could cause an impact on pK performance during co-dosing with acid-reducing agents.  Various in vitro biorelevant dissolution techniques were employed to evaluate the oral suspension, direct compressed tablets and amorphous solid dispersion (ASD) oral formulations.

Methods: Two-stage biorelevant dissolution with acid media (simulated gastric fluid) in the first stage and fasted state intestinal fluid (FaSSIF) as a second stage was used to mimic transfer from the stomach to the duodenum in the healthy volunteers. A biorelevant dissolution mimicking Acid-reducing agents (ARAs) effect was also utilized to assess the in-vitro release of different formulations of compound A with ARAs.

Results: Two-stage biorelevant dissolution (SGF-FaSSIF) testing revealed that the ASD formulation demonstrated significantly higher solubility than the crystalline free base in biorelevant media at elevated pH conditions, therefore predicting to have better drug release performance when compared to the conventional tablet formulation. Amorphous solubility of the ASD formulation was confirmed by solvent shift method using scattered lighter detection. Acid-reducing agents (ARAs) can impact the drug release of weak base oral product due to the lower solubility of weak base in elevated gastric pH. The ARA effect mimicking biorelevant dissolution results showed ASD formulations and acidified conventional formulations exhibited superior performance than other formulations. The in vivo performance of selected formulation was further evaluated and verified by dog studies.

Conclusion: Predictive biorelevant dissolutions, normal biorelevant dissolution and ARA condition mimicking dissolution guided the formulation development and selection of the weak base Compound A successfully to support clinical study.

References: Litou C, Vertzoni M, Goumas C, Vasdekis V, Xu W, Kesisoglou F, Reppas C. Characteristics of the Human Upper Gastrointestinal Contents in the Fasted State Under Hypo- and A-chlorhydric Gastric Conditions Under Conditions of Typical Drug - Drug Interaction Studies. Pharm Res. 2016 Jun;33(6):1399-412.

Acknowledgments: The authors would like to thank Andre Hermans and Sanjaykumar Patel for their constructive discussion and suggestions on the preparation of the presentation.

Figure 1. Biorelevant dissolution of Compound A in different formulations