Purpose: The development of formulations to mitigate drug-drug interactions (DDIs) such as proton-pump inhibitors (PPIs) or histamine H2-receptor antagonists (H2-RAs) which are often referred to as “stomach-acid drugs”- requires predictive tools to guide selection of API form, excipients and manufacturing process. Depending on the nature of the specific API and formulation strategies to overcome undesired interactions with stomach-acid drugs, prototype formulations often achieve supersaturation in aqueous dissolution media. This creates new challenges from a development perspective and requires improved analytical screening tools to monitor API supersaturation and precipitation with correlation to in vivo conditions. In this study we present two case studies that illustrate the application of discriminating biorelevant dissolution tools to characterize formulations designed to mitigate PPI and H2-RA effects.
Methods: A dissolution screening approach was developed which incorporated UV detection for on-line monitoring of dissolution, supersaturation and precipitation and biorelevant media that simulate human elevated stomach pH conditions. These dissolution media are based upon recent advances in understanding of stomach fluid characteristics after treatment with stomach-acid lowering drugs.1 Modification was made to the recommended dissolution media in order to improve robustness with online monitoring and sensitivity to different formulation factors.
1. C. Litou, W. Xu, F. Kesisoglou, C. Reppas . The impact of reduced gastric acid secretion on dissolution of salts of weak bases in the fasted upper gastrointestinal lumen: Data in biorelevant media and in human aspirates. European J. Pharm & Biopharm 115 (2017) 94–101.
Results: The combination of both updated biorelevant media simulating hypo and a-chlorhydric state and on-line dissolution monitoring, produced a detailed understanding of the formulation performance and mechanism of supersaturation. The screening approach was successfully applied to drug products formulated with crystalline API and also formulations based upon amorphous solid dispersions. For both case studies, the dissolution screening revealed significant super saturation as well as processing and excipient effects.
Conclusion: These findings and detailed formulation understanding might not have been possible without the combination of data dense dissolution profiles via fiber optic monitoring coupled with biorelevant media. As such we believe that the benefits of online monitoring outweigh the risks and warrants broader integration of fiber optic dissolution monitoring as part of formulation screening when coupled with biorelevant dissolution media and conditions.