Nasrallah, S.; Alhadid, A.; Minceva, M. Revealing the Solubility Enhancement of Active Pharmaceutical Ingredients through Eutectic Mixtures Formation: A Parameter Study. Crystal Growth & Design. 2024, In press. https://doi.org/10.1021/acs.cgd.4c00617
Abstract
The active pharmaceutical ingredient (API) solubility is critical for their bioavailability, dosing precision, stability, and overall efficacy. Forming eutectic mixtures between an API and an excipient has been widely used to improve API solubility. However, from a thermodynamic perspective, this approach is still relatively underexplored. This study explores the parameters influencing the solubility enhancement of an API with poor solubility in water by eutectic mixture formation. A hypothetical ternary system consisting of an API, excipient, and water was considered. The study investigated the impact of excipient melting properties and molecular interactions among the API, excipient, and water on API solubility in water. The two-suffix Margules equation was used to model the liquid phase nonideality. The study revealed that strong API–excipient and excipient–water interactions notably enhanced API solubility in water. However, this effect was counteracted when excipient–water interactions surpassed API–excipient interactions in strength. Additionally, the melting properties of the excipient had a significant influence on the composition of the mixture at the eutectic point and API solubility enhancement factor. This research underscores the essential characteristics a potential excipient should possess to maximize API solubility in water and other solvents. The results emphasize the importance of eutectic mixture formation in addressing the challenges associated with water-insoluble APIs.
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