The development of a weakly basic compound is often challenging due to changes in pH that the drug experiences throughout the gastrointestinal tract. As the drug transitions from the low pH of the stomach to the higher pH of the small intestine, drug solubility decreases. A stomach with a higher pH, caused by food or achlorhydric conditions brought about by certain medications, decreases even the initial solubility. This decreased drug solubility is reflected in lower in vivo exposures. In many cases, a solubility-enabling approach is needed to counteract the effect of gastrointestinal pH changes. Solid dispersions of amorphous drug in a polymer matrix have been demonstrated to be an effective tool to enhance bioavailability, with the potential to mitigate the food and achlorhydric effects frequently observed with conventional formulations. Because solid dispersions are in a metastable state, they are particularly sensitive to processing routes that may control particle attributes, stability, drug release profile, and bioperformance. A better understanding of the impacts of processing routes on the solid dispersion properties will not only enhance our ability to control the product properties, but also lower development risks. In this study, a weakly basic compound with greatly reduced solubility in higher pHs was incorporated into a solid dispersion via both spray drying and hot melt extrusion. The properties of the solid dispersion via these two processing routes were compared, and the impact on dissolution behavior and in vivo performance of the dispersions was investigated.
Lipid-based drug delivery systems have been intensively investigated as a means of delivering poorly water-soluble drugs. Upon ingestion, the lipases in the gastrointestinal tract digest lipid ingredients, mainly triglycerides, within the formulation into monoglycerides and fatty acids. While numerous studies have addressed the solubility of drugs in triglycerides, comparatively few publications have addressed the solubility of drugs in fatty acids, which are the end product of digestion and responsible for the solubility of drug within mixed micelles. The objective of this investigation was to explore the solubility of a poorly water-soluble drug in fatty acids and raise the awareness of the importance of drug solubility in fatty acids. The model API (active pharmaceutical ingredient), a weak acid, is considered a BCS II compound with an aqueous solubility of 0.02 μg/mL and predicted partition coefficient >7. The solubility of API ranged from 120 mg/mL to over 1 g/mL in fatty acids with chain lengths across the range C18 to C6. Hydrogen bonding was found to be the main driver of the solubilization of API in fatty acids. The solubility of API was significantly reduced by water uptake in caprylic acid but not in oleic acid. This report demonstrates that solubility data generated in fatty acids can provide an indication of the solubility of the drug after lipid digestion. This report also highlights the importance of measuring the solubility of drugs in fatty acids in the course of lipid formulation development.
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