INVESTIGATING PHARMACEUTICAL CO-CRYSTALS AS A MEANS TO IMPROVE THE SOLUBILITY OF A DRUG

Abstract

Recently co-crystals have emerged as a potential approach to improve the solubility, dissolution, and bioavailability of active pharmaceutical ingredients (API). Often co-crystal formation is studied in the development stage in order to solve an issue (with solid form or formulation) or to expand intellectual property. However, co-crystals may have the potential of enhancing the developability of a poorly soluble lead candidate in the discovery stage. In this study, piroxicam, a BCS (Biopharmaceutical Classification System) Class II compound with low solubility, was chosen as a model drug to explore this possibility. The solution phase reaction crystallization method was chosen over slow evaporation as a way to make co-crystals because it can produce pure co-crystals that can be scaled by simply using the solubility data of the parent and coformer. A screen of carboxylic acid coformers yielded six piroxicam co-crystals which were characterized. Co-crystal aqueous solubility was measured and models were used to calculate co-crystal pH dependent solubility. Intrinsic dissolution rates of the co-crystals were measured in biorelevant media. Co-crystals were found to be more soluble and the dissolution rates were lower than the parent. Piroxicam oral exposure in rat from the co-crystals was determined and was similar to free piroxicam.