Supercritical Carbon Dioxide for Pharmaceutical Co-Crystal Production

Pharmaceuticals in Biopharmaceutics Classification System (BCS) Class II (low solubility, high permeability) are often modified to improve kinetic solubility. Co-crystallization and micronization are common methods for improving kinetic solubility. The basis of understanding co-crystallization processes is solubility and phase stability. In the majority of co-crystallizations, conventional solvents are utilized. Co-crystallization using supercritical carbon dioxide as a co-solvent and antisolvent can offer advantages over conventional co-crystallization including a greener solvent choice and the production of small, uniform particles without additional micronization. Gas antisolvent is the most widely reported supercritical fluid (SCF) co-crystallization process possibly due to its versatility in solvent selection and similarities to conventional antisolvent processes. This review focused on exploring critical co-crystallization parameters and feasibility of SCF techniques. In this review, it was identified that solvent choice proves to be one of the most critical parameters, impacting morphology, yield, phase purity, or polymorph to different extents. It was also identified that a systematic study of solubility to design co-crystallization processes is needed to optimize SCF co-crystallization yield and throughput. Furthermore, a focus on solubility and modeling of multicomponent systems and development of ternary phase diagrams can lead to robust, tailored co-crystallization processes in SCF systems, transitioning this technology to become more common in industry.