Influence of pressure, polymers and particle size on the solubility of crystalline pharmaceuticals

Poor aqueous solubility and dissolution of active pharmaceutical ingredients (APIs) remain key challenges in pharmaceutical development, particularly for long-acting injectables (LAIs). These formulations often utilize micro- or nanoscale API particles stabilized by polymers and/or surfactants. Antisolvent precipitation using supercritical CO2 (scCO2) or water is commonly employed to generate particles with controlled properties. However, these processes often rely on trial-and-error, making them time- and resource-intensive. This work combines experimental and theoretical approaches—using Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT)—to systematically investigate the impact of process parameters on API particle formation. For scCO2-based systems, PC-SAFT was applied to optimize high-pressure solubility experiments and predict API solubility in scCO2 and scCO2/organic solvent mixtures. Findings revealed pressure-dependent changes in API crystal structure and enhanced solubility with increased organic solvent content. In water-based systems, the influence of polymers on API solubility was examined and modeled with PC-SAFT. These insights enabled the identification of optimal conditions for solvent/antisolvent crystallization to produce stable LAI suspensions. Furthermore, a novel theoretical framework was introduced to predict particle size-dependent solubility. By integrating Pawlow’s Equation with PC-SAFT, the effect of particle size on melting temperature and solubility was quantified. Overall, this study enhances understanding of API solubility in complex systems and supports more efficient design of LAI formulations.