Formulation and assessment of long-acting pharmaceutical co-formulated crystals.

Abstract

Drug crystallization is a fundamental approach to extending release through enhanced solid‑state stability and tunable particle size. Drug-release kinetics can be further modulated through co-crystallization, which alters drug-molecule-to-drug-molecule interactions, and can be used to simultaneously deliver agents with synergistic potency. However, co-formulating physicochemically diverse drugs into a common system can be challenging. Here, we investigate solvent/anti‑solvent crystallization as a simple and versatile method for producing single‑drug as well as co‑formulated crystalline depots using curcumin and piperine as a model system. We evaluate the effects of drug concentration, drug ratio, and solvent/anti‑solvent ratio on crystal formation, structure, and release behavior. Our results demonstrate that the solvent/anti-solvent ratio strongly modulates crystal properties and accelerated release kinetics for single‑drug formulations. In co‑formulated systems, the interaction between drug ratio and solvent/anti-solvent ratio mediates actual (as opposed to theoretical) curcumin or piperine loading within the crystals and solids yield. In vivo, all formulations exhibited low and extended curcumin release, consistent with solubility‑limited kinetics, while piperine release was more sensitive to formulation composition. Additionally, most crystals remained within bead explants after 14 days, suggesting the potential for longer release of curcumin. These findings illustrate the tunability of solvent/anti‑solvent crystallization for engineering single‑ and multi‑drug crystalline depots and provide insight into how crystallization parameters influence release from co‑formulated small‑molecule systems.