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

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.药物结晶（Drug Crystallization）是通过提升固态稳定性与调控粒径以延长药物释放的核心途径。共结晶（Co-crystallization）可进一步调控药物释放动力学：其通过改变药物分子间的相互作用，还可实现具有协同药效的活性成分的共递送。然而，将理化性质各异的药物共配制至同一体系中颇具挑战。本研究以姜黄素（Curcumin）与胡椒碱（Piperine）为模型体系，探究了溶剂/反溶剂结晶法（Solvent/Anti-solvent Crystallization）这一简便通用的方法，用于制备单药及共配制型晶型储库制剂。我们评估了药物浓度、药物配比以及溶剂/反溶剂配比对晶体形成、晶体结构与释放行为的影响。研究结果表明，溶剂/反溶剂配比对单药制剂的晶体性质与加速释放动力学具有显著调控作用。在共配制体系中，药物配比与溶剂/反溶剂配比的相互作用会介导晶体及固体产物中的实际（而非理论）姜黄素或胡椒碱载药量与固体收率。体内实验显示，所有制剂均表现出姜黄素释放量较低且持续缓释的特征，符合溶解度限制型动力学规律；而胡椒碱的释放则对制剂组成更为敏感。此外，多数晶体在微球植入物中留存达14天之久，提示姜黄素可实现更长时间的释放。本研究成果证实了溶剂/反溶剂结晶法可用于构建可调性的单药及多药晶型储库制剂，并阐明了结晶参数如何影响共配制小分子药物体系的药物释放行为。