A rapid solid form risk assessment workflow for ophthalmic drug candidates

This work introduces a material-sparing process that rapidly screens the solid form landscape for ophthalmic compound candidates. Crystalline form of compound candidates generated by a Form Risk Assessment (FRA) can be used to reduce their downstream development risk. This workflow evaluated nine model compounds with various molecular and polymorphic profiles by using less than 350 mg of drug substances. Kinetic solubility of the model compounds in a variety of solvents was screened to support the experimental design. The FRA workflow integrated several crystallization methods such as temperature-cycled slurrying (thermocycling), cooling, and evaporation. The FRA was also applied on ten ophthalmic compound candidates for verification. X-ray powder diffractometry (XRPD) was used for form identification. For the nine model compounds studied, multiple crystalline forms were generated. This demonstrates the potential of the FRA workflow to reveal polymorphic tendency. In addition, thermocycling process was found to be the most effective technique to capture the thermodynamically most stable form. Satisfactory results were observed with the discovery compounds intended for ophthalmic formulations. This work introduces a form risk assessment workflow by using sub-gram level of drug substances. The capability of this material-sparing workflow to discover polymorphs and capture the thermodynamically most stable forms within 2–3 weeks makes it suitable for discovery stage compounds, especially for ophthalmic candidates.

本研究介绍了一种节省物料的工艺，可快速筛选眼科候选化合物的固体晶型全景。通过晶型风险评估（Form Risk Assessment, FRA）得到的候选化合物晶型，可降低其后续开发风险。该流程仅使用不足350 mg的原料药，便对9种具备不同分子特性与多晶型特征的模型化合物开展了评估。为支撑实验设计，研究还筛选了模型化合物在多种溶剂中的动力学溶解度。FRA流程整合了多种结晶技术，包括温度循环浆化法（temperature-cycled slurrying, 热循环法）、冷却结晶法与蒸发结晶法。该FRA流程还被应用于10种眼科候选化合物以完成验证。晶型鉴定采用X射线粉末衍射法（X-ray powder diffractometry, XRPD）。针对所研究的9种模型化合物，实验成功获得了多种晶型，这证实了FRA流程具备揭示多晶型趋势的潜力。此外，研究发现热循环法是捕获热力学最稳定晶型的最有效手段。针对用于眼科制剂的候选化合物，该流程同样取得了令人满意的结果。本研究提出了一种基于亚克级原料药的晶型风险评估流程。该节省物料的流程可在2~3周内完成多晶型发现与热力学最稳定晶型的捕获，因此适用于药物发现阶段的化合物，尤其是眼科候选药物。