A rapid solid form risk assessment workflow for ophthalmic drug candidates.

ABSTRACT

OBJECTIVE: This work introduces a material-sparing process that rapidly screens the solid form landscape for ophthalmic compound candidates. SIGNIFICANCE: Crystalline form of compound candidates generated by a Form Risk Assessment (FRA) can be used to reduce their downstream development risk. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.