Discovering the Differences of the Individual Batches of API and its Polymorphs Using Hansen Solubility Parameters.

PURPOSE: Physicochemical stability of drug products depends on excipient-API (active pharmaceutical ingredient) compatibility, where interfacial interactions at the particle surface can initiate degradation pathways and solid-state transformations. Conventional compatibility approaches often emphasise bulk properties and may under-represent surface effects.

METHODS

A methodology based on Hansen solubility parameters (HSPs) determined by inverse gas chromatography (IGC) was applied to characterise API surface properties. Three model compounds (ramipril, sertraline hydrochloride, agomelatine) were analysed to compare polymorphic forms and production batches. Measurements were performed at infinite dilution using multiple molecular probes at several temperatures.

RESULTS

The HSP profiles showed pronounced differences between polymorphs and, importantly, between batches sharing the same polymorphic form. The data indicate that molecular packing, stereochemistry and processing history can measurably alter surface energetics, with direct implications for excipient compatibility and formulation robustness.

CONCLUSION

IGC-derived HSP analysis provides complementary, surface-sensitive information that can support excipient selection during early formulation development and help manage risks related to polymorphic variability and supplier-to-supplier differences. Further work should link HSP profiles to formulation performance metrics such as processability, compatibility and stability.