Coupling Polymorphism/Solvatomorphism and Physical Stability Evaluation with Early Salt Synthesis Optimization of an Investigational Drug

The need for effective solid-form screening approaches, especially designed for the early discovery phases, is well recognized within the pharmaceutical industry. Here we report on the early polymorphism and solvatomorphism evaluation of a new drug candidate for selective α2C-adrenoceptor antagonists ORM10921·HCl. The approach we use is based on the systematic batch-to-batch characterization of the solids generated during the salt synthesis optimization. Within this study three crystalline forms, two anhydrous and one hemihydrate, were discovered and identified by X-ray powder diffraction (XRPD), differential scanning calorimery (DSC), and thermal gravimetry (TGA). Moreover, coupling the gravimetric vapor sorption analysis with a conventional XRPD enabled the relative stability of these solid-state forms at ambient conditions to be established and the most stable form, the hemihydrate, to be selected for further development. Hence, the utilized approach has proven to be an effective and fast tool for initial polymorphism and solvatomorphism tendency evaluation of drug candidates. While it is not obvious that this approach is sufficient for a comprehensive assessment of polymorphism, it demonstrates the importance of mindful solid-state characterization during crystallization process development.