Structural studies of active pharmaceutical ingredients: polymorphism and solid-state reactivity.

Polymorphism, the ability of a substance to crystallize in two or more different structures, is a fundamental issue in the Pharmaceutical Industry because API’s can indeed afford multiple solid phases. As different crystalline forms can have different properties, polymorphic identity can have influence on processability, handling, formulability and also the physico-chemical and pharmacological properties of the finished drug product. Characterizing the various crystalline forms of API’s is therefore crucial. Structural studies can help interpreting the origin, and the consequences, of polymorphism, yielding important information on phase transitions or thermal and chemical stability. As the classical technique for structural analysis, single crystal X-ray diffraction, is not always applicable to solid forms of API’s, structure solution from powder diffraction data is an ideal solution. Here, structure determination from laboratory X-ray powder diffraction (XRPD) data is successfully carried out on different API’s, illustrating the potential and usefulness of the technique. Three different species are studied (bupropion hydrohalide salts, nortriptyline hydrochloride and ibuprofen lysine salt), exploring different aspects (conformational and packing polymorphism, solvation/desolvation processes, thermodynamic relations and thermally-induced phase transitions). Finally, a new approach to Quantitative Phase Analysis, implemented in a publicly available software, has been tested on an API, particularly relevant when accessibility to the complete structural model is hampered by the complexity of the molecular/crystal form, not amenable to ab-initio XRPD characterization.