Study of polymorphism in pharmaceutical compounds using vibrational spectroscopic approach and quantum chemical methods

Complete text of publication follows. Solids provide a convenient form to deliver active pharmaceutical ingredients (APIs) as part of a formulated product. However, pharmaceuticals may exist in numerous solid forms, which may feature different physical and chemical properties. These solid forms include 'true' polymorphs, solvates (pseudopolymorphs), co-crystals and amorphous solids. Polymorphism is often characterized as the ability of a drug substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice. Solvates and co-crystals are multicomponent systems that may be formally defined based on the state of the isolated pure components: if one component is a liquid at room temperature, the crystals are designated as solvates; if both components are solids at room temperature, the crystals are designated as co-crystals. The different structural arrangements of the APIs lead to by changes in the physical and chemical properties (e.g. thermodynamic, spectroscopic, kinetic, interfacial, mechanical, etc.), which may induce differences in manufacturability, solubility, bioavailability and stability between the different solid forms. Understanding and controlling the solid-state chemistry of APIs, both as pure drug substances and in formulated products, is therefore an important aspect of the drug development and formulation processes and has a direct impact on the quality as well as the protection of the intellectual property against possible patentrelated infringements. In order to obtain an accurate description of the solid forms of an API, analytical techniques sensitive to the crystalline structure must be applied. In principle, single crystal X-ray diffraction is the most effective technique since it directly determines the packing, conformation and intermolecular interaction of molecules. However, due to the problems associated with obtaining good quality single crystals, and the need of reliable routine analytical methods (sometimes suitable as on-line monitoring tools), the use of vibrational spectroscopy in this field is gaining increasing attention. Differently to X-ray diffraction techniques, which are sensitive to the long-range order, vibrational spectroscopy (mid-infrared, near-infrared and Raman scattering) is primarily sensitive to the short-range structure of molecular solids. Both Raman and infrared spectroscopies provide information on the structure, configuration and conformation in the solid state by probing the vibrations of atoms. Qualitative as well as quantitative analysis can be performed with both techniques. In this presentation, we will review the main applications of the vibrational spectroscopy techniques in the characterization of the solid forms of pharmaceutical substances. Specific examples of qualitative and quantitative investigations of raw materials and formulated products will be discussed and correlated with the results of other experimental techniques and quantum mechanical calculations.