Solid-State Characterization of Amorphous and Mesomorphous Calcium Ketoprofen

This article is concerned with exploring the application of pair distribution in pharmaceutical analysis. The solid-state characterization of amorphous and mesomorphous (liquid crystalline) calcium ketoprofen is used as an example and the structures of the amorphous and mesomorphous phases of calcium ketoprofen are compared to that of the crystalline phase. An approach to calculating the optimal experimental parameters in pair distribution function (PDF) analysis as well as a suggested method to help assign the many different peaks in a PDF diagram of an organic material are discussed. The studied salts were analyzed by X-ray powder diffraction (XRPD), single crystal X-ray diffraction, Raman spectroscopy, polarized light microscopy (PLM), solid-state NMR (SSNMR), variable-temperature SSNMR, and PDF. Raman and SSNMR were useful techniques in identifying and differentiating the crystalline phase from the other two phases but failed, alone, to differentiate between the amorphous and mesomorphous phases. The absence of significant changes in chemical shifts in SSNMR and peak shifts in Raman spectra suggested that the differences in the molecular environment of the major chemical groups in the amorphous and mesomorphous phases were minimal. However, the broadening of the Raman and SSNMR peaks in the noncrystalline phases indicated an increase in the disorder in these systems. PDF analysis of the disordered phases revealed that upon dehydration or quench cooling where the system transformed from crystalline to become disordered, the calcium calcium and calcium oxygen (oxygen of the carboxylic acid) distances remained intact meanwhile the rest of the molecule became disordered. The preliminary results from variable-temperature SSNMR showed two different T-1 relaxation time profiles for the amorphous and mesomorphous phases. This was consistent with the hypothesis that part of the molecule remained ordered while the rest of the molecule became disordered and the amorphous phase was more disordered than the mesomorphous phase. In conclusions, SSNMR and PDF supported the hypothesis that part of the anhydrous salt remained ordered while the rest of the molecule became disordered and the amorphous phase was more disordered than the mesomorphous phase. (C) 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3684-3697, 2010