Eli Lilly and Company, Indianapolis, Indiana, USA.
J Pharm Sci. 2010 Sep;99(9):3684-97. doi: 10.1002/jps.21925.
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.
本文探讨了 pair distribution 在药物分析中的应用。以无定形和介晶（液晶）钙酮洛芬为例，比较了钙酮洛芬无定形相和介晶相的结构与晶相的结构。讨论了计算 pair distribution 函数（PDF）分析中最佳实验参数的方法以及一种有助于为有机材料的 PDF 图中的许多不同峰分配的方法。所研究的盐通过 X 射线粉末衍射（XRPD）、单晶 X 射线衍射、拉曼光谱、偏光显微镜（PLM）、固态 NMR（SSNMR）、变温 SSNMR 和 PDF 进行分析。拉曼和 SSNMR 是识别和区分晶相与其他两相的有用技术，但单独使用时无法区分无定形相和介晶相。SSNMR 中化学位移和拉曼光谱中峰位移没有明显变化表明，无定形相和介晶相中大化学基团的分子环境差异最小。然而，无定形相中拉曼和 SSNMR 峰的展宽表明这些体系中的无序度增加。无序相的 PDF 分析表明，在脱水或淬火冷却过程中，系统从晶态转变为无序态时，钙-钙和钙-氧（羧酸的氧）距离保持完整，而分子的其余部分变得无序。变温 SSNMR 的初步结果显示，无定形相和介晶相有两个不同的 T(1)弛豫时间分布。这与部分分子保持有序而其余分子变得无序且无定形相比介晶相更无序的假设一致。总之，SSNMR 和 PDF 支持了部分无水盐保持有序而其余分子变得无序且无定形相比介晶相更无序的假设。
