C.S.G.I. - Department of Chemistry, Physical-Chemistry Section, University of Pavia, Viale Taramelli 16, 27100 Pavia, Italy.
J Phys Chem B. 2013 Jul 11;117(27):8113-21. doi: 10.1021/jp404273x. Epub 2013 Jun 26.
Cocrystallization is a powerful method to improve the physicochemical properties of drugs. Loperamide hydrochloride is a topical analgesic for the gastrointestinal tract showing low and pH-dependent solubility; for this reason, an enhancement of its solubility or dissolution rate, particularly at the pH of the intestinal tract, could improve its local efficacy. Here we prepared cocrystals of this active principle with glutaric acid and so obtained a new crystalline solid representing a viable alternative to improve the physicochemical properties and thus the pharmaceutical behavior of the drug. Differential scanning calorimetry, X-ray powder diffraction, Fourier infrared spectroscopy, solid-state NMR, and scanning electron microscopy coupled to the energy-dispersive X-ray spectrometry were used to investigate the new solid-phase formation. DFT calculations at B3LYP/6-31G(d) level of theory, in the gas phase, including frequencies computation, provided a rationale for the interaction between loperamide hydrochloride and glutaric acid. The cocrystals showed improved water solubility in comparison with loperamide HCl, and the pharmaceutical formulation proposed was able to release the drug more rapidly in comparison with three reference commercial products when tested at neutral pH values.
共晶化是一种提高药物物理化学性质的有效方法。盐酸洛哌丁胺是一种局部胃肠道止痛剂，其溶解度低且依赖于 pH 值；因此，提高其溶解度或溶解速率，特别是在肠道的 pH 值下，可以提高其局部疗效。在这里，我们用戊二酸制备了该活性成分的共晶，从而获得了一种新的结晶固体，这是一种可行的替代方法，可以改善药物的物理化学性质和药物行为。使用差示扫描量热法、X 射线粉末衍射、傅里叶变换红外光谱、固态 NMR 和扫描电子显微镜结合能量色散 X 射线光谱法研究了新的固相形成。在气相中使用 B3LYP/6-31G(d) 理论水平进行的 DFT 计算，包括频率计算，为盐酸洛哌丁胺和戊二酸之间的相互作用提供了依据。与盐酸洛哌丁胺相比，共晶的水溶解度得到了提高，并且当在中性 pH 值下测试时，所提出的药物制剂能够比三种参考商业产品更快地释放药物。
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