An Experimental and Theoretical Investigation of Loperamide Hydrochloride鈥揋lutaric Acid Cocrystals

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• 作者：Giovanna Bruni ; Mariarosa Maietta ; Lauretta Maggi ; Piercarlo Mustarelli ; Chiara Ferrara ; Vittorio Berbenni ; Mauro Freccero ; Federico Scotti ; Chiara Milanese ; Alessandro Girella ; Amedeo Marini
• 刊名：The Journal of Physical Chemistry B
• 出版年：2013
• 出版时间：July 11, 2013
• 年：2013
• 卷：117
• 期：27
• 页码：8113-8121
• 全文大小：518K
• 年卷期：v.117,no.27(July 11, 2013)
• ISSN：1520-5207

文摘

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.