Mechanochemical Synthesis of Bumetanide鈥?-Aminobenzoic Acid Molecular Cocrystals: A Facile and Green Approach to Drug Optimization

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• 作者：Giovanna Bruni ; Mariarosa Maietta ; Vittorio Berbenni ; Piercarlo Mustarelli ; Chiara Ferrara ; Mauro Freccero ; Vincenzo Grande ; Lauretta Maggi ; Chiara Milanese ; Alessandro Girella ; Amedeo Marini
• 刊名：Journal of Physical Chemistry B
• 出版年：2014
• 出版时间：August 7, 2014
• 年：2014
• 卷：118
• 期：31
• 页码：9180-9190
• 全文大小：741K
• ISSN：1520-5207

文摘

Molecular cocrystals are of growing interest in pharmaceutics for their improved physicochemical properties. Their mechanochemical synthesis is very promising, being easy, cheap, and 鈥済reen鈥? Here, for the first time, we report on cocrystallization of bumetanide, a diuretic and natriuretic active principle, and 4-aminobenzoic acid. The synthesis is performed both by wet and dry grinding. The cocrystal formation was investigated with a wide range of techniques, including solid-state NMR, IR, XRD, microscopy, and thermal analysis. Wet and dry grinding procedures led to different cocrystal polymorphs. In particular, the dry method gave a cocrystal by powder amorphization and subsequent crystallization. DFT calculations at the B3LYP/6-31+G(d,p) level of theory shed light on the H-bond scheme at the basis of cocrystal formation. The cocrystals showed improved solubility and dissolution rate with respect to the drug alone. This could guarantee a faster absorption and a better bioavailability of the active principle.