An Experimental and Theoretical Investigation of Loperamide Hydrochloride-Glutaric Acid Co-Crystals.

Co-crystallization is a powerful method to improve the physico-chemical properties of drugs. Loperamide hydrochloride is a topical analgesic for the gastro intestinal tract showing low and pH-dependent solubility, for this reason an enhancement of its solubility and/or dissolution rate, particularly at the pH of the intestinal tract, could improve its local efficacy. Here, we prepared co-crystals of this active principle with glutaric acid, so obtaining a new crystalline solid representing a viable alternative to improve the physico-chemical 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 with 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 co-crystals showed improved water solubility in comparison to loperamide HCl, and the pharmaceutical formulation proposed was able to release the drug more rapidly in comparison to three reference commercial products, when tested at neutral pHs

Mechanochemical Synthesis of Bumetanide–4-Aminobenzoic Acid Molecular Cocrystals: A Facile and Green Approach to Drug Optimization

Molecular cocrystals are of growing interest in pharmaceutics for their improved physicochemical properties. Their mechanochemical synthesis is very promising, being easy, cheap, and “green”. 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

An Experimental and Theoretical Investigation of Loperamide Hydrochloride–Glutaric Acid Cocrystals

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