Structural Characterization of Co-Crystals of Chlordiazepoxide with p-Aminobenzoic Acid and Lorazepam with Nicotinamide by DSC, X-Ray Diffraction, FTIR and Raman Spectroscopy

Patrycja Garbacz; Dominik Paukszta; Artur Sikorski; Marek Wesolowski

doi:10.3390/pharmaceutics12070648

Structural Characterization of Co-Crystals of Chlordiazepoxide with p-Aminobenzoic Acid and Lorazepam with Nicotinamide by DSC, X-Ray Diffraction, FTIR and Raman Spectroscopy

Pharmaceutics. 2020 Jul 9;12(7):648. doi: 10.3390/pharmaceutics12070648.

Authors

Patrycja Garbacz¹, Dominik Paukszta², Artur Sikorski³, Marek Wesolowski¹

Affiliations

¹ Department of Analytical Chemistry, Faculty of Pharmacy, Medical University of Gdansk, Gen. J. Hallera 107, 80-416 Gdansk, Poland.
² Institute of Chemical Technology and Engineering, Poznan University of Technology, Berdychowo 4, 60-695 Poznan, Poland.
³ Department of Physical Chemistry, Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland.

Abstract

The low water solubility of benzodiazepines seriously affects their bioavailability and, in consequence, their biological activity. Since co-crystallization has been found to be a promising way to modify undesirable properties in active pharmaceutical ingredients, the objective of this study was to prepare co-crystals of two benzodiazepines, chlordiazepoxide and lorazepam. Using different co-crystallization procedures, slurry evaporation and liquid-assisted grinding, co-crystals of chlordiazepoxide with p-aminobenzoic acid and lorazepam with nicotinamide were prepared for the first time. Confirmation that co-crystals were obtained was achieved through a comparison of the data acquired for both co-crystals using differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier-transform infrared (FTIR) and Raman spectroscopy, with comparisons acquired for the physical mixtures of both benzodiazepines and coformers. The compatibility of PXRD patterns of both benzodiazepines co-crystals with those contained in the base Powder Diffraction File (PDF-4+) suggests that new crystal structures were indeed created under the co-crystallization procedure. Single-crystal X-ray diffraction revealed that a chlordiazepoxide co-crystal with p-aminobenzoic acid and a lorazepam co-crystal with nicotinamide crystallized in the monoclinic P2₁/n and P2₁/c space group, respectively, with one molecule of benzodiazepine and one of coformer in the asymmetric unit. FTIR and Raman spectroscopy corroborated that benzodiazepine and coformer are linked by a hydrogen bond without proton exchange. Furthermore, a DSC study revealed that single endothermic DSC peaks assigned to the melting of co-crystals differ slightly depending on the co-crystallization procedures and solvent used, as well as differing from those of starting components.

Keywords: Fourier-transform infrared (FTIR); Raman spectroscopy; chlordiazepoxide; co-crystals; differential scanning calorimetry (DSC); lorazepam; powder X-ray diffraction (PXRD); single-crystal x-ray diffraction (SCXRD).

Abstract

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