Garbacz Patrycja, Paukszta Dominik, Sikorski Artur, Wesolowski Marek
Department of Analytical Chemistry, Faculty of Pharmacy, Medical University of Gdansk, Gen. J. Hallera 107, 80-416 Gdansk, Poland.
Institute of Chemical Technology and Engineering, Poznan University of Technology, Berdychowo 4, 60-695 Poznan, Poland.
Pharmaceutics. 2020 Jul 9;12(7):648. doi: 10.3390/pharmaceutics12070648.
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 -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 -aminobenzoic acid and a lorazepam co-crystal with nicotinamide crystallized in the monoclinic 2/n and 2/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.
苯二氮䓬类药物的低水溶性严重影响其生物利用度，进而影响其生物活性。由于共结晶已被发现是改善活性药物成分不良性质的一种有前景的方法，本研究的目的是制备两种苯二氮䓬类药物（氯氮䓬和劳拉西泮）的共晶体。使用不同的共结晶方法，即浆液蒸发和液相助磨，首次制备了氯氮䓬与对氨基苯甲酸的共晶体以及劳拉西泮与烟酰胺的共晶体。通过使用差示扫描量热法（DSC）、粉末X射线衍射（PXRD）、傅里叶变换红外光谱（FTIR）和拉曼光谱对两种共晶体获得的数据与两种苯二氮䓬类药物和共形成剂的物理混合物进行比较，确认获得了共晶体。两种苯二氮䓬类药物共晶体的PXRD图谱与基础粉末衍射文件（PDF - 4 +）中包含的图谱的兼容性表明，在共结晶过程中确实形成了新的晶体结构。单晶X射线衍射表明，氯氮䓬与对氨基苯甲酸的共晶体和劳拉西泮与烟酰胺的共晶体分别在单斜2/n和2/c空间群中结晶，不对称单元中含有一个苯二氮䓬分子和一个共形成剂分子。FTIR和拉曼光谱证实苯二氮䓬类药物和共形成剂通过氢键相连且无质子交换。此外，DSC研究表明，归属于共晶体熔化的单吸热DSC峰根据共结晶方法和所用溶剂的不同而略有差异，并且与起始组分的峰也不同。
