Komisarek Daniel, Taskiran Ebru, Vasylyeva Vera
Inorganic and Structural Chemistry I, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
Materials (Basel). 2023 Mar 10;16(6):2242. doi: 10.3390/ma16062242.
In this study, we compare the mechanochemical and classical solvent crystallization methods for forming maleates of GABA and its pharmaceutically active derivatives: Pregabalin, Gabapentin, Phenibut, and Baclofen. Common characterization techniques, like powder and single crystal X-ray diffraction, IR-spectroscopy, differential scanning calorimetry, thermogravimetric analysis and H-NMR spectroscopy, are used for the evaluation of structural and physicochemical properties. Our work shows that maleate formation is possible with all investigated target compounds. Large increases in solubility can be achieved, especially for Pregabalin, where up to twentyfold higher solubility in its maleate compared to the pure form can be reached. We furthermore compare the mechanochemical and solvent crystallization regarding quickness, reliability of phase production, and overall product quality. A synthetic route is shown to have an impact on certain properties such as melting point or solubility of the same obtained products, e.g., for Gabapentin and Pregabalin, or lead to the formation of hydrates vs. anhydrous forms. For the GABA and Baclofen maleates, the method of crystallization is not important, and similarly, good results can be obtained by either route. In contrast, Phenibut maleate cannot be obtained pure and single-phase by either method. Our work aims to elucidate promising candidates for the multicomponent crystal formation of blockbuster GABA pharmaceuticals and highlight the usefulness of mechanochemical production routes.
在本研究中，我们比较了用于形成GABA及其药学活性衍生物（普瑞巴林、加巴喷丁、苯乙哌啶酮和巴氯芬）马来酸盐的机械化学法和传统溶剂结晶法。使用常见的表征技术，如粉末和单晶X射线衍射、红外光谱、差示扫描量热法、热重分析和氢核磁共振光谱，来评估结构和物理化学性质。我们的工作表明，所有研究的目标化合物都可以形成马来酸盐。可以实现溶解度的大幅提高，特别是对于普瑞巴林，其马来酸盐的溶解度比纯形式高可达二十倍。此外，我们比较了机械化学法和溶剂结晶法在速度、相生成的可靠性和整体产品质量方面的差异。结果表明，合成路线会对某些性质产生影响，例如相同所得产物的熔点或溶解度，例如对于加巴喷丁和普瑞巴林，或者导致水合物与无水形式的形成。对于GABA和巴氯芬的马来酸盐，结晶方法并不重要，同样，通过任何一种路线都可以获得良好的结果。相比之下，通过任何一种方法都无法获得纯的单相苯乙哌啶酮马来酸盐。我们的工作旨在阐明用于重磅炸弹GABA药物多组分晶体形成的有前景的候选物，并突出机械化学生产路线的实用性。
