卡马西平与氢氯噻嗪共晶的表征与性质的研究

目的：制备卡马西平与氢氯噻嗪共晶，并对共晶的性质进行研究。方法：采用溶液结晶法制备卡马西平与氢氯噻嗪共晶，通过X-射线单晶衍射法（SCXRD）、X-射线粉末衍射法（PXRD）、差示扫描量热法（DSC）、热重分析（TGA）、红外光谱法（IR）对共晶进行表征，并通过HPLC对共晶的溶解度以及在人工胃液中、水中，在高温、高湿、光照条件下的稳定性进行考察；同时考察共晶在高湿条件下的吸湿性。结果：在75%、90%的高湿条件下，卡马西平与氢氯噻嗪的物理混合物10 d的吸湿性分别为0.022 9%、0.028 0%，共晶的吸湿性分别为0.003 5%、0.004 0%；在光照条件下，卡马西平、氢氯噻嗪10 d产生的杂质含量为0.36%、0.13%，共晶中的卡马西平、氢氯噻嗪10 d产生的杂质含量为0.13%、0.00%；在水中的溶解度，共晶中的卡马西平比原料药卡马西平的溶解度提高约1倍。结论：卡马西平和氢氯噻嗪形成共晶可以降低药物在高湿条件下的吸湿性，同时对原料药在光照条件下的稳定性有小幅度提高，并提高了卡马西平在水中溶解度。

Objective:To prepare carbamazepine and hydrochlorothiazide cocrystal and to study its properties. Methods:The carbamazepine and hydrochlorothiazide cocrystal was prepared by using the solution crystallization method. Then the cocrystal was characterized by X-ray single crystal diffraction (SCXRD), X-ray powder diffraction(PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and infrared spectroscopy (IR). In addition, the solubility of the cocrystal and the stability (including in artificial gastric juice, in water, high temperature, high humidity and light) of the cocrystal were analyzed by high performance liquid chromatography. Simultaneously, the hygroscopicity of the cocrystal under high humidity conditions was investigated. Results:Under 75% and 90% humidity, the hygroscopicity of the physical mixture of carbamazepine and hydrochlorothiazide was 0.022 9% and 0.028 0%, respectively;the hygroscopicity of the cocrystal was 0.003 5% and 0.004 0%, respectively. Under light conditions, the contents of impurities produced by carbamazepine and hydrochlorothiazide were 0.36%, and 0.13% after 10 days;the contents of impurities in cocrystal were 0.13% and 0.00%. In water, the solubility of carbamazepine in cocrystal was about 1 times higher than that of the drug substance carbamazepine. Conclusion:Formation of cocrystal of carbamazepine and hydrochlorothiazide can reduce the hygroscopicity of the drug under high humidity conditions. At the same time, the cocrystal slightly improves the stability of the drug substance under light conditions and improves the solubility of carbamazepine in water.