School of Pharmacy, University of Reading, Reading RG6 6AD, UK.
School of Pharmacy, University of Reading, Reading RG6 6AD, UK.
Eur J Pharm Biopharm. 2024 Mar;196:114202. doi: 10.1016/j.ejpb.2024.114202. Epub 2024 Feb 2.
The crystal structure of a new Progesterone (PROG) co-crystal with para-aminobenzoic acid (PABA) showing enhanced solution properties is reported. PROG-PABA co-crystal was first identified though an in silico coformer screening process using the CSD Co-crystal deign function, then confirmed through a solution evaporation crystallisation experiment. The resulting co-crystal was characterized using single crystal X-ray diffraction, differential scanning calorimetry and Fourier-transform infrared spectroscopy. Liquid assisted grinding was selected as a suitable scale up method compared to spray drying and antisolvent methods due to minimal starting material phases in the final product. Following scale up, aqueous solubility, stability and dissolution measurements were carried out. PROG-PABA showed increased distinct aqueous solubility and dissolution compared to PROG starting material and was shown to be stable at 75 % relative humidity for 3 months. Tablets containing co-crystal were produced then compared to the Utrogestan® soft gel capsule formulation through a dissolution experiment. PROG-PABA tablets showed a substantial increase in dissolution over the course of the experiment with over 30× the amount of PROG dissolved at the 3-hour time point. This co-crystal shows positive implications for developing an improved oral PROG formulation.
报道了一种新的孕激素（PROG）与对氨基苯甲酸（PABA）共晶的晶体结构，该共晶具有增强的溶液性质。通过使用 CSD 共晶设计功能的计算共晶筛选过程首次鉴定了 PROG-PABA 共晶，然后通过溶液蒸发结晶实验进行了确认。使用单晶 X 射线衍射、差示扫描量热法和傅里叶变换红外光谱对所得共晶进行了表征。与喷雾干燥和反溶剂方法相比，由于最终产物中起始材料相较少，因此选择液辅助研磨作为合适的放大方法。在放大后，进行了水溶解度、稳定性和溶解测量。与 PROG 起始材料相比，PROG-PABA 表现出明显增加的独特水溶解度和溶解度，并且在 75%相对湿度下稳定 3 个月。然后通过溶解实验制备了含有共晶的片剂，并与 Utrogestan®软胶囊制剂进行了比较。在整个实验过程中，PROG-PABA 片剂的溶解度显著增加，在 3 小时时溶解的 PROG 量超过 30 倍。这种共晶对开发改进的口服 PROG 制剂具有积极意义。
