Chen An, Cai Peishan, Luo Minqian, Guo Minshan, Cai Ting
Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 211198, China.
Pharm Res. 2023 Feb;40(2):567-577. doi: 10.1007/s11095-022-03427-3. Epub 2022 Nov 8.
The fixed-dose combination drug products have been increasingly used to treat some complex diseases. A cocrystal containing two therapeutic components, named as a drug-drug cocrystal, is an ideal solid form to formulate as a fixed-dose combination product. The aim of the study is to prepare celecoxib-carbamazepine (CEL-CBZ) cocrystals by melt crystallization to achieve the synchronized release of drugs.
The crystal structure of the CEL-CBZ cocrystal was determined from the cocrystals harvested from melt by single crystal X-ray diffraction. The binary phase diagram and crystal growth kinetics of the CEL-CBZ cocrystal from melt were studied to optimize the process parameters of hot-melt extrusion for manufacturing large-scale cocrystals. The intrinsic dissolution rate studies were conducted to compare the dissolution profiles of drugs in the cocrystal and their individual forms.
The CEL-CBZ cocrystal crystallized in the triclinic space group with one CEL and one CBZ molecule in the asymmetric unit. The crystallization of CEL-CBZ cocrystals were observed both in the supercooled liquid and glassy state. The formation of drug-drug cocrystals significantly alter the intrinsic dissolution rates of the parent drugs to favor the synchronized release.
Melt crystallization is an alternative, efficient and eco-friendly approach for preparing drug-drug cocrystals on a large scale. The synchronized drug release by drug-drug cocrystals can be used to modulate the release profiles of parent drugs in the fixed-dose combination products.
固定剂量复方药物产品越来越多地用于治疗一些复杂疾病。包含两种治疗成分的共晶体，即药物 - 药物共晶体，是制备固定剂量复方产品的理想固体形式。本研究的目的是通过熔融结晶制备塞来昔布 - 卡马西平（CEL - CBZ）共晶体，以实现药物的同步释放。
通过单晶X射线衍射从熔融收获的共晶体中确定CEL - CBZ共晶体的晶体结构。研究了CEL - CBZ共晶体从熔体中的二元相图和晶体生长动力学，以优化用于大规模制备共晶体的热熔挤出工艺参数。进行了固有溶解速率研究，以比较药物在共晶体及其单一形式中的溶解曲线。
CEL - CBZ共晶体在三斜空间群中结晶，不对称单元中有一个CEL分子和一个CBZ分子。在过冷液体和玻璃态中均观察到CEL - CBZ共晶体的结晶。药物 - 药物共晶体的形成显著改变了母体药物的固有溶解速率，有利于同步释放。
熔融结晶是一种大规模制备药物 - 药物共晶体的替代、高效且环保的方法。药物 - 药物共晶体的同步药物释放可用于调节固定剂量复方产品中母体药物的释放曲线。
