Melt Crystallization of Celecoxib-Carbamazepine Cocrystals with the Synchronized Release of Drugs

Abstract

Purpose: 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.

Method: 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.

Result: 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.

Conclusion: 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.

Keywords: celecoxib-carbamazepine cocrystals; hot-melt extrusion; melt crystallization; synchronized release.