Continuous Cocrystallization for Dissolution Rate Optimization of a Poorly Water-Soluble Drug

Abstract

A continuous manufacturing process, hot melt extrusion (HME), was employed for the development of high quality carbamazepine−saccharin (CBZ−SCH) cocrystals. The produced cocrystals were compared with a prototype prepared by a solvent method. It was found that processing parameters such as temperature, screw speed, and screw configuration were the critical processing parameters. In-line near-infrared analysis demonstrated that cocrystallization takes place gradually during the process along the extruder's mixing zones. Further characterization of the extruded cocrystals proved that the manufactured highly crystalline cocrystals were similar to the prototype but had improved CBZ dissolution rates. Continuous manufacturing of cocrystals of water-insoluble drugs is a novel and robust approach.

In - situ synchrotron wide-angle X-ray diffraction as a rapid method for cocrystal/salt screening

“…Therefore, heat-induced cocrystallization might be the dominant mechanism for the successful extrusion of CBZ-SAC cocrystal. It was reported that the conversion to CBZ-SAC cocrystal can be highly improved as extrusion temperature was higher than the eutectic point of physical mixture (Moradiya et al, 2013) or melting point of cocrystal (Daurio et al, 2011). Therefore, we speculated that heating-induced cocrystallization for CBZ-SAC system was based on eutectics/melts-mediated mechanism, rather than amorphousmediated mechanism.…”

“…Guidance to the manufacture of salt/cocrystal by hot melt extrusion HME has been explored as a scalable and solvent-free method to achieve continuous manufacture of cocrystal, such as CBZ-SAC cocrystal (Moradiya et al, 2013), CBZ-trans-cinnamic acid cocrystal (Moradiya et al, 2014) and theophylline-citric acid cocrystal (Daurio et al, 2011). Processing temperature is the most important parameter in the successful extrusion of cocrystal for some temperature-sensitive systems, such as ibuprofen-nicotinamide cocrystal (Dhumal et al, 2010) and nicotinamide-trans cinnamic acid cocrystal (Daurio et al, 2011).…”

“…Processing temperature is the most important parameter in the successful extrusion of cocrystal for some temperature-sensitive systems, such as ibuprofen-nicotinamide cocrystal (Dhumal et al, 2010) and nicotinamide-trans cinnamic acid cocrystal (Daurio et al, 2011). High-purity cocrystal was reported to be extruded beyond the eutectic point of physical mixture (Moradiya et al, 2013) or melting temperature of cocrystal (Daurio et al, 2011). However, many cocrystals were heat-sensitive and decomposed upon melting.…”

“…The strong shear force in HME might destroy the physical shielding, expose new surfaces of API/coformer and thus promote the continuous growth of the cocrystal in the first growth stagnation period. Moradiya et al (2013) successfully extruded high-purity CBZ-SAC cocrystal at 135 C, which is in the first growth stagnation period (shown in Fig. 10B).…”

Implementation of transmission NIR as a PAT tool for monitoring drug transformation during HME processing

“…The application of in-line NIR spectroscopy to monitor the extrusion process was demonstrated by Fischer et al [19] who successfully determined the content of ethylene vinyl acetate in a polypropylene matrix. Off-line and in-line reflectance NIR has also been used to monitor the formation of car bamazepine-saccharine [20] and carbamazepine-trans-cinnamic acid [21] cocrystals. However, reflectance NIR contains large amount of noise in the spectra when monitoring a transparent formulation.…”