Continuous Manufacture and Scale-Up of Theophylline-Nicotinamide Cocrystals

Abstract

The aim of the study was the manufacturing and scale-up of theophylline-nicotinamide (THL-NIC) pharmaceutical cocrystals processed by hot-melt extrusion (HME). The barrel temperature profile, feed rate and screw speed were found to be the critical processing parameters with a residence time of approximately 47 s for the scaled-up batches. Physicochemical characterization using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffraction of bulk and extruded materials revealed the formation of high purity cocrystals (98.6%). The quality of THL-NIC remained unchanged under accelerated stability conditions.

Optimization of Hot-Melt Extrusion Processing for the Synthesis of Ionic Cocrystals

“…The feed rate has a significant influence on the cocrystal purity as it affects the residence time. Low feed rates increase residence time, allowing more time for conversion of drug and coformer to the cocrystal, whereas higher feed rates reduce residence time, increasing the throughput and potentially protecting thermolabile materials from exposure to high temperatures. , For the purposes of this study, a low feed rate of 0.25 kg/h was selected to allow for a longer residence time to ensure the complete conversion of the raw materials to a cocrystal form. The assumption is supported by the literature findings where low feed rate resulted in higher purity cocrystals. ,− On the other hand, low screw speeds can increase the contact between the starting materials through increased residence time .…”

Opportunities and Challenges in Mechanochemical Cocrystallization toward Scaled-Up Pharmaceutical Manufacturing

“…Therefore, it is simple to redesign the extrusion process when boosting the throughput and maintaining the acceptable quality at the same scale are needed. 139 Medina et al 140 successfully manufactured AMG 517− sorbic acid cocrystal via TSE with a conversion rate higher than 99%, which was also found to be higher compared to the solution crystallization process. Galant et al 141 evaluated a continuous TSE process against conventional solvent-batch cocrystallization methods and observed a considerable decrease in numerous sustainability and green chemistry parameters, including energy efficiency, impact on climate change, and human and ecological health, as well as cost due by minimizing excessive reactant consumption and solvent usage while retaining high product selectivity.…”

“…The geometric similarities between mid-size and large-scale extruders make the extrusion process easy to scale-up to an industrial scale without compromising the final product quality. Therefore, it is simple to redesign the extrusion process when boosting the throughput and maintaining the acceptable quality at the same scale are needed …”