A solvent free process for the formation of carbamazepine (CBZ)–trans-cinnamic acid (TCA) cocrystals, in stoichiometric ratios, was developed using continuous hot melt extrusion processing. Physicochemical characterization of the CBZ–TCA extrudates included scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and hot stage microscopy to evaluate the shape, morphology, purity and crystallinity of the freshly made cocrystals. The obtained cocrystals were of high quality compared to the prototype produced by a solvent crystallization technique. Furthermore, an in-line NIR probe was used to investigate the gradual formation of cocrystals during extrusion processing. The quality of the CBZ–TCA cocrystals was found to depend on the processing parameters such as temperature and the screw type. The extruded cocrystals showed faster dissolution rates compared to bulk CBZ and the prototype cocrystals

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.

A continuous manufacturing process for pharmaceutical indomethacin−saccharine cocrystals was achieved by extrusion processing with high throughput. Down-stream milling and blending of the extrudates was followed by feeding the formulated cocrystals in a capsule-filling machine. By applying a quality by design approach, the process was optimized and scaled up to produce 3000 capsules/h of pharmaceutical cocrystals. Process analytical tools such as near infrared reflectance and spatial filter velocimetry probes were coupled at various process stages for in-line monitoring and quality control. Further physicochemical characterization of extruded batches confirmed the manufacturing of high quality cocrystals. A fully integrated continuous process starting from raw materials to produce a finished product was assembled with only six unit operations and a small footprint. The study is a paradigm of continuous manufacturing of pharmaceutical cocrystals.

The aim of the work reported herein was to implement process analytical technology (PAT) tools during hot melt extrusion (HME) in order to obtain a better understanding of the relationship between HME processing parameters and the extruded formulations. For the first time two in-line NIR probes (transmission and reflectance) have been coupled with HME to monitor the extrusion of the water insoluble drug indomethacin (IND) in the presence of Soluplus (SOL) or Kollidon VA64 hydrophilic polymers. In-line extrusion monitoring of sheets, produced via a specially designed die, was conducted at various drug/polymer ratios and processing parameters. Characterisation of the extruded transparent sheets was also undertaken by using DSC, XRPD and Raman mapping. Analysis of the experimental findings revealed the production of molecular solutions where IND is homogeneously blended (ascertained by Raman mapping) in the polymer matrices, as it acts as a plasticizer for both hydrophilic polymers. PCA analysis of the recorded NIR signals showed that the screw speed used in HME affects the recorded spectra but not the homogeneity of the embedded drug in the polymer sheets. The IND/VA64 and IND/SOL extruded sheets displayed rapid dissolution rates with 80% and 30% of the IND being released, respectively within the first 20min.

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