8 research outputs found
Continuous manufacturing of high quality pharmaceutical cocrystals integrated with process analytical tools for in-line process control
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
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Development of cocrystals of water insoluble active substances with inactive excipients by using hot melt extrusion
The major aim of the research reported herein was to develop and optimise hot melt extrusion (HME) as a robust technique for the cocrystallisation of poorly water soluble drugs and their coformers. Two pairs of cocrystals of a poorly water soluble drug, carbamazepine, with saccharin and trans-cinnamic acid, were produced by using single (SSE) and twin screw (TSE) hot melt extrusion. The optimum barrel temperature for TSE was chosen from various temperature profiles applied in the SSE experiments. Physicochemical characterisation of extrudates was undertaken by using differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD); it was found that the screw configuration in TSE plays an important role in the production of high quality cocrystals compared to cocrystals produced using SSE. Furthermore, samples collected from the three zones of the barrel of the extruder during CBZ-TCA extrusion, confirmed the gradual formation of cocrystals in TSE. The TSE extruded cocrystals exhibited faster dissolution rates compared to bulk CBZ, the prototype cocrystals and those produced by SSE. In a further study, a hydrophilic carrier, D-glucono--lactone (DGL) was extruded with CBZ, at various molar ratios, by using HME processing. XRPD and HSM characterisation of extrudates revealed polymorphic transformation of bulk carbamazepine (form III) into polymorphic form I. DGL was shown to be a suitable carrier for CBZ in order to enhance its dissolution rate. The extrudates showed faster dissolution rates compared to the physical mixtures in the ascending order: 2:1<1:1<1.5:1 (CBZ:DGL molar ratio). Different HME variables were examined in order to optimise the formation of indomethacin-saccharin cocrystals by using TSE. Important HME processing parameters-screw speed and extruder barrel temperature -were found to have an influence on the production of the cocrystals. Indomethacin-saccharin cocrystals improved the dissolution performance of indomethacin. In-line NIR (near infrared spectroscopy) was used as a process analytical tool during the continuous manufacture of the cocrystals for further insight into the HME process. Scale-up of cocrystals was performed by increasing the throughput rate in the laboratory scale extruder without compromising the quality of the extrudates. Whilst scaling-up the HME process, the downstream process was operated in continuous mode in order to prepare the final dosage (capsule) form of the indomethacin-saccharin cocrystals. In-line particle size monitoring was performed during the extrusion and milling processes. Particle size had a significant influence on the dissolution properties of the milled compared to the non-milled cocrystals
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Increased dissolution rates of carbamazepine – gluconolactone binary blends processed by hot melt extrusion
Carbamazepine (CBZ) shows a poor dissolution, therefore, it is important to enhance its dissolution in GI tract to improve its bioavailability. In the present study, a new hydrophilic carrier, d-gluconolactone (GNL), was extruded with CBZ at various molar ratios to produce granules by using hot melt extrusion (HME) processing. The granular extrudates were characterised by X-ray powder diffraction, differential scanning calorimetry and hot stage microscopy to determine the solid state of CBZ. It was found that bulk CBZ (Form-III) transformed to the polymorphic Form-I during the HME processing. GNL was proved to be an efficient carrier for CBZ to enhance the dissolution rate. The increase in the dissolution rate was observed for both physical mixtures and the extrudates of CBZ-GNL. However, the extrudates showed faster dissolution rates compared to physical mixtures in an ascending order of 2:1 < 1:1 < 1.5:1 (CBZ:GNL). The increase in the dissolution rates was attributed to the transformation of CBZ III to Form-I and also to the increased drug wettability/solubilisation in the presence of the carrie
Continuous cocrystallisation of carbamazepine and trans-cinnamic acid via melt extrusion processing
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
Prediction of polymorphic transformations of paracetamol in solid dispersions
A novel approach employing variable-temperature X-ray powder diffraction (VTXRPD) was used to exploit its suitability as an off-line predictive tool to study the polymorphic transformations of paracetamol (PMOL) in melt-extruded hydrophilic polymer matrices. Physical mixtures (PMs) and extruded formulations of PMOL with either polyvinyl caprolactam graft copolymer (Soluplus®) or vinylpyrrolidone-vinyl acetate copolymer (Kollidon®) in the solid state were characterized by using differential scanning calorimetry, hot- stage microscopy, and scanning electron microscopy. The experimental findings from VTXRPD showed that the stable Form I (monoclinic) of PMOL transformed to the metastable polymorph Form II (orthorhombic) at temperatures varying from 112°C to 120°C, in both the PMs and extrudates suggesting an effect of both temperature and identity of the polymers. The findings obtained from VTXRD analysis for both the PMs and the extruded formulations were confirmed by in-line near-infrared (NIR) monitoring during the extrusion processing. In the NIR study, PMOL underwent the same pattern of polymorphic transformations as those detected using VTXPRD. The results of this study suggest that VTXRPD can be used to predict the polymorphic transformation of drugs in polymer matrices during extrusion processing and provides a better understanding of extrusion processing parameters. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1819–1828,201
Implementation of transmission NIR as a PAT tool for monitoring drug transformation during HME processing
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 20 min
Continuous cocrystallization for dissolution rate optimization of a poorly water-soluble drug
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