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Development of cocrystals of water insoluble active substances with inactive excipients by using hot melt extrusion

Development of cocrystals of water insoluble active substances with inactive excipients by using hot melt extrusion

Moradiya, Hiren G. (2014) Development of cocrystals of water insoluble active substances with inactive excipients by using hot melt extrusion. PhD thesis, University of Greenwich.

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Abstract

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.

Item Type: Thesis (PhD)
Uncontrolled Keywords: Pharmaceutical cocrystals; hot melt extrusion (HME); cocrystallisation;
Subjects: Q Science > QD Chemistry
Faculty / Department / Research Group: Faculty of Engineering & Science
Faculty of Engineering & Science > Department of Pharmaceutical, Chemical & Environmental Sciences
Last Modified: 10 Apr 2019 16:50
Selected for GREAT 2016: None
Selected for GREAT 2017: None
Selected for GREAT 2018: None
Selected for GREAT 2019: None
URI: http://gala.gre.ac.uk/id/eprint/23527

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