Abukhamees, Shorooq Mohammad Issa; (2023) Nanocrystal Manufacture using a High Throughput Microfluidic Reactor for the Preparation of Rapid Release Solid Dosage Forms via Direct Ink Writing. Doctoral thesis (Ph.D), UCL (University College London).

Text Nanocrystal Manufacture using a High Throughput Microfluidic Reactor for the Preparation of Rapid Release Solid Dosage Forms via Direct Ink Writing .pdf - Other Access restricted to UCL open access staff until 1 August 2024. Download (11MB)

Abstract

Drug nanocrystals represent a well-recognized and effective approach to addressing low drug solubility issues. Nonetheless, the effective production of high-quality nanocrystals faces manufacturing and formulation challenges. In this project, the optimisation of nanocrystal production in the form of nanosuspension using a high throughput microfluidics technique was examined. Microfluidics was demonstrated to provide precise control over reaction conditions, producing high-quality nanocrystals under continuous flow conditions mitigating against batch-to-batch variation. Two microfluidics reactors were used to produce Ibuprofen nanosuspension via continuous antisolvent crystallisation. The influence of process and formulation parameters were investigated and optimised. Under optimal process parameters, nanocrystals with an average size of 108.03 ±0.94 nm and narrow particle size distribution (0.236±0.001) were produced at a production volume of 80 mL/minute using the microjet reactor. While the jet mixer allowed high-throughput production of ibuprofen nanosuspension (13.2 litres per hour), the produced nanosuspension had a particle size of 81.10±2.52 nm with PdI value equals to 0.23±0.01. The manufactured nanosuspension showed higher saturation solubility and faster dissolution velocity compared to a marketed ibuprofen suspension. The nanoparticles produced were crystalline as confirmed by powder X-ray diffraction and differential scanning calorimetry analysis. Finally, the nanosuspension produced in a microfluidics reactor was used to produce printing ink for 3D printing. It has been demonstrated that the direct ink writing 3D printing technique was used successfully to transfer ibuprofen nanosuspension into tablets. The optimal tablet formulation showed superior dissolution properties compared to the same tablets made of ibuprofen microcrystals. Overall, the findings propose that continuous crystallisation performed at high flow rates in microfluidics reactors can overcome nanosuspension manufacturing limitations and produce high-quality nanocrystals. Further, semisolid extrusion 3D printing offers an alternative manufacturing approach to transfer nanosuspension to a solid dosage form.

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