Teoh, Xin Yi; Parhizkar, Maryam; Gavriilidis, Asterios; Mazzei, Luca; Gkogkos, Georgios; Abdelhakim, Hend; Craig, Duncan QM; (2024) Continuous Manufacturing of Ketoprofen Nanosuspensions using a Miniaturised Flow Reactor. Presented at: Asia Pacific Delivery Science Conference (APDSC) 2024, Kuala Lumpur, Malaysia.

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Abstract

Continuous manufacturing has emerged as a transformative approach in pharmaceutical production as it avoids the intermittent processes inherent in traditional batch manufacturing. More specifically, the transition from batch to continuous manufacturing solves various challenges, including fixed batch size, numerous sequential steps, interruptions and difficulties with upscaling batch processes. Here, we describe the potential of a flow millireactor to continuously manufacture ketoprofen nanosuspensions in comparison to batch manufacturing. The aim is to develop a platform for the continuous manufacture of a viable formulation for a poorly soluble drug. We used a Design of Experiments approach to identify the optimal parameters to produce nanosuspensions, whose properties and dissolution behaviour were also characterized. Ketoprofen nanosuspensions were produced via antisolvent precipitation using ethanol as solvent and water as anti-solvent with a miniaturised continuous stirred tank reactor (mCSTR, 3 mL) and a batch reactor. Optimisation of the nanosuspension production method was conducted adopting 33 response surface designs with the following parameters: concentration of stabilising agent (polyvinyl pyrrolidone vinyl acetate 64 at 2.5%, 5% and 10% w/v), solvent flow rate (0.25, 0.50 and 1.00 mL/min) and stirring rate (250, 500 and 1000 rpm). The physicochemical properties of the samples were characterised using dynamic light scattering, transmission electron microscopy and small angle x-ray scattering. Optimal conditions were identified to be a stabilising agent concentration of 5% w/v, solvent flow rate of 1.0 mL/min and stirring rate of 1000 rpm. The continuous production of nanosuspensions using the mCSTR generated smaller ketoprofen particles (mean: 320 ± 18 nm) compared to the batch (mean: 402 ± 29 nm). No significant difference in dissolution rate was reported between the mCSTR and the batch-manufactured nanosuspensions. The continuous production of nanosuspensions using mCSTR therefore shows great promise as an alternative to batch reactors due to its potential for a higher throughput production yield.

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