Teoh, Xin Yi; Parhizkar, Maryam; Gavriilidis, Asterios; Mazzei, Luca; Gkogkos, Georgios; Abdelhakim, Hend; Craig, Duncan QM; (2024) Optimisation of the production of ketoprofen nanosuspensions using a continuous flow millireactor. Presented at: CRS 2024 Annual Meeting and Expo, Bologna, Italy.

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Abstract

Introduction: Nanotechnology has attracted considerable interest as a means of improving the dissolutionrates and bioavailability of poorly soluble drugs. The production of nano-sized particles using top-down (sizereduction) approaches requires high energy/pressure input, while bottom-up approaches (typically antisolventprecipitation) involve minimal mechanical energy input and may confer advantages of size uniformity andscalability. Here we describe the use of a flow millireactor for the continuous generation of ketoprofennanosuspensions, assessing both production optimisation and performance. Design of Experiment (DoE)approach was used to identify optimal production characteristics while also assessing dissolution behaviourcompared to batch reactor-generated nanosuspensions and mechanical sieved reconstitutedmicrosuspensions. The aim is to develop a platform for the continuous manufacture of a viable formulation fora poorly soluble drug. / Methods: Ketoprofen nanosuspensions were produced using a miniaturised continuous stirred tank reactor(mCSTR, 3 mL) and a batch reactor via antisolvent precipitation using ethanol as solvent and water as anti-solvent. Optimisation of the nanosuspension production method was conducted using 2 full factorial designswith the following parameters: concentration of stabilising agent (polyvinyl pyrrolidone vinyl acetate 64 at 5%and 10% w/v), solvent flow rate (0.5 and 1.0 mL/min) and stirring rate (250 and 500 rpm). The physicochemicalproperties of the samples were characterised using dynamic light scattering, polarised light microscopy anddifferential scanning calorimetry. The dissolution profiles of nanosuspensions were compared to amicrosuspension (125-180 μm) of the same composition. / Results: An optimised condition at 5% w/v stabilising agent, 1.0 mL/min flow rate and 500 rpm stirring ratewere identified from the DoE approach. The continuous production of nanosuspensions using the mCSTRgenerated smaller crystalline ketoprofen particles (mean: 226 ± 4 nm) as compared to the batch reactor-generated nanosuspension (mean: 281 ± 8 nm). Both nanosuspensions showed no significant difference indissolution rate from each other but were significantly higher compared to the microsuspension. / Conclusions/Impact: The continuous production of nanosuspensions in mCSTRs is more promising than thatin batch reactors because the former offers the potential for a higher throughput production yield. No significantdifference in dissolution profile was reported between mCSTR and batch reactor-generated nanosuspension.

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