Optimization of Lipid-Based Nanoparticles Formulation Loaded with Biological Product Using A Novel Design Vortex Tube Reactor via Flow Chemistry

Abstract

Kittipat Suwanpitak,1 Kampanart Huanbutta,2 Nopphon Weeranoppanant,3 Pornsak Sriamornsak,4,5 Chonlada Panpipat,1 Tanikan Sangnim1 1Faculty of Pharmaceutical Sciences, Burapha University, Chonburi, 20131, Thailand; 2Department of Manufacturing Pharmacy, College of Pharmacy, Rangsit University, Pathum Thani, 12000, Thailand; 3Department of Chemical Engineering, Faculty of Engineering, Burapha University, Chonburi, 20131, Thailand; 4Department of Industrial Pharmacy, Faculty of Pharmacy, Silpakorn University, Nakhon Pathom, 73000, Thailand; 5Academy of Science, the Royal Society of Thailand, Bangkok, 10300, ThailandCorrespondence: Tanikan Sangnim, Faculty of Pharmaceutical Sciences, Burapha University, 169, Seansook, Muang, Chonburi, 20131, Thailand, Email [email protected]: Lipid-based nanoparticles (LNPs) is increasingly recognized for their potential in drug delivery, offering protection to hydrophobic drugs from degradation. Industrial synthesis of LNPs, exemplified by Pfizer-BioNTech and Moderna mRNA vaccines, utilizes flow chemistry or microfluidics, showcasing its scalability. This study explores the utilization of a novel design reactor, the vortex tube reactor, within flow chemistry for LNPs synthesis, aiming to optimize its conditions and compare them with batch synthesis.Methods: LNPs were synthesized using the vortex tube reactor, incorporating bovine serum albumin (BSA) as a model drug in the aqueous phase, alongside 1.2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and cholesterol in the organic phase. Design of experiments (DoE), specifically Box-Behnken design, was employed to optimize parameters, including X1: the flow rate ratio (10– 100 mL/min), X2: the aqueous-to-organic volumetric ratio (1:1– 10:1), and X3: the number of reactor units (1– 5 units). Responses evaluated encompassed physical properties and productivity. Optimized conditions were determined by minimizing particle size (Y1), polydispersity index (Y2), and zeta potential (Y3), while maximizing entrapment efficiency (Y4), drug loading (Y5), and productivity (Y5).Results: Results indicated that optimal conditions were achieved at X1 of 100 mL/min, X2 of 5.278, and X3 of 1 unit. LNPs synthesized under these conditions exhibited favorable physical properties and productivity, with uniformity maintained across batches. The vortex tube reactor demonstrated superiority over batch synthesis, yielding smaller particles (166.23 ± 0.98 nm), more uniform nanoparticles (PDI 0.17 ± 0.01), and higher entrapment (67.75 ± 1.55%) and loading capacities (36.39 ± 0.83%), indicative of enhanced productivity (313.4 ± 12.88 mg/min).Conclusion: This study elucidates the potential of flow chemistry, particularly utilizing the vortex tube reactor, for large-scale LNPs formulation, offering insights into parameter relationships and advancing nanoparticle synthesis for drug delivery applications. Keywords: flow chemistry, lipid-based nanoparticles, nanoparticles synthesis, biological product

Keywords

• flow chemistry
• lipid-based nanoparticles
• nanoparticles synthesis
• biological product