title: Millifluidic synthesis of amorphous drug-polysaccharide nanoparticle complex with tunable size intended for supersaturating drug delivery applications.
abstract: The conventional bulk mixing method to prepare amorphous drug-polysaccharide nanoparticle complex (or drug nanoplex in short) has a major drawback in the lack of size control for the nanoplex produced, hence limiting its potential applications as a supersaturating drug delivery system for bioavailability enhancement of poorly soluble drugs. For this reason, we developed a continuous millifluidic synthesis platform of the drug nanoplex exhibiting high size tunability using curcumin (CUR) and chitosan (CHI) as the models for drug and polysaccharides, respectively. The nanoplex size tunability was achieved by controlling the residence time of the CUR and CHI solutions in the millifluidic reactor, where their slow diffusive mixing at the liquid-liquid interface resulted in a well-regulated nanoplex growth as a function of the residence time. The effects of the preparation pH, molecular weight of CHI, millifluidic tube diameter, and flowrate on the nanoplex size tunability were investigated from which the optimal preparation condition was determined. At the optimal condition, the CUR nanoplex was roughly ≈115nm in size with zeta potential of ≈15mV and ≈72% (w/w) CUR payload. The millifluidic synthesis also maintained the high CUR utilization rate (≈80%) exhibited by the bulk mixing method. Most importantly, the ability to produce significantly smaller nanoplex (sixfold smaller) via millifluidics led to the generation of higher (≈8.5× of CUR saturation solubility) and prolonged (≈8h) supersaturation level. These results bode well for the bioavailability enhancement potential of the drug nanoplex.
authors.affiliation: School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore 637459, Singapore.
authors.forename: The-Thien
authors.initials: TT
authors.lastname: Tran
authors.affiliation: Radiation Technology Center, Nuclear Research Institute, Dalat City, Viet Nam.
authors.forename: Minh-Hiep
authors.initials: MH
authors.lastname: Nguyen
authors.affiliation: School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore 637459, Singapore.
authors.forename: Yong Zen
authors.initials: YZ
authors.lastname: Tan
authors.affiliation: School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore 637459, Singapore.
authors.forename: Jia Wei
authors.initials: JW
authors.lastname: Chew
authors.affiliation: Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore 117576, Singapore.
authors.forename: Saif A
authors.initials: SA
authors.lastname: Khan
authors.affiliation: School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore 637459, Singapore. Electronic address: kunnong@ntu.edu.sg.
authors.forename: Kunn
authors.initials: K
authors.lastname: Hadinoto
mesh_terms: D004337:Drug Carriers; D044085:Microfluidics / Q000379:methods*; D008855:Microscopy, Electron, Scanning; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D033362:Powder Diffraction
chemical_list: D004337:Drug Carriers; D004364:Pharmaceutical Preparations
keywords: Continuous pharmaceutical manufacturing; Curcumin nanoparticles; Drug-polymer complexation; Microfluidics; Millifluidics