title: Downscaling drug nanosuspension production: processing aspects and physicochemical characterization.
abstract: In this study, scaling down nanosuspension production to 10 mg of drug compound and evaluation of the nanosuspensions to 1 mg of drug compound per test were investigated. Media milling of seven model drug compounds (cinnarizine-indomethacin-itraconazole-loviride-mebendazole-naproxen-phenytoin) was evaluated in a 96-well plate setup (10, 20, and 30 mg) and a glass-vial-based system in a planetary mill (10, 100, and 1,000 mg). Physicochemical properties evaluated on 1 mg of drug compound were drug content (high-performance liquid chromatography), size [dynamic light scattering (DLS)], morphology (scanning electron microscopy), thermal characteristics (differential scanning calorimetry), and X-ray powder diffraction (XRPD). Scaling down nanosuspension production to 10 mg of drug compound was feasible for the seven model compounds using both designs, the planetary mill design being more robust. Similar results were obtained for both designs upon milling 10 mg of drug compound. Drug content determination was precise and accurate. DLS was the method of choice for size measurements. Morphology evaluation and thermal analysis were feasible, although sample preparation had a big influence on the results. XRPD in capillary mode was successfully performed, both in the suspended state and after freeze-drying in the capillary. Results obtained for the latter were superior. Both the production and the physicochemical evaluation of nanosuspensions can be successfully downscaled, enabling nanosuspension screening applications in preclinical development settings.
authors.affiliation: Laboratory for Pharmacotechnology and Biopharmacy, K.U. Leuven, Gasthuisberg O&N2, Herestraat 49, Leuven, Belgium.
authors.forename: Bernard
authors.initials: B
authors.lastname: Van Eerdenbrugh
authors.forename: Bernard
authors.initials: B
authors.lastname: Stuyven
authors.forename: Ludo
authors.initials: L
authors.lastname: Froyen
authors.forename: Jan
authors.initials: J
authors.lastname: Van Humbeeck
authors.forename: Johan A
authors.initials: JA
authors.lastname: Martens
authors.forename: Patrick
authors.initials: P
authors.lastname: Augustijns
authors.forename: Guy
authors.initials: G
authors.lastname: Van den Mooter
mesh_terms: D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D005079:Excipients / Q000737:chemistry; D005240:Feasibility Studies; D008027:Light; D008855:Microscopy, Electron, Scanning; D053758:Nanoparticles; D036103:Nanotechnology; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000592:standards; D033362:Powder Diffraction; D011786:Quality Control; D012542:Scattering, Radiation; D013499:Surface Properties; D013678:Technology, Pharmaceutical / Q000379:methods* / Q000592:standards; D013997:Time Factors
chemical_list: D005079:Excipients; D004364:Pharmaceutical Preparations