title: Low-dose capsule filling of inhalation products: critical material attributes and process parameters.
abstract: The aim of the present work was to identify the material attributes and process parameters of a dosator-nozzle capsule filling machine that are critical in low-fill weight capsule filling for inhalation therapies via hard-gelatin capsules. Twelve powders, mostly inhalation carriers, some fines and one proprietary active pharmaceutical ingredient (API), were carefully characterized and filled into size 3 capsules. Since different process conditions are required to fill capsules with powders that have very different material attributes, the powders were divided into two groups. A design of experiments (DOE) based exclusively on process parameters was developed for each group, to identify the critical material attributes (CMA) and critical process parameters (CPP). The fill weight (4-45 mg) of the group I powders (larger particles, higher density, better flowability and less cohesion) correlated with the nozzle diameter (1.9-3.4mm), the dosing chamber length (2.5-5mm), the powder layer depth (5-12.5mm) and the powder density (bulk and tapped density). The RSDs were acceptable in most cases, even for very low doses. The fill weight (1.5-21 mg) of group II powders (very fine and low dense particles with a particle size <10 μm, poor flowability and higher cohesion) depended also on the nozzle diameter (1.9-2.8mm), the dosing chamber length (2.5-5mm) and the powder layer depth (5-10mm), albeit in a different way, indicating that for these powders dosator filling was not volumetric. Moreover, frictional (wall friction angle) and powder-flow characteristics (bulk density and basic flowability energy) have an influence on the mass. Thus, in summary, group I and group II powders can be filled successfully via dosator systems at low fill weights. However, the group II powders were more challenging to fill, especially without automated process control. This study is the first scientific qualification of dosator nozzles for low-fill weight (1-45 mg) capsule filling.
authors.affiliation: Technical University, Inffeldgasse 13, 8010 Graz, Austria; Research Center Pharmaceutical Engineering, Inffeldgasse 13, 8010 Graz, Austria.
authors.forename: Eva
authors.initials: E
authors.lastname: Faulhammer
authors.affiliation: Technical University, Inffeldgasse 13, 8010 Graz, Austria; Research Center Pharmaceutical Engineering, Inffeldgasse 13, 8010 Graz, Austria.
authors.forename: Marlies
authors.initials: M
authors.lastname: Fink
authors.affiliation: Research Center Pharmaceutical Engineering, Inffeldgasse 13, 8010 Graz, Austria.
authors.forename: Marcos
authors.initials: M
authors.lastname: Llusa
authors.affiliation: GlaxoSmithKline (GSK), New Frontiers Science Park, Harlow, Essex CM19 5AW, UK.
authors.forename: Simon M
authors.initials: SM
authors.lastname: Lawrence
authors.affiliation: MG2, Via del Savena 18, I-40065, Pian di Macina di Pianoro, Bologna, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Biserni
authors.affiliation: MG2, Via del Savena 18, I-40065, Pian di Macina di Pianoro, Bologna, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Calzolari
authors.affiliation: Technical University, Inffeldgasse 13, 8010 Graz, Austria; Research Center Pharmaceutical Engineering, Inffeldgasse 13, 8010 Graz, Austria. Electronic address: khinast@tugraz.at.
authors.forename: Johannes G
authors.initials: JG
authors.lastname: Khinast
mesh_terms: D000280:Administration, Inhalation; D002214:Capsules; D007785:Lactose / Q000737:chemistry; D008353:Mannitol / Q000737:chemistry; D011208:Powders / Q000737:chemistry*; D013678:Technology, Pharmaceutical / Q000379:methods*
chemical_list: D002214:Capsules; D011208:Powders; D008353:Mannitol; D007785:Lactose
keywords: Critical quality attributes; Dosator nozzle machine; Inhalation powders; Low-dose capsule filling; Low-fill weight; Multivariate data analysis