title: Engineered particles demonstrate improved flow properties at elevated drug loadings for direct compression manufacturing.
abstract: Optimizing powder flow and compaction properties are critical for ensuring a robust tablet manufacturing process. The impact of flow and compaction properties of the active pharmaceutical ingredient (API) becomes progressively significant for higher drug load formulations, and for scaling up manufacturing processes. This study demonstrated that flow properties of a powder blend can be improved through API particle engineering, without critically impacting blend tabletability at elevated drug loadings. In studying a jet milled API (D50=24μm) and particle engineered wet milled API (D50=70μm and 90μm), flow functions of all API lots were similarly poor despite the vast difference in average particle size (ffc<4). This finding strays from the common notion that powder flow properties are directly correlated to particle size distribution. Upon adding excipients, however, clear trends in flow functions based on API particle size were observed. Wet milled API blends had a much improved flow function (ffc>10) compared with the jet milled API blends. Investigation of the compaction properties of both wet and jet milled powder blends also revealed that both jet and wet milled material produced robust tablets at the drug loadings used. The ability to practically demonstrate this uncommon observation that similarly poor flowing APIs can lead to a marked difference upon blending is important for pharmaceutical development. It is especially important in early phase development during API selection, and is advantageous particularly when material-sparing techniques are utilized.
authors.affiliation: Biogen, Cambridge, MA 02142, United States.
authors.forename: Andrea N
authors.initials: AN
authors.lastname: Trementozzi
authors.affiliation: Biogen, Cambridge, MA 02142, United States.
authors.forename: Cheuk-Yui
authors.initials: CY
authors.lastname: Leung
authors.affiliation: Biogen, Cambridge, MA 02142, United States.
authors.forename: Frederick
authors.initials: F
authors.lastname: Osei-Yeboah
authors.affiliation: Biogen, Cambridge, MA 02142, United States.
authors.forename: Erwin
authors.initials: E
authors.lastname: Irdam
authors.affiliation: Biogen, Cambridge, MA 02142, United States.
authors.forename: Yiqing
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Biogen, Cambridge, MA 02142, United States.
authors.forename: J Michael
authors.initials: JM
authors.lastname: MacPhee
authors.affiliation: Biogen, Cambridge, MA 02142, United States.
authors.forename: Pierre
authors.initials: P
authors.lastname: Boulas
authors.affiliation: Biogen, Cambridge, MA 02142, United States.
authors.forename: Shyam B
authors.initials: SB
authors.lastname: Karki
authors.affiliation: Biogen, Cambridge, MA 02142, United States. Electronic address: peter.zawaneh@biogen.com.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Zawaneh
mesh_terms: D002266:Carboxymethylcellulose Sodium / Q000737:chemistry; D002482:Cellulose / Q000737:chemistry; D008855:Microscopy, Electron, Scanning; D010316:Particle Size; D011208:Powders / Q000737:chemistry*; D012212:Rheology; D012822:Silicon Dioxide / Q000737:chemistry; D013229:Stearic Acids / Q000737:chemistry; D013607:Tablets / Q000737:chemistry; D013678:Technology, Pharmaceutical
chemical_list: D011208:Powders; D013229:Stearic Acids; D013607:Tablets; C031183:stearic acid; D012822:Silicon Dioxide; D002482:Cellulose; D002266:Carboxymethylcellulose Sodium; C109691:microcrystalline cellulose
keywords: Compaction profile; Flow function; Particle morphology; Particle size distribution; Permeability