BPB Reports

Paper Details

BPB Reports
Vol. 5 No. 3 p.45-49 2022
Regular Article
Optimization of Milling Parameters for Low Metal Contamination in Bead Milling Technology
  • Hironori Tanaka (Formulation R&D Laboratory, CMC R&D Division, Shionogi & Co., Ltd. / Laboratory of Pharmaceutics, Kobe Pharmaceutical University / hironori.tanaka@shionogi.co.jp)
Hironori Tanaka 1) 2) , Yuya Ochii 1) , Yasushi Moroto 1) , Daisuke Hirata 3) , Tetsuharu Ibaraki 3) , Ken-ichi Ogawara 2)
1) Formulation R&D Laboratory, CMC R&D Division, Shionogi & Co., Ltd. , 2) Laboratory of Pharmaceutics, Kobe Pharmaceutical University , 3) Hiroshima Metal & Machinery Co., Ltd.
Received: March 31, 2022;   Accepted: May 20, 2022;   Released: June 07, 2022
Keywords: bead milling, milling parameters, drug nanocrystal, metal contamination, zirconia beads

This study aimed to develop a contamination-less bead milling technology using zirconia beads, by optimizing milling parameters. We evaluated the effects of bead milling parameters on milling time and metal contamination; focusing on bead diameter, rotation speed, and bead filling rate as they are the critical parameters determining bead milling efficiency. We studied the milling time required to grind a drug to 0.2 μm size and quantified the extent of metal contamination that arises from the grinding procedure. With optimal bead milling parameters, the minimum concentration of the metal contaminants was 1.27 ± 0.08 μg/mL (zirconium: 0.73 ± 0.09 μg/mL; yttrium: 0.35 ± 0.03 μg/mL; aluminum: 0.19 ± 0.05 μg/mL), when the rotation speed, bead diameter, and bead filling rate were set to 2 m/s, 0.3 mm, and 75% (v/v), respectively. Additionally, under optimized conditions, it was possible to reduce the metal contamination per weight of the drug by increasing the drug concentration to up to 40% (w/w). Under the optimized conditions for drug concentrations of 30–40% (w/w), metal contamination from the grinding process was minimized and reduced to < 10 μg/g, which is comparable to that achieved by the NanoCrystal® technology. These results indicate that contamination-less bead milling using zirconia beads can be achieved when bead milling parameters are optimized.