Implementation of design of experiments approach for the micronization of a drug with a high brittle–ductile transition particle diameter

Abstract

Objective: To optimize air-jet milling conditions of ibuprofen (IBU) using design of experiment (DoE) method, and to test the generalizability of the optimized conditions for the processing of another non-steroidal anti-inflammatory drug (NSAID).

Methods: Bulk IBU was micronized using an Aljet mill according to a circumscribed central composite (CCC) design with grinding and pushing nozzle pressures (GrindP, PushP) varying from 20 to 110 psi. Output variables included yield and particle diameters at the 50th and 90th percentile (D₅₀, D₉₀). Following data analysis, the optimized conditions were identified and tested to produce IBU particles with a minimum size and an acceptable yield. Finally, indomethacin (IND) was milled using the optimized conditions as well as the control.

Results: CCC design included eight successful runs for milling IBU from the ten total runs due to powder “blowback” from the feed hopper. DoE analysis allowed the optimization of the GrindP and PushP at 75 and 65 psi. In subsequent validation experiments using the optimized conditions, the experimental D₅₀ and D₉₀ values (1.9 and 3.6 μm) corresponded closely with the DoE modeling predicted values. Additionally, the optimized conditions were superior over the control conditions for the micronization of IND where smaller D₅₀ and D₉₀ values (1.2 and 2.7 μm vs. 1.8 and 4.4 μm) were produced.

Conclusion: The optimization of a single-step air-jet milling of IBU using the DoE approach elucidated the optimal milling conditions, which were used to micronize IND using the optimized milling conditions.

Keywords:

• Air-jet milling
• pushing nozzle pressure
• grinding nozzle pressure
• response
• factor

Acknowledgements

Authors would like to thank Nazareth Eliana Ceschan and Dr. María Verónica Ramírez-Rigo for the generous donation of indomethacin. Furthermore, authors would like to thank Dr. Kristin Fathe for assistance in editing and reviewing this manuscript.

Disclosure statement

Hugh D.C. Smyth is a consultant to Respira Therapeutics. The terms of this arrangement have been reviewed and approved by the University of Texas at Austin in accordance with its policy on objectivity in research.