Benchmarking excipient-free submicron celecoxib particle production: a DoE approach comparing supercritical enhanced atomization and electrospraying towards particle size and polymorphic control

Controlling polymorphism represents a significant challenge in the pharmaceutical industry, particularly when atomization-based methods are used to produce particles. In this study, a comparison between two different bottom-up atomization techniques - supercritical enhanced atomization (SEA) and electrospraying - was conducted to produce submicron celecoxib (CLX) particles with controlled size and polymorphic purity. A Design of Experiments (DoE) approach was employed to assess the impact of critical process parameters for both techniques on the critical quality attributes of submicron CLX particles, including particle size and polymorphic form. CLX particles with the lowest particle size of 248 ± 54 nm and 99 ± 1% purity of the thermodynamically stable polymorphic form III were obtained using SEA, at a drug concentration of 60 mg/mL, solution flow rate of 0.8 mL/min and a CO₂ temperature of 40°C. For electrospraying, CLX particles with a particle size of 519 ± 138 nm and 95 ± 7% purity of form III were obtained at a drug concentration of 15 mg/mL, voltage of 20 kV, and a solution flow rate of 9 mL/h. The tabletability, compressibility, and compactability properties of the submicron CLX particles formulated into microcrystalline cellulose tablets were evaluated. All formulations demonstrated good flowability and mechanical strength, highlighting the effectiveness of these continuous manufacturing processes in producing excipient-free submicron particles with controlled polymorphism.