For a rapidly accelerated BCS class II drug with low solubility, a thorough understanding and control over the particle size distribution is required to be able to produce desired particle size for both in vivo and in vitro studies. To achieve this, a combined experimental and modelling approach was developed to maximize the knowledge and minimize resource cost. Our work closely examines the traditional scaling rule of wet milling by turnover number (TON)1 and compares it to advanced mechanistic models2,3. And we found that matching mill geometry and TON not always lead to transferrable results across scales. It was discovered that flowrate has noticeable impact on the wet milling outcomes, though conventionally not controlled during the process. Additionally, across wet-milling processes at different scales, we find that while specific PSD percentiles (D50, D90) can be matched, the overall shape of the PSD may change with scale, presenting a comparability risk for using small-scale wet milled API for formulation and process testing.
As a result, we propose our workflow for developing and scaling-up wet milling processes and guidelines when using scale-down model for particle engineering problems. Specifically, a population balance model is fitted with small-scale wet mill experimental results. The model is then verified with plant wet mill results to guide further scale-up campaigns and improve process control through measurement and control of the recirculation flowrate. Mill geometries with higher shear rate can be used in scale-down models to mimic the PSD shape expected in large mills to generate representative material at small scale.
1. Rotor-stator milling of APIs - Empirical scale-up parameters and theoretical relationships between the morphology and breakage of crystals. Lee, I. & Variankaval, N. & Lindemann, C. & Starbuck, C.. American Pharmaceutical Review. 2004 7. 120-123+128.
2. High-Shear Rotor–Stator Wet Milling for Drug Substances: Expanding Capability with Improved Scalability. Allison Harter, Luke Schenck, Ivan Lee, and Aaron Cote. Organic Process Research & Development 2013 17 (10), 1335-1344. DOI: 10.1021/op4001143
3. Impact of Process Parameters on the Grinding Limit in High-Shear Wet Milling. Carla V. Luciani. Organic Process Research & Development 2018, 22 (9) , 1328-1333. https://doi.org/10.1021/acs.oprd.8b00251