API Milling is a key step in many drug development processes. Advantages of milling vs. crystallization as the final drug substance unit operation include:
- Reaching particle size distributions not attainable via crystallization
- Normalization - ensuring consistent drug substance physical properties and quality for drug product unit operation.
- Yield losses
- Industrial hygiene concerns & corresponding containment costs
- Process train portability
- Physical property instability occurring due to surface defects, amorphous phase generation, etc.
Wet milling equipment, such as high-pressure homogenizers and media mills, offer a solution to many of the challenges associated with dry milling, albeit they are restricted by low capacities, high energy consumption and frequent maintenance requirements. On the other hand, traditional rotor-stator technology methods can only yield a practical lower mean volume (mV) of ~30 micron (compared to <5 micron via jet milling and ~ 10 micron for dry pin milling).
Quadro Engineering has developed a new, alternative approach to wet milling with the Quadro® HV-Emulsifier. Via independent testing, it was determined that Quadro’s HV offered more than fifty-five times (55x) the high shear energy of a traditional rotor-stator wet mill.1 Results also demonstrated precise process scaling from lab formulation to pilot and production processing.
During field tests across multiple compounds with a range of starting particle sizes, morphologies and mechanical properties, the following was noted:
API size reduction achieved a mean volume (mV) particle size of between 12 - 17 micron for compounds with typical starting PSD’s of between 84 - 179 micron.
- Increased tip speed achieved an additional 30 - 60% reduction of mV & d95 for a wide range of APIs – whether the starting crystals were needle, plate or block-shaped (see figures 1 through 3).
- Testing did not indicate additional fines generation at elevated tip speeds.
- Tip velocity appeared to have more size reduction impact on block-shaped compounds than needle/plate crystals, with reduction efficiency averages ranging from 81% - 29%, respectively (reduction efficiency calculated as a percentage of Final PSD/Incoming PSD). Crystals with combined aspect ratio shapes (combination of block and needle/plate crystals) were reduced at an average efficiency of 61%.
- Lab scale model (HV0) could be run using significantly small quantities of API materials. This enabled numerous tests to be performed with a lower percentage of APIs (i.e. 20 mg/ml slurries) whilst still achieving a PSD profile that matched full formulation API slurries.
The restricted capacity, high energy consumption, and frequent maintenance requirements of High-Pressure Homogenizers (HPH) and media mills can now be overcome with the Quadro Ytron® HV-Emulsifier thus maximizing productivity while cutting development and production costs.
1An Evaluation of an Enhanced Wet Milling Technology for Further API Particle Size Reduction; AAPS 2011; Ivan Lee(1) Jonathan Ostrosky(2) Mark Walker(3) Eric Sirota(1) Luke Schenck(1) Chemical Process Development and Commercialization(2) Penn State University(3) MMD Finance
High-Shear Rotor–Stator Wet Milling for Drug Substances: Expanding Capability with Improved Scalability | Organic Process Research & Development (acs.org)