(74c) Bridging Crystallization and Mechanical Properties to Particle Size Reduction Efficiency in Jet Milling Industrial Pharmaceutical Processes | AIChE

(74c) Bridging Crystallization and Mechanical Properties to Particle Size Reduction Efficiency in Jet Milling Industrial Pharmaceutical Processes


Dias, A., Hovione Farmaciência SA
Sobral, L., Hovione Farmaciência SA
Sequeira, J., Hovione Farmaciência SA
Porfirio, T., Hovione
Santos, R., Hovione Farmaciência SA
In the pharmaceutical industry, jet milling is a preferred operation for the particle size reduction of active pharmaceutical ingredients (APIs) for inhalation products. Nevertheless, the establishment of structured relationships between the mechanical properties of API crystals and particle size reduction processes efficiency is yet scarce, often impacting scale-up, tech-transfer and process throughput [1-2]. A better understanding of this interdependency is thus essential to improve process control, reduce in-process variability and potentiate process design simplifications [3].

For that, a two-staged study at scale evaluated the impact of:

  • Particle size reduction conditions on a jet milling industrial process, and link critical process parameters (CPPs) like specific energy (through pressure and nozzle orifice diameter), to critical quality attributes (CQAs) as final product PSD, morphology, and amorphous content.
  • Recrystallization process conditions (i.e., water flow rate, agitation and distillation rates) in a four-variable design of experiments (DoE), linking critical material attributes (CMAs), like raw materials’ PSD, crystal morphology and mechanical properties (e.g., hardness, flaws density and Young’s module) to the CPPs and CQAs of the micronization stage.

With the study it is demonstrated that the energy input technique and process specific energy play an important role in reducing the number of process steps to achieve the targeted PSD, but also in reducing crystal growth after jet milling. Results show as well that different crystallizations are correlated with different Dv50 and Dv90 reductions, that vary respectively between 38 - 93% and 88 – 96 % of the initial PSD. This correlation between the physical properties of API crystals and particle reduction efficiency highlights the importance of the former as an enabler for improvements and better control over jet milling processes performance.


[1] Onno de Vegt, et al., Influence of flaws and crystal properties on particle fracture in a jet mill. Powder Technology 2009, 191 (1-2), 72-77. DOI: 10.1016/j.powtec.2008.09.014.

[2] Sascha Zügner, et al., Influence of nanomechanical crystal properties on the comminution process of particulate solids in spiral jet mills. European Journal of Pharmaceutics and Biopharmaceutics 2006, 62 (2), 194-201. DOI: 10.1016/j.ejpb.2005.08.002.

[3] Mostafa Nakach, et al., Jet milling industrialization of sticky active pharmaceutical ingredient using quality-by-design approach, Pharmaceutical Development and Technology 2019, 24 (7), 849-863. DOI: 10.1080/10837450.2019.1608449