Quantifying Dry Milling in Pharmaceutical Processing: A Review on Experimental and Modeling Approaches

Particle size reduction by mechanical means is an important unit operation in the pharmaceutical industry, used to improve flow, solubility, and in amorphization of drugs. It is usually achieved by the fracturing of particles under the action of applied energy. Despite being pervasive in the pharmaceutical field, it is one of the least understood processes owing to the complexity of material and process variables involved during milling. To comprehend the process, efforts should be focused on techniques that measure the particle size as well as the control the process. With the ongoing initiative of US FDA to encourage design in quality, the review is focused on some process analytical tools to characterize particle size distribution as well as process modeling tools to simulate particle size reduction. Additionally, an overview of some fundamental aspects related to milling is provided. To this end, the review is limited, mainly concentrating on some of experimental and modeling approaches used to quantify and understand the physics behind the process of dry milling. Particle size reduction by mechanical means is an important unit operation in the pharmaceutical industry, used to improve flow, solubility, and in amorphization of drugs. It is usually achieved by the fracturing of particles under the action of applied energy. Despite being pervasive in the pharmaceutical field, it is one of the least understood processes owing to the complexity of material and process variables involved during milling. To comprehend the process, efforts should be focused on techniques that measure the particle size as well as the control the process. With the ongoing initiative of US FDA to encourage design in quality, the review is focused on some process analytical tools to characterize particle size distribution as well as process modeling tools to simulate particle size reduction. Additionally, an overview of some fundamental aspects related to milling is provided. To this end, the review is limited, mainly concentrating on some of experimental and modeling approaches used to quantify and understand the physics behind the process of dry milling.