(264f) Modeling the Amorphous Transformation Kinetics of APIs During Dry Ball Milling

Amorphous active pharmaceutical ingredients (APIs) can attain higher solubility than their crystalline counterparts resulting in higher dissolution rates and bioavailability.  While amorphous solids offer a method to engineer efficacious dosage forms, particularly for BCS Class II drugs (low solubility, higher permeability), the proper processing knowledge is lacking.  Among the various methods to prepare amorphous solids, dry milling is among the most common techniques used to induce the transformation from crystalline to amorphous in processes known as amorphization. While the phenomenon of particle breakage is well understood and characterized in ball milling, amorphization lacks similar modeling and predictive tools.  Particle breakage is traditionally modeled as a first order rate process [1] and the same methodology is extended in this study to describe amorphization.  This study investigates the dynamics in the amorphization process of the model API acetaminophen using a vibrational ball mill.  The transformation dynamics are modeled using a modified form of the “event-based” milling model commonly used in the population balance modeling of particle breakage.  It is found that the transformation dynamics can be modeled using this approach and may be used as a predictive tool in amorphization processes.  Mechanical alloying (i.e. milling) acetaminophen with stabilizing polymers is also investigated to improve the stability of the amorphous API and is also incorporated into the model.  It is found that stabilizing polymers may be necessary to decrease the re-crystallization rate of the API in order to achieve complete amorphous transformation and allow amorphization processes via milling to be successful.

[1] Prasher, C.L., 1987. Crushing and Grinding Process Handbook. Wiley, Chichester.