Mechano-Chemical Activation and Stabilization of APIs by Co-Milling

Poor solubility is one of the main reasons a promising API does not reach adequate bioavailability. Milling can act on this problem in two ways at the same time: it reduces particle size and, under the right conditions, turns the crystalline form into an amorphous one. The challenge is to control both effects in a predictable way.

This white paper, co-published by Micromacinazione and Microsize, presents a study carried out by Micromacinazione with the University of Applied Sciences and Arts Northwestern Switzerland (FHNW) and the University of Applied Sciences and Arts of Southern Switzerland (SUPSI). Using a small-scale vibrational mill, the team worked on lactose monohydrate, itraconazole (a BCS Class II antifungal) and an itraconazole/HPMC blend (1:3).

The study shows that two parameters drive the outcome: stressing energy (SE) and stressing number (SN). When SE is high enough, the particle breaks. When it is too low, the energy stays in the particle and gradually disrupts its crystal structure until it is fully amorphous. The same particle size can be reached with high SE and low SN, or the other way around.

Amorphous forms dissolve better but are less stable. The white paper shows how co-milling with a polymer carrier addresses this: itraconazole milled alone showed only slight amorphization, while co-milling with HPMC produced an amorphous solid dispersion, confirmed by XRD and SEM/EDS. The white paper also explains how bead size can shorten the milling time needed to get there.

Because the findings are based on a stressing model, they can be applied to other mill types, not only the one used in the study.

The work received financial support from the Swiss Commission for Technology and Innovation (CTI), today Innosuisse. For background on polymer-based stabilization, see Baghel et al., 2016.

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