Comparison study of physicochemical and biopharmaceutics properties of hydrophobic drugs ground by two dry milling processes

Abstract

This study focuses on the dry milling of biopharmaceutical classification system (BCS) class II molecules. These molecules have a limited bioavailability because of their low aqueous solubility, poor water wettability and low dissolution rate. In order to improve these properties, indomethacin (IND) and niflumic acid (NIF) were milled using two different types of equipment: Pulverisette 0^® and CryoMill^®. Milled samples were characterized and compared to commercial molecules. IND shows a modified solid state, like surface crystallinity reduction and an increase in water vapor adsorption from to 2- up to 5-fold due to milling processes. The obtained solubility data resulted in an improvement in solubility up to 1.2-fold and an increase in initial dissolution kinetics: 2% of dissolved drug for original crystals against 25% for milled samples. For NIF no crystallinity reduction, no change of surface properties and no solubility improvement after milling were noticed. In addition, milled particles seemed more agglomerated resulting in no changes in dissolution rate compared to the original drug. IND solubility and dissolution enhancement can be attributed to the modification of surface area, drug crystallinity reduction, and water sorption increase due to specific behavior related to the drug crystal disorder induced by milling process.

Keywords:

• Dry milling
• indomethacin
• niflumic acid
• solid state
• crystallinity
• solubility
• dissolution kinetics

Acknowledgements

The authors are grateful to P. Accart, S. Del Confetto, V. Nallet, and S. Patry from Rapsodee Center for respectively analyses of particle size, DSC, XRD, and DVS.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.