Amorphization of itraconazole by inorganic pharmaceutical excipients: comparison of excipients and processing methods

Abstract

The aim of this study was to investigate the effects of solid carriers and processing routes on the properties of amorphous solid dispersions of itraconazole. Three solid carriers with a range of surface properties were studied, (1) a mesoporous silicate, magnesium aluminum silicate (Neusilin US2), (2) a nonporous silicate of corresponding composition (Veegum) and (3) a non-silicate, inorganic excipient, calcium phosphate dibasic anhydrous (A-TAB). The drug was incorporated via either solvent-deposition or ball milling. Both the maximum drug deposited by solvent-based method that produced an amorphous composite and the time for complete amorphization by co-milling was determined by X-ray powder diffraction (XRPD). Changes in the drug and excipients were monitored by nitrogen adsorption and wettability of the powder. The ability of the excipients to amorphize the drug and enhance its dissolution was related to the powder characteristics. Neusilin provided the fastest amorphization time in the mill and highest drug loading by solvent-deposition, compared with the other two excipients. Solvent-deposition provided greater dissolution enhancement than milling, due to the reduction in Neusilin porosity during high energy milling.This study confirms that substrates as well as the processing routes have notable influence on the drug deposition, amorphization, physical stability and drug in vitro release.

• Amorphization
• itraconazole
• milling
• Neusilin US2
• solvent-deposition

Acknowledgements

The authors would like to thank Arushi Manchanda from University of Connecticut for her technical assistance with dissolution studies. The authors also acknowledge helpful discussions with Dr. Steven Wang from Merck Research Laboratories.

Declaration of interest

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

Notes

¹Milling is often referred to as grinding in the pharmaceutical literature. In the mechanochemical literature, the term grinding is reserved for abrasive machining involving shear stress.

²See product literature on the MM series by Retsch, Hann, Germany and the Mixer/Mill series by SPEX, Metuchen, NJ, US.

³Assuming the same percent of water is found in the amorphous phase and other mesophase42.