Structural evolution of indomethacin particles upon milling: time-resolved quantification and localization of disordered structure studied by IGC and DSC.

The amorphization of indomethacin was induced by milling. The mass fraction of the amorphous phase in the drug milled for various time intervals was determined with differential scanning calorimetry (DSC). Because the surface fraction amorphized by milling can be much higher than the mass fraction, which can have a large impact on the powder properties, a method for quantification of surface fraction amorphized by milling using inverse gas chromatography (IGC) was developed. A calibration curve was constructed by mixing completely amorphous indomethacin (obtained after milling for 120 min) with various amounts of the initial crystalline sample. Linear part of the curve was then used to quantify the surface amorphous content of samples milled for different time intervals. Surface and mass amorphization kinetics were determined and fitted to a first-order model. It was found that the surface amorphization rate is an order of magnitude higher than the mass amorphization rate. Results confirmed that IGC is a sensitive method for detection and quantification of the fraction of amorphous surface of milled indomethacin powder. If suitably combined with other techniques, this method represents a relatively general approach for the localization and quantification of the surface amorphous fraction in crystalline substances that transform into amorphous ones upon intensive milling. 2009 Wiley-Liss, Inc. and the American Pharmacists Association