The use of isothermal microcalorimetry in the study of small degrees of amorphous content of a hydrophobic powder

The crystallinity of a hydrophobic drug (L-365,260) has been investigated by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and isothermal microcalorimetry. The crystallinity was assessed in the isothermal microcalorimeter by taking a ratio of the responses seen when an unknown sample and an amorphous standard were exposed to ethanol vapour. It was found that large amounts of the material (up to 75%) became amorphous with protracted micronisation. The XRPD, DSC and isothermal microcalorimetry methods could all be used to characterise the amorphous content for these highly disordered samples. When the drug was milled in a ball mill, considerably less of the sample mass became amorphous (less than 10% even for reasonably long milling times) and for such samples, only isothermal microcalorimetry was a suitable technique for quantifying the degree of disorder as no difference was observed by use of DSC or XRPD for materials with up to 10% amorphous content. Microcalorimetry is a suitable approach for crystallinity studies on hydrophobic powders, giving a lower limit of detection for amorphous content that is in the order of 1% or less, which is well below that seen for XRPD.