Use of heat of adsorption to quantify amorphous content in milled pharmaceutical powders

Isothermal calorimetry operated in gas perfusion mode (IGPC) is often used to quantify the amorphous content of pharmaceutical powders. Typically, the calibration line is constructed using the heat of crystallisation as the sample is exposed to high levels of a plasticising vapour. However, since the physical form to which the amorphous fraction crystallises may be dependent on the presence of any crystalline seed, the calibration line is often seen to be non-linear, especially as the amorphous content of the sample approaches 100% w/w. Redesigning the experiment so that the calibration line is constructed with the heat of adsorption is an alternative approach that, because it is not dependent upon crystallisation to a physical form should ameliorate this problem. The two methods are compared for a model compound, salbutamol sulphate, which forms either a hydrate or an anhydrate depending on the amorphous content. The heat of adsorption method was linear between amorphous contents of 0 and 100% w/w and resulted in a detection limit of 0.3% w/w and a quantification limit of 0.92% w/w. The heat of crystallisation method was linear only between amorphous contents of 0 and 80% w/w and resulted in a detection limit of 1.7% w/w and a quantification limit of 5.28% w/w. Thus, the use of heat of adsorption is shown to be a better method for quantifying amorphous contents to better than 1% w/w.