Quantification of low levels (<10%) of amorphous content in micronised active batches using dynamic vapour sorption and isothermal microcalorimetry.

During the processing of pharmaceutical solids (e.g. milling, spray drying, tablet compaction, wet granulation and lyophilisation), various degrees of disorder in the form of crystal defects and/or amorphous regions may be generated. Even relatively low levels of amorphous material (<10%) may have a detrimental impact on the stability, manufacturability and dissolution characteristics of the formulated drug product. In this paper an isothermal heat conduction microcalorimetry and dynamic vapour sorption technique have been evaluated for the quantification of low levels (<10%) of amorphous material within a crystalline active. Both techniques were able to detect a 0.5% amorphous content, and in each case the limit of detection may be further lowered by increasing the sample size. The impact of micronisation on the crystallinity of a batch of active was evaluated using the two methods. The isothermal microcalorimetry and dynamic vapour sorption data showed excellent agreement (+/-0.2% amorphous content) and indicated that the amount of amorphous material generated is extremely sensitive to small changes in the operating conditions of the microniser. The techniques described in this paper have been developed at a very early stage of the actives development program such that the impact of small quantities of amorphous material on the quality attributes of the formulation can be fully assessed. The methods can be applied to any active, the only criteria is that the amorphous material will recrystallise on exposure to moisture or solvent vapours, and no hydrates or solvates are formed.