THE USE OF ISOTHERMAL MICROCALORIMETRY IN THE STUDY OF CHANGES IN CRYSTALLINITY OF SPRAY-DRIED SALBUTAMOL SULFATE

Isothermal microcalorimetry has been used to monitor the recrystallisation of spray-dried salbutamol sulphate. The drug recrystallises in water vapour, by a cooperative process. The cooperative nature demonstrates that the water must first absorb to saturate the entire powder bed before recrystallisation occurs. Consequently, recrystallisation is slower for low humidities, due to a slower arrival of water vapour. The data have been compared with previous data for recrystallisation of spray-dried lactose. The heat change for the crystallisation was significantly lower for salbutamol sulphate than for lactose. In terms of apparent enthalpy of crystallisation, the large exothermic responses are indicative of the fact that the crystal form is the thermodynamically stable state. The salbutamol which had been recrystallised at the lower humidities showed that the process, whilst being rapid, was discontinuous. In each case, the exothermic recrystallisation was followed by an endothermic response for the expulsion of water as the amorphous region recrystallised. There was a repeating sequence of crystallisation, followed by water expulsion, followed by further recrystallisation. With each repeat of the cycle the responses decreased in size. This ability to follow crystallisation in real time provides a novel insight into the process.