Following mechanical activation of salbutamol sulphate during ball-milling with isothermal calorimetry.

Formulation of actives for pulmonary delivery with dry powder inhaler devices frequently requires a particle size reduction step. The high-energy forces imparted to a material during milling, as well as reducing particle size, can cause a significant change in physicochemical properties, in particular mechanical activation of the surface (manifested as generation of amorphous regions) which can affect formulated product performance. It is not clear whether particle size reduction occurs prior to, or concomitantly with, generation of amorphous content. In this study the formation of amorphous content with time in crystalline salbutamol sulphate was quantified with isothermal gas perfusion calorimetry as the sample was ball-milled. The data showed that the most particle size reduction occurred initially (d(0.5) dropping from 12.83+/-0.4 to 4.2+/-0.4 within 5 min). During this time period, no detectable amorphous content was observed. Between 5 and 15 min milling time the particle size distribution remained relatively constant but the amorphous content increased non-linearly with time. After 20 min milling time the particle size increased slightly. The data suggest that particle size reduction occurs initially upon application of a force to the crystal. Once maximum particle size reduction has occurred the crystal absorbs the force being applied and the crystal lattice becomes disordered. After extended milling the conditions in the ball mill (heat and/or humidity) may cause crystallisation of some of the amorphous material resulting in particle-particle fusion. It would appear that the ball-milling process could be optimised to achieve the desired particle size distribution but without any loss of crystalline structure.