Investigations on the Humidity-Induced Transformations of Salbutamol Sulphate Particles Coated with l-Leucine

PURPOSE: The crystallization and structural integrity of micron-sized inhalable salbutamol sulphate particles coated with L: -leucine by different methods are investigated at different humidities. The influence of the L: -leucine coating on the crystallization of salbutamol sulphate beneath the coating layer is explored. METHODS: The coated particles are prepared by an aerosol flow reactor method, the formation of the L: -leucine coating being controlled by the saturation conditions of the L: -leucine. The coating is formed by solute diffusion within a droplet and/or by vapour deposition of L: -leucine. The powders are humidified at 0%, 44%, 65% and 75% of relative humidity and the changes in physical properties of the powders are investigated with dynamic vapour sorption analysis (DVS), a differential scanning calorimeter (DSC), and a scanning electron microscope (SEM). RESULTS: Visual observation show that all the coated particles preserve their structural integrity whereas uncoated salbutamol sulphate particles are unstable at 65% of relative humidity. The coating layer formed by diffusion performs best in terms of its physical stability against moisture and moisture-induced crystallization. The degree of crystallization of salbutamol in the as-prepared powders is within the range 24-35%. The maximum degree of crystallization after drying ranges from 55 to 73% when the salbutamol crystallizes with the aid of moisture. In addition to providing protection against moisture, the L: -leucine coating also stabilizes the particle structure against heat at temperatures up to 250 degrees C. CONCLUSION: In order to preserve good flowability together with good physical stability, the best coating would contain two L: -leucine layers, the inner layer being formed by diffusion (physical stability) and the outer layer by vapour deposition (flowability).