Production and surface modification of pharmaceutical nano- and microparticles with the aerosol flow reactor

This thesis introduces an aerosol flow reactor method for the preparation of nano- and micron-sized drug particles and coated particles in the gas phase. First, the formation of micron-sized beclomethasone dipropionate particles by droplet drying was studied along the crystallization mechanisms of the particles. The aim was to understand the crystallization process within a droplet. Especially the effect of temperature, saturation ratio and residence time during the particle formation process was studied. The process conditions during the droplet drying stage and the dry particle formation determined the final particle properties, including the crystallinity and stability of the particles. Secondly, L-Leucine particle formation by the evaporation-condensation processes was studied. The studies concentrated on the sublimation kinetics, nucleation, crystallization and growth of L-leucine particles. The conversion of aqueous L-leucine droplets via droplet drying and subsequent evaporation to L-leucine vapour and further to solid L-leucine nanoparticles was accomplished by varying the concentrations of L-leucine. The L-leucine vapor concentration and temperature in the reactor determined the resulting particle properties (e.g. size, shape). The in situ gas phase coating of various type core particles (e.g. salbutamol sulphate, lactose, NaCl) was demonstrated with L-leucine. The method that was developed allowed the coating of individual particles in the gas phase. The properties L-leucine coating was dependent on the amount of vaporised L-leucine vs. solid state L-leucine and on the core particle properties (e.g. size, shape, crystallinity). The formation of L-leucine-coated nano- and microparticles was classified into three different mechanisms according to the partial vapour pressure of L-leucine in the reactor: (A) diffusion inside the L-leucine-drug composite particle, (B) partial vaporisation of L-leucine and diffusion through the particle surface, and (C) physical vapour deposition (PVD) of L-leucine on the core particle surface. In general, the particle size increased with increasing amounts of L-leucine up to several hundred nanometers. A crystalline L-leucine coating with distinct leafy nanostructures was formed during the coating process. The coating layer around the core particles reduced the interparticle forces, stabilized the particle and improved the aerosolization of the particles.