Developing an environmentally benign process for the production of microparticles: Amphiphilic crystallization

The production of microparticles for inhalation typically employs jet-milling which can be destructive to the solid-state properties of the particles. The objective of the current work was to develop a crystallization process for the production of respirable microparticles of salmeterol xinafoate (SX) with a controlled particle size distribution (PSD). Solvation of SX in aqueous poly(ethylene glycol) 400 (PEG 400) was investigated using HPLC and FTIR. SX was crystallized from PEG 400 solutions by the addition of water under a variety of conditions of supersaturation, addition rate of antisolvent and stirring speed. The crystals were filtered, dried at 50 °C and their PSDs were determined by laser diffraction. A logarithmic increase in solubility of SX was observed with increasing concentration of PEG 400 in water enabling the aqueous antisolvent crystallization of SX from PEG. Similar to antisolvent crystallization from conventional solvents, a 24 factorial study showed the particle size to decrease with increasing supersaturation. The PSD also depended on the balance of meso- and micromixing determined by the crystallization conditions. In particular a high addition rate (200 g min−1) and low stirrer speed (400 rpm) minimized the median diameter (2.54 ± 0.40 μm) and produced a narrow PSD (90% < 8.67 ± 0.77 μm) of SX particles. Amphiphilic crystallization provided a novel, environmentally benign method to produce microparticles of SX with a controlled size range.