In situ and Ex situ analysis of salmeterol xinafoate microcrystal formation from poly(ethylene glycol) 400 - Water cosolvent mixtures

Salmeterol xinafoate (SX) crystallization was investigated under different conditions of stirring, antisolvent addition, and supersaturation to identify factors limiting particle growth to enable the production of respirable SX microcrystals from PEG 400. Plastic behavior was observed,from rheometry of SX-PEG 400 crystallization media indicating a three-dimensional structure following formation of the crystal phase. Above the yield point, the plastic viscosity of the crystallization medium was identical to PEG solutions. Crystallization was concurrent with mixing regardless of the antisolvent addition method. The crystal size distribution (CSD) depended on the stirring conditions indicating that the CSD depended on a balance of the micro-, meso-, and macromixing steps in the turbulent mixing process arising from the viscous and microviscous properties of PEG. Crystallization from PEG 400 followed nucleation theory with the smallest microcrystals being produced at higher SX supersaturation. The degree of nucleation depended on the initial supersaturation and determined the final crystal median diameter. The latter finding was supported by focused beam reflectance measurement and particle vision and measurement analysis. The nascent microcrystals appeared to be stabilized against agglomeration and extensive particle growth by reversible flocculation.