Direct Precipitation of Micron-Size Salbutamol Sulfate: New Insights into the Action of Surfactants and Polymeric Additives

Direct precipitation of salbutamol sulfate (SS) by antisolvent crystallization in the presence of surfactants and polymeric additives was investigated to obtain micrometer-sized SS for use in inhaled drug delivery. Among the additives studied — hydroxypropyl methyl cellulose (HPMC), polyvinylpyrrolidone (PVP K25), lecithin (from soybean), and Span 85 — PVP K25 showed the strongest effect on crystal growth inhibition. By adding 2.5 mg/mL PVP K25 into the SS solution, the habit of SS crystallized was modified from a needle-like shape to a block-like shape with a lower aspect ratio, and the crystal size was reduced to less than 10 μm. On the basis of the predicted morphology of SS and the possible intermolecular interaction of the additives with a developing SS crystal in solution, we propose that PVP has a higher propensity to form hydrogen bonds with the functional groups that are exposed at the crystal surface. Further supporting evidence based on the effects of PVP concentration and molecular weight on SS crystallization, together with the trends of dispersive surface energy of crystallized SS particles as determined by inverse gas chromatography, strongly suggest that PVP adsorbs on the SS crystals and thereafter inhibits growth.