SURFACTANT PROMOTED CRYSTAL-GROWTH OF MICRONIZED METHYLPREDNISOLONE IN TRICHLOROMONOFLUOROMETHANE

The effect of drug concentration and particle size, as well as surfactant type and composition, on the apparent solubilities and crystal growth of methylprednisolone (MP) in trichloromonofluoromethane (CFC-11) was examined. Apparent solubilities of micronized MP in CFC-11 were consistently greater than those of the unmicronized drug. Although the micronized and unmicronized drug were the same polymorph (form I), micronized MP was higher in amorphous content. Despite the existence of apparent supersaturation, micronized MP suspended in CFC-11 in the absence of surfactant showed no crystal growth over a 120 day period. Lipophilic surfactants showed differing abilities to solubilize MP in CFC-11. High concentrations of sorbitan trioleate (Span 85; 10(-2) M) increased the apparent solubility of micronized MP 3-fold. This resulted in net crystal growth (increasing volume median diameter, Dvm) of drug suspended at concentrations less than or equal to 0.01% by weight. Oleic acid and lower concentrations of Span 85 solubilized drug to lesser extents and failed to promote detectable growth. Greater suspension concentrations of drugs (greater than or equal to 0.03% w/w) also showed negligible changes in Dvm, even when formulated with 10(-2) M Span 85. Preformulation of drugs in metered dose inhalers (MDIs) should include crystal size measurements in propellant-surfactant blends as functions of time. In some cases, changes in crystal size may be avoided by appropriate selection of surfactant, surfactant concentration and drug concentration in suspension.