DRY POWDER AEROSOL GENERATION IN DIFFERENT ENVIRONMENTS - PERFORMANCECOMPARISONS OF ALBUTEROL, ALBUTEROL SULFATE, ALBUTEROL ADIPATE AND ALBUTEROL STEARATE

Aerosols formed by three salts and the free base of albuterol were com pared following their formation from similarly micronized crystalline powders held in a model dry powder inhaler (DPI) under varying environ mental conditions. Aqueous solubility at 22 degrees C was the greatest for albuterol adipate diethanolate (353 mg/ml), followed by albuterol sulfate (250 mg/ml), albuterol free base (15.7 mg/ml) and albuterol s tearate (0.6 mg/ml). Temperature and relative humidity (RH) of the air drawn through the inhaler was systematically varied in the range 20-4 5 degrees C and 30-95% RH. Several inhaler performance outcomes were c ompared statistically between physical forms and across the applied en vironmental conditions. Significant differences (P < 0.05) existed bet ween powder forms with respect to emptying of the metering disk, inhal er emptying, powder deaggregation, fine particle dose (mass < 6.4 mu m aerodynamic diameter), and each compound's susceptibility to temperat ure and relative humidity. The free base emptied poorly from the inhal er compared to all salt forms. Inhaler emptying for all four compounds was unaffected by temperature and humidity over most environments tes ted (P > 0.05) although only albuterol adipate diethanolate and albute rol sulfate were insensitive at 94% RH and 45 degrees C. At 20 degrees C and 50% RH, the fine particle percent of the emitted doses [mean (e xperimental range)] were 77.7 (7.3)%, 63.6 (4.2)%,9.0 (1.8)% and 55.7 (3.4)% for the free base, sulfate, adipate diethanolate and stearate s alts of albuterol, respectively. Fine particle doses and percents of a lbuterol and albuterol sulfate decreased progressively with increasing relative humidity and temperature while albuterol adipate diethanolat e and albuterol stearate aerosol performance remained largely unaffect ed; these latter salts showed changes in fine particle percents only a t 45 degrees C and 95% RH although the adipate diethanolate deaggregat ed very poorly under all conditions. Overall, albuterol stearate, the most hydrophobic salt, emptied and aerosolized best from the inhaler a nd showed least sensitivity to temperature and humidity. Neither solub ility nor moisture sorption correlated directly with inhaler performan ce in high humidity environments, showing that the multiplicity of fac tors controlling the quality of the emitted aerosol from DPIs prevents straightforward prediction of optimal physical forms and mandates the ir experimental review. Nevertheless, salt selection is an important a rea to screen as new compounds are developed for inhalation and DPI de vice performance continues to improve.