Assessing the temperature of thermally generated inhalation aerosols.

BACKGROUND: Condensation aerosols are produced when a drug is vaporized and then cools in the inhalation air. Because energy is applied to vaporize the drug, there is a potential concern that the air temperature might not be well tolerated. A literature review indicates that the proper metric for this is the wet-bulb temperature (T(wb)) of the inhaled air. T(wb) measures the total energy of the air, including moisture content, and reflects the potential impact on safety and tolerability. METHODS: The Staccato® system (Alexza Pharmaceuticals, Mountain View, CA) uses thermal vaporization for aerosol generation and was used in a series of studies to characterize the peak transient value (peak T(wb)) of the air coming out of the device. These studies evaluated peak T(wb) over a range of air flow rates (15-45 L/min), ambient conditions [15-30°C and 15 to 90% relative humidity (RH)] and vaporization temperatures. RESULTS: Under nominal conditions (30 L/min air flow, 25°C and 50% RH), peak T(wb) was 28.8 ± 0.6°C (mean ± standard deviation). Over the range of operating conditions tested, mean values for peak T(wb) ranged from 26.2 to 33.3°C with similarly low variances. When operated under a combination of extreme conditions, peak T(wb) was measured to be 39.9 ± 0.1°C (mean ± standard deviation). CONCLUSIONS: Technical standards indicate that the upper limit on inhaled T(wb) for safety and tolerability is 50°C, and inhalation at that temperature can be sustained for 1 h. Peak values of T(wb) from the Staccato system are well below that threshold, approximately 30°C at nominal conditions and approximately 40°C at a combination of extreme conditions. Moreover, the peak lasts for only a few seconds, well under the time limit of 1 h. These results suggest that aerosols generated with the Staccato system will be safe and well tolerated.

Nicotine aerosol generation from thermally reversible zinc halide complexes using the Staccato system.

Application of the Staccato system to liquid drugs presents unique technological challenges. Liquids, such as nicotine, do not form physically stable films on vaporization substrates. We identified two thermally reversible zinc halides (ZnCl2 and ZnBr2) that complex with nicotine in a 1:2 mol ratio (zinc halide: nicotine) that can be coated as a solid film. Feasibility studies indicated that the chloride complex liberates a higher fraction of nicotine upon heating whereas the nicotine aerosol purity for both complexes was approximately 99%. Using a multidose Staccato device previously used in a Phase I clinical trial, we demonstrated that highly pure nicotine aerosol can be reliably generated from the chloride complex with the following qualities: aerosol purity approximately 99%, single emitted dose approximately 117 microg, particle fraction approximately 57%, and mean particle size approximately 0.8 microm. These results were supported by thermogravimetric analysis and differential scanning calorimetry.

The effect of film thickness on thermal aerosol generation.

PURPOSE: Rapid heating of thin films of pharmaceutical compounds can vaporize the molecules, which leads to formation of aerosol particles of optimal size for pulmonary drug delivery. The aim of this work was to assess the effect of coated film thickness on the purity of a thermally generated (condensation) drug aerosol. MATERIALS AND METHODS: Pharmaceuticals in their free base form were spray-coated onto stainless steel foils and subsequently heated and vaporized in airflow via a rapid resistive heating of the foil. Aerosol particles were collected on filters, extracted, and analyzed using reverse phase HPLC to assess the amount of degradation induced during the vaporization process. RESULTS: Condensation aerosols of five pharmaceuticals were formed from a wide range of film coating thicknesses. All five showed a roughly linear trend of increasing aerosol purity with decreasing film thickness, although with quite different slopes. These findings are consistent with a model based on general vaporization and degradation kinetics. Small non-uniformities in the film do not significantly alter aerosol purity. CONCLUSIONS: Rapid vaporization of pharmaceuticals coated as thin films on substrates is an efficient way of generating drug aerosols. By controlling the film thickness, the amount of aerosol decomposition can be minimized to produce high purity aerosols.