Influence of the Size of Micronized Active Pharmaceutical Ingredient on the Aerodynamic Particle Size and Stability of a Metered Dose Inhaler

Abstract

Pharmaceutical inhalers are often used to treat pulmonary diseases. Only active pharmaceutical ingredient (API) particles from these inhalers that are less than approximately 5 µm are likely to reach the lung and be efficacious. This study was designed to investigate the impact of micronized API particle size on the aerodynamic particle size distribution (PSD) profile and the particle size stability of a suspension metered dose inhaler (MDI) containing propellant HFA‐227 (1,1,1,2,3,3,3 heptafluoropropane) and a corticosteroid. The median API particle size ranged from 1.1 µm to 1.8 µm (97% to 70% of particles < 3 µm, respectively). This study showed that increasing the particle size of the API used to manufacture a suspension MDI product increased the aerodynamic PSD of the MDI product. Furthermore, upon storage of the MDI product under temperature cycling conditions, samples containing larger‐size API particles were less stable with respect to their aerodynamic PSD than those with smaller‐size API particles. It was found that size‐dependent particle growth and/or aggregation of the suspended API may be occurring as a result of temperature cycling. In conclusion, this study has shown that the particle size of the raw API impacts the properties and stability of the emitted aerosol spray. Based on the findings from this study, it is recommended that the API particle size be carefully controlled in order to meet specifications set for the finished MDI product.

Key Words:

• Cascade impaction
• Particle size distribution (PSD)
• Metered dose inhalers (MDI)
• Sympatec laser diffraction
• Micronization
• Aerosol
• Temperature cycling