Supercritical fluid-micronized ipratropium bromide for pulmonary drug delivery

Ipratropium bromide (IB) was micronized by means of a CO2-based aerosol solvent extraction system (ASES) in order to improve the particle shape and size characteristics for use in inhalation therapy. The particle size parameter most relevant to pulmonary delivery is the aerodynamic diameter. In this study, ASES experiments were conducted using various liquid solvents for IB such as dimethylformamide (DMF), ethanol (EtOH), and mixtures of ethanol and acetone (EtOH/Ac). Several operating parameters were varied including temperature, pressure, IB concentration in the liquid solution, and the solution injection rate. The particles were analyzed by scanning electron microscopy (SEM). The true density of the particles was measured using a pycnometer and the mass median aerodynamic diameter (MMAD) determined. The results indicate that the size and morphology of the microparticles are most sensitive to solvent choice. Optimum results were obtained when IB particles were precipitated from DMF. The particles were more regular in shape, slightly elliptical, not agglomerated, and within the aerodynamic diameter range of 0.6–3.0 μm. Fourier transform infrared (FTIR) studies indicate no structural deformation as result of the ASES process. The regional depositions of inhaled IB particles were estimated using a multiple-path model of particle deposition (MPPD). The results indicate that IB particles with MMAD in the range of 2–3 μm deposited mainly in the respiratory airways in the lung.