Freeze-dried mannitol for superior pulmonary drug delivery via dry powder inhaler

Purpose: To show for the first time the superior dry powder inhaler (DPI) performance of freeze dried mannitol in comparison to spray dried mannitol and commercial mannitol. Methods: Different mannitol powders were sieved to collect 63-90 µm particles and then analyzed in terms of size, shape, surface morphology, solid state, density, flowability. Salbutamol sulphate-mannitol aerosol formulations were evaluated in terms of homogeneity, SS-mannitol adhesion, and in vitro aerosolization performance. Results: Freeze dried mannitol demonstrated superior DPI performance with a fine particle fraction believed to be highest so far reported in literature for salbutamol sulphate under similar protocols (FPF = 46.9%). To lesser extent, spray dried mannitol produced better aerosolization performance than commercial mannitol. Freeze dried mannitol demonstrated elongated morphology, a-+ß-+d- polymorphic forms, and poor flowability whereas spray dried mannitol demonstrated spherical morphology, a-+ß- polymorphic forms, and excellent flowability. Commercial mannitol demonstrated angular morphology, ß- polymorphic form, and good flowability. Freeze dried mannitol demonstrated smoother surface than spray dried mannitol which in turn demonstrated smoother surface than commercial mannitol. FPF of SS increased as mannitol powder porosity increase. Conclusions: Freeze drying under controlled conditions can be used as a potential technique to generate aerodynamically light mannitol particles for superior DPI performance. © 2012 Springer Science+Business Media New York.