Design, characterization, and aerosol dispersion performance modeling of advanced spray-dried microparticulate/nanoparticulate mannitol powders for targeted pulmonary delivery as dry powder inhalers

Abstract

Background: The purpose was to design and characterize inhalable microparticulate/nanoparticulate dry powders of mannitol with essential particle properties for targeted dry powder delivery for cystic fibrosis mucolytic treatment by dilute organic solution spray drying, and, in addition, to tailor and correlate aerosol dispersion performance delivered as dry powder inhalers based on spray-drying conditions and solid-state physicochemical properties.

Methods: Organic solution advanced spray drying from dilute solution followed by comprehensive solid-state physicochemical characterization and in vitro dry powder aerosolization were used.

Results: The particle size distribution of the spray-dried (SD) powders was narrow, unimodal, and in the range of ∼500 nm to 2.0 μm. The particles possessed spherical particle morphology, relatively smooth surface morphology, low water content and vapor sorption (crystallization occurred at exposure above 65% relative humidity), and retention of crystallinity by polymorphic interconversion. The emitted dose, fine particle fraction (FPF), and respirable fraction (RF) were all relatively high. The mass median aerodynamic diameters were below 4 μm for all SD mannitol aerosols.

Conclusion: The in vitro aerosol deposition stage patterns could be tailored based on spray-drying pump rate. Positive linear correlation was observed between both FPF and RF values with spray-drying pump rates. The interplay between various spray-drying conditions, particle physicochemical properties, and aerosol dispersion performance was observed and examined, which enabled tailoring and modeling of high aerosol deposition patterns.

FIG. 1.

SEM micrographs of raw (magnification 100×) and SD mannitol particles (magnification 10,000×) for: (a) raw D-mannitol; (b) SD mannitol (10% pump rate); (c) SD mannitol (50% pump rate); and (d) SD mannitol (100% pump rate).

FIG. 2.

XRPD patterns for raw and SD mannitol particles.

FIG. 3.

Representative DSC thermograms of raw and SD mannitol particles for: (a) raw D-mannitol; (b) SD mannitol (10% pump rate; (c) SD mannitol (50% pump rate); and (d) SD mannitol (100% pump rate) (n=3).

FIG. 4.

Representative HSM micrographs of raw and SD mannitol particles for: (a) raw D-mannitol; and (b) SD mannitol (50% pump rate).

FIG. 5.

Water vapor sorption isotherms at 25°C for raw and SD mannitol (50% pump rate) particles (weight change % vs. RH).

FIG. 6.

(a) FT-Raman spectra of bulk phases of mannitol; (b) CRM map of a region of flattened SD mannitol (50% pump rate) particles obtained using a 50× objective, showing Raman band intensity between 2,910 and 2,940 cm^–1 as blue intensity; and (c) expanded CRM spectra of three points on the map in (b).

FIG. 7.

ATR-FTIR spectra for raw and SD mannitol particles.

FIG. 8.

In vitro aerosol dispersion performance using the NGI at an airflow rate (Q) of 60 L/min with the HandiHaler DPI device for SD mannitol (n=3).

FIG. 9.

Reference X-ray patterns of different polymorphs of mannitol obtained from the Cambridge structure database program of ConQuest 1.10 (The Cambridge Crystallographic Data Centre, Cambridge, UK). The solid star symbol indicates characteristic peaks of alpha, beta, and delta mannitol, respectively, which were used for identification in this study.

FIG. 10.

Water vapor sorption isotherms at 25°C for raw and SD mannitol (50% pump rate) particles (water vapor sorbed/dry compound mole/mole vs. RH).

FIG. 11.

Linear correlation plots of (a) FPF and (b) RF versus spray-drying pump rates for SD mannitol (n=3).