A novel particle engineering method for the production of inhalable cromolyn sodium powders by a combination of spray drier and nebulizer

Abstract

Cromolyn sodium is a promising treatment for respiratory disease, especially asthma. Cromolyn sodium is mostly used in the form of a dry powder inhaler (DPI). Morphology of the powder, particle size, dispersibility, and stability are features that greatly influence the absorption efficiency of the given formulation and can be controlled through particle engineering. Although spray drying is the most common production method of cromolyn sodium, this method has some drawbacks including wide droplet size distribution, clogging risk, and lack of direct control over the mean droplet size. To enhance the aerosol performance of the powder, a new method known as a nebulizer-spray drier coupling (NSD) is proposed which affects the particle size distribution, surface features, and aerodynamic properties of the formulation. Ammonium bicarbonate and ethanol were added to assess the variation of produced powder porosity. The morphology, surface and crystallographic features of particles were analyzed with scanning electron microscopy (SEM), Brunauer-Emmett-Teller (BET, and X-ray diffraction (XRD) techniques respectively. Aerosol performance was measured with the next generation impactor (NGI). The results show that unlike the needle-like particle shape of the commercial (CS) cromolyn sodium and untreated (raw) cromolyn sodium, the NSD samples have a mushroom-like and spherical particle shape. In the same condition, NSD samples show higher fine particle fraction (FPF) and lower aerodynamic size distribution compared to their counterpart samples (spray-dried). The amorphous structure of the generated powder was confirmed through XRD and DSC analysis. Also, the addition of ammonium bicarbonate produced wider size distribution for particles, providing spherical, hollow, smooth-surface particles. Moreover, the influence of using ethanol (in spray drying process) as a solvent was explored, where the aerosolization performance was found to be improved when ethanol was added to the spray dried solutions. It was concluded that the newly developed powder preparation method (NSD method) could successfully provide cromolyn sodium powder for inhalation and can be introduced as a novel technique for particle engineering of DPIs.