Use of a fundamental approach to spray-drying formulation design to facilitate the development of multi-component dry powder aerosols for respiratory drug delivery.

PURPOSE: A fundamental approach incorporating current theoretical models into aerosol formulation design potentially reduces experimental work for complex formulations. A D-amino acid mixture containing D-Leucine (D-Leu), D-Methionine, D-Tryptophan, and D-Tyrosine was selected as a model formulation for this approach. METHODS: Formulation design targets were set, with the aim of producing a highly dispersible D-amino acid aerosol. Particle formation theory and a spray dryer process model were applied with boundary conditions to the design targets, resulting in a priori predictions of particle morphology and necessary spray dryer process parameters. Two formulations containing 60% w/w trehalose, 30% w/w D-Leu, and 10% w/w remaining D-amino acids were manufactured. RESULTS: The design targets were met. The formulations had rugose and hollow particles, caused by deformation of a crystalline D-Leu shell while trehalose remained amorphous, as predicted by particle formation theory. D-Leu acts as a dispersibility enhancer, ensuring that both formulations: 1) delivered over 40% of the loaded dose into the in vitro lung region, and 2) achieved desired values of lung airway surface liquid concentrations based on lung deposition simulations. CONCLUSIONS: Theoretical models were applied to successfully achieve complex formulations with design challenges a priori. No further iterations to the design process were required.

The use of computational fluid dynamics in inhaler design.

INTRODUCTION: Computational fluid dynamics (CFD) has recently seen increased use in the design of pharmaceutical inhalers. The use of CFD in the design of inhalers is made difficult by the complex nature of aerosol generation. At present, CFD has provided valuable insight into certain aspects of inhaler performance, though limitations in computational power have prevented the full implementation of numerical methods in the design of inhalers. AREAS COVERED: This review examines the application of CFD in the design of aerosol drug delivery technologies with a focus on pressurized metered-dose inhalers (pMDI), nebulizers and dry powder inhalers (DPIs). Challenges associated with the application of CFD in inhaler design are discussed along with relevant investigations in the literature. Discussions of discrete element modeling (DEM) and the simulation of pharmaceutical aerosol dispersion are included. EXPERT OPINION: The extreme complexity of coupled fluid and aerosol dynamics associated with aerosol generation has somewhat limited the use of CFD in inhaler design. Combined CFD--DEM simulations provide a useful tool in the design of DPIs, though aerosol generation in pMDIs and nebulizers has eluded CFD modeling. The most beneficial use of CFD typically occurs when concurrent CFD and experimental analyses are performed, significantly enhancing the knowledge provided by experiment alone.