Aerodynamic Factors Responsible for the Deaggregation of Carrier-Free Drug Powders to Form Micrometer and Submicrometer Aerosols

Abstract

Purpose The objective of this study was to employ in vitro experiments combined with computational fluid dynamics (CFD) analysis to determine which aerodynamic factors were most responsible for deaggregating carrier-free powders to form micrometer and submicrometer aerosols from a capsule-based platform. Methods Eight airflow passages were evaluated for deaggregation of the aerosol including a standard constricted tube, impaction surface, 2D mesh, inward radial jets, and newly proposed 3D grids and rod arrays. CFD simulations were implemented to evaluate existing and new aerodynamic factors for deaggregation and in vitro experiments were used to evaluate performance of each inhaler. Results For the carrier-free formulation considered, turbulence was determined to be the primary deaggregation mechanism. A strong quantitative correlation was established between the mass median diameter (MMD) and newly proposed non-dimensional specific dissipation (NDSD) factor, which accounts for turbulent energy, inverse of the turbulent length scale, and exposure time. A 3D rod array design with unidirectional elements maximized NDSD and produced the best deaggregation with MMD<1μm. Conclusions The new NDSD parameter can be used to develop highly effective dry powder inhalers like the 3D rod array that can efficiently produce submicrometer aerosols for next-generation respiratory drug delivery applications.

Aerosol Drug Delivery During Noninvasive Positive Pressure Ventilation: Effects of Intersubject Variability and Excipient Enhanced Growth

“…As with the CFD simulations, the inhaler was the in-line DPI based on the 3D rod array design, specifically the 2.3-232 version, which was developed by our group. (28,(33)(34)(35)(36) The inlet of the DPI was connected to a manual ventilation bag with tubing, where the bag was actuated manually for *1 second during each inhalation cycle, for multiple cycles. The EEG formulation consisted of submicrometer combination primary particles of a drug:excipient powder (36) containing CP, mannitol (MN), L-leucine, and poloxamer 188 (ratio 30:48:20:2).…”

“…The aerosol inlet entrance length was *2.5 cm, while the diameter was 8 mm. Aerosol delivery from an inline DPI was simulated for comparison with corresponding in vitro experiments, which implemented the 3D rod array inline design that has been developed by our group, specifically the 2.3-232 version, (28,(33)(34)(35)(36) which is actuated with a manual ventilation bag. Only the exit nozzle of the DPI was included in the CFD mask model since the internal particle deagglomeration mechanism was not simulated.…”

Validating Whole-Airway CFD Predictions of DPI Aerosol Deposition at Multiple Flow Rates

“…Currently, in vitro impactor-based experiments are the only available method to characterize drug emitted aerosol size distributions without the use of inhaler-specific correlations. (71) With most DPIs, the inhalation flow rate has a significant influence on the PSD. (72,73) For the Novolizer, a range of flow rates was selected to capture the inhalation profiles described in Table 1.…”

Challenges Associated with the Pulmonary Delivery of Therapeutic Dry Powders for Preclinical Testing

“…Current DPIs use carrier-based dry pow-ders that worsen the above concerns, in addition to the significant deposition in the mouth and throat area observed with such powders, irrespective of the inhaler used. Carrier-free dry powders were evaluated using the HandiHaler ® device and turbulence was shown to be their primary deaggregation mechanism (Longest et al, 2013). Highly effective passive inhalers may be required for carrier-free powders in order to improve the respirable fraction (10-70 %) currently achieved with the marketed DPIs (Islam and Cleary, 2012;Behara et al, 2014).…”