A real-time and modular approach for quick detection and mechanism exploration of DPIs with different carrier particle sizes

Abstract

Dry powder inhalers (DPIs) had been widely used in lung diseases on account of direct pulmonary delivery, good drug stability and satisfactory patient compliance. However, an indistinct understanding of pulmonary delivery processes (PDPs) hindered the development of DPIs. Most current evaluation methods explored the PDPs with over-simplified models, leading to uncompleted investigations of the whole or partial PDPs. In the present research, an innovative modular process analysis platform (MPAP) was applied to investigate the detailed mechanisms of each PDP of DPIs with different carrier particle sizes (CPS). The MPAP was composed of a laser particle size analyzer, an inhaler device, an artificial throat and a pre-separator, to investigate the fluidization and dispersion, transportation, detachment and deposition process of DPIs. The release profiles of drug, drug aggregation and carrier were monitored in real-time. The influence of CPS on PDPs and corresponding mechanisms were explored. The powder properties of the carriers were investigated by the optical profiler and Freeman Technology four powder rheometer. The next generation impactor was employed to explore the aerosolization performance of DPIs. The novel MPAP was successfully applied in exploring the comprehensive mechanism of PDPs, which had enormous potential to be used to investigate and develop DPIs.

Keywords: AE, aerated energy; APIs, active pharmaceutical ingredients; AR, aeration ratio; BFE, basic flow Energy; C.OPT, optical concentration; CFD-DEM, computational fluid dynamics-discrete element method; CPS, carrier particle size; Carrier particle size; DPIs, dry powder inhalers; Dry powder inhaler; ED, emitted dose; EDXS, energy-dispersive X-ray spectroscopy; FC, centrifugal force; FD, drag force; FF, friction force; FG, gravity; FI, interaction force; FP, press-on force; FPD, fine particle dose; FPF, fine particle fraction; FT4, Freeman Technology 4; HPLC, high performance liquid chromatography; HPMC, hydroxypropyl methyl cellulose; LAC, lactose; MFV, minimum fluidization velocity; MMAD, mass median aerodynamic diameter; MOC, micro orifice collector; MPAP, modular process analysis platform; MSS, micronized salbutamol sulfate; NGI, Next Generation Impactor; O, oxygen; PD, pressure drop; PDP, pulmonary delivery process; PSF, particle size fractions; Pulmonary delivery process; Quick detection; R, release amount; RAUC, total release amount; Real-time monitor; Rmax, maximum of release amount; S, stopping distance; SE, specific energy; SEM, scanning electron microscope; SSA, specific surface area; T, time; TE, total engery; Tmax, the time to reach Rmax; Tt, terminal time; U0, air flow rate; V0, velocity; dQ3, the volume percentage of particles within certain range; dae, aerodynamic diameter.