Investigation of Dry Powder Inhaler (DPI) Resistance and Aerosol Dispersion Timing on Emitted Aerosol Aerodynamic Particle Sizing by Multistage Cascade Impactor when Sampled Volume Is Reduced from Compendial Value of 4 L

Abstract

Compendial methods determining dry powder inhaler (DPI)-emitted aerosol aerodynamic particle size distribution (APSD) collect a 4-L air sample containing the aerosol bolus, where the flow, which propagates through the cascade impactor (CI) measurement system from the vacuum source, is used to actuate the inhaler. A previous article described outcomes with two CIs (Andersen eight-stage cascade impactor (ACI) and Next-Generation Pharmaceutical Impactor (NGI)) when the air sample volume was ≤4 L with moderate-resistance DPIs. This article extends that work, examining the hypothesis that DPI flow resistance may be a factor in determining outcomes. APSD measurements were made using the same CI systems with inhalers representing low and high flow resistance extremes (Cyclohaler® and HandiHaler® DPIs, respectively). The ratio of sample volume to internal dead space (normalized volume (V*)) was varied from 0.25 to 1.98 (NGI) and from 0.43 to 3.46 (ACI). Inhaler resistance was a contributing factor to the rate of bolus transfer; the higher resistance DPI completing bolus relocation to the NGI pre-separator via the inlet when V* was as small as 0.25, whereas only ca. 50% of the bolus mass was collected at this condition with the Cyclohaler® DPI. Size fractionation of the bolus from either DPI was completed within the ACI at smaller values of V* than within the NGI. Bolus transfer from the Cyclohaler® capsule and from the HandiHaler® to the ACI system were unaffected by the different flow rise time observed in the two different flow controller systems, and the effects the ACI-based on APSD measurements were marginal.

The contribution of patients’ lung function to the inspiratory airflow rate achievable through a DPIs’ simulator reproducing different intrinsic resistance rates

“…Though DPIs are widely and increasingly prescribed in clinical practice, the choice of the most convenient DPI to prefer still is a critical challenge in real-life [23] because available DPIs provide a wide range of inhalation and deposition patterns due to different physical, physiological and technological differences [3,24,25]. The relative role of these factors has been extensively investigated, even if evidence on optimal flow rates still largely derive from experimental or in vitro delivery data that only partially reproduce real-life clinical conditions [26][27][28].…”

Determination of Passive Dry Powder Inhaler Aerodynamic Particle Size Distribution by Multi-Stage Cascade Impactor: International Pharmaceutical Aerosol Consortium on Regulation & Science (IPAC-RS) Recommendations to Support Both Product Quality Control and Clinical Programs

“…It follows that if the sample volume is reduced, the proportion of the period during which the flow rate has not stabilized at the target value (previously discussed) compared with the measurement duration is also increased. In a follow-on study, Mohammed et al (25), by studying the behavior of low and high resistance DPIs, were able to show that incomplete capsule emptying took place with low resistance Cyclohaler® DPIs only at the smallest sample volume investigated (1 L). Furthermore, capsule emptying was apparently efficient, regardless of comparable reductions in sample volume, with the higher resistance HandiHaler® DPIs that were also evaluated in the same investigation.…”

“…This strategy results in a procedure in which the flow rate of air entering the inhaler starts from zero when vacuum is applied to the CI by operation of a solenoid gate valve, rises rapidly to reach the final target value during the measurement procedure and then quickly returns back to zero after a fixed volume of air has been sampled. It is selfevident from the challenges previously identified for such a testing methodology; the nature of the measurement procedure itself has the potential to influence the size properties of the sampled aerosol by controlling the energetics of both the initial powder dispersion and later the transfer of the resulting aerosol from the inhaler via the inlet to the pre-separator (if used) and subsequently to the sizefractionating stages of the CI (24,25). These methods utilize standardized profiles of sampling flow rate versus time that are not intended to be perfect representations of patient inhalation profiles (26).…”

“…Attempts have been made to reduce the sampled volume to mirror the IV of a patient to make the measurements more clinically relevant (50,51). However, there is evidence from another EPAG-led laboratory study by Mohammed et al (24,25), in which the sample volume was progressively reduced from 4 L, that significant bias in the APSD to larger sizes can occur at smaller sample volumes, because not all of the aerosol bolus from the DPI has had time to penetrate through the entire set of sizefractionating stages. In their first study, Mohammed et al found that this behavior was particularly apparent with the NGI, whose internal volume is almost twice that of the ACI.…”

A cross-industry assessment of the flow rate-elapsed time profiles of test equipment typically used for dry-powder inhaler (DPI) testing: Part 2– analysis of transient air flow in the testing of DPIs with compendial cascade impactors

“…There is currently a limited understanding of this process. The development of an improved knowledge-base for the flow rate startup kinetics is therefore of fundamental importance, since the energy available both for powder dispersion from the original source inside the inhaler (bulk powder, blister or capsule) and the subsequent transfer of the resulting aerosol to the CI for size classification is time-dependent (Mohammed et al 2012(Mohammed et al , 2014. In consequence, a multi-participant experimental study of these flow startup kinetics was undertaken cooperatively by members of the European Pharmaceutical Aerosol Group (EPAG).…”