The aim of this research project was to investigate a potential standardized test method to characterize the dissolution properties of numerous formulation types available for pulmonary delivery. A commercially available dissolution tester was adapted for use as a testing apparatus by the incorporation of a membrane-containing holder. The holder was designed to enclose previously air-classified formulations so that they could be uniformly tested in the dissolution apparatus. Dissolution procedures, the apparatus, dose collection, medium, and test conditions were developed relying on USP General Chapter <1092>. To collect an active pharmaceutical ingredient (API) fraction from the devices for subsequent dissolution studies, aerodynamic particle separation on the membrane holder was achieved using the Next Generation Impactor (NGI) for two commercially available products, Ventolin HFA and Pulmicort Flexhaler. The dissolution profiles of budesonide (BD) and albuterol sulfate (AS) were successfully estimated by analyzing the amount of drug released from the membrane holder. This dissolution method may be applied to quality control studies for various inhalation products. In particular, the in vitro dissolution profiles of the drugs may provide an estimate of their dispersion characteristics, which directly relate to the device or aerosol performances.

Current pharmacopeial methods for testing dry powder inhalers (DPIs) require that 4.0 L be drawn through the inhaler to quantify aerodynamic particle size distribution of "inhaled" particles. This volume comfortably exceeds the internal dead volume of the Andersen eight-stage cascade impactor (ACI) and Next Generation pharmaceutical Impactor (NGI) as designated multistage cascade impactors. Two DPIs, the second (DPI-B) having similar resistance than the first (DPI-A) were used to evaluate ACI and NGI performance at 60 L/min following the methodology described in the European and United States Pharmacopeias. At sampling times ≥2 s (equivalent to volumes ≥2.0 L), both impactors provided consistent measures of therapeutically important fine particle mass (FPM) from both DPIs, independent of sample duration. At shorter sample times, FPM decreased substantially with the NGI, indicative of incomplete aerosol bolus transfer through the system whose dead space was 2.025 L. However, the ACI provided consistent measures of both variables across the range of sampled volumes evaluated, even when this volume was less than 50% of its internal dead space of 1.155 L. Such behavior may be indicative of maldistribution of the flow profile from the relatively narrow exit of the induction port to the uppermost stage of the impactor at start-up. An explanation of the ACI anomalous behavior from first principles requires resolution of the rapidly changing unsteady flow and pressure conditions at start up, and is the subject of ongoing research by the European Pharmaceutical Aerosol Group. Meanwhile, these experimental findings are provided to advocate a prudent approach by retaining the current pharmacopeial methodology.

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Background: Determination of aerosol aerodynamic particle size distributions (APSD) from dry-powder inhalers (DPIs), following quality control procedures in the pharmacopeial compendia, requires that the flow through the measurement apparatus, comprising induction port, optional pre-separator, and cascade impactor, starts from zero on actuation of the inhaler, using a solenoid valve to apply vacuum to the apparatus exit. The target flow rate, governed by the inhaler resistance, is reached some time afterward. Understanding the behavior of the DPI design-specific flow rate-rise time curve can provide information about the kinetics of the initial powder dispersion in the inhaler and subsequent transport through the APSD measurement equipment. Accurate and precise measures of the internal volume of each component of this apparatus are required to enable reliable relationships to be established between this parameter and those defining the flow rate-rise time curve. Methods: An improved method is described that involves progressive withdrawal of an accurately known volume of air from the interior passageways of the apparatus-on-test that are closed to the outside atmosphere. This approach is applicable for determining internal volumes of components having complex internal geometries. Filling some components with water, along with volumetric or gravimetric measurement, has proven valuable for the induction port and for checking other measurements. Results: Values of internal volume are provided for the USP (United States Pharmacopeia)/PhEur (European Pharmacopoeia) induction port, the Next-Generation Impactor (NGI™) with and without its pre-separator, and various Andersen 8-stage cascade impactor configurations with and without their pre-separators. Conclusion: These data are more accurate and precise, and therefore update those reported by Copley et al.

2020) 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,