A Novel High-Speed Imaging Technique to Predict the Macroscopic Spray Characteristics of Solution Based Pressurised Metered Dose Inhalers
Non-volatile agents such as glycerol are being introduced into solution-based pMDI formulations in order to control mean precipitant droplet size. To assess their biopharmaceutical efficacy, both microscopic and macroscopic characteristics of the plume must be known, including the effects of external factors such as the flow generated by the patient’s inhalation. We test the hypothesis that the macroscopic properties (e.g. spray geometry) of a pMDI spray can be predicted using a self-similarity model, avoiding the need for repeated testing.
Glycerol-containing and glycerol-free pMDI formulations with matched mass median aerodynamic diameters are investigated. High-speed schlieren imaging is used to extract time-resolved velocity, penetration and spreading angle measurements of the pMDI spray plume. The experimental data are used to validate the analytical model.
The pMDI spray develops in a manner characteristic of a fully-developed steady turbulent jet, supporting the hypothesis. Equivalent glycerol-containing and non glycerol-containing formulations exhibit similar non-dimensional growth rates and follow a self-similar scaling behaviour over a range of physiologically relevant co-flow rates.
Using the proposed model, the mean leading edge penetration, velocity and spreading rate of a pMDI spray may be estimated a priori for any co-flow conditions. The effects of different formulations are captured in two scaling constants. This allows formulators to predict the effects of variation between pMDIs without the need for repeated testing. Ultimately, this approach will allow pharmaceutical scientists to rapidly test a number of variables during pMDI development.
KEY WORDSco-flow glycerol HFA high-speed schlieren imaging modelling pMDI
Andersen Cascade Impactor
Fine particle dose
Mass median aerodynamic diameter
Pressurised Metered Dose Inhaler
ACKNOWLEDGMENTS AND DISCLOSURES
The authors would like to acknowledge the financial support of the Australian Research Council (grant number DP120103510).
- 2.Finlay WH. The mechanics of inhaled pharmaceutical aerosols - an introduction. Academic Press; 2001.Google Scholar
- 4.Lewis DA, Young PM, Buttini F, Church T, Colombo P, Forbes B, et al. Towards the bioequivalence of pressurised metered dose inhalers 1: design and characterisation of aero-dynamically equivalent beclomethasone dipropionate inhalers with and without glycerol 2 as a non-volatile excipient. Eur J Pharm Biopharm. 2013.Google Scholar
- 6.Haghi M, Bebawy M, Colombo P, Forbes B, Lewis DA, Salama R, et al. Towards the bioequivalence of pressurised metered dose inhalers 2. Aerodynamically equivalent particles (with and without glycerol) exhibit different biopharmaceutical profiles in vitro. Eur J Pharm Biopharm. 2013.Google Scholar
- 24.Settles GS. Schlieren and shadowgraph techniques. experimental fluid mechanics. Springer-Verlag; 2001.Google Scholar
- 33.Clark AR. Metered atomisation for respiratory drug delivery. Loughborough University; 1991.Google Scholar
- 34.Hiroyasu H, Arai M. Structures of fuel sprays in diesel engines. SAE J. 1990 Feb;900475.Google Scholar
- 37.Shaik AQ. Numerical modeling of two-phase flashing propellant flow inside the twin-orifice system of pressurized metered dose inhalers (PMDIs). Loughborough University; 2010.Google Scholar
- 39.White FM. Fluid mechanics. 4th ed. Singapore: McGraw-Hill; 1999.Google Scholar
- 41.Huber ML, McLinden MO. Thermodynamic properties of R134a (1, 1, 1, 2-tetrafluoroethane). In: International Refridgeration and Air Conditioning Conference; 1992.Google Scholar