In Vitro Investigation of Drug Particulates Interactions and Aerosol Performance of Pressurised Metered Dose Inhalers
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To determine a relationship between adhesive and cohesive inter-particulate forces of interactions and in vitro performance in pressurised metered dose inhalers (pMDIs) suspension formulations.
Interparticulate forces of salbutamol sulphate (SS), budesonide (BUD) and formoterol fumarate dihydrate (FFD) were investigated by in situ atomic force microscopy (AFM) in a model propellant 2H, 3H perfluoropentane (HPFP). Experimental data were analysed using the recently developed cohesive/adhesive analysis method (CAB) and compared with in vitro deposition performances in pMDIs systems using Andersen cascade impactor (ACI).
The in vitro investigation suggested that the micronised drug materials had significantly different aerosolisation profiles when manufactured as single or combination formulations. In general, the greatest significant differences were observed between SS single drug and SS-BUD and SS-FFD combinations. Analysis of the in vitro performance for the SS only formulation suggested that the cohesive nature of SS (as predicted by the CAB and observed with AFM) led to tightly bound flocs that did not fully deaggregate upon aerosolisation.
It is suggested that the relationship between interparticulate interactions and in vitro performance of pMDIs suspension systems, when compared to direct measurement of the adhesion/cohesion forces, indicated good correlation. This approach may be useful in expediting the development of pMDI formulation and predicting performance.
Key wordsadhesive/cohesive forces AFM in vitro testing pMDI suspensions
- 1.P. J. Barnes, M. M. Grunstein, A. R. Leff, and A. J. Woolcock. Asthma, Lippincott-Raven, Philadelphia, 1997.Google Scholar
- 6.R. J. Good and L. A. Girifalco. A theory for estimation of surface and interfacial energies. III. Estimation of surface energies of solids from contact angle data. J. Phys. Chem. 64:561–565 (1960).Google Scholar
- 7.F. M. Fowkes. Determination of interfacial tension, contact angles and dispersion forces in surface by assuming additivity of intermolecular interactions in surfaces. J. Phys. Chem. 66:382 (1962).Google Scholar
- 8.C. J. van Oss. Interfacial Forces in Aqueous Media. Marcel Dekker, New York, U.S.A., 1994.Google Scholar
- 10.Apparatus D, British Pharmacopoeia. The Stationery Office on behalf of the Medicines and Healthcare Products Regulatory Agency (MHRA). London, UK, 2005.Google Scholar
- 13.P. A. Webb and C. Orr. Analytical Methods in Fine Particle Technology, Micrometrics Instrument Corp., Norcross, Georgia, U.S.A., 1997.Google Scholar
- 14.G. Rhodes. Crystallography—Made Crystal Clear, Academic, New York, USA, 1993.Google Scholar
- 15.J. Albertsson, A. Oskarsson, and C. Svensson. X-ray study of budesonide: molecular structure and solid solution of the (22S) and (22R) epimers of 11B,21-dihydroxy-16alfa,17 alfa-propylmethylenedioxy-1,4-pregnadiene-3,20-dione. Acta Crystallogr. B34:3027–3036 (1978).Google Scholar
- 16.Ertan, B. Stensland, and I. Ymen. Crystal and molecular structure of formoterol fumarate dihydrate, Astra Production Chemicals AB, Confidential Report N. 117/97, 1997.Google Scholar
- 17.P. J. M. Leger, M. Goursolle, and M. Gadret. Structure cristalline du sulphate de salbutamol [ter-butylamino-2-(hydroxy-4hydroxymethyl-3 phenyl)-1 ethanol.1/2 H2SO4]. Acta Crystallogr. B34:1203–1208 (1978).Google Scholar
- 19.P. M. Young. Characterisation of particle–particle interactions using the atomic force microscope, Pharmacy and Pharmacology, University of Bath, Bath, UK, 2002.Google Scholar
- 24.W. Neumann, D. R. Renzow, H. Reumuth, and J. E. Richter. Vol. 55, Fortschr. Kolloide Polymere 49–54 (1971)Google Scholar
- 25.G. Buckton. Interfacial Phenomena in Drug Delivery and Targeting, Harwood Academic Publishers, Chur, Switzerland, 1995.Google Scholar