Direct particle size distribution measurement of an active ingredient suspended in pressurised metered dose inhalers and parameters, which influence migration rate

Cristina Rey Blanes¹, Luca Serratore¹, Katie Reichwald¹, William J Ganley¹, Jose Ferrao², Marie-Laure Vicenty², Guillaume Lemahieu³, Matthias Sentis³, Giovanni Brambilla³, Robert Price¹, Jagdeep Shur¹ and Irene Rossi¹

¹Nanopharm, An Aptar Pharma Company, Grange Road, Cwmbran, NP44 3WY, United Kingdom

²Aptar Pharma, Route des Falaises, Le Vaudreuil, 27100, France

³Formulaction, 3-5 Rue Paule Raymondis, Toulouse, 31200, France

Summary

pMDIs make up 70% of inhalers used in the United Kingdom. In the transition from HFA 134a and HFA 227ea to low-GWP propellants, the understanding of the propellants’ properties is important for a successful re-formulation of life-saving medications, such as salbutamol MDI, in greener propellants. We have already explored propellant properties and API solubility, particle aerosolisation, electrostatic charge, deposition and distribution, which are highly valuable when making key decisions around formulation and device development. In this study, we looked into the evaluation of the direct measurement of migration rate and particle size distribution (PSD) of an API suspended in traditional and low-GWP propellants. APIs with different PSD were employed and their average diameters obtained from the PSD measured in line by static multiple light scattering were compared with the raw PSD measured by laser light scattering (un-processed > milled > micronised API) utilising the wet cell accessory and scanning electron microscopy. No correlation was found for PSD and migration rate for HFA 125a, however a correlation was found for HFA 134a and HFO 1234ze with the micronised API showing the slowest sedimentation. Finally, it was found that propellant density, raw API PSD, and PSD of suspension significantly affected the migration rate in such formulated systems. Particularly, migration rate influences the aerodynamic particle size distribution and drug delivered. Therefore, being able to contemporary measure PSD and migration rate of API suspended in MDI can facilitate the re-formulation of current pMDIs in low-GWP propellants and the development of bioequivalent products.

Key Message

In the re-formulation of suspension pMDIs in low-GWP propellants, the investigation of the influence of the active ingredient’s PSD on sedimentation is fundamental. In this study, we directly measured the particle size of a suspended API in pMDIs and we correlated this average diameter, propellant density and raw API PSD with migration rate.