Most Metered Dose Inhaler (MDI) products are formulated as suspensions rather than solutions and this is primarily due to solubility constraints of the active pharmaceutical ingredient/s (API/s) in the hydrofluoroalkane (HFA) based formulations.(1) In order to achieve the desired respirable performance of the product, the input API/s need to be reduced in particle size. This is typically performed by air jet milling, commonly referred to as micronisation. However, micronisation, in addition to the creation of particles of the target size; typically <5μm in diameter, also creates many sub-micron particles as well as amorphous crystal regions. The latter, upon storage, can give rise to agglomerated particles which, if not effectively broken up during MDI manufacture, may adversely affect product performance. The agglomerated particle clusters behave aerodynamically as larger particles and can deposit in the throat instead of being inhaled. Hence formulations in which agglomerates are not properly broken up will exhibit sub-optimal performance which may be manifest in terms of both lowered respirability and more variable dosing behaviour.
This paper compares the use of conventional high shear mixing processing employing the rotor/stator principle, with a new process using powerful ultrasonic probes to effect de-agglomeration during MDI formulation manufacture. Malvern laser diffraction and Andersen Cascade impactor data are presented to show that ultrasonic probe processing can give rise to MDI product with a greater degree of dispersion and higher respirability than product made using conventional high shear mixing.(2)
Finally, data demonstrating successful employment of the sonic probe approach at the pilot manufacturing scale are shown, where a bulk concentrate was processed and monitored over time until full dispersion was complete.