Re-designing the colistimethate sodium Twincer^® for large-scale production

Floris Grasmeijer^1,2, Paul Hagedoorn¹ & Anne Haaije de Boer¹

¹University of Groningen, Department of Pharmaceutical Technology and Biopharmacy, Antonius Deusinglaan 1, Groningen, 9713 AV, the Netherlands

²PureIMS B.V., Ceintuurbaan Noord 152, Roden, 9301 NZ, the Netherlands

The disposable Twincer^® dry powder inhaler was designed and developed to disperse high doses of pure micronised drug for pulmonary administration, such as antibiotics. In this study we tested vacuum drum filling with the Ominidose^TM as powder filling principle for the large-scale production of the Twincer. We studied the effect of powder densification and pelletisation with this technique on the dose emission and dispersion with the Twincer. Reproducible dosing of pure micronised colistimethate sodium was possible with the production scale Omnidose^TM, despite the fact that poor powder flowability resulted in large dosing variations with the lab scale Omnidose^TM TT. The vacuum drum filling process resulted in powder pellets with considerable structural integrity at the partial vacuum pressures required for reproducible dosing. Even with small boreholes of 3.6 mm3, which restricted the size of pellets formed during drum filling, the powder passageways in the Twincer were clogged by the pellets during dispersion. A new Twincer model was developed with wider powder passageways, improved air flow through the dose compartment and improved circulation in its air classifiers. With this newly developed Twincer the pellets resulting from drum filling with the Omnidose^TM could be successfully emitted and dispersed, which enables the large-scale colistimethate sodium Twincer production. The considerable cost and risk involved in adapting a dry powder inhaler to changing formulation properties during upscaling stresses the importance of taking into account large-scale production processes during the small-scale development phase of dry powder inhalation products.