A method for determination of the Aerodynamic Droplet size of Nebulised Colistimethate Sodium using a Next Generation Impactor with UHPLC-UV detection.  

Ian Carter¹, Thomas Keogh¹ & Tejas Parekh¹

¹PPD Clinical Research Services, Thermo Fisher Scientific, IDA Business Park, Garrycastle, Athlone, Ireland

Summary

Colistimethate sodium is used in the treatment of Chromic pulmonary bacterial infection. It is a sulfomethylated pro-drug of colistin (primarily polymyxin E₁ and E₂), a poly cationic peptide produced by biosynthesis and is delivered via nebulisation of a reconstituted powder. In aqueous solutions the Colistimethate Sodium undergoes hydrolysis to produce colistin with a variety of partially sulfomethylated chains of varying molecular sizes and chain lengths. This makes chromatographic analysis challenging due to the number of and varying quantities of each polymyxin and the degree of sulfomethylation. Non chromatographic methodologies used for determination of the aerodynamic droplet size distribution of nebulised colistimethate sodium can be labour intensive involving manual measurements and calculations. Ultra-high performance liquid chromatography (UHPLC) offers automated rapid analysis and processing of data, making this a more suitable technique for higher throughput testing, which is advantageous for aerodynamic droplet size determinations. Therefore, a UHPLC method has been developed that allows quantitation of the colistimethate sodium content delivered by the nebuliser directly against the un nebulised material from the same batch, which does not require integration of the full complex chromatogram, making the method suitable for routine determination of the aerodynamic size distribution and additionally the emitted dose.

Key Message

This method takes learning from existing publications to create a procedure that allows a simplified chromatographic assessment of the aerodynamic droplet size distribution of nebulised colistimethate sodium. Complexity and variability are reduced and the need for external reference standards removed by utilising a comparison of un-nebulised and nebulised material from the same batch. This is an improved approach for quality control testing when compared to other labour intensive methodologies.