The Challenges of Developing a Purity Method for the Analysis of a Single Dose DPI Inhaler
Victoria Sillis1, Frank Chambers1 & Bob Lott2
1Inhalytic Ltd, Discovery Park, Sandwich, Kent, CT13 9ND, United Kingdom
2 CI Informatics, PO Box 300, Didcot, OX11 1EU, United Kingdom
Summary
The USP HPLC method for albuterol was redeveloped using Fusion QbD to reduce solvent use, improve sensitivity, and enable impurity analysis of albuterol within a lactose formulation matrix. The original USP method employed a high mobile phase flow rate, increasing consumables cost and environmental impact, and lacked sufficient sensitivity. The redevelopment was particularly important because of a requirement for a single-dose test. Fusion QbD was used to optimize the method by adjusting flow rate, column dimensions, UV wavelength, gradient conditions, and particle size.
Firstly, the flow rate was reduced to conserve solvent and enable Fusion QbD optimization. Column dimensions were shortened using an online Merck™ HPLC method transfer calculator, reducing solvent consumption thus providing a more environmentally sustainable method.
Secondly, sensitivity was enhanced to allow lower sample concentrations. The UV wavelength was shifted from 230 nm to 225 nm, aligning with albuterol’s peak maxima and improving UV response. Fusion QbD then evaluated the impact of gradient, organic content, oven temperature, and flow rate on method performance.
Thirdly, Fusion QbD was used to assess the impact of gradient, organic percentage, oven temperature and column flow rate on sensitivity and robustness of the critical pair resolution, both key method performance requirements set out in the Analytical Target Profile.
With these modifications, it was possible to take the USP method and improve it to allow the analysis of impurities from a single dose DPI inhaler.