Analytical Quality by Design in the development of a solvent-modified micellar electrokinetic chromatography method for the determination of omeprazole and its impurities

Impurity profiling constitutes a fundamental part of Quality Control (QC) and consists in the detection and determination of impurities which may be present in a drug substance or a drug product. The aim of this study was to set-up a Capillary Electrophoresis (CE) method for the QC of omeprazole (OME) capsules. OME is a proton pump inhibitor used to treat gastroesophageal reflux disease associated conditions such as heartburn and gastric acid hypersecretion. The method was developed in the Analytical Quality by Design’s framework, as recommended by recent ICH guideline Q14. According to the Analytical Target Profile, the method should be able to simultaneously quantify OME and seven of its related impurities in the drug product, with specified analytical performances. The selected operative mode was solvent-modified Micellar ElectroKinetic Chromatography (MEKC), based on sodium dodecyl sulfate (SDS) micelles with the addition of n-butanol to the background electrolyte (BGE). In the screening phase, a symmetric screening matrix was employed to evaluate the effect of seven critical method parameters on critical method attributes (resolution, analysis time, OME peak width). The critical method parameters included voltage, temperature, BGE pH and concentration, SDS concentration, n-butanol concentration, dimethyl-β-cyclodextrin (CyD) concentration. Based on the screening results, the addition of CyD to the BGE was discarded and temperature was fixed at 21 °C. Response Surface Methodology was carried out using an Orthogonal Central Composite Design. The calculated regression models, combined with Monte Carlo simulations, allowed probability maps to be drawn and a Method Operable Design Region (MODR) to be identified. The MODR intervals were defined as follows: borate buffer concentration, 65-80 mM; pH, 9.80-10.20; SDS concentration, 90-110 mM; n-butanol concentration, 1.04-1.75 %v/v; voltage, 23-25 kV.