Quality by Design approach in the development of hydrophilic interaction liquid chromatographic method for the analysis of iohexol and its impurities

Abstract

This study presents the development of hydrophilic interaction liquid chromatographic method for the analysis of iohexol, its endo-isomer and three impurities following Quality by Design (QbD) approach. The main objective of the method was to identify the conditions where adequate separation quality in minimal analysis duration could be achieved within a robust region that guarantees the stability of method performance. The relationship between critical process parameters (acetonitrile content in the mobile phase, pH of the water phase and ammonium acetate concentration in the water phase) and critical quality attributes is created applying design of experiments methodology. The defined mathematical models and Monte Carlo simulation are used to evaluate the risk of uncertainty in models prediction and incertitude in adjusting the process parameters and to identify the design space. The borders of the design space are experimentally verified and confirmed that the quality of the method is preserved in this region. Moreover, Plackett-Burman design is applied for experimental robustness testing and method is fully validated to verify the adequacy of selected optimal conditions: the analytical column ZIC HILIC (100 mm × 4.6 mm, 5 μm particle size); mobile phase consisted of acetonitrile-water phase (72 mM ammonium acetate, pH adjusted to 6.5 with glacial acetic acid) (86.7:13.3) v/v; column temperature 25 °C, mobile phase flow rate 1 mL min(-1), wavelength of detection 254 nm.

Design of Experiments (DoE) applied to Pharmaceutical and Analytical Quality by Design (QbD)

“…Retention time of exo-iohexol, endo-iohexol, and their related compound (A, B, and C) using liquid chromatographic method (Jovanovic et al, 2015) 2-level factorial design and central composite design…”

Development and Optimization of Liquid Chromatography Analytical Methods by Using AQbD Principles: Overview and Recent Advances

“…For an impurity-profiling HPLC method, where the separation quality is evaluated, the usual key CMA is the resolution of the critical peak pair ( R s ), ,,− ,, which may be exchanged with measuring time differences between chromatographic peaks or their selectivity factors (α). , …”

“…In several publications, ,,− ,− the term critical quality attribute (CQA) is used for the critical attribute of an analytical method. According to Kochling et al, a CMA for an analytical method is an analogue of a CQA for a drug product.…”

“…Once the experimental work by a higher-order response-surface design is completed, the responses may be modeled. In the modeling process, the polynomial model is fitted to the experimental data to link the responses with the factors studied and their interactions. , Model fitting is usually performed using a multiple linear regression (MLR) method, − ,,, in which the regression coefficients ( b 0 , b 1 , b 2 , b 11 , b 22 , b 12 , ...) corresponding to the different factor terms of the polynomial equation are calculated in order to evaluate factor and factor-interaction effects on the response . By application of analysis of variance (ANOVA), it is possible to determine the statistical significance of the model.…”

“…In line with increased awareness of regulatory authorities regarding implementation of the lifecycle concept for analytical methods, application of the AQbD approach has become a current area of focus for many pharmaceutical companies, medicine agencies, research institutes, and universities . As of 2016, applications of AQbD in LC method development had been reported and discussed in several publications. − In most cases, stability-indicating methods are discussed, either for determination of degradation products or an assay of the main API in pharmaceutical dosage forms. − Some publications also discuss multiple assay determination because two or more APIs are combined in a single dosage form. , There are several publications in which a method for determination of an API and its impurities needed to be optimized or newly developed, − and a few cases discussing the determination of the assay of a preservative in final dosage forms. , …”