Development of a CZE method for the determination of mizolastine and its impurities in pharmaceutical preparations using response surface methodology

Orlandini, Serena; Giannini, Iacopo; Gotti, Roberto; Pinzauti, S.; Porta, E. La; Furlanetto, Sandra

doi:10.1002/elps.200600380

Cited by 17 publications

(5 citation statements)

References 32 publications

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“…The progressive implementation of CE in industrial quality control of pharmaceuticals [42][43][44] is related to its advanced selectivity [38,39], especially in the separation of closely related proteins [45][46][47]. Further advances of CE compared to alternative separation strategies comprise minute sample consumption in the nL domain and the resolution of different conformations, even if the pI and the hydrodynamic radius are only slightly altered by structural changes [47,48].…”

Section: Introductionmentioning

confidence: 99%

Validation of capillary zone electrophoresis and capillary isoelectric focusing separations optimized for the characterization of two recombinant products of the birch pollen allergen Bet v 1a

2008

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CZE and CIEF separation systems, both developed previously for a quality control of two recombinant products of the major birch pollen allergen Bet v 1a of Betula verrucosa, were validated including aspects of the International Conference on Harmonization. One product contained carbamylated variants as impurities. Linearity of response was confirmed by Mandel's fitting test between 0.028 and 1.90 mg/mL for CZE and between 0.016 and 0.26 mg/mL for CIEF. Repeatability and intermediate precision were evaluated for the effective mobility (mu(eff)) in CZE, for relative mobilization time in CIEF and the peak area ratio of Bet v 1a. LOQ for Bet v 1a was between 10 and 23 microg/mL for both methods. Evaluation of robustness for CZE revealed susceptibility of micro(eff) of Bet v 1a to alterations in of buffer pH and separation temperature. Selectivity was impaired by an increase in temperature, pH, and buffer concentration. In addition, pH variations influenced the separation profile of impurities. For CIEF, the ratio of narrow pH range carrier ampholytes is the critical parameter to retain robustness. Results demonstrate the suitability of both separation systems to discriminate between nonmodified Bet v 1a and carbamylated variants in the selected recombinant allergen products.

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Section: Introductionmentioning

confidence: 99%

Validation of capillary zone electrophoresis and capillary isoelectric focusing separations optimized for the characterization of two recombinant products of the birch pollen allergen Bet v 1a

2008

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“…CQAs requirements were set as Rs 1 > 0.5, Rs 4 > 1.5, t ≤ 10 min. The difference in the desired values for the separation CQAs is due to the fact that Rs 1 describes the separation of two peaks of different area (an impurity and the main compound), while Rs 4 describes the separation of two impurity peaks, which present similar characteristics of width and height .…”

Section: Resultsmentioning

confidence: 99%

Analytical quality by design in the development of a cyclodextrin‐modified capillary electrophoresis method for the assay of metformin and its related substances

et al. 2014

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Quality by Design (QbD) is a new paradigm of quality to be applied to pharmaceutical products and processes, recently encouraged by International Conference on Harmonisation guidelines. In this paper QbD approach was applied to the development of a CE method for the simultaneous assay of metformin hydrochloride (MET) and its main impurities. QbD strategy was focused on electrophoretic process understanding, and the analytical method was thoroughly evaluated by applying risk assessment and chemometric tools. Method scouting allowed CD-CZE based on the addition of carboxymethyl-β-CD to Britton-Robinson acidic buffer to be chosen as operative mode. Seven critical process parameters (CPPs) were selected, related to capillary, injection, BGE and instrumental settings. The effect of the different levels of the CPPs on critical quality attributes (CQAs), e.g. critical resolution values and analysis time, was evaluated in a screening study. Response surface methodology led to draw contour plots and sweet spot plots. The definition of design space was accomplished by applying Monte-Carlo simulations, thus identifying by risk of failure maps a multivariate zone where the CQAs fulfilled the requirements with a selected probability. Finally, a control strategy was designed and the method was applied to a real sample of MET tablets.

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“…In fact, applying the test concentration values for BD (10 mg/mL) and related substances (100 mg/mL), the obtained peaks for BD epimers and I 4 were very different for width and symmetry. Using the statistical method instead of the USP formula, it is possible to obtain a more reliable value for resolution [44]. The other resolutions were not considered because no problem was pointed out.…”

Section: Response Surface Methodologymentioning

confidence: 99%

“…In the second experimental design, due to the different concentrations of the analytes (BD, 10 mg/mL; BD impurities, 100 mg/mL), resolution values between I 4 and the previous peak BD 1 (R 1 ) or the following peak BD 2 (R 2 ) were calculated using the statistical method as the involved peaks were significantly different for area and width [43,44]:…”

Section: Calculations and Softwarementioning

confidence: 99%

Pitfalls and success of experimental design in the development of a mixed MEKC method for the analysis of budesonide and its impurities

et al. 2009

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A mixed MEKC method for the analysis of budesonide and its related substances is presented. The micelles were formed from sodium cholate (CHOL) and 3-(N,N-dimethylmyristylammonio)propanesulfonate (MAPS). A multivariate optimisation was carried out with the aim of obtaining a baseline separation of all compounds. The influence of voltage, borate concentration, cholate concentration, MAPS concentration and pH was evaluated on the responses, corresponding to critical resolution values. Problems with the investigated experimental design were encountered due to the complexity of the separation process. As a consequence, a first design was not sufficient to reach the optimal conditions, but was needed in order to obtain the necessary information to successfully plan a second in-depth study by means of response surface methodology. The optimal conditions were as follows: capillary total and effective lengths of 48.5 and 40.0 cm, respectively, with 50 microm id; 70 mM borate buffer (pH 8.8) containing 65 mM CHOL and 10 mM MAPS; temperature 20 degrees C and voltage 16 kV. Separation of all the compounds, including R- and S-epimers of budesonide, was obtained in a reasonable time. Validation of the method was performed for both drug substances and drug product.

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Development of a CZE method for the determination of mizolastine and its impurities in pharmaceutical preparations using response surface methodology

Cited by 17 publications

References 32 publications

Validation of capillary zone electrophoresis and capillary isoelectric focusing separations optimized for the characterization of two recombinant products of the birch pollen allergen Bet v 1a

Validation of capillary zone electrophoresis and capillary isoelectric focusing separations optimized for the characterization of two recombinant products of the birch pollen allergen Bet v 1a

Analytical quality by design in the development of a cyclodextrin‐modified capillary electrophoresis method for the assay of metformin and its related substances

Pitfalls and success of experimental design in the development of a mixed MEKC method for the analysis of budesonide and its impurities

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