publications

HI Mokhtar, RA Abdel-Salam, GM Hadad (2015)
Journal of chromatographic science 53 (4), 467-477
Abstract
In this study, three-dimensional desirability spaces were introduced as a graphical representation method of design space. This was illustrated in the context of application of quality-by-design concepts on development of a stability indicating gradient reversed-phase high-performance liquid chromatography method for the determination of vinpocetine and α-tocopheryl acetate in a capsule dosage form. A mechanistic retention model to optimize gradient time, initial organic solvent concentration and ternary solvent ratio was constructed for each compound from six experimental runs. Then, desirability function of each optimized criterion and subsequently the global desirability function were calculated throughout the knowledge space. The three-dimensional desirability spaces were plotted as zones exceeding a threshold value of desirability index in space defined by the three optimized method parameters. Probabilistic mapping of desirability index aided selection of design space within the potential desirability subspaces. Three-dimensional desirability spaces offered better visualization and potential design spaces for the method as a function of three method parameters with ability to assign priorities to this critical quality as compared with the corresponding resolution spaces.

Last edit: 2018-10-09
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HI Mokhtar, RA Abdel-Salam, GM Haddad (2015)
Journal of Chromatography A 1399, 32-44
Abstract
Robustness of RP-HPLC methods is a crucial method quality attribute which has gained an increasing interest throughout the efforts to apply quality by design concepts in analytical methodology. Improvement to design space modeling approaches to represent method robustness was the goal of many previous works. Modeling of design spaces regarding to method robustness fulfils quality by design essence of ensuring method validity throughout the design space. The current work aimed to describe an improvement to robustness modeling of design spaces in context of RP-HPLC method development for screening of eight antidiabetic drugs. The described improvement consisted of in-silico simulation of practical robustness testing procedures thus had the advantage of modeling design spaces with higher confidence in estimated of method robustness. The proposed in-silico robustness test was performed as a full factorial design of simulated method conditions deliberate shifts for each predicted point in knowledge space with modeling error propagation. Design space was then calculated as zones exceeding a threshold probability to pass the simulated robustness testing. Potential design spaces were mapped for three different stationary phases as a function of gradient elution parameters, pH and ternary solvent ratio. A robust and fast separation for the eight compounds within less than 6 min was selected and confirmed through experimental robustness testing. The effectiveness of this approach regarding definition of design spaces with ensured robustness and desired objectives was demonstrated.

Last edit: 2018-10-09
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HI Mokhtar, RA Abdel-Salam, GM Hadad (2015)
Chromatographia, 78 (7-8), 457-466
Abstract
Robustness of chromatographic methods is a key element in method validation that should be ensured within the method development stage. Several approaches in the literature were proposed to incorporate robustness in design space mapping for quality by design compliant HPLC method development. However, these approaches were far from the robustness definition within ICH Q2(R1). The current work proposed and evaluated an alternative approach for design space representation as the probability to pass an improved in silico robustness test that complies with ICH Q2(R1) robustness definition. This proposed procedure test was performed as a full factorial design of simulated deliberate shifts in each method variable for each predicted point in knowledge space with propagation of peak location error into predicted retention times. This approach was applied on the optimization of the separation of a test mixture of six compounds as a function of three experimental variables: gradient time, pH and ternary solvent ratio and two calculated parameters; initial organic solvent composition and instrument dwell volume. Design space was calculated as zones exceeding a threshold probability to pass the simulated robustness testing. The proposed approach of robustness simulation had advantages upon comparison with other approaches of design space calculation with respect to ensuring robustness of calculated zones. The proposed approach had the value of providing design spaces that represent more confidence of predicted method robustness as compared with other approaches described in this field.


Last edit: 2018-10-04
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