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Kormany R.,Egis Pharmaceuticals Plc. | Molnar I.,Molnar Institute for Applied Chromatography | Fekete J.,Budapest University of Technology and Economics | Guillarme D.,University of Geneva | Fekete S.,University of Geneva
Chromatographia | Year: 2014

This paper describes a new and fast ultra-high pressure liquid chromatographic separation of amlodipine and bisoprolol and all their closely related compounds, for impurity profiling purposes. Computer-assisted method development was applied and the impact of several state-of-the-art stationary phase column chemistries (50 x 2.1 mm, sub-2 μm, and core-shell type materials) on the achievable selectivity and resolution was investigated. The work was performed according to quality by design principles using design of experiment with three experimental factors; namely the gradient time (t G), temperature (T), and mobile phase pH. Thanks to modeling software, it was proved that the separation of all compounds was feasible on numerous column chemistries within <10 min, by proper adjustments of variables. It was also demonstrated that the reliability of predictions was good, as the predicted retention times and resolutions were in good agreement with the experimental ones. The final, optimized method separates 16 peaks related to amlodipine and bisoprolol within 7 min, ensuring baseline resolution between all peak-pairs. © 2014 Springer-Verlag.


Racz N.,Budapest University of Technology and Economics | Kormany R.,Egis Pharmaceuticals PLC | Fekete J.,Budapest University of Technology and Economics | Molnar I.,Molnar Institute for Applied Chromatography
Journal of Pharmaceutical and Biomedical Analysis | Year: 2015

Column technology needs further improvement even today. To get information of batch-to-batch repeatability, intelligent modeling software was applied. Twelve columns from the same production process, but from different batches were compared in this work. In this paper, the retention parameters of these columns with real life sample solutes were studied. The following parameters were selected for measurements: gradient time, temperature and pH. Based on calculated results, batch-to-batch repeatability of BEH columns was evaluated. Two parallel measurements on two columns from the same batch were performed to obtain information about the quality of packing. Calculating the average of individual working points at the highest critical resolution (Rs,crit) it was found that the robustness, calculated with a newly released robustness module, had a success rate >98% among the predicted 36=729 experiments for all 12 columns. With the help of retention modeling all substances could be separated independently from the batch and/or packing, using the same conditions, having high robustness of the experiments. © 2015 Elsevier B.V.


PubMed | Egis Pharmaceuticals PLC, Budapest University of Technology and Economics and Molnar Institute for Applied Chromatography
Type: | Journal: Journal of pharmaceutical and biomedical analysis | Year: 2015

Column technology needs further improvement even today. To get information of batch-to-batch repeatability, intelligent modeling software was applied. Twelve columns from the same production process, but from different batches were compared in this work. In this paper, the retention parameters of these columns with real life sample solutes were studied. The following parameters were selected for measurements: gradient time, temperature and pH. Based on calculated results, batch-to-batch repeatability of BEH columns was evaluated. Two parallel measurements on two columns from the same batch were performed to obtain information about the quality of packing. Calculating the average of individual working points at the highest critical resolution (R(s,crit)) it was found that the robustness, calculated with a newly released robustness module, had a success rate >98% among the predicted 3(6) = 729 experiments for all 12 columns. With the help of retention modeling all substances could be separated independently from the batch and/or packing, using the same conditions, having high robustness of the experiments.


Monks K.E.,Molnar Institute for Applied Chromatography | Rieger H.-J.,Molnar Institute for Applied Chromatography | Molnar I.,Molnar Institute for Applied Chromatography
Journal of Pharmaceutical and Biomedical Analysis | Year: 2011

The current article presents a novel approach to applying Quality by Design (QbD) principles to the development of high pressure reversed phase liquid chromatography (HPLC) methods. Four common critical parameters in HPLC - gradient time, temperature, pH of the aqueous eluent, and stationary phase - are evaluated within the Quality by Design framework by the means of computer modeling software and a column database, to a satisfactory degree. This work proposes the establishment of two mutually complimentary Design Spaces to fully depict a chromatographic method; one Column Design Space (CDS) and one Eluent Design Space (EDS) to describe the influence of the stationary phase and of the mobile phase on the separation selectivity, respectively. The merge of both Design Spaces into one is founded on the continuous nature of the mobile phase influence on retention and the great variety of the stationary phases available. © 2011 Elsevier B.V.


Molnar I.,Molnar Institute for Applied Chromatography | Monks K.E.,Molnar Institute for Applied Chromatography
Chromatographia | Year: 2011

The present paper starts by taking a look back at some of the pioneering work in high pressure liquid chromatography (HPLC) that went on in Csaba Horváth's laboratory in 1970s, through the eyes of I. Molnár. It then goes on to describe a very modern approach to HPLC method development within the Quality by Design framework: the multifactorial optimization of three critical HPLC method parameters, i.e. gradient time (t G), temperature (T), and ternary composition (B1:B2) based on 12 experiments. The effect of these experimental variables on critical resolution and selectivity was carried out in such a way as to systematically vary all three factors simultaneously. © 2011 Springer-Verlag.


Chamseddin C.,University of Greifswald | Molnar I.,Molnar Institute for Applied Chromatography | Jira T.,University of Greifswald
Journal of Chromatography A | Year: 2013

The recently dramatic increase in the available choices of reversed-phase columns could be an advantage of this mode of separation. However, due to the insufficiency of available information in terms of the exact functionality of these phases and the similarities and differences between these newly introduced and conventional reversed-phase columns, it is now somehow problematic to determine which could be the best column for a given analytical problem. There is no single column that will give us a good separation for all applications. As a result, there have been several attempts to develop testing strategies to characterize column chemistries. In this study three of the most widely used and acceptable approaches for the characterization of reversed-phase columns, which are Tanaka, United States Pharmacopeia (USP), and Snyder-Dolan, are systemically applied to investigate the chromatographic properties of calixarene- and resorcinarene-bonded stationary phases, polar-embedded and polar-endcapped stationary phases, phenyl and ether-linked phenyl with the presence of conventional alkyl-bonded phases (octyl- and octadecylsilane). Although all column classification systems aim to evaluate "more or less" the same characteristics, each system uses different test mixtures in different chromatographic conditions. It is therefore very important to evaluate the similarities and differences in the resulted "column parameters" and the possible interchangeability of them. The results of this comparative study show that the used parameters of Tanaka and of Snyder-Dolan have in many cases a good to very good correlation. The USP approach, which is based on single run, is related to Tanaka and Snyder-Dolan only in terms of hydrophobic characters, and no relation could establish in the other parameters. The hydrophobic-subtraction model could be extended to describe the ligand-solute interactions of calixarene- and resorcinarene-bonded stationary phases, which are belonging to reversed phase material. However they show, depending on the analytes, some additional interactions, since their steric, polar and ionic properties are different compared to those of conventional alkyl-bonded phases. © 2013 Elsevier B.V.


PubMed | Egis Pharmaceuticals Plc. and Molnar Institute for Applied Chromatography
Type: | Journal: Journal of pharmaceutical and biomedical analysis | Year: 2016

An older method for terazosin was reworked in order to reduce the analysis time from 90min (245min) to below 5min. The method in European Pharmacopoeia (Ph.Eur.) investigates the specified impurities separately. The reason of the different methods is that the retention of two impurities is not adequate in reversed phase, not even with 100% water. Therefore ion-pair-chromatography has to be applied and since that two impurities absorb at low UV-wavelength they had to be analyzed by different method than the other specified impurities. In our new method we could improve the retention with pH elevation using a new type of stationary phases available for high pH applications. Also a detection wavelength could be selected that is appropriate for the detection and quantification of all impurities. The method development is the bottleneck of liquid chromatography even today, when more and more fast chromatographic systems are used. Expert knowledge with intelligent programs is available to reduce the time of method development and offer extra information about the robustness of the separation. Design of Experiments (DoE) for simultaneous optimization of gradient time (t


Monks K.,Molnar Institute for applied chromatography | Molnar I.,Molnar Institute for applied chromatography | Rieger H.-J.,Molnar Institute for applied chromatography | Bogati B.,TEVA Pharmaceutical Works Private Ltd Company | Szabo E.,TEVA Pharmaceutical Works Private Ltd Company
Journal of Chromatography A | Year: 2012

Robust HPLC separations lead to fewer analysis failures and better method transfer as well as providing an assurance of quality. This work presents the systematic development of an optimal, robust, fast UHPLC method for the simultaneous assay of two APIs of an eye drop sample and their impurities, in accordance with Quality by Design principles. Chromatography software is employed to effectively generate design spaces (Method Operable Design Regions), which are subsequently employed to determine the final method conditions and to evaluate robustness prior to validation. © 2011 Elsevier B.V.


PubMed | Molnar Institute for Applied Chromatography
Type: Journal Article | Journal: Journal of pharmaceutical and biomedical analysis | Year: 2011

The current article presents a novel approach to applying Quality by Design (QbD) principles to the development of high pressure reversed phase liquid chromatography (HPLC) methods. Four common critical parameters in HPLC--gradient time, temperature, pH of the aqueous eluent, and stationary phase--are evaluated within the Quality by Design framework by the means of computer modeling software and a column database, to a satisfactory degree. This work proposes the establishment of two mutually complimentary Design Spaces to fully depict a chromatographic method; one Column Design Space (CDS) and one Eluent Design Space (EDS) to describe the influence of the stationary phase and of the mobile phase on the separation selectivity, respectively. The merge of both Design Spaces into one is founded on the continuous nature of the mobile phase influence on retention and the great variety of the stationary phases available.


PubMed | Molnar Institute for applied chromatography
Type: | Journal: Journal of chromatography. A | Year: 2012

Robust HPLC separations lead to fewer analysis failures and better method transfer as well as providing an assurance of quality. This work presents the systematic development of an optimal, robust, fast UHPLC method for the simultaneous assay of two APIs of an eye drop sample and their impurities, in accordance with Quality by Design principles. Chromatography software is employed to effectively generate design spaces (Method Operable Design Regions), which are subsequently employed to determine the final method conditions and to evaluate robustness prior to validation.

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