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Berlin, Germany

Schmidt A.H.,Steiner and Co. | Molnar I.,Molnar Institute
Journal of Pharmaceutical and Biomedical Analysis | Year: 2013

A stability-indicating ultra high performance liquid chromatographic (UHPLC) method has been developed for purity testing of ebastine and its pharmaceutical formulations.Successful chromatographic separation of the API from impurities was achieved on a Waters Acquity UPLC BEH C18, 50mm×2.1mm, 1.7μm particle size column with gradient elution of 10mM acetate buffer pH 6.2 and a mixture of acetonitrile/2-propanol (1:1) as the mobile phase. Incorporating Quality by Design (QbD) principles to the method development approach by using the chromatography modeling software DryLab®4 allows the visualization of a " Design Space" , a region in which changes to method parameters will not significantly affect the results as defined in the ICH guideline Q8 (R2). A verification study demonstrated that the established model for Design Space is accurate with a relative error of prediction of only 0.6%.The method was fully validated for specificity, linearity, accuracy and precision, and robustness in compliance to the ICH guideline Q2 (R1). The method was found to be linear in the concentration range from the quantification limit (LOQ) to 125% of the specification limit for ebastine and each of the impurities with correlation coefficients of not less than 0.999. The recovery rate was between 98.15 and 100.30% for each impurity. The repeatability and intermediate precision (RSD) were less than 3.2% for ebastine and each of the impurities.The robustness of the developed method was studied by varying the six parameters: gradient time, temperature, ternary composition of the eluent, flow rate and start and end concentration of the gradient at 3 levels (+1, 0, -1). The resulting 729 experiments were performed in silico from the previously constructed model for Design Space and showed that the required resolution of 2.0 can be reached in all experiments. To prove the stability-indicating performance of the method, forced degradation (acid and base hydrolysis, oxidation, photolytic and thermal stress conditions) of ebastine was carried out. Baseline separation could be achieved for all peaks of the impurities, the degradation products and the API. Total run time was only 4. min, which is an impressive 40-fold increase in productivity in comparison to the method published in the Ph. Eur. monograph and allowed purity testing of more than 360 samples per day. © 2013 Elsevier B.V. Source


Schmidt A.H.,Steiner and Co. | Schmidt A.H.,Free University of Berlin | Stanic M.,Steiner and Co. | Molnar I.,Molnar Institute
Journal of Pharmaceutical and Biomedical Analysis | Year: 2014

Purity testing of the active pharmaceutical ingredient (API) pramipexole is performed using an official (compendial) and harmonized method published in the European Pharmacopeia (E.P.) and United States Pharmacopeia (USP). According to this monograph the successful chromatographic separation of the API from impurities is achieved on a C18 column with gradient elution of an ion pairing buffer of pH 3.0 (mobile phase A) and acetonitrile (mobile phase B).Although not recommended in general, compendial methods are often adapted for purity testing of generic formulations. In this paper a novel approach to evaluate method robustness of an adapted method - prior of full method validation - is described. Based on Quality-by-Design (QbD) principles, a small number of experiments are performed, which after entering them into a chromatography modeling software allow to visualize a multidimensional "Design Space", a region, in which changes in method parameters will not significantly affect the results as defined in the ICH guideline Q8(R2) leading to a more flexible method handling in routine analysis.For two different recommended C18 columns a multidimensional Design Space (Method Operating Design Region, MODR) was constructed to study the robustness of the adapted method with a newly developed Robustness Module. In a full factorial design the following six parameters were varied at three levels (low, nominal, high): gradient time, temperature, pH of the aqueous eluent (A), flow rate, start- and end concentration of the organic mobile phase component (eluent B). The resulting 36=729 experiments were performed in silico from the previously constructed models for Design Space in less than 1min and showed that the required resolution of 2.0 could not be reached in all experiments for the two columns which were recommended by the E.P. (failure rate 25% and 16%, respectively). However, by adjusting the gradient time, we were able to fulfill the requirements with a failure rate of zero.For the aqueous eluent a separate "Eluent Design Space" study was performed, which allows the construction of ionic strength vs. ion pairing concentration models to identify the optimum combination of the concentrations for the buffer and the ion-pairing reagent. © 2013 Elsevier B.V. Source


Kormany R.,Egis Plc. | Molnar I.,Molnar Institute | Rieger H.-J.,Molnar Institute
Journal of Pharmaceutical and Biomedical Analysis | Year: 2013

An older method for amlodipine was reworked with the goal to reduce the analysis time of 60. min below 6. min. To select the best column for short and robust analysis, 9 different UHPLC column chemistries were investigated using 3-dimensional resolution spaces based on 12 experiments using modelling software. The main variables used were gradient time (tG), temperature (T) and the pH of eluent A. The best critical resolution was calculated and located in a 3-dimensional space in an automated fashion and the corresponding best experiments were carried out. The work (9 × 12 = 108 runs) was finished with an UHPLC instrument in less than 24. h. The comparison between predictions and real experiments showed an excellent correlation with differences typically less than 0.04. min (<3. s) in average, although the set points were located at quite different conditions on gradient times, pH's and temperatures for the individual columns. All columns could perform the required baseline separation at their individual best working points with satisfactory results. © 2013 Elsevier B.V. Source

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