Literature

DryLab draws on the philosophy described in the three most famous Solvophobic Theory papers IIIIII of Csaba Horváth, which were developed in the years 1975-1977 at Yale University (see also literature by Dr. Imre Molnár). Read more about the Fundamentals of DryLab...

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Reliability of simulated robustness testing in fast liquid chromatography, using state-of-the-art column technology, instrumentation and modelling software

Kormány, Róbert; Fekete, Jenő; Guillarme, Davy; Fekete, Szabolcs
Journal of Pharmaceutical and Biomedical Analysis, 89, 67-75 (2014), http://dx.doi.org/10.1016/j.jpba.2013.10.029

Keywords: Robustness, UHPLC, DryLab, Method development, Modeling software, Column interchangeability

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The goal of this study was to evaluate the accuracy of simulated robustness testing using commercial mod- elling software (DryLab) and state-of-the-art stationary phases. For this purpose, a mixture of amlodipine and its seven related impurities was analyzed on short narrow bore columns (50 × 2.1 mm, packed with sub-2  m particles) providing short analysis times. The performance of commercial modelling software for robustness testing was systematically compared to experimental measurements and DoE based pre- dictions. We have demonstrated that the reliability of predictions was good, since the predicted retention times and resolutions were in good agreement with the experimental ones at the edges of the design space. In average, the retention time relative errors were <1.0%, while the predicted critical resolution errors were comprised between 6.9 and 17.2%. Because the simulated robustness testing requires signif- icantly less experimental work than the DoE based predictions, we think that robustness could now be investigated in the early stage of method development.

Moreover, the column interchangeability, which is also an important part of robustness testing, was investigated considering five different C8 and C18 columns packed with sub-2  m particles. Again, thanks to modelling software, we proved that the separation was feasible on all columns within the same analysis time (less than 4 min), by proper adjustments of variables.


Reliability of computer-assisted method transfer between several column dimensions packed with 1.3–5 µm core–shell particles and between various instruments

Kormány, Róbert; Fekete, Jenő; Guillarme, Davy; Fekete, Szabolcs
Journal of Pharmaceutical and Biomedical Analysis, 94, 188–195 (2014), http://dx.doi.org/10.1016/j.jpba.2014.01.037

Keywords: Method transfer, Method development, DryLab, Modeling software, Core–shell particles

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In this contribution, the possibility to automatically transfer RPLC methods between different column dimensions and instruments was evaluated using commercial modelling software. The method transfer reliability was tested with loratadine and its 7 related pharmacopeial impurities. In this study, state- of-the-art columns packed with superficially porous particles of 5, 2.6, 1.7 and 1.3 µm particles were exclusively employed. A fast baseline separation of loratadine and related impurities (Rs,min = 2.49) was achieved under the best analytical conditions (i.e. column of 50 mm × 2.1 mm, 1.3 µm, 10–90% ACN in 5 min, T = 40 ◦ C, pH = 3, F = 0.5 ml/min). This optimal method was successfully tested on columns packed with other particle sizes, namely 1.7 and 2.6 µm, to reduce pressure drop. The selectivities and retentions remained identical, while the peak widths were logically wider, leading to a reduction of peak capacity from 203 to 181 and 159 on the 1.3, 1.7 and 2.6 µm particles, respectively. On the minimum, the reso- lution was equal to 1.54 on the 50 mm × 2.1 mm, 2.6 µm stationary phase. Next to this, the method was transferred to columns of different lengths, inner diameters and particle sizes (100 mm × 3 mm, 2.6 m or 150 mm × 4.6 mm, 5 µm). These columns were used on other LC instruments possessing larger dwell volumes. The modelling software employed for developing the original method was able to calculate the new gradient conditions to be used. The accuracy of prediction was excellent, as the average retention time errors between predicted and observed chromatograms were −0.11% and 0.45% when transferring the method to 100 mm × 3 mm and 150 mm × 4.6 mm columns, respectively. This work proves the use- fulness and validity of HPLC modelling software for transferring methods between different instruments, column dimensions and/or flow rates. 

 


Quality by Design in Pharmaceutical Analysis Using Computer Simulation with UHPLC

Kormány, Róbert; Molnár, Imre; Fekete, Jenő
LCGC North America, 32, 5, 354–363 (2014)

In this study, the quality-by-design principle is applied instead of trial-and-error in the development of a liquid chromatography method. With few measurements, the appropriate stationary phase and chromatographic conditions such as the composition of mobile phase, gradient time, temperature, and pH can be determined. A mixture of an active pharmaceutical ingredient and its 13 impurities was analyzed on a short narrow-bore column (50 mm × 2.1 mm, packed with sub-2-µm particles) providing short analysis times. The performance of commercial modeling software for robustness testing was systematically compared to experimental measurements and design-of-experiment–based predictions.


In silico robustness testing of a compendial HPLC purity method by using of a multidimensional design space build by chromatography modeling — Case study pramipexole

Alexander H. Schmidt, Mijo Stanic, Imre Molnár
J. Pharm. Biomed. Anal., 91, 97-107 (2014)

Keywords: HPLC method development, Quality by Design, Design Space, Robustness in routine quality control, Pramipexole

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http://dx.doi.org/10.1016/j.jpba.2013.12.023

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 num- ber 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 1 min 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 con- struction of ionic strength vs. ion pairing concentration models to identify the optimum combination of the concentrations for the buffer and the ion-pairing reagent.


Analysis of Sulfonamide Residues in Real Honey Samples using Liquid Chromatography with Fluorescence and Tandem Mass Spectrometry Detection

A. Tölgyesi et. al
J. Liq. Chrom. Rel. Technol., 36, 8, 1105-1125 (2013), DOI: 10.1080/10826076.2012.685911

Keywords: DryLab software, high performance liquid chromatography, food science, honey, kinetex XB HPLC column, optimization, sulfonamides

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This paper presents new reversed phase liquid chro-matographic methods (HPLC-FLD and LC-MS/MS) for the quantification of sulfonamides in spiked and incurred honey samples. The sample preparation was optimized using Oasis HLB (hydrophilic–lipophilic balance) solid-phase extraction (SPE) cartridge. Elution of sulfonamides was carried out under acidic, neutral, and basic conditions using methanol. The sample clean-up was also tested using Strata-XL cartridges. The HPLC-FLD separation was performed using a Varian C18 column and a ternary (methanol-acetonitrile-phosphate buffer, pH 5) mobile phase resulting good selectivity for the determination. The robustness of the ternary gradient method was evaluated by computer simulation with DryLab4. LC-MS/MS separation was carried out on a Kinetex XB core-shell type HPLC column that enabled a low limit of detection (0.01–0.5 µg/kg) and faster separation (6 min). The developed methods were validated in accordance with the European Union Commission Decision 2002/657/EC and were applied successfully for more than four hundred honey samples under a national monitoring program.


Application of Quality by Design Principles to a Pharmaceutical Sample Using UHPLC Method Development With Modeling Technologies

Róbert Kormány, Hans-Jürgen Rieger, Imre Molnár
LCGC, 31, 20-27 (2013)

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A new type of method development that uses modeling by DryLab4 to find the "best" separation for high performance liquid chromatography (HPLC) was investigated. Principles of Quality by Design (QbD) were followed when planning the investigation. A simple Design of Experiments (DoE) with only three measured factors — gradient time, pH, and temperature — was used with different columns. The basic experiments were saved in an electronic file with the peak tracking results. After calculating a Design Space, the best prediction was compared with a confirmation run. The process delivered precise results and the method was able be transferred to a routine quality control (QC) laboratory.


Optimizing Selectivity During Reversed-Phase HPLC Method Development: Prioritizing Experimental Conditions

L.R. Snyder, J.W. Dolan
 J. Chromatography , 1302, 45–54 (2013)

Several different conditions can be varied to improve selectivity for reversed-phase chromatography (RPC). A reexamination of literature data suggests that changes in selectivity due to a change of column or mobile phase pH are largely replicated by changes in temperature or mobile phase composition (concentrations of acetonitrile and/or methanol). This suggests a reconsideration of the role of mobile phase pH and the column during method development.

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