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...

Keyword Year

Robust UHPLC Separation Method Development for Multi-API Product Amlodipine and Bisoprolol: The Impact of Column Selection

Róbert Kormány, Imre Molnár, Jenő Fekete, Davy Guillarme, Szabolcs Fekete
Chromatographia, 77, 17-18, 1119-1127 (2014)

Keywords: UHPLC, Method development, Quality by design (QbD), DryLab, Amlodipine, Bisoprolol

PDF
http://dx.doi.org/10.1007/s10337-014-2633-9

A new and fast ultra-high pressure liquid chromatographic separation of amlodipine and bisoprolol and all their closely related compounds is described for impurity profiling purposes. Computer-assisted method development with DryLab was applied and the impact of several state-of- the-art stationary phase column chemistries (50 × 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 QbD-principles using design of experiment with three experimental factors: gradient time (tG), temperature (T), and mobile phase pH. DryLab proves 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 separation between all peak-pairs.


Rapid UHPLC Method Development for Omeprazole Analysis in a Quality-by-Design Framework and Transfer to HPLC Using Chromatographic Modeling

Schmidt, Alexander H., Stanic, Mijo
LCGC North America, 32, 2, 126-148 (2014)

Keywords: UHPLC, DryLab, QbD, Design Space, Method Development, Method Modeling, Method Transfer, Omeprazole, Impurities

PDF

The aim of this study was to apply quality-by-design principles to build in a more scientific and risk-based multifactorial strategy in the development of an ultrahigh-pressure liquid chromatography (UHPLC) method for omeprazole and its related impurities.

The work presents a quality-by-design–based method development strategy for a method that tests the purity of omeprazole. The scientific and risk-based multifactorial method development strategy uses visual chro- matographic modeling as a fast and easy-to-use development tool. To speed up the method development process, all experiments are performed on a UHPLC system. The final method is successfully transferred to HPLC conditions. Predicted and experimental retention times are verified to confirm accuracy of the model.


UHPLC Method Development and Modelling in the Framework of Quality by Design

I. Molnár, H.-J. Rieger, A. Schmidt, J. Fekete, R. Kormány
The Column, 10, 6, 16-21 (2014)

PDF
http://images2.advanstar.com/PixelMags/lctc/dig...

The goals in ultrahigh-pressure liquid chromatography (UHPLC) method development are to first find the best separation, second find the best column, and third find the most robust method in a multifactorial Design Space. Trial and error methods are not sufficient anymore and solid science based on Quality by Design (QbD) principles is required.


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)

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

PDF
http://dx.doi.org/10.1016/j.jpba.2013.10.029

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)

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

PDF
http://dx.doi.org/10.1016/j.jpba.2014.01.037

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

PDF
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.

BACK 1 ...
  1. 3
  2. 4
  3. 5
  4. 6
  5. 7
... 33 NEXT