TY  - CONF
AU  - Malenović, Anđelija
AU  - Rmandić, Milena
AU  - Dotsikas, Yannis
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5554
AB  - When using DBS as sample collection tool, several specific factors can contribute to assay bias and compromise regulatory-based acceptance criteria. Certain factors like hematocrit (Hct) level, pipettes, sample volume and laboratory personnel have a potential to contribute bioanalytical method bias inherently. The proper understanding of Hct effect and the efficient resolving of the related concerns may determine the future of DBS sampling practice in regulated bioanalysis. Therefore, we aimed at reaching a procedure that enables accurate and precise blood spotting onto the filter paper by simultaneous investigation of factors that were suggested to be scientifically relevant in this context. The effects of five qualitative factors - temperature of blood samples, type of pipettes, pipetting technique, age of blood samples and analyst - were investigated using a multilevel categorical D-optimal design. Five responses were observed in the study (RSD22%Hct, RSD30%Hct, RSD39%Hct, RSD51%Hct, RSD62%Hct) as they can provide information on the influence of factor settings on the consistency of DBS areas. DBS cards with four spot replicates, corresponding to particular combination of investigated factors defined by experimental plan, were scanned and the area of blood spots was determined by image processing. The principle of backward elimination was applied in computation of the adequate qualitative linear mathematical models with added appropriate two-factor interactions to relate selected responses with studied factors. It was concluded that %RSD value of DBS, regardless Hct levels, is completely independent of type of pipettes and age of blood samples, but can significantly be affected by blood sample temperature, pipetting technique and level of training of analyst. Consequently, the procedure for precise and accurate formation of DBS of uniform area, regardless the Hct value, implies samples at body/room temperature, reversed pipetting technique for rigorous delivery of a sample volume onto the card and a properly trained analyst for handling blood samples. The adequacy of the suggested procedure was confirmed by a verification experiment. Identification of the factors affecting the consistency of DBS formation provided the evidence that this contribution to total assay bias can be successfully controlled and reduced.
C3  - IV Poznańska Konferencja Naukowo – Szkoleniowej - „Modern pharmaceutical and biomedical analytics in health care”
T1  - Critical issues in quantitative bioanalysis of Dried Blood Spot samples
SP  - 48
EP  - 48
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5554
ER  - 

@conference{
author = "Malenović, Anđelija and Rmandić, Milena and Dotsikas, Yannis",
year = "2023",
abstract = "When using DBS as sample collection tool, several specific factors can contribute to assay bias and compromise regulatory-based acceptance criteria. Certain factors like hematocrit (Hct) level, pipettes, sample volume and laboratory personnel have a potential to contribute bioanalytical method bias inherently. The proper understanding of Hct effect and the efficient resolving of the related concerns may determine the future of DBS sampling practice in regulated bioanalysis. Therefore, we aimed at reaching a procedure that enables accurate and precise blood spotting onto the filter paper by simultaneous investigation of factors that were suggested to be scientifically relevant in this context. The effects of five qualitative factors - temperature of blood samples, type of pipettes, pipetting technique, age of blood samples and analyst - were investigated using a multilevel categorical D-optimal design. Five responses were observed in the study (RSD22%Hct, RSD30%Hct, RSD39%Hct, RSD51%Hct, RSD62%Hct) as they can provide information on the influence of factor settings on the consistency of DBS areas. DBS cards with four spot replicates, corresponding to particular combination of investigated factors defined by experimental plan, were scanned and the area of blood spots was determined by image processing. The principle of backward elimination was applied in computation of the adequate qualitative linear mathematical models with added appropriate two-factor interactions to relate selected responses with studied factors. It was concluded that %RSD value of DBS, regardless Hct levels, is completely independent of type of pipettes and age of blood samples, but can significantly be affected by blood sample temperature, pipetting technique and level of training of analyst. Consequently, the procedure for precise and accurate formation of DBS of uniform area, regardless the Hct value, implies samples at body/room temperature, reversed pipetting technique for rigorous delivery of a sample volume onto the card and a properly trained analyst for handling blood samples. The adequacy of the suggested procedure was confirmed by a verification experiment. Identification of the factors affecting the consistency of DBS formation provided the evidence that this contribution to total assay bias can be successfully controlled and reduced.",
journal = "IV Poznańska Konferencja Naukowo – Szkoleniowej - „Modern pharmaceutical and biomedical analytics in health care”",
title = "Critical issues in quantitative bioanalysis of Dried Blood Spot samples",
pages = "48-48",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5554"
}

Malenović, A., Rmandić, M.,& Dotsikas, Y.. (2023). Critical issues in quantitative bioanalysis of Dried Blood Spot samples. in IV Poznańska Konferencja Naukowo – Szkoleniowej - „Modern pharmaceutical and biomedical analytics in health care”, 48-48.
https://hdl.handle.net/21.15107/rcub_farfar_5554

Malenović A, Rmandić M, Dotsikas Y. Critical issues in quantitative bioanalysis of Dried Blood Spot samples. in IV Poznańska Konferencja Naukowo – Szkoleniowej - „Modern pharmaceutical and biomedical analytics in health care”. 2023;:48-48.
https://hdl.handle.net/21.15107/rcub_farfar_5554 .

Malenović, Anđelija, Rmandić, Milena, Dotsikas, Yannis, "Critical issues in quantitative bioanalysis of Dried Blood Spot samples" in IV Poznańska Konferencja Naukowo – Szkoleniowej - „Modern pharmaceutical and biomedical analytics in health care” (2023):48-48,
https://hdl.handle.net/21.15107/rcub_farfar_5554 .

TY  - JOUR
AU  - Gkountanas, Kostas
AU  - Dagla, Ioanna
AU  - Gikas, Evangelos
AU  - Malenović, Anđelija
AU  - Dotsikas, Yannis
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4998
AB  - Chromatograms with overlapping peaks and a baseline rise or upset constitute a great challenge for analysts. Such a case regarding the analysis of bupropion hydrochloride and its 5 impurities in a tablet formulation was used as a model. A baseline correction technique for liquid chromatography coupled with diode array detection is described by using Rstudio. The asymmetry least squares (ALS) algorithm was used as implemented in the “baseline” package, with parameters lambda and p set to 4 and 0.05, respectively. Peak deconvolution and subsequent integration and area quantification were accomplished through Fytik software. Chromatographic data from the validation procedure were utilized to demonstrate the feasibility of the suggested method and whether this correction affects the outcome of the validation study. Finally, a robustness study was carried out in order to shed light on the factors that have a more significant influence on the baseline correction, showing the reliability of this procedure through random changes in its parameters.
PB  - MDPI
T2  - Analytica
T1  - Baseline Correction for HPLC Chromatograms by Using Free
Open-Source Software
VL  - 4
IS  - 1
SP  - 45
EP  - 53
DO  - 10.3390/analytica4010005
ER  - 

@article{
author = "Gkountanas, Kostas and Dagla, Ioanna and Gikas, Evangelos and Malenović, Anđelija and Dotsikas, Yannis",
year = "2023",
abstract = "Chromatograms with overlapping peaks and a baseline rise or upset constitute a great challenge for analysts. Such a case regarding the analysis of bupropion hydrochloride and its 5 impurities in a tablet formulation was used as a model. A baseline correction technique for liquid chromatography coupled with diode array detection is described by using Rstudio. The asymmetry least squares (ALS) algorithm was used as implemented in the “baseline” package, with parameters lambda and p set to 4 and 0.05, respectively. Peak deconvolution and subsequent integration and area quantification were accomplished through Fytik software. Chromatographic data from the validation procedure were utilized to demonstrate the feasibility of the suggested method and whether this correction affects the outcome of the validation study. Finally, a robustness study was carried out in order to shed light on the factors that have a more significant influence on the baseline correction, showing the reliability of this procedure through random changes in its parameters.",
publisher = "MDPI",
journal = "Analytica",
title = "Baseline Correction for HPLC Chromatograms by Using Free
Open-Source Software",
volume = "4",
number = "1",
pages = "45-53",
doi = "10.3390/analytica4010005"
}

Gkountanas, K., Dagla, I., Gikas, E., Malenović, A.,& Dotsikas, Y.. (2023). Baseline Correction for HPLC Chromatograms by Using Free
Open-Source Software. in Analytica
MDPI., 4(1), 45-53.
https://doi.org/10.3390/analytica4010005

Gkountanas K, Dagla I, Gikas E, Malenović A, Dotsikas Y. Baseline Correction for HPLC Chromatograms by Using Free
Open-Source Software. in Analytica. 2023;4(1):45-53.
doi:10.3390/analytica4010005 .

Gkountanas, Kostas, Dagla, Ioanna, Gikas, Evangelos, Malenović, Anđelija, Dotsikas, Yannis, "Baseline Correction for HPLC Chromatograms by Using Free
Open-Source Software" in Analytica, 4, no. 1 (2023):45-53,
https://doi.org/10.3390/analytica4010005 . .

TY  - JOUR
AU  - Gkountanas, Kostas
AU  - Malenović, Anđelija
AU  - Dotsikas, Yannis
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4312
AB  - A novel chaotropic chromatography method for the quantitative determination of bupropion and its impurities, following analytical quality-by-design (AQbD) principles, is presented. The analytical target profile (ATP) was defined on the basis of the efficient separation and reliable determination of bupropion and its five impurities in tablets. Preliminary experiments revealed the need for the addition of a gradient elution part. A screening fractional factorial experimental design was employed to select the critical method parameters (CMPs) and a Box–Behnken design (BBD) was utilized to investigate their influence on predefined critical method attributes (CMAs). In order to compute the design space (DS), where CMPs meet predefined acceptance limits with a high level of probability (π ≥ 85%), Monte Carlo simulations were performed. The working point selected from the DS corresponded to the following conditions: 37.5% acetonitrile at the start of the gradient program (up to 70% at the end of the gradient program), 45 mM of potassium hexafluorophosphate in the water phase, and the start of the linear gradient step in the gradient program at 10 min. The method was validated according to ICH guidelines and applied to the analysis of Wellbutrin® tablets containing bupropion hydrochloride.
PB  - MDPI
T2  - Pharmaceuticals
T1  - Determination of Bupropion and Its Impurities via a Chaotropic Chromatography Method Following Analytical Quality-by-Design Principles for Method Development
VL  - 15
IS  - 10
DO  - 10.3390/ph15101196
ER  - 

@article{
author = "Gkountanas, Kostas and Malenović, Anđelija and Dotsikas, Yannis",
year = "2022",
abstract = "A novel chaotropic chromatography method for the quantitative determination of bupropion and its impurities, following analytical quality-by-design (AQbD) principles, is presented. The analytical target profile (ATP) was defined on the basis of the efficient separation and reliable determination of bupropion and its five impurities in tablets. Preliminary experiments revealed the need for the addition of a gradient elution part. A screening fractional factorial experimental design was employed to select the critical method parameters (CMPs) and a Box–Behnken design (BBD) was utilized to investigate their influence on predefined critical method attributes (CMAs). In order to compute the design space (DS), where CMPs meet predefined acceptance limits with a high level of probability (π ≥ 85%), Monte Carlo simulations were performed. The working point selected from the DS corresponded to the following conditions: 37.5% acetonitrile at the start of the gradient program (up to 70% at the end of the gradient program), 45 mM of potassium hexafluorophosphate in the water phase, and the start of the linear gradient step in the gradient program at 10 min. The method was validated according to ICH guidelines and applied to the analysis of Wellbutrin® tablets containing bupropion hydrochloride.",
publisher = "MDPI",
journal = "Pharmaceuticals",
title = "Determination of Bupropion and Its Impurities via a Chaotropic Chromatography Method Following Analytical Quality-by-Design Principles for Method Development",
volume = "15",
number = "10",
doi = "10.3390/ph15101196"
}

Gkountanas, K., Malenović, A.,& Dotsikas, Y.. (2022). Determination of Bupropion and Its Impurities via a Chaotropic Chromatography Method Following Analytical Quality-by-Design Principles for Method Development. in Pharmaceuticals
MDPI., 15(10).
https://doi.org/10.3390/ph15101196

Gkountanas K, Malenović A, Dotsikas Y. Determination of Bupropion and Its Impurities via a Chaotropic Chromatography Method Following Analytical Quality-by-Design Principles for Method Development. in Pharmaceuticals. 2022;15(10).
doi:10.3390/ph15101196 .

Gkountanas, Kostas, Malenović, Anđelija, Dotsikas, Yannis, "Determination of Bupropion and Its Impurities via a Chaotropic Chromatography Method Following Analytical Quality-by-Design Principles for Method Development" in Pharmaceuticals, 15, no. 10 (2022),
https://doi.org/10.3390/ph15101196 . .

TY  - CONF
AU  - Rmandić, Milena
AU  - Dotsikas, Yannis
AU  - Stajić, Ana
AU  - Malenović, Anđelija
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4703
PB  - MSBM
C3  - XIII Mass Spectrometry in Biotechnology and Medicine (MSBM). July 7-13, 2019, Dubrovnik, Croatia.
T1  - Development of UHPLC- MS/MS Bioanalytical Method for Determination of Zonisamide in the Samples Collected in the Form of Dried Plasma Spots
SP  - 46
EP  - 46
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4703
ER  - 

@conference{
author = "Rmandić, Milena and Dotsikas, Yannis and Stajić, Ana and Malenović, Anđelija",
year = "2019",
publisher = "MSBM",
journal = "XIII Mass Spectrometry in Biotechnology and Medicine (MSBM). July 7-13, 2019, Dubrovnik, Croatia.",
title = "Development of UHPLC- MS/MS Bioanalytical Method for Determination of Zonisamide in the Samples Collected in the Form of Dried Plasma Spots",
pages = "46-46",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4703"
}

Rmandić, M., Dotsikas, Y., Stajić, A.,& Malenović, A.. (2019). Development of UHPLC- MS/MS Bioanalytical Method for Determination of Zonisamide in the Samples Collected in the Form of Dried Plasma Spots. in XIII Mass Spectrometry in Biotechnology and Medicine (MSBM). July 7-13, 2019, Dubrovnik, Croatia.
MSBM., 46-46.
https://hdl.handle.net/21.15107/rcub_farfar_4703

Rmandić M, Dotsikas Y, Stajić A, Malenović A. Development of UHPLC- MS/MS Bioanalytical Method for Determination of Zonisamide in the Samples Collected in the Form of Dried Plasma Spots. in XIII Mass Spectrometry in Biotechnology and Medicine (MSBM). July 7-13, 2019, Dubrovnik, Croatia.. 2019;:46-46.
https://hdl.handle.net/21.15107/rcub_farfar_4703 .

Rmandić, Milena, Dotsikas, Yannis, Stajić, Ana, Malenović, Anđelija, "Development of UHPLC- MS/MS Bioanalytical Method for Determination of Zonisamide in the Samples Collected in the Form of Dried Plasma Spots" in XIII Mass Spectrometry in Biotechnology and Medicine (MSBM). July 7-13, 2019, Dubrovnik, Croatia. (2019):46-46,
https://hdl.handle.net/21.15107/rcub_farfar_4703 .

TY  - CONF
AU  - Rmandić, Milena
AU  - Dotsikas, Yannis
AU  - Malenović, Anđelija
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4707
PB  - University of Milano-Bicocca
C3  - 48th International Symposium on High-Performance Liquid Phase Separations and Related Techniques HPLC 2019, June 16-20, 2019, Milan, Italy.
T1  - Setting up procedure for precise and accurate formation of DBS of uniform area via experimental design and image processing methodology
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4707
ER  - 

@conference{
author = "Rmandić, Milena and Dotsikas, Yannis and Malenović, Anđelija",
year = "2019",
publisher = "University of Milano-Bicocca",
journal = "48th International Symposium on High-Performance Liquid Phase Separations and Related Techniques HPLC 2019, June 16-20, 2019, Milan, Italy.",
title = "Setting up procedure for precise and accurate formation of DBS of uniform area via experimental design and image processing methodology",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4707"
}

Rmandić, M., Dotsikas, Y.,& Malenović, A.. (2019). Setting up procedure for precise and accurate formation of DBS of uniform area via experimental design and image processing methodology. in 48th International Symposium on High-Performance Liquid Phase Separations and Related Techniques HPLC 2019, June 16-20, 2019, Milan, Italy.
University of Milano-Bicocca..
https://hdl.handle.net/21.15107/rcub_farfar_4707

Rmandić M, Dotsikas Y, Malenović A. Setting up procedure for precise and accurate formation of DBS of uniform area via experimental design and image processing methodology. in 48th International Symposium on High-Performance Liquid Phase Separations and Related Techniques HPLC 2019, June 16-20, 2019, Milan, Italy.. 2019;.
https://hdl.handle.net/21.15107/rcub_farfar_4707 .

Rmandić, Milena, Dotsikas, Yannis, Malenović, Anđelija, "Setting up procedure for precise and accurate formation of DBS of uniform area via experimental design and image processing methodology" in 48th International Symposium on High-Performance Liquid Phase Separations and Related Techniques HPLC 2019, June 16-20, 2019, Milan, Italy. (2019),
https://hdl.handle.net/21.15107/rcub_farfar_4707 .

TY  - JOUR
AU  - Rmandić, Milena
AU  - Dotsikas, Yannis
AU  - Malenović, Anđelija
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3325
AB  - In the present study we aimed at reaching a procedure for control of factors that have a potential to contribute to bioanalytical method bias and consistent dried blood spot (DBS) formation. The most influencing factors were identified via experimental design and image processing methodology. The effects of five qualitative factors temperature of blood samples, type of pipettes, pipetting technique, age of blood samples and analysts were investigated by multilevel categorical D-optimal design. Due to well-known influence of hematocrit (Hct) level on rheological characteristic of blood samples, five responses were observed through the study (RSD22%Hct, RSD30%Hct, RSD39%Hct, RSD51%Hct, RSD62%Hct) for their ability to provide insights into influence of factor settings onto DBS areas consistency. The area of blood spots was determined by image processing after scanning DBS cards with four spot replicates, corresponding to particular combination of investigated factors, as defined by experimental plan. The qualitative linear mathematical models with added appropriate two-factor interactions were derived by the principle of backward elimination. It was concluded that %RSD value of DBS, for all investigated Hct levels, is completely independent of type of pipettes and age of blood samples, but can significantly be affected by blood sample temperature, pipetting technique and training of analyst. Therefore, the procedure for precise and accurate formation of DBS of uniform area, regardless the Hct value, implies samples at body/room temperature, reversed pipetting technique for rigorous delivery of a sample volume onto the card and a properly trained analyst for handling samples. Finally, a verification experiment was performed and the adequacy of the suggested procedure was confirmed. Identification of the factors affecting the consistency of DBS formation provided the evidence that this contribution to total assay bias can be successfully controlled and reduced.
PB  - Elsevier Science BV, Amsterdam
T2  - Microchemical Journal
T1  - Identification of the factors affecting the consistency of DBS formation via experimental design and image processing methodology
VL  - 145
SP  - 1003
EP  - 1010
DO  - 10.1016/j.microc.2018.12.016
ER  - 

@article{
author = "Rmandić, Milena and Dotsikas, Yannis and Malenović, Anđelija",
year = "2019",
abstract = "In the present study we aimed at reaching a procedure for control of factors that have a potential to contribute to bioanalytical method bias and consistent dried blood spot (DBS) formation. The most influencing factors were identified via experimental design and image processing methodology. The effects of five qualitative factors temperature of blood samples, type of pipettes, pipetting technique, age of blood samples and analysts were investigated by multilevel categorical D-optimal design. Due to well-known influence of hematocrit (Hct) level on rheological characteristic of blood samples, five responses were observed through the study (RSD22%Hct, RSD30%Hct, RSD39%Hct, RSD51%Hct, RSD62%Hct) for their ability to provide insights into influence of factor settings onto DBS areas consistency. The area of blood spots was determined by image processing after scanning DBS cards with four spot replicates, corresponding to particular combination of investigated factors, as defined by experimental plan. The qualitative linear mathematical models with added appropriate two-factor interactions were derived by the principle of backward elimination. It was concluded that %RSD value of DBS, for all investigated Hct levels, is completely independent of type of pipettes and age of blood samples, but can significantly be affected by blood sample temperature, pipetting technique and training of analyst. Therefore, the procedure for precise and accurate formation of DBS of uniform area, regardless the Hct value, implies samples at body/room temperature, reversed pipetting technique for rigorous delivery of a sample volume onto the card and a properly trained analyst for handling samples. Finally, a verification experiment was performed and the adequacy of the suggested procedure was confirmed. Identification of the factors affecting the consistency of DBS formation provided the evidence that this contribution to total assay bias can be successfully controlled and reduced.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "Microchemical Journal",
title = "Identification of the factors affecting the consistency of DBS formation via experimental design and image processing methodology",
volume = "145",
pages = "1003-1010",
doi = "10.1016/j.microc.2018.12.016"
}

Rmandić, M., Dotsikas, Y.,& Malenović, A.. (2019). Identification of the factors affecting the consistency of DBS formation via experimental design and image processing methodology. in Microchemical Journal
Elsevier Science BV, Amsterdam., 145, 1003-1010.
https://doi.org/10.1016/j.microc.2018.12.016

Rmandić M, Dotsikas Y, Malenović A. Identification of the factors affecting the consistency of DBS formation via experimental design and image processing methodology. in Microchemical Journal. 2019;145:1003-1010.
doi:10.1016/j.microc.2018.12.016 .

Rmandić, Milena, Dotsikas, Yannis, Malenović, Anđelija, "Identification of the factors affecting the consistency of DBS formation via experimental design and image processing methodology" in Microchemical Journal, 145 (2019):1003-1010,
https://doi.org/10.1016/j.microc.2018.12.016 . .

TY  - JOUR
AU  - Daousani, C
AU  - Karalis, V
AU  - Malenović, Anđelija
AU  - Dotsikas, Yannis
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3278
AB  - Dried blood spots (DBS) are formed by deposition of a small amount of blood on specific adsorbent paper and its physical drying. DBS are employed as a sampling method in several fields of life sciences and drug research. A concern about DBS is the so-called ‘Hematocrit (Ht) effect’, as a different Ht leads, due to different viscosity, to different spot size, affecting assay bias. Solutions have been proposed, including the correction of quantified concentrations with a suitable correction factor. In order to quantitatively assess Ht impact on the DBS measurements, a computational approach was developed and implemented in R® language. First, the % relative error was modeled with respect to Ht. Then, Monte Carlo simulations were performed in virtual men/women populations with different Ht levels and the % relative error in relation to the Ht used for calibrators was quantified. An upper level for % relative error being a ‘tolerable contribution’ of Ht effect to % total analytical error was finally suggested, defining, for the first time, a potential Ht range for analysis of adults’ samples, where correction of concentrations of unknown samples may be omitted. Such tolerable level for % relative error may be defined in each laboratory, also based on experimental parameters (type of paper and blood volume). Using a Ht calibration value representing the study population is fully rationalized, leading to reduced probability for concentration corrections. Regulatory criteria for bioanalysis can thus be targeted, moving towards wider utilization of DBS in human pharmacokinetic and clinical trials.
PB  - Taylor and Francis Ltd
T2  - Scandinavian Journal of Clinical and Laboratory Investigation
T1  - Hematocrit effect on dried blood spots in adults: a computational study and theoretical considerations
DO  - 10.1080/00365513.2019.1622033
ER  - 

@article{
author = "Daousani, C and Karalis, V and Malenović, Anđelija and Dotsikas, Yannis",
year = "2019",
abstract = "Dried blood spots (DBS) are formed by deposition of a small amount of blood on specific adsorbent paper and its physical drying. DBS are employed as a sampling method in several fields of life sciences and drug research. A concern about DBS is the so-called ‘Hematocrit (Ht) effect’, as a different Ht leads, due to different viscosity, to different spot size, affecting assay bias. Solutions have been proposed, including the correction of quantified concentrations with a suitable correction factor. In order to quantitatively assess Ht impact on the DBS measurements, a computational approach was developed and implemented in R® language. First, the % relative error was modeled with respect to Ht. Then, Monte Carlo simulations were performed in virtual men/women populations with different Ht levels and the % relative error in relation to the Ht used for calibrators was quantified. An upper level for % relative error being a ‘tolerable contribution’ of Ht effect to % total analytical error was finally suggested, defining, for the first time, a potential Ht range for analysis of adults’ samples, where correction of concentrations of unknown samples may be omitted. Such tolerable level for % relative error may be defined in each laboratory, also based on experimental parameters (type of paper and blood volume). Using a Ht calibration value representing the study population is fully rationalized, leading to reduced probability for concentration corrections. Regulatory criteria for bioanalysis can thus be targeted, moving towards wider utilization of DBS in human pharmacokinetic and clinical trials.",
publisher = "Taylor and Francis Ltd",
journal = "Scandinavian Journal of Clinical and Laboratory Investigation",
title = "Hematocrit effect on dried blood spots in adults: a computational study and theoretical considerations",
doi = "10.1080/00365513.2019.1622033"
}

Daousani, C., Karalis, V., Malenović, A.,& Dotsikas, Y.. (2019). Hematocrit effect on dried blood spots in adults: a computational study and theoretical considerations. in Scandinavian Journal of Clinical and Laboratory Investigation
Taylor and Francis Ltd..
https://doi.org/10.1080/00365513.2019.1622033

Daousani C, Karalis V, Malenović A, Dotsikas Y. Hematocrit effect on dried blood spots in adults: a computational study and theoretical considerations. in Scandinavian Journal of Clinical and Laboratory Investigation. 2019;.
doi:10.1080/00365513.2019.1622033 .

Daousani, C, Karalis, V, Malenović, Anđelija, Dotsikas, Yannis, "Hematocrit effect on dried blood spots in adults: a computational study and theoretical considerations" in Scandinavian Journal of Clinical and Laboratory Investigation (2019),
https://doi.org/10.1080/00365513.2019.1622033 . .

TY  - JOUR
AU  - Iliou, Katerina
AU  - Malenović, Anđelija
AU  - Loukas, Yannis L.
AU  - Dotsikas, Yannis
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3190
AB  - A novel Liquid Chromatography-tandem mass spectrometry (LC-MS/MS) method is presented for the quantitative determination of two potential genotoxic impurities (PGIs) in rabeprazole active pharmaceutical ingredient (API). In order to overcome the analytical challenges in the trace analysis of PGIs, a development procedure supported by Quality-by-Design (Q1313) principles was evaluated. The efficient separation between rabeprazole and the two PGIs in the shortest analysis time was set as the defined analytical target profile (ATP) and to this purpose utilization of a switching valve allowed the flow to be sent to waste when rabeprazole was eluted. The selected critical quality attributes (CQAs) were the separation criterion s between the critical peak pair and the capacity factor k of the last eluted compound. The effect of the following critical process parameters (CPPs) on the CQAs was studied: %ACN content, the pH and the concentration of the buffer salt in the mobile phase, as well as the stationary phase of the analytical column. D-Optimal design was implemented to set the plan of experiments with UV detector. In order to define the design space, Monte Carlo simulations with 5000 iterations were performed. Acceptance criteria were met for Cs column (50 x 4 mm, 5 p.m), and the region having probability pi >= 95% to achieve satisfactory values of all defined CQAs was computed. The working point was selected with the mobile phase consisting of ACN, ammonium formate 11 mM at a ratio 31/69 v/v with pH-6,8 for the water phase. The LC protocol was transferred to LC-MS/MS and validated according to ICH guidelines.
PB  - Elsevier Science BV, Amsterdam
T2  - Journal of Pharmaceutical and Biomedical Analysis
T1  - Analysis of potential genotoxic impurities in rabeprazole active pharmaceutical ingredient via Liquid Chromatography-tandem Mass Spectrometry, following quality-by-design principles for method development
VL  - 149
SP  - 410
EP  - 418
DO  - 10.1016/j.jpba.2017.11.037
ER  - 

@article{
author = "Iliou, Katerina and Malenović, Anđelija and Loukas, Yannis L. and Dotsikas, Yannis",
year = "2018",
abstract = "A novel Liquid Chromatography-tandem mass spectrometry (LC-MS/MS) method is presented for the quantitative determination of two potential genotoxic impurities (PGIs) in rabeprazole active pharmaceutical ingredient (API). In order to overcome the analytical challenges in the trace analysis of PGIs, a development procedure supported by Quality-by-Design (Q1313) principles was evaluated. The efficient separation between rabeprazole and the two PGIs in the shortest analysis time was set as the defined analytical target profile (ATP) and to this purpose utilization of a switching valve allowed the flow to be sent to waste when rabeprazole was eluted. The selected critical quality attributes (CQAs) were the separation criterion s between the critical peak pair and the capacity factor k of the last eluted compound. The effect of the following critical process parameters (CPPs) on the CQAs was studied: %ACN content, the pH and the concentration of the buffer salt in the mobile phase, as well as the stationary phase of the analytical column. D-Optimal design was implemented to set the plan of experiments with UV detector. In order to define the design space, Monte Carlo simulations with 5000 iterations were performed. Acceptance criteria were met for Cs column (50 x 4 mm, 5 p.m), and the region having probability pi >= 95% to achieve satisfactory values of all defined CQAs was computed. The working point was selected with the mobile phase consisting of ACN, ammonium formate 11 mM at a ratio 31/69 v/v with pH-6,8 for the water phase. The LC protocol was transferred to LC-MS/MS and validated according to ICH guidelines.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "Journal of Pharmaceutical and Biomedical Analysis",
title = "Analysis of potential genotoxic impurities in rabeprazole active pharmaceutical ingredient via Liquid Chromatography-tandem Mass Spectrometry, following quality-by-design principles for method development",
volume = "149",
pages = "410-418",
doi = "10.1016/j.jpba.2017.11.037"
}

Iliou, K., Malenović, A., Loukas, Y. L.,& Dotsikas, Y.. (2018). Analysis of potential genotoxic impurities in rabeprazole active pharmaceutical ingredient via Liquid Chromatography-tandem Mass Spectrometry, following quality-by-design principles for method development. in Journal of Pharmaceutical and Biomedical Analysis
Elsevier Science BV, Amsterdam., 149, 410-418.
https://doi.org/10.1016/j.jpba.2017.11.037

Iliou K, Malenović A, Loukas YL, Dotsikas Y. Analysis of potential genotoxic impurities in rabeprazole active pharmaceutical ingredient via Liquid Chromatography-tandem Mass Spectrometry, following quality-by-design principles for method development. in Journal of Pharmaceutical and Biomedical Analysis. 2018;149:410-418.
doi:10.1016/j.jpba.2017.11.037 .

Iliou, Katerina, Malenović, Anđelija, Loukas, Yannis L., Dotsikas, Yannis, "Analysis of potential genotoxic impurities in rabeprazole active pharmaceutical ingredient via Liquid Chromatography-tandem Mass Spectrometry, following quality-by-design principles for method development" in Journal of Pharmaceutical and Biomedical Analysis, 149 (2018):410-418,
https://doi.org/10.1016/j.jpba.2017.11.037 . .

TY  - JOUR
AU  - Grigori, Katerina
AU  - Loukas, Yannis L.
AU  - Malenović, Anđelija
AU  - Samara, Vicky
AU  - Kalaskani, Anastasia
AU  - Dimovasili, Efi
AU  - Kalovidouri, Magda
AU  - Dotsikas, Yannis
PY  - 2017
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2832
AB  - A sensitive Liquid Chromatography tandem mass spectrometry (LC MS/MS) method was developed and validated for the quantitative analysis of three potential genotoxic impurities (318BP, M9, S5) in meropenem Active Pharmaceutical Ingredient (API). Due to the requirement for LOD values in ppb range, a high concentration of meropenem API (30 ing/mL) had to be injected. Therefore, efficient determination of meropenem from its impurities became a critical aim of this study, in order to divert meropenem to waste, via a switching valve. After the selection of the important factors affecting analytes' elution, a Box-Behnken design was utilized to set the plan of experiments conducted with UV detector. As responses, the separation factors between the last eluting impurity and meropenem, as well as meropenem retention factor k were used. Grid point search methodology was implemented aiming to obtain the optimal conditions that simultaneously comply to the conflicted criteria. Optimal mobile phase consisted of ACN, methanol and 0.09% HCOOH at a ratio 71/3.5/15.5 v/v. All impurities and internal standard omeprazole were eluted before 7.5 min and at 8.0 min the eluents were directed to waste. The protocol was transferred to LC-MS/MS and validated according to ICH guidelines.
PB  - Elsevier Science BV, Amsterdam
T2  - Journal of Pharmaceutical and Biomedical Analysis
T1  - Chemometrically assisted development and validation of LC-MS/MS method for the analysis of potential genotoxic impurities in meropenem active pharmaceutical ingredient
VL  - 145
SP  - 307
EP  - 314
DO  - 10.1016/j.jpba.2017.06.061
ER  - 

@article{
author = "Grigori, Katerina and Loukas, Yannis L. and Malenović, Anđelija and Samara, Vicky and Kalaskani, Anastasia and Dimovasili, Efi and Kalovidouri, Magda and Dotsikas, Yannis",
year = "2017",
abstract = "A sensitive Liquid Chromatography tandem mass spectrometry (LC MS/MS) method was developed and validated for the quantitative analysis of three potential genotoxic impurities (318BP, M9, S5) in meropenem Active Pharmaceutical Ingredient (API). Due to the requirement for LOD values in ppb range, a high concentration of meropenem API (30 ing/mL) had to be injected. Therefore, efficient determination of meropenem from its impurities became a critical aim of this study, in order to divert meropenem to waste, via a switching valve. After the selection of the important factors affecting analytes' elution, a Box-Behnken design was utilized to set the plan of experiments conducted with UV detector. As responses, the separation factors between the last eluting impurity and meropenem, as well as meropenem retention factor k were used. Grid point search methodology was implemented aiming to obtain the optimal conditions that simultaneously comply to the conflicted criteria. Optimal mobile phase consisted of ACN, methanol and 0.09% HCOOH at a ratio 71/3.5/15.5 v/v. All impurities and internal standard omeprazole were eluted before 7.5 min and at 8.0 min the eluents were directed to waste. The protocol was transferred to LC-MS/MS and validated according to ICH guidelines.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "Journal of Pharmaceutical and Biomedical Analysis",
title = "Chemometrically assisted development and validation of LC-MS/MS method for the analysis of potential genotoxic impurities in meropenem active pharmaceutical ingredient",
volume = "145",
pages = "307-314",
doi = "10.1016/j.jpba.2017.06.061"
}

Grigori, K., Loukas, Y. L., Malenović, A., Samara, V., Kalaskani, A., Dimovasili, E., Kalovidouri, M.,& Dotsikas, Y.. (2017). Chemometrically assisted development and validation of LC-MS/MS method for the analysis of potential genotoxic impurities in meropenem active pharmaceutical ingredient. in Journal of Pharmaceutical and Biomedical Analysis
Elsevier Science BV, Amsterdam., 145, 307-314.
https://doi.org/10.1016/j.jpba.2017.06.061

Grigori K, Loukas YL, Malenović A, Samara V, Kalaskani A, Dimovasili E, Kalovidouri M, Dotsikas Y. Chemometrically assisted development and validation of LC-MS/MS method for the analysis of potential genotoxic impurities in meropenem active pharmaceutical ingredient. in Journal of Pharmaceutical and Biomedical Analysis. 2017;145:307-314.
doi:10.1016/j.jpba.2017.06.061 .

Grigori, Katerina, Loukas, Yannis L., Malenović, Anđelija, Samara, Vicky, Kalaskani, Anastasia, Dimovasili, Efi, Kalovidouri, Magda, Dotsikas, Yannis, "Chemometrically assisted development and validation of LC-MS/MS method for the analysis of potential genotoxic impurities in meropenem active pharmaceutical ingredient" in Journal of Pharmaceutical and Biomedical Analysis, 145 (2017):307-314,
https://doi.org/10.1016/j.jpba.2017.06.061 . .

TY  - JOUR
AU  - Foivas, Anargyros
AU  - Malenović, Anđelija
AU  - Kostić, Nada
AU  - Božić, Marija
AU  - Knežević, Miroslav
AU  - Loukas, Yannis L.
AU  - Dotsikas, Yannis
PY  - 2016
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2566
AB  - In the current study, a rapid and sensitive LC-QTOF-MS/MS method for the determination of brinzolamide in dried blood spots (DBS) was developed and validated. This novel sample collection, storage and transfer technique was suitable for analyzing a drug with high distribution into red blood cells and negligible plasma levels. The method included an isocratic mobile phase consisting of methanol and 10 mM ammonium formate (90:10, v/v) and detection in positive electrospray mode (ESI+). The flow rate was adjusted to 0.350 mL/min yielding retention times of 1.7 min for both brinzolamide and internal standard (IS) rabeprazole on a Cyano analytical column, respectively. The validation of the proposed method over the concentration range 0.500-20.0 mu g/mL was performed in compliance with EMEA and FDA guidelines, assessing all major performance characteristics. Inter- and intra- assay precisions were less than 14%, while inter- and intra- assay accuracies varied from 922 to 111%. No matrix effect was observed and the mean brinzolamide extraction recovery was 93.5%. The method was successfully applied to real DBS samples from patients in steady state condition, receiving brinzolamide ophthalmic suspension 1% (w/v) for several months. Initial concentrations were corrected due to hematocrit effect, using image processing algorithm written in Matlab.
PB  - Elsevier Science BV, Amsterdam
T2  - Journal of Pharmaceutical and Biomedical Analysis
T1  - Quantitation of brinzolamide in dried blood spots by a novel LC-QTOF-MS/MS method
VL  - 119
SP  - 84
EP  - 90
DO  - 10.1016/j.jpba.2015.11.043
ER  - 

@article{
author = "Foivas, Anargyros and Malenović, Anđelija and Kostić, Nada and Božić, Marija and Knežević, Miroslav and Loukas, Yannis L. and Dotsikas, Yannis",
year = "2016",
abstract = "In the current study, a rapid and sensitive LC-QTOF-MS/MS method for the determination of brinzolamide in dried blood spots (DBS) was developed and validated. This novel sample collection, storage and transfer technique was suitable for analyzing a drug with high distribution into red blood cells and negligible plasma levels. The method included an isocratic mobile phase consisting of methanol and 10 mM ammonium formate (90:10, v/v) and detection in positive electrospray mode (ESI+). The flow rate was adjusted to 0.350 mL/min yielding retention times of 1.7 min for both brinzolamide and internal standard (IS) rabeprazole on a Cyano analytical column, respectively. The validation of the proposed method over the concentration range 0.500-20.0 mu g/mL was performed in compliance with EMEA and FDA guidelines, assessing all major performance characteristics. Inter- and intra- assay precisions were less than 14%, while inter- and intra- assay accuracies varied from 922 to 111%. No matrix effect was observed and the mean brinzolamide extraction recovery was 93.5%. The method was successfully applied to real DBS samples from patients in steady state condition, receiving brinzolamide ophthalmic suspension 1% (w/v) for several months. Initial concentrations were corrected due to hematocrit effect, using image processing algorithm written in Matlab.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "Journal of Pharmaceutical and Biomedical Analysis",
title = "Quantitation of brinzolamide in dried blood spots by a novel LC-QTOF-MS/MS method",
volume = "119",
pages = "84-90",
doi = "10.1016/j.jpba.2015.11.043"
}

Foivas, A., Malenović, A., Kostić, N., Božić, M., Knežević, M., Loukas, Y. L.,& Dotsikas, Y.. (2016). Quantitation of brinzolamide in dried blood spots by a novel LC-QTOF-MS/MS method. in Journal of Pharmaceutical and Biomedical Analysis
Elsevier Science BV, Amsterdam., 119, 84-90.
https://doi.org/10.1016/j.jpba.2015.11.043

Foivas A, Malenović A, Kostić N, Božić M, Knežević M, Loukas YL, Dotsikas Y. Quantitation of brinzolamide in dried blood spots by a novel LC-QTOF-MS/MS method. in Journal of Pharmaceutical and Biomedical Analysis. 2016;119:84-90.
doi:10.1016/j.jpba.2015.11.043 .

Foivas, Anargyros, Malenović, Anđelija, Kostić, Nada, Božić, Marija, Knežević, Miroslav, Loukas, Yannis L., Dotsikas, Yannis, "Quantitation of brinzolamide in dried blood spots by a novel LC-QTOF-MS/MS method" in Journal of Pharmaceutical and Biomedical Analysis, 119 (2016):84-90,
https://doi.org/10.1016/j.jpba.2015.11.043 . .

TY  - JOUR
AU  - Kostić, Nada
AU  - Dotsikas, Yannis
AU  - Jović, Nebojša
AU  - Stevanović, Galina
AU  - Malenović, Anđelija
AU  - Medenica, Mirjana
PY  - 2015
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2410
AB  - In this paper, novel LC-MS/MS methods for the determination of antiepileptic drug pregabalin in dried matrix spots (DMS) are presented. This attractive technique of sample collection in micro amount was utilized in the form of dried blood spots (DBS) and dried plasma spots (DPS). Following a pre-column derivatization procedure, using n-propyl chloroformate in the presence of n-propanol, and consecutive liquid-liquid extraction, derivatized pregabalin and its internal standard, 4-aminocyclohexanecarboxylic acid, were detected in positive ion mode by applying two SRM transitions per analyte. A YMC-Pack Octyl column (50 mm x 4.0 mm, 3 mu m particle size) maintained at 30 degrees C, was utilized with running mobile phase composed of acetonitrile: 0.15% formic acid (85:15, v/v). Flow rate was 550 mu L/min and total run time 2 min. Established methods were fully validated over the concentration range of 0.200-20.0 mu g/mL for DBS and 0.400-40.0 mu g/mL for DPS, respectively, while specificity, accuracy, precision, recovery, matrix-effect, stability, dilution integrity and spot homogeneity were found within acceptance criteria. Validated methods were applied for the determination of pregabalin levels in dried blood and plasma samples obtained from patients with epilepsy, after per os administration of commercial capsules. Comparison of drug level in blood and plasma, as well as correction steps undertaken in order to overcome hematocrit issue, when analyzing DBS, are also given.
PB  - Elsevier Science BV, Amsterdam
T2  - Journal of Pharmaceutical and Biomedical Analysis
T1  - Quantitation of pregabalin in dried blood spots and dried plasma spots by validated LC-MS/MS methods
VL  - 109
SP  - 79
EP  - 84
DO  - 10.1016/j.jpba.2015.02.023
ER  - 

@article{
author = "Kostić, Nada and Dotsikas, Yannis and Jović, Nebojša and Stevanović, Galina and Malenović, Anđelija and Medenica, Mirjana",
year = "2015",
abstract = "In this paper, novel LC-MS/MS methods for the determination of antiepileptic drug pregabalin in dried matrix spots (DMS) are presented. This attractive technique of sample collection in micro amount was utilized in the form of dried blood spots (DBS) and dried plasma spots (DPS). Following a pre-column derivatization procedure, using n-propyl chloroformate in the presence of n-propanol, and consecutive liquid-liquid extraction, derivatized pregabalin and its internal standard, 4-aminocyclohexanecarboxylic acid, were detected in positive ion mode by applying two SRM transitions per analyte. A YMC-Pack Octyl column (50 mm x 4.0 mm, 3 mu m particle size) maintained at 30 degrees C, was utilized with running mobile phase composed of acetonitrile: 0.15% formic acid (85:15, v/v). Flow rate was 550 mu L/min and total run time 2 min. Established methods were fully validated over the concentration range of 0.200-20.0 mu g/mL for DBS and 0.400-40.0 mu g/mL for DPS, respectively, while specificity, accuracy, precision, recovery, matrix-effect, stability, dilution integrity and spot homogeneity were found within acceptance criteria. Validated methods were applied for the determination of pregabalin levels in dried blood and plasma samples obtained from patients with epilepsy, after per os administration of commercial capsules. Comparison of drug level in blood and plasma, as well as correction steps undertaken in order to overcome hematocrit issue, when analyzing DBS, are also given.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "Journal of Pharmaceutical and Biomedical Analysis",
title = "Quantitation of pregabalin in dried blood spots and dried plasma spots by validated LC-MS/MS methods",
volume = "109",
pages = "79-84",
doi = "10.1016/j.jpba.2015.02.023"
}

Kostić, N., Dotsikas, Y., Jović, N., Stevanović, G., Malenović, A.,& Medenica, M.. (2015). Quantitation of pregabalin in dried blood spots and dried plasma spots by validated LC-MS/MS methods. in Journal of Pharmaceutical and Biomedical Analysis
Elsevier Science BV, Amsterdam., 109, 79-84.
https://doi.org/10.1016/j.jpba.2015.02.023

Kostić N, Dotsikas Y, Jović N, Stevanović G, Malenović A, Medenica M. Quantitation of pregabalin in dried blood spots and dried plasma spots by validated LC-MS/MS methods. in Journal of Pharmaceutical and Biomedical Analysis. 2015;109:79-84.
doi:10.1016/j.jpba.2015.02.023 .

Kostić, Nada, Dotsikas, Yannis, Jović, Nebojša, Stevanović, Galina, Malenović, Anđelija, Medenica, Mirjana, "Quantitation of pregabalin in dried blood spots and dried plasma spots by validated LC-MS/MS methods" in Journal of Pharmaceutical and Biomedical Analysis, 109 (2015):79-84,
https://doi.org/10.1016/j.jpba.2015.02.023 . .

TY  - JOUR
AU  - Kostić, Nada
AU  - Dotsikas, Yannis
AU  - Malenović, Anđelija
PY  - 2014
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2228
AB  - Drugs with antiepileptic activity constitute a group of heterogeneous compounds and therefore their determination cannot follow a universal procedure. Among them, vigabatrin, pregabalin, and gabapentin are of similar nature, due to their zwitterionic structure. This structure enables similar approaches for their determination, including derivatization protocols. This article presents a thorough survey on published methods for the determination of this subgroup of antiepileptic compounds in bulk and pharmaceutical preparations. Spectrophotometric and spectrofluorimetric methods, with or without derivatization reagents, as thin-layer chromatography, high-performance liquid chromatography with various detectors, gas chromatography, capillary electrophoresis, infrared, and potentiometric methods, have been extensively applied for these compounds, providing reliable results. Additionally, the number of citations and purpose for each method were discussed with critical commentary.
PB  - Taylor & Francis Inc, Philadelphia
T2  - Instrumentation Science & Technology
T1  - Critical review on the analytical methods for the determination of zwitterionic antiepileptic drugs-Vigabatrin, Pregabalin, and Gabapentin - In bulk and formulations
VL  - 42
IS  - 4
SP  - 486
EP  - 512
DO  - 10.1080/10739149.2013.876545
ER  - 

@article{
author = "Kostić, Nada and Dotsikas, Yannis and Malenović, Anđelija",
year = "2014",
abstract = "Drugs with antiepileptic activity constitute a group of heterogeneous compounds and therefore their determination cannot follow a universal procedure. Among them, vigabatrin, pregabalin, and gabapentin are of similar nature, due to their zwitterionic structure. This structure enables similar approaches for their determination, including derivatization protocols. This article presents a thorough survey on published methods for the determination of this subgroup of antiepileptic compounds in bulk and pharmaceutical preparations. Spectrophotometric and spectrofluorimetric methods, with or without derivatization reagents, as thin-layer chromatography, high-performance liquid chromatography with various detectors, gas chromatography, capillary electrophoresis, infrared, and potentiometric methods, have been extensively applied for these compounds, providing reliable results. Additionally, the number of citations and purpose for each method were discussed with critical commentary.",
publisher = "Taylor & Francis Inc, Philadelphia",
journal = "Instrumentation Science & Technology",
title = "Critical review on the analytical methods for the determination of zwitterionic antiepileptic drugs-Vigabatrin, Pregabalin, and Gabapentin - In bulk and formulations",
volume = "42",
number = "4",
pages = "486-512",
doi = "10.1080/10739149.2013.876545"
}

Kostić, N., Dotsikas, Y.,& Malenović, A.. (2014). Critical review on the analytical methods for the determination of zwitterionic antiepileptic drugs-Vigabatrin, Pregabalin, and Gabapentin - In bulk and formulations. in Instrumentation Science & Technology
Taylor & Francis Inc, Philadelphia., 42(4), 486-512.
https://doi.org/10.1080/10739149.2013.876545

Kostić N, Dotsikas Y, Malenović A. Critical review on the analytical methods for the determination of zwitterionic antiepileptic drugs-Vigabatrin, Pregabalin, and Gabapentin - In bulk and formulations. in Instrumentation Science & Technology. 2014;42(4):486-512.
doi:10.1080/10739149.2013.876545 .

Kostić, Nada, Dotsikas, Yannis, Malenović, Anđelija, "Critical review on the analytical methods for the determination of zwitterionic antiepileptic drugs-Vigabatrin, Pregabalin, and Gabapentin - In bulk and formulations" in Instrumentation Science & Technology, 42, no. 4 (2014):486-512,
https://doi.org/10.1080/10739149.2013.876545 . .

TY  - JOUR
AU  - Kostić, Nada
AU  - Dotsikas, Yannis
AU  - Jović, Nebojša
AU  - Stevanović, Galina
AU  - Malenović, Anđelija
AU  - Medenica, Mirjana
PY  - 2014
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2212
AB  - This paper presents a LC-MS/MS method for the determination of antiepileptic drug vigabatrin in dried plasma spots (DPS). Due to its zwitterionic chemical structure, a pre-column derivatization procedure was performed, aiming to yield enhanced ionization efficiency and improved chromatographic behaviour. Propyl chloroformate, in the presence of propanol, was selected as the best derivatization reagent, providing a strong signal along with reasonable run time. A relatively novel sample collection technique, DPS, was utilized, offering easy sample handling and analysis, using a sample in micro amount (similar to 5 mu L). Derivatized vigabatrin and its internal standard, 4-aminocyclohexanecarboxylic acid, were extracted by liquid-liquid extraction (LLE) and determined in positive ion mode by applying two SRM transitions per analyte. A Zorbax Eclipse XDB-C8 column (150 x 4.6 mm, 5 mu m particle size) maintained at 30 degrees C, was utilized with running mobile phase composed of acetonitrile: 0.15% formic acid (85:15, v/v). Flow rate was 550 mu L/min and total run time 4.5 min. The assay exhibited excellent linearity over the concentration range of 0.500-50.0 mu g/mL, which is suitable for the determination of vigabatrin level after per os administration in children and youths with epilepsy, who were on vigabatrin therapy, with or without co-medication. Specificity, accuracy, precision, recovery, matrix-effect and stability were also estimated and assessed within acceptance criteria.
PB  - Elsevier Science BV, Amsterdam
T2  - Journal of Chromatography B-Analytical Technologies in the Biomedical and Life Sciences
T1  - Vigabatrin in dried plasma spots: Validation of a novel LC-MS/MS method and application to clinical practice
VL  - 962
SP  - 102
EP  - 108
DO  - 10.1016/j.jchromb.2014.05.037
ER  - 

@article{
author = "Kostić, Nada and Dotsikas, Yannis and Jović, Nebojša and Stevanović, Galina and Malenović, Anđelija and Medenica, Mirjana",
year = "2014",
abstract = "This paper presents a LC-MS/MS method for the determination of antiepileptic drug vigabatrin in dried plasma spots (DPS). Due to its zwitterionic chemical structure, a pre-column derivatization procedure was performed, aiming to yield enhanced ionization efficiency and improved chromatographic behaviour. Propyl chloroformate, in the presence of propanol, was selected as the best derivatization reagent, providing a strong signal along with reasonable run time. A relatively novel sample collection technique, DPS, was utilized, offering easy sample handling and analysis, using a sample in micro amount (similar to 5 mu L). Derivatized vigabatrin and its internal standard, 4-aminocyclohexanecarboxylic acid, were extracted by liquid-liquid extraction (LLE) and determined in positive ion mode by applying two SRM transitions per analyte. A Zorbax Eclipse XDB-C8 column (150 x 4.6 mm, 5 mu m particle size) maintained at 30 degrees C, was utilized with running mobile phase composed of acetonitrile: 0.15% formic acid (85:15, v/v). Flow rate was 550 mu L/min and total run time 4.5 min. The assay exhibited excellent linearity over the concentration range of 0.500-50.0 mu g/mL, which is suitable for the determination of vigabatrin level after per os administration in children and youths with epilepsy, who were on vigabatrin therapy, with or without co-medication. Specificity, accuracy, precision, recovery, matrix-effect and stability were also estimated and assessed within acceptance criteria.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "Journal of Chromatography B-Analytical Technologies in the Biomedical and Life Sciences",
title = "Vigabatrin in dried plasma spots: Validation of a novel LC-MS/MS method and application to clinical practice",
volume = "962",
pages = "102-108",
doi = "10.1016/j.jchromb.2014.05.037"
}

Kostić, N., Dotsikas, Y., Jović, N., Stevanović, G., Malenović, A.,& Medenica, M.. (2014). Vigabatrin in dried plasma spots: Validation of a novel LC-MS/MS method and application to clinical practice. in Journal of Chromatography B-Analytical Technologies in the Biomedical and Life Sciences
Elsevier Science BV, Amsterdam., 962, 102-108.
https://doi.org/10.1016/j.jchromb.2014.05.037

Kostić N, Dotsikas Y, Jović N, Stevanović G, Malenović A, Medenica M. Vigabatrin in dried plasma spots: Validation of a novel LC-MS/MS method and application to clinical practice. in Journal of Chromatography B-Analytical Technologies in the Biomedical and Life Sciences. 2014;962:102-108.
doi:10.1016/j.jchromb.2014.05.037 .

Kostić, Nada, Dotsikas, Yannis, Jović, Nebojša, Stevanović, Galina, Malenović, Anđelija, Medenica, Mirjana, "Vigabatrin in dried plasma spots: Validation of a novel LC-MS/MS method and application to clinical practice" in Journal of Chromatography B-Analytical Technologies in the Biomedical and Life Sciences, 962 (2014):102-108,
https://doi.org/10.1016/j.jchromb.2014.05.037 . .

TY  - JOUR
AU  - Kostić, Nada
AU  - Dotsikas, Yannis
AU  - Malenović, Anđelija
AU  - Jančić-Stojanović, Biljana
AU  - Rakić, Tijana
AU  - Ivanović, Darko
AU  - Medenica, Mirjana
PY  - 2013
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1967
AB  - In this article, a step-by-step optimization procedure for improving analyte response with implementation of experimental design is described. Zwitterionic antiepileptics, namely vigabatrin, pregabalin and gabapentin, were chosen as model compounds to undergo chloroformate-mediated derivatization followed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analysis. Application of a planned stepwise optimization procedure allowed responses of analytes, expressed as areas and signal-to-noise ratios, to be improved, enabling achievement of lower limit of detection values. Results from the current study demonstrate that optimization of parameters such as scan time, geometry of ion source, sheath and auxiliary gas pressure, capillary temperature, collision pressure and mobile phase composition can have a positive impact on sensitivity of LC-MS/MS methods. Optimization of LC and MS parameters led to a total increment of 53.9%, 83.3% and 95.7% in areas of derivatized vigabatrin, pregabalin and gabapentin, respectively, while for signal-to-noise values, an improvement of 140.0%, 93.6% and 124.0% was achieved, compared to autotune settings. After defining the final optimal conditions, a time-segmented method was validated for the determination of mentioned drugs in plasma. The method proved to be accurate and precise with excellent linearity for the tested concentration range (40.0ngml(-1)-10.0x10(3)ngml(-1)). Copyright
PB  - Wiley-Blackwell, Hoboken
T2  - Journal of Mass Spectrometry
T1  - Stepwise optimization approach for improving LC-MS/MS analysis of zwitterionic antiepileptic drugs with implementation of experimental design
VL  - 48
IS  - 7
SP  - 875
EP  - 884
DO  - 10.1002/jms.3236
ER  - 

@article{
author = "Kostić, Nada and Dotsikas, Yannis and Malenović, Anđelija and Jančić-Stojanović, Biljana and Rakić, Tijana and Ivanović, Darko and Medenica, Mirjana",
year = "2013",
abstract = "In this article, a step-by-step optimization procedure for improving analyte response with implementation of experimental design is described. Zwitterionic antiepileptics, namely vigabatrin, pregabalin and gabapentin, were chosen as model compounds to undergo chloroformate-mediated derivatization followed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analysis. Application of a planned stepwise optimization procedure allowed responses of analytes, expressed as areas and signal-to-noise ratios, to be improved, enabling achievement of lower limit of detection values. Results from the current study demonstrate that optimization of parameters such as scan time, geometry of ion source, sheath and auxiliary gas pressure, capillary temperature, collision pressure and mobile phase composition can have a positive impact on sensitivity of LC-MS/MS methods. Optimization of LC and MS parameters led to a total increment of 53.9%, 83.3% and 95.7% in areas of derivatized vigabatrin, pregabalin and gabapentin, respectively, while for signal-to-noise values, an improvement of 140.0%, 93.6% and 124.0% was achieved, compared to autotune settings. After defining the final optimal conditions, a time-segmented method was validated for the determination of mentioned drugs in plasma. The method proved to be accurate and precise with excellent linearity for the tested concentration range (40.0ngml(-1)-10.0x10(3)ngml(-1)). Copyright",
publisher = "Wiley-Blackwell, Hoboken",
journal = "Journal of Mass Spectrometry",
title = "Stepwise optimization approach for improving LC-MS/MS analysis of zwitterionic antiepileptic drugs with implementation of experimental design",
volume = "48",
number = "7",
pages = "875-884",
doi = "10.1002/jms.3236"
}

Kostić, N., Dotsikas, Y., Malenović, A., Jančić-Stojanović, B., Rakić, T., Ivanović, D.,& Medenica, M.. (2013). Stepwise optimization approach for improving LC-MS/MS analysis of zwitterionic antiepileptic drugs with implementation of experimental design. in Journal of Mass Spectrometry
Wiley-Blackwell, Hoboken., 48(7), 875-884.
https://doi.org/10.1002/jms.3236

Kostić N, Dotsikas Y, Malenović A, Jančić-Stojanović B, Rakić T, Ivanović D, Medenica M. Stepwise optimization approach for improving LC-MS/MS analysis of zwitterionic antiepileptic drugs with implementation of experimental design. in Journal of Mass Spectrometry. 2013;48(7):875-884.
doi:10.1002/jms.3236 .

Kostić, Nada, Dotsikas, Yannis, Malenović, Anđelija, Jančić-Stojanović, Biljana, Rakić, Tijana, Ivanović, Darko, Medenica, Mirjana, "Stepwise optimization approach for improving LC-MS/MS analysis of zwitterionic antiepileptic drugs with implementation of experimental design" in Journal of Mass Spectrometry, 48, no. 7 (2013):875-884,
https://doi.org/10.1002/jms.3236 . .

TY  - JOUR
AU  - Kostić, Nada
AU  - Dotsikas, Yannis
AU  - Malenović, Anđelija
AU  - Medenica, Mirjana
PY  - 2013
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1911
AB  - In the current study, three antiepileptic drugs with zwitterionic properties, namely vigabatrin, pregabalin and gabapentin, were chosen as model analytes to undergo derivatization by applying various n-alkyl chloroformate/n-alcohol combinations, followed by LC-ESI-MS/MS analysis. The employment of 16 combinations per drug using methyl, ethyl, propyl or butyl chloroformate coupled with methanol, ethanol, propanol or butanol, greatly affected a series of parameters of the derivatives, such as retention time on C8 column, signal expressed via areas, limit of detection values, as well as the yields of the main and side reactions. Practically, even slight modification of n-alkyl group of either chloroformate or alcohol resulted in significant changes in the chromatographic and mass spectrometric behavior of the novel derivative. It was clearly demonstrated that all the estimated parameters were highly correlated with the length of n-alkyl groups of the involved chloroformate and alcohol. The most significant influence was monitored in peak area values, indicating that the length of the n-alkyl chain plays an important role in electrospray ionization efficiency. For this parameter, increasing the n-alkyl chain from methyl to butyl led to increment up to 2089%, 508.7% and 1075% for area values of derivatized vigabatrin, pregabalin and gabapentin, respectively. These changes affected also the corresponding values of limits of detection, with the estimated improvements up to 1553%, 397.7% and 875.0% for the aforementioned derivatized drugs, respectively. Besides the obvious utilization of these conclusions in the development of bioanalytical methods for these analytes with the current protocol, this study offers valuable data which can be useful in more general approaches, giving insights into the effects of this derivatization reaction and its performances.
PB  - Elsevier Science BV, Amsterdam
T2  - Talanta
T1  - Effects of derivatization reagents consisting of n-alkyl chloroformate/n-alcohol combinations in LC-ESI-MS/MS analysis of zwitterionic antiepileptic drugs
VL  - 116
SP  - 91
EP  - 99
DO  - 10.1016/j.talanta.2013.04.082
ER  - 

@article{
author = "Kostić, Nada and Dotsikas, Yannis and Malenović, Anđelija and Medenica, Mirjana",
year = "2013",
abstract = "In the current study, three antiepileptic drugs with zwitterionic properties, namely vigabatrin, pregabalin and gabapentin, were chosen as model analytes to undergo derivatization by applying various n-alkyl chloroformate/n-alcohol combinations, followed by LC-ESI-MS/MS analysis. The employment of 16 combinations per drug using methyl, ethyl, propyl or butyl chloroformate coupled with methanol, ethanol, propanol or butanol, greatly affected a series of parameters of the derivatives, such as retention time on C8 column, signal expressed via areas, limit of detection values, as well as the yields of the main and side reactions. Practically, even slight modification of n-alkyl group of either chloroformate or alcohol resulted in significant changes in the chromatographic and mass spectrometric behavior of the novel derivative. It was clearly demonstrated that all the estimated parameters were highly correlated with the length of n-alkyl groups of the involved chloroformate and alcohol. The most significant influence was monitored in peak area values, indicating that the length of the n-alkyl chain plays an important role in electrospray ionization efficiency. For this parameter, increasing the n-alkyl chain from methyl to butyl led to increment up to 2089%, 508.7% and 1075% for area values of derivatized vigabatrin, pregabalin and gabapentin, respectively. These changes affected also the corresponding values of limits of detection, with the estimated improvements up to 1553%, 397.7% and 875.0% for the aforementioned derivatized drugs, respectively. Besides the obvious utilization of these conclusions in the development of bioanalytical methods for these analytes with the current protocol, this study offers valuable data which can be useful in more general approaches, giving insights into the effects of this derivatization reaction and its performances.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "Talanta",
title = "Effects of derivatization reagents consisting of n-alkyl chloroformate/n-alcohol combinations in LC-ESI-MS/MS analysis of zwitterionic antiepileptic drugs",
volume = "116",
pages = "91-99",
doi = "10.1016/j.talanta.2013.04.082"
}

Kostić, N., Dotsikas, Y., Malenović, A.,& Medenica, M.. (2013). Effects of derivatization reagents consisting of n-alkyl chloroformate/n-alcohol combinations in LC-ESI-MS/MS analysis of zwitterionic antiepileptic drugs. in Talanta
Elsevier Science BV, Amsterdam., 116, 91-99.
https://doi.org/10.1016/j.talanta.2013.04.082

Kostić N, Dotsikas Y, Malenović A, Medenica M. Effects of derivatization reagents consisting of n-alkyl chloroformate/n-alcohol combinations in LC-ESI-MS/MS analysis of zwitterionic antiepileptic drugs. in Talanta. 2013;116:91-99.
doi:10.1016/j.talanta.2013.04.082 .

Kostić, Nada, Dotsikas, Yannis, Malenović, Anđelija, Medenica, Mirjana, "Effects of derivatization reagents consisting of n-alkyl chloroformate/n-alcohol combinations in LC-ESI-MS/MS analysis of zwitterionic antiepileptic drugs" in Talanta, 116 (2013):91-99,
https://doi.org/10.1016/j.talanta.2013.04.082 . .

TY  - JOUR
AU  - Masković, Marija
AU  - Dotsikas, Yannis
AU  - Malenović, Anđelija
AU  - Jančić-Stojanović, Biljana
AU  - Ivanović, Darko
AU  - Medenica, Mirjana
PY  - 2011
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1560
AB  - This paper describes the development and validation of a microemulsion liquid chromatography (MELC) method for simultaneous determination of perindopril tert-butylamine and its impurities in bulk active substances and the pharmaceutical dosage form of tablets. An appropriate resolution with reasonable retention times was obtained for a microemulsion containing 0.24% (w/v) butyl acetate, 0.30% (w/v) ethyl acetate, 2% (w/v) sodium dodecyl sulfate, 7.75% (w/v) n-butanol, and 20.0 mM potassium dihydrogen phosphate, the pH of which was adjusted to 3.70 with 85% orthophosphoric acid. Separations were performed on a Nucleosil 120-5 butyl modified (C4), 250 x 4 mm, 5 pm particle size silica column at 40 degrees C, with a mobile phase flow rate of 1.25 mL/min. UV detection was performed at 254 nm. The established method was subjected to method validation, and required validation parameters were defined. Robustness testing, an important part of method validation, was performed as well. Since robustness validation can be conducted using different experimental designs, the Plackett-Burman design was applied due to its possibility of testing many factors at the same time. The validated MELC method was found to be suitable for the simultaneous determination of perindopril tert-butylamine and its impurities in pharmaceuticals.
PB  - AOAC Int, Gaithersburg
T2  - Journal of AOAC International
T1  - Validation of an Oil-in-Water Microemulsion Liquid Chromatography Method for Analysis of Perindopril tert-Butylamine and Its Impurities
VL  - 94
IS  - 3
SP  - 723
EP  - 734
UR  - https://hdl.handle.net/21.15107/rcub_farfar_1560
ER  - 

@article{
author = "Masković, Marija and Dotsikas, Yannis and Malenović, Anđelija and Jančić-Stojanović, Biljana and Ivanović, Darko and Medenica, Mirjana",
year = "2011",
abstract = "This paper describes the development and validation of a microemulsion liquid chromatography (MELC) method for simultaneous determination of perindopril tert-butylamine and its impurities in bulk active substances and the pharmaceutical dosage form of tablets. An appropriate resolution with reasonable retention times was obtained for a microemulsion containing 0.24% (w/v) butyl acetate, 0.30% (w/v) ethyl acetate, 2% (w/v) sodium dodecyl sulfate, 7.75% (w/v) n-butanol, and 20.0 mM potassium dihydrogen phosphate, the pH of which was adjusted to 3.70 with 85% orthophosphoric acid. Separations were performed on a Nucleosil 120-5 butyl modified (C4), 250 x 4 mm, 5 pm particle size silica column at 40 degrees C, with a mobile phase flow rate of 1.25 mL/min. UV detection was performed at 254 nm. The established method was subjected to method validation, and required validation parameters were defined. Robustness testing, an important part of method validation, was performed as well. Since robustness validation can be conducted using different experimental designs, the Plackett-Burman design was applied due to its possibility of testing many factors at the same time. The validated MELC method was found to be suitable for the simultaneous determination of perindopril tert-butylamine and its impurities in pharmaceuticals.",
publisher = "AOAC Int, Gaithersburg",
journal = "Journal of AOAC International",
title = "Validation of an Oil-in-Water Microemulsion Liquid Chromatography Method for Analysis of Perindopril tert-Butylamine and Its Impurities",
volume = "94",
number = "3",
pages = "723-734",
url = "https://hdl.handle.net/21.15107/rcub_farfar_1560"
}

Masković, M., Dotsikas, Y., Malenović, A., Jančić-Stojanović, B., Ivanović, D.,& Medenica, M.. (2011). Validation of an Oil-in-Water Microemulsion Liquid Chromatography Method for Analysis of Perindopril tert-Butylamine and Its Impurities. in Journal of AOAC International
AOAC Int, Gaithersburg., 94(3), 723-734.
https://hdl.handle.net/21.15107/rcub_farfar_1560

Masković M, Dotsikas Y, Malenović A, Jančić-Stojanović B, Ivanović D, Medenica M. Validation of an Oil-in-Water Microemulsion Liquid Chromatography Method for Analysis of Perindopril tert-Butylamine and Its Impurities. in Journal of AOAC International. 2011;94(3):723-734.
https://hdl.handle.net/21.15107/rcub_farfar_1560 .

Masković, Marija, Dotsikas, Yannis, Malenović, Anđelija, Jančić-Stojanović, Biljana, Ivanović, Darko, Medenica, Mirjana, "Validation of an Oil-in-Water Microemulsion Liquid Chromatography Method for Analysis of Perindopril tert-Butylamine and Its Impurities" in Journal of AOAC International, 94, no. 3 (2011):723-734,
https://hdl.handle.net/21.15107/rcub_farfar_1560 .

TY  - JOUR
AU  - Malenović, Anđelija
AU  - Dotsikas, Yannis
AU  - Masković, Marija
AU  - Jančić-Stojanović, Biljana
AU  - Ivanović, Darko
AU  - Medenica, Mirjana
PY  - 2011
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1456
AB  - In the current paper the application of multiobjective optimization (MOOP) technique, via Derringer's desirability function, to a microemulsion liquid chromatographic (MELC) method is described. Chromatographic separation of perindopril tert-butylamine and its four impurities was selected as the case study. Central composite design (CCD) with fractional factorial design, +/- 0.5 alpha star design and four replications in central point was applied for a response surface study, in order to examine in depth the effects of the most important factors. As factors that influence the system mostly (i) content of ethyl acetate and (ii) butyl acetate in composite internal phase, (iii) content of sodium dodecyl sulfate (surfactant) and (iv) n-butanol (co-surfactant). as well as (v) pH of the mobile phase were selected. Retention factor of (a) perindoprilat and (b) impurity Y 31 and
PB  - Elsevier Science BV, Amsterdam
T2  - Microchemical Journal
T1  - Desirability-based optimization and its sensitivity analysis for the perindopril and its impurities analysis in a microemulsion LC system
VL  - 99
IS  - 2
SP  - 454
EP  - 460
DO  - 10.1016/j.microc.2011.06.022
ER  - 

@article{
author = "Malenović, Anđelija and Dotsikas, Yannis and Masković, Marija and Jančić-Stojanović, Biljana and Ivanović, Darko and Medenica, Mirjana",
year = "2011",
abstract = "In the current paper the application of multiobjective optimization (MOOP) technique, via Derringer's desirability function, to a microemulsion liquid chromatographic (MELC) method is described. Chromatographic separation of perindopril tert-butylamine and its four impurities was selected as the case study. Central composite design (CCD) with fractional factorial design, +/- 0.5 alpha star design and four replications in central point was applied for a response surface study, in order to examine in depth the effects of the most important factors. As factors that influence the system mostly (i) content of ethyl acetate and (ii) butyl acetate in composite internal phase, (iii) content of sodium dodecyl sulfate (surfactant) and (iv) n-butanol (co-surfactant). as well as (v) pH of the mobile phase were selected. Retention factor of (a) perindoprilat and (b) impurity Y 31 and",
publisher = "Elsevier Science BV, Amsterdam",
journal = "Microchemical Journal",
title = "Desirability-based optimization and its sensitivity analysis for the perindopril and its impurities analysis in a microemulsion LC system",
volume = "99",
number = "2",
pages = "454-460",
doi = "10.1016/j.microc.2011.06.022"
}

Malenović, A., Dotsikas, Y., Masković, M., Jančić-Stojanović, B., Ivanović, D.,& Medenica, M.. (2011). Desirability-based optimization and its sensitivity analysis for the perindopril and its impurities analysis in a microemulsion LC system. in Microchemical Journal
Elsevier Science BV, Amsterdam., 99(2), 454-460.
https://doi.org/10.1016/j.microc.2011.06.022

Malenović A, Dotsikas Y, Masković M, Jančić-Stojanović B, Ivanović D, Medenica M. Desirability-based optimization and its sensitivity analysis for the perindopril and its impurities analysis in a microemulsion LC system. in Microchemical Journal. 2011;99(2):454-460.
doi:10.1016/j.microc.2011.06.022 .

Malenović, Anđelija, Dotsikas, Yannis, Masković, Marija, Jančić-Stojanović, Biljana, Ivanović, Darko, Medenica, Mirjana, "Desirability-based optimization and its sensitivity analysis for the perindopril and its impurities analysis in a microemulsion LC system" in Microchemical Journal, 99, no. 2 (2011):454-460,
https://doi.org/10.1016/j.microc.2011.06.022 . .