TY  - JOUR
AU  - Krmar, Jovana
AU  - Tolić Stojadinović, Ljiljana
AU  - Đurkić, Tatjana
AU  - Protić, Ana
AU  - Otašević, Biljana
PY  - 2023
UR  - http://TechnoRep.tmf.bg.ac.rs/handle/123456789/6373
AB  - A priori estimation of analyte response is crucial for the efficient development of liquid chromatography–electrospray ionization/mass spectrometry (LC–ESI/MS) methods, but remains a demanding task given the lack of knowledge about the factors affecting the experimental outcome. In this research, we address the challenge of discovering the interactive relationship between signal response and structural properties, method parameters and solvent-related descriptors throughout an approach featuring quantitative structure–property relationship (QSPR) and design of experiments (DoE). To systematically investigate the experimental domain within which QSPR prediction should be undertaken, we varied LC and instrumental factors according to the Box-Behnken DoE scheme. Seven compounds, including aripiprazole and its impurities, were subjected to 57 different experimental conditions, resulting in 399 LC–ESI/MS data endpoints. To obtain a more standard distribution of the measured response, the peak areas were log-transformed before modeling. QSPR predictions were made using features selected by Genetic Algorithm (GA) and providing Gradient Boosted Trees (GBT) with training data. Proposed model showed satisfactory performance on test data with a RMSEP of 1.57 % and a of 96.48 %. This is the first QSPR study in LC–ESI/MS that provided a holistic overview of the analyte's response behavior across the experimental and chemical space. Since intramolecular electronic effects and molecular size were given great importance, the GA–GBT model improved the understanding of signal response generation of model compounds. It also highlighted the need to fine-tune the parameters affecting desolvation and droplet charging efficiency.
PB  - Elsevier B.V.
T2  - Journal of Pharmaceutical and Biomedical Analysis
T1  - Predicting liquid chromatography−electrospray ionization/mass spectrometry signal from the structure of model compounds and experimental factors; case study of aripiprazole and its impurities
SP  - 115422
VL  - 233
DO  - 10.1016/j.jpba.2023.115422
ER  - 

@article{
author = "Krmar, Jovana and Tolić Stojadinović, Ljiljana and Đurkić, Tatjana and Protić, Ana and Otašević, Biljana",
year = "2023",
abstract = "A priori estimation of analyte response is crucial for the efficient development of liquid chromatography–electrospray ionization/mass spectrometry (LC–ESI/MS) methods, but remains a demanding task given the lack of knowledge about the factors affecting the experimental outcome. In this research, we address the challenge of discovering the interactive relationship between signal response and structural properties, method parameters and solvent-related descriptors throughout an approach featuring quantitative structure–property relationship (QSPR) and design of experiments (DoE). To systematically investigate the experimental domain within which QSPR prediction should be undertaken, we varied LC and instrumental factors according to the Box-Behnken DoE scheme. Seven compounds, including aripiprazole and its impurities, were subjected to 57 different experimental conditions, resulting in 399 LC–ESI/MS data endpoints. To obtain a more standard distribution of the measured response, the peak areas were log-transformed before modeling. QSPR predictions were made using features selected by Genetic Algorithm (GA) and providing Gradient Boosted Trees (GBT) with training data. Proposed model showed satisfactory performance on test data with a RMSEP of 1.57 % and a of 96.48 %. This is the first QSPR study in LC–ESI/MS that provided a holistic overview of the analyte's response behavior across the experimental and chemical space. Since intramolecular electronic effects and molecular size were given great importance, the GA–GBT model improved the understanding of signal response generation of model compounds. It also highlighted the need to fine-tune the parameters affecting desolvation and droplet charging efficiency.",
publisher = "Elsevier B.V.",
journal = "Journal of Pharmaceutical and Biomedical Analysis",
title = "Predicting liquid chromatography−electrospray ionization/mass spectrometry signal from the structure of model compounds and experimental factors; case study of aripiprazole and its impurities",
pages = "115422",
volume = "233",
doi = "10.1016/j.jpba.2023.115422"
}

Krmar, J., Tolić Stojadinović, L., Đurkić, T., Protić, A.,& Otašević, B.. (2023). Predicting liquid chromatography−electrospray ionization/mass spectrometry signal from the structure of model compounds and experimental factors; case study of aripiprazole and its impurities. in Journal of Pharmaceutical and Biomedical Analysis
Elsevier B.V.., 233, 115422.
https://doi.org/10.1016/j.jpba.2023.115422

Krmar J, Tolić Stojadinović L, Đurkić T, Protić A, Otašević B. Predicting liquid chromatography−electrospray ionization/mass spectrometry signal from the structure of model compounds and experimental factors; case study of aripiprazole and its impurities. in Journal of Pharmaceutical and Biomedical Analysis. 2023;233:115422.
doi:10.1016/j.jpba.2023.115422 .

Krmar, Jovana, Tolić Stojadinović, Ljiljana, Đurkić, Tatjana, Protić, Ana, Otašević, Biljana, "Predicting liquid chromatography−electrospray ionization/mass spectrometry signal from the structure of model compounds and experimental factors; case study of aripiprazole and its impurities" in Journal of Pharmaceutical and Biomedical Analysis, 233 (2023):115422,
https://doi.org/10.1016/j.jpba.2023.115422 . .

TY  - CONF
AU  - Krmar, Jovana
AU  - Tolić-Stojadinović, Ljiljana
AU  - Vukićević, Milan
AU  - Đurkić, Tatjana
AU  - Protić, Ana
AU  - Otašević, Biljana
PY  - 2022
UR  - http://TechnoRep.tmf.bg.ac.rs/handle/123456789/6488
PB  - University of Mons (Belgium)
C3  - 12th International Symposium on Drug Analysis & 32nd International Symposium on Pharmaceutical and Biomedical Analysis, From 11th to 14th September 2022, Mons, Belgium, Abstract book
T1  - The modern age of chemomometrics: What is the secret behind LC–ESI(+)/MS response generation?
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4691
ER  - 

@conference{
author = "Krmar, Jovana and Tolić-Stojadinović, Ljiljana and Vukićević, Milan and Đurkić, Tatjana and Protić, Ana and Otašević, Biljana",
year = "2022",
publisher = "University of Mons (Belgium)",
journal = "12th International Symposium on Drug Analysis & 32nd International Symposium on Pharmaceutical and Biomedical Analysis, From 11th to 14th September 2022, Mons, Belgium, Abstract book",
title = "The modern age of chemomometrics: What is the secret behind LC–ESI(+)/MS response generation?",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4691"
}

Krmar, J., Tolić-Stojadinović, L., Vukićević, M., Đurkić, T., Protić, A.,& Otašević, B.. (2022). The modern age of chemomometrics: What is the secret behind LC–ESI(+)/MS response generation?. in 12th International Symposium on Drug Analysis & 32nd International Symposium on Pharmaceutical and Biomedical Analysis, From 11th to 14th September 2022, Mons, Belgium, Abstract book
University of Mons (Belgium)..
https://hdl.handle.net/21.15107/rcub_farfar_4691

Krmar J, Tolić-Stojadinović L, Vukićević M, Đurkić T, Protić A, Otašević B. The modern age of chemomometrics: What is the secret behind LC–ESI(+)/MS response generation?. in 12th International Symposium on Drug Analysis & 32nd International Symposium on Pharmaceutical and Biomedical Analysis, From 11th to 14th September 2022, Mons, Belgium, Abstract book. 2022;.
https://hdl.handle.net/21.15107/rcub_farfar_4691 .

Krmar, Jovana, Tolić-Stojadinović, Ljiljana, Vukićević, Milan, Đurkić, Tatjana, Protić, Ana, Otašević, Biljana, "The modern age of chemomometrics: What is the secret behind LC–ESI(+)/MS response generation?" in 12th International Symposium on Drug Analysis & 32nd International Symposium on Pharmaceutical and Biomedical Analysis, From 11th to 14th September 2022, Mons, Belgium, Abstract book (2022),
https://hdl.handle.net/21.15107/rcub_farfar_4691 .

TY  - JOUR
AU  - Malesević, M.
AU  - Živanović, Ljiljana
AU  - Protić, Ana
AU  - Radisić, Marina
AU  - Lausević, M.
AU  - Jović, Žarko
AU  - Zečević, Mira
PY  - 2014
UR  - http://TechnoRep.tmf.bg.ac.rs/handle/123456789/5785
AB  - The present study was designed to characterize the possible degradation products of zolpidem tartrate under various stress conditions according to International Conference on Harmonization (ICH) guidelines Q1A(R2). After exposure to light, heat, hydrolysis, and oxidation, the drug significantly degraded under photolytic and acid/base hydrolytic conditions. Degradation resulted in the formation of four key degradants. Degradation products were resolved from each other and the drug by employing an isocratic elution method on Luna C-18 column with mobile phase consisting of methanol-10 mM ammonium acetate (68.4: 31.6, v/v), wherein pH was adjusted to 5.4 with glacial acetic acid. To characterize the degradation products, a method was extended to LC-MS and a mass fragmentation pattern was established using single quad-rupole. The degradants were identified as zolpacid, oxozolpidem, zolpaldehyde, and zolpyridine. Finally, the most possible degradation mechanism of zolpidem tartrate in different environments was proposed.
PB  - Akademiai Kiado Zrt, Budapest
T2  - Acta Chromatographica
T1  - Stress Degradation Studies on Zolpidem Tartrate Using LC-DAD and LC-MS Methods
EP  - 96
IS  - 1
SP  - 81
VL  - 26
DO  - 10.1556/AChrom.26.2014.1.8
ER  - 

@article{
author = "Malesević, M. and Živanović, Ljiljana and Protić, Ana and Radisić, Marina and Lausević, M. and Jović, Žarko and Zečević, Mira",
year = "2014",
abstract = "The present study was designed to characterize the possible degradation products of zolpidem tartrate under various stress conditions according to International Conference on Harmonization (ICH) guidelines Q1A(R2). After exposure to light, heat, hydrolysis, and oxidation, the drug significantly degraded under photolytic and acid/base hydrolytic conditions. Degradation resulted in the formation of four key degradants. Degradation products were resolved from each other and the drug by employing an isocratic elution method on Luna C-18 column with mobile phase consisting of methanol-10 mM ammonium acetate (68.4: 31.6, v/v), wherein pH was adjusted to 5.4 with glacial acetic acid. To characterize the degradation products, a method was extended to LC-MS and a mass fragmentation pattern was established using single quad-rupole. The degradants were identified as zolpacid, oxozolpidem, zolpaldehyde, and zolpyridine. Finally, the most possible degradation mechanism of zolpidem tartrate in different environments was proposed.",
publisher = "Akademiai Kiado Zrt, Budapest",
journal = "Acta Chromatographica",
title = "Stress Degradation Studies on Zolpidem Tartrate Using LC-DAD and LC-MS Methods",
pages = "96-81",
number = "1",
volume = "26",
doi = "10.1556/AChrom.26.2014.1.8"
}

Malesević, M., Živanović, L., Protić, A., Radisić, M., Lausević, M., Jović, Ž.,& Zečević, M.. (2014). Stress Degradation Studies on Zolpidem Tartrate Using LC-DAD and LC-MS Methods. in Acta Chromatographica
Akademiai Kiado Zrt, Budapest., 26(1), 81-96.
https://doi.org/10.1556/AChrom.26.2014.1.8

Malesević M, Živanović L, Protić A, Radisić M, Lausević M, Jović Ž, Zečević M. Stress Degradation Studies on Zolpidem Tartrate Using LC-DAD and LC-MS Methods. in Acta Chromatographica. 2014;26(1):81-96.
doi:10.1556/AChrom.26.2014.1.8 .

Malesević, M., Živanović, Ljiljana, Protić, Ana, Radisić, Marina, Lausević, M., Jović, Žarko, Zečević, Mira, "Stress Degradation Studies on Zolpidem Tartrate Using LC-DAD and LC-MS Methods" in Acta Chromatographica, 26, no. 1 (2014):81-96,
https://doi.org/10.1556/AChrom.26.2014.1.8 . .

TY  - JOUR
AU  - Jović, Žarko
AU  - Živanović, Ljiljana
AU  - Protić, Ana
AU  - Radisić, Marina
AU  - Laušević, Mila
AU  - Malešević, Marija
AU  - Zečević, Mira
PY  - 2013
UR  - http://TechnoRep.tmf.bg.ac.rs/handle/123456789/5699
AB  - Torasemide was subjected to forced degradation studies. Stress conditions were varied concerning hydrolysis (acid, base, and neutral), oxidation, photolysis, and thermal degradation in order to identify the potential degradation products and consequently establish the possible degradation pathways and intrinsic stability of the drug. The study was performed according to ICH guidelines and drug was found to be relatively stable in the solid form. It showed that torasemide degraded significantly under acidic, neutral and alkaline conditions and resulted in formation of degradation product R2. When temperature was increased the degradation was accelerated. Also, the drug showed slight instability under extreme oxidative stress conditions which resulted in formation of two degradation products in total. The drug and degradation products have been separated employing gradient elution method on Zorbax SB C-18 analytical column. To characterize the degradation products LC-MSn was applied. The mass fragmentation pattern was established using single quadrupole and ion trap mass analyzers. Finally, the most possible degradation mechanism of torasemide in different experimental conditions was proposed.
PB  - Taylor & Francis Inc, Philadelphia
T2  - Journal of Liquid Chromatography & Related Technologies
T1  - Forced degradation study of torasemide: Characterization of its degradation products
EP  - 2094
IS  - 15
SP  - 2082
VL  - 36
DO  - 10.1080/10826076.2012.712932
ER  - 

@article{
author = "Jović, Žarko and Živanović, Ljiljana and Protić, Ana and Radisić, Marina and Laušević, Mila and Malešević, Marija and Zečević, Mira",
year = "2013",
abstract = "Torasemide was subjected to forced degradation studies. Stress conditions were varied concerning hydrolysis (acid, base, and neutral), oxidation, photolysis, and thermal degradation in order to identify the potential degradation products and consequently establish the possible degradation pathways and intrinsic stability of the drug. The study was performed according to ICH guidelines and drug was found to be relatively stable in the solid form. It showed that torasemide degraded significantly under acidic, neutral and alkaline conditions and resulted in formation of degradation product R2. When temperature was increased the degradation was accelerated. Also, the drug showed slight instability under extreme oxidative stress conditions which resulted in formation of two degradation products in total. The drug and degradation products have been separated employing gradient elution method on Zorbax SB C-18 analytical column. To characterize the degradation products LC-MSn was applied. The mass fragmentation pattern was established using single quadrupole and ion trap mass analyzers. Finally, the most possible degradation mechanism of torasemide in different experimental conditions was proposed.",
publisher = "Taylor & Francis Inc, Philadelphia",
journal = "Journal of Liquid Chromatography & Related Technologies",
title = "Forced degradation study of torasemide: Characterization of its degradation products",
pages = "2094-2082",
number = "15",
volume = "36",
doi = "10.1080/10826076.2012.712932"
}

Jović, Ž., Živanović, L., Protić, A., Radisić, M., Laušević, M., Malešević, M.,& Zečević, M.. (2013). Forced degradation study of torasemide: Characterization of its degradation products. in Journal of Liquid Chromatography & Related Technologies
Taylor & Francis Inc, Philadelphia., 36(15), 2082-2094.
https://doi.org/10.1080/10826076.2012.712932

Jović Ž, Živanović L, Protić A, Radisić M, Laušević M, Malešević M, Zečević M. Forced degradation study of torasemide: Characterization of its degradation products. in Journal of Liquid Chromatography & Related Technologies. 2013;36(15):2082-2094.
doi:10.1080/10826076.2012.712932 .

Jović, Žarko, Živanović, Ljiljana, Protić, Ana, Radisić, Marina, Laušević, Mila, Malešević, Marija, Zečević, Mira, "Forced degradation study of torasemide: Characterization of its degradation products" in Journal of Liquid Chromatography & Related Technologies, 36, no. 15 (2013):2082-2094,
https://doi.org/10.1080/10826076.2012.712932 . .