TY  - JOUR
AU  - Protić, Ana
AU  - Radisić, Marina
AU  - Golubović, Jelena
AU  - Otašević, Biljana
AU  - Zečević, Mira
AU  - Lausević, Mila
PY  - 2016
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2746
AB  - Unknown degradation products of mycophenolate mofetil formed under oxidative stress conditions have been characterized via LC-MSn, using an RP-LC column (50 mm length, 2.1 mm i.d., 1.9 A mu m). The mobile phase consisted of 26 % acetonitrile and 74 % 9 mM ammonium acetate pH 5.87, the column temperature was set at 40 A degrees C, and the flow rate of the mobile phase was 400 A mu L min(-1). Four degradation products formed under the influence of 15 % hydrogen peroxide after an hour. Two of the degradation products had previously been identified as mycophenolic acid (m/z 321) and the N-oxide of mycophenolate mofetil (m/z 450). The other two unknown degradation products, denoted DP I (m/z 319) and DP II (m/z 466), were investigated in depth in order to identify their structures. The fragmentation patterns of DP I and DP II were established, analyzed, and compared to the fragmentation patterns of mycophenolate mofetil and the N-oxide of mycophenolate mofetil, which aided the elucidation of the structures of the unknown degradation products. The unknown degradation product DP I (m/z 319.2) was proposed to be an oxidized unsaturated mycophenolate aldehyde which also appeared as an ammonium adduct ion at m/z 336.3. The second unknown degradation product, DP II (m/z 466.3), was characterized as a doubly oxidized derivative of mycophenolate mofetil. A possible degradation pathway of mycophenolate mofetil under the influence of an oxidizing agent was also proposed.
PB  - Springer Heidelberg, Heidelberg
T2  - Chromatographia
T1  - Structural Elucidation of Unknown Oxidative Degradation Products of Mycophenolate Mofetil Using LC-MSn
VL  - 79
IS  - 13-14
SP  - 919
EP  - 926
DO  - 10.1007/s10337-016-3092-2
ER  - 

@article{
author = "Protić, Ana and Radisić, Marina and Golubović, Jelena and Otašević, Biljana and Zečević, Mira and Lausević, Mila",
year = "2016",
abstract = "Unknown degradation products of mycophenolate mofetil formed under oxidative stress conditions have been characterized via LC-MSn, using an RP-LC column (50 mm length, 2.1 mm i.d., 1.9 A mu m). The mobile phase consisted of 26 % acetonitrile and 74 % 9 mM ammonium acetate pH 5.87, the column temperature was set at 40 A degrees C, and the flow rate of the mobile phase was 400 A mu L min(-1). Four degradation products formed under the influence of 15 % hydrogen peroxide after an hour. Two of the degradation products had previously been identified as mycophenolic acid (m/z 321) and the N-oxide of mycophenolate mofetil (m/z 450). The other two unknown degradation products, denoted DP I (m/z 319) and DP II (m/z 466), were investigated in depth in order to identify their structures. The fragmentation patterns of DP I and DP II were established, analyzed, and compared to the fragmentation patterns of mycophenolate mofetil and the N-oxide of mycophenolate mofetil, which aided the elucidation of the structures of the unknown degradation products. The unknown degradation product DP I (m/z 319.2) was proposed to be an oxidized unsaturated mycophenolate aldehyde which also appeared as an ammonium adduct ion at m/z 336.3. The second unknown degradation product, DP II (m/z 466.3), was characterized as a doubly oxidized derivative of mycophenolate mofetil. A possible degradation pathway of mycophenolate mofetil under the influence of an oxidizing agent was also proposed.",
publisher = "Springer Heidelberg, Heidelberg",
journal = "Chromatographia",
title = "Structural Elucidation of Unknown Oxidative Degradation Products of Mycophenolate Mofetil Using LC-MSn",
volume = "79",
number = "13-14",
pages = "919-926",
doi = "10.1007/s10337-016-3092-2"
}

Protić, A., Radisić, M., Golubović, J., Otašević, B., Zečević, M.,& Lausević, M.. (2016). Structural Elucidation of Unknown Oxidative Degradation Products of Mycophenolate Mofetil Using LC-MSn. in Chromatographia
Springer Heidelberg, Heidelberg., 79(13-14), 919-926.
https://doi.org/10.1007/s10337-016-3092-2

Protić A, Radisić M, Golubović J, Otašević B, Zečević M, Lausević M. Structural Elucidation of Unknown Oxidative Degradation Products of Mycophenolate Mofetil Using LC-MSn. in Chromatographia. 2016;79(13-14):919-926.
doi:10.1007/s10337-016-3092-2 .

Protić, Ana, Radisić, Marina, Golubović, Jelena, Otašević, Biljana, Zečević, Mira, Lausević, Mila, "Structural Elucidation of Unknown Oxidative Degradation Products of Mycophenolate Mofetil Using LC-MSn" in Chromatographia, 79, no. 13-14 (2016):919-926,
https://doi.org/10.1007/s10337-016-3092-2 . .

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  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2150
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
VL  - 26
IS  - 1
SP  - 81
EP  - 96
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",
volume = "26",
number = "1",
pages = "81-96",
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  - Lausević, Mila
AU  - Malešević, Marija
AU  - Zečević, Mira
PY  - 2013
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1961
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3431
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
VL  - 36
IS  - 15
SP  - 2082
EP  - 2094
DO  - 10.1080/10826076.2012.712932
ER  - 

@article{
author = "Jović, Žarko and Živanović, Ljiljana and Protić, Ana and Radisić, Marina and Lausević, 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",
volume = "36",
number = "15",
pages = "2082-2094",
doi = "10.1080/10826076.2012.712932"
}

Jović, Ž., Živanović, L., Protić, A., Radisić, M., Lausević, 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, Lausević 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, Lausević, 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 . .

TY  - JOUR
AU  - Jović, Žarko
AU  - Živanović, Ljiljana
AU  - Protić, Ana
AU  - Radisić, Marina
AU  - Lausević, Mila
AU  - Malešević, Marija
AU  - Zečević, Mira
PY  - 2013
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1961
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
VL  - 36
IS  - 15
SP  - 2082
EP  - 2094
DO  - 10.1080/10826076.2012.712932
ER  - 

@article{
author = "Jović, Žarko and Živanović, Ljiljana and Protić, Ana and Radisić, Marina and Lausević, 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",
volume = "36",
number = "15",
pages = "2082-2094",
doi = "10.1080/10826076.2012.712932"
}

Jović, Ž., Živanović, L., Protić, A., Radisić, M., Lausević, 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, Lausević 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, Lausević, 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 . .

TY  - JOUR
AU  - Jović, Žarko
AU  - Živanović, Ljiljana
AU  - Radisić, Marina
AU  - Protić, Ana
AU  - Malesevic, Marija
PY  - 2012
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1700
PB  - Oxford Univ Press Inc, Cary
T2  - Journal of Chromatographic Science
T1  - Chemometrically Assisted Development and Validation of LC-UV and LC-MS Methods for Simultaneous Determination of Torasemide and its Impurities
VL  - 50
IS  - 4
SP  - 324
EP  - 334
DO  - 10.1093/chromsci/bms033
ER  - 

@article{
author = "Jović, Žarko and Živanović, Ljiljana and Radisić, Marina and Protić, Ana and Malesevic, Marija",
year = "2012",
publisher = "Oxford Univ Press Inc, Cary",
journal = "Journal of Chromatographic Science",
title = "Chemometrically Assisted Development and Validation of LC-UV and LC-MS Methods for Simultaneous Determination of Torasemide and its Impurities",
volume = "50",
number = "4",
pages = "324-334",
doi = "10.1093/chromsci/bms033"
}

Jović, Ž., Živanović, L., Radisić, M., Protić, A.,& Malesevic, M.. (2012). Chemometrically Assisted Development and Validation of LC-UV and LC-MS Methods for Simultaneous Determination of Torasemide and its Impurities. in Journal of Chromatographic Science
Oxford Univ Press Inc, Cary., 50(4), 324-334.
https://doi.org/10.1093/chromsci/bms033

Jović Ž, Živanović L, Radisić M, Protić A, Malesevic M. Chemometrically Assisted Development and Validation of LC-UV and LC-MS Methods for Simultaneous Determination of Torasemide and its Impurities. in Journal of Chromatographic Science. 2012;50(4):324-334.
doi:10.1093/chromsci/bms033 .

Jović, Žarko, Živanović, Ljiljana, Radisić, Marina, Protić, Ana, Malesevic, Marija, "Chemometrically Assisted Development and Validation of LC-UV and LC-MS Methods for Simultaneous Determination of Torasemide and its Impurities" in Journal of Chromatographic Science, 50, no. 4 (2012):324-334,
https://doi.org/10.1093/chromsci/bms033 . .

TY  - JOUR
AU  - Protić, Ana
AU  - Živanović, Ljiljana
AU  - Radisić, Marina
AU  - Lusevic, Mila
PY  - 2011
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/1559
AB  - Multicriteria decision making methodology in combination with experimental design has been applied for optimization of stability-indicating LC/DAD method of Mycophenolate mofetil and its degradation products. Via fractional factorial design variables with statistically significant impact on retention parameters of the investigated substances were defined and then thoroughly optimized toward four chromatographic responses combining central composition design and desirability function. The separation was achieved on Chromolith column (C18e, 100x4.6mm) with the mobile phase consisted of acetonitrile0.015M KH2PO4 (pH 4.4) (28:72, v/v). The flow rate of the mobile phase was 2mL/min and the detection was performed using PDA detector at 215nm. The method has been suitably modified for LC/MS/MS analysis. The ammonium-acetate buffer was used instead of phosphate buffer and pH of the water phase was adjusted with acetic acid. The flow rate was 1mLmin-1. The substance was subjected to stress conditions (0.01M NaOH, 1M HCl, 3-30% H2O2, 70 degrees C and day light). It resulted in formation of Mycophenolic acid and two oxidation products. The substance showed to be stable only towards photolysis. The LC/MS/MS values and fragmentation pattern of two unknown oxidation products were used in its characterization.
PB  - Taylor & Francis Inc, Philadelphia
T2  - Journal of Liquid Chromatography & Related Technologies
T1  - Impurity profiling of mycophenolate mofetil with the assisstance of desirability function in method development
VL  - 34
IS  - 12
SP  - 1014
EP  - 1035
DO  - 10.1080/10826076.2011.569809
ER  - 

@article{
author = "Protić, Ana and Živanović, Ljiljana and Radisić, Marina and Lusevic, Mila",
year = "2011",
abstract = "Multicriteria decision making methodology in combination with experimental design has been applied for optimization of stability-indicating LC/DAD method of Mycophenolate mofetil and its degradation products. Via fractional factorial design variables with statistically significant impact on retention parameters of the investigated substances were defined and then thoroughly optimized toward four chromatographic responses combining central composition design and desirability function. The separation was achieved on Chromolith column (C18e, 100x4.6mm) with the mobile phase consisted of acetonitrile0.015M KH2PO4 (pH 4.4) (28:72, v/v). The flow rate of the mobile phase was 2mL/min and the detection was performed using PDA detector at 215nm. The method has been suitably modified for LC/MS/MS analysis. The ammonium-acetate buffer was used instead of phosphate buffer and pH of the water phase was adjusted with acetic acid. The flow rate was 1mLmin-1. The substance was subjected to stress conditions (0.01M NaOH, 1M HCl, 3-30% H2O2, 70 degrees C and day light). It resulted in formation of Mycophenolic acid and two oxidation products. The substance showed to be stable only towards photolysis. The LC/MS/MS values and fragmentation pattern of two unknown oxidation products were used in its characterization.",
publisher = "Taylor & Francis Inc, Philadelphia",
journal = "Journal of Liquid Chromatography & Related Technologies",
title = "Impurity profiling of mycophenolate mofetil with the assisstance of desirability function in method development",
volume = "34",
number = "12",
pages = "1014-1035",
doi = "10.1080/10826076.2011.569809"
}

Protić, A., Živanović, L., Radisić, M.,& Lusevic, M.. (2011). Impurity profiling of mycophenolate mofetil with the assisstance of desirability function in method development. in Journal of Liquid Chromatography & Related Technologies
Taylor & Francis Inc, Philadelphia., 34(12), 1014-1035.
https://doi.org/10.1080/10826076.2011.569809

Protić A, Živanović L, Radisić M, Lusevic M. Impurity profiling of mycophenolate mofetil with the assisstance of desirability function in method development. in Journal of Liquid Chromatography & Related Technologies. 2011;34(12):1014-1035.
doi:10.1080/10826076.2011.569809 .

Protić, Ana, Živanović, Ljiljana, Radisić, Marina, Lusevic, Mila, "Impurity profiling of mycophenolate mofetil with the assisstance of desirability function in method development" in Journal of Liquid Chromatography & Related Technologies, 34, no. 12 (2011):1014-1035,
https://doi.org/10.1080/10826076.2011.569809 . .