TY  - JOUR
AU  - Mladenović, Aleksandar R.
AU  - Jadranin, Milka
AU  - Pavlović, Aleksandar D.
AU  - Petrović, Slobodan
AU  - Drmanić, Saša
AU  - Avramov-Ivić, Milka
AU  - Mijin, Dušan
PY  - 2015
UR  - http://TechnoRep.tmf.bg.ac.rs/handle/123456789/2927
AB  - This study describes the investigation of degradation products of donepezil (DP) using a stability-indicating RP-HPLC method for determination of donepezil, which is a centrally acting reversible acetyl cholinesterase inhibitor. In order to investigate the stability of the drug and formed degradation products, a forced degradation study of the drug sample and finished product under different forced degradation conditions was conducted. Donepezil hydrochloride and donepezil tablets were subjected to stress degradation conditions recommended by the International Conference on Harmonization (ICH). Donepezil hydrochloride solutions were subjected to acid and alkali hydrolysis, chemical oxidation and thermal degradation. Significant degradation was observed under alkali hydrolysis and oxidative degradation conditions. Additional degradation products were observed under the conditions of oxidative degradation. The degradation products observed during forced degradation studies were monitored using the developed high performance liquid chromatography (HPLC) method. The parent method was modified in order to obtain LC-MS compatible method, which was used to identify the degradation products from forced degradation samples using high resolution mass spectrometry. The mass spectrum provided the precise mass from which the molecular formula of the drug substance and formed degradation products was derived, and proved the specificity of the method unambiguously.
AB  - Proučavanje degradacionih proizvoda donepezila je izvršeno korišćenjem RP-HPLC metode za određivanje stabilnosti donepezila, leka koji pripada grupi reverzibilnih inhibitora acetilholinesteraze. U cilju ispitivanja stabilnosti leka i njegovih degradacionih proizvoda sprovedena je studija forsirane degradacije čiste supstance kao i farmaceutskog proizvoda pod različitim uslovima. Donepezil-hidrohlorid i donepezil tablete su podvrgnuti različitim uslovima degradacije prema preporukama Internacionalne konferencije za harmonizaciju. Rastvori donepezil-hidrohlorida su podvrgnuti kiseloj i baznoj hidrolizi, hemijskoj oksidaciji i termalnoj degradaciji. Pri baznoj hidrolizi i hemijskoj oksidaciji uočena je značajna degradacija polaznog molekula. Oksidativnom degradacijom nastaju i proizvodi koji nisu uočeni kod ostalih postupaka forsirane degradacije. Nastali proizvodi analizirani su novorazvijenom HPLC metodom. Osnovna metoda je modifikovana u cilju dobijanja LC-MS kompatibilne metode kako bi se identifikovali nastali degradacioni proizvodi. Na osnovu resultata dobijenih masenom spektrometrijom dobijene su tačne mase proizvoda degradacije, čime je omogućeno određivanje njihovih molekulskih formula.
PB  - Association of the Chemical Engineers of Serbia
T2  - Chemical Industry & Chemical Engineering Quarterly
T1  - Liquid chromatography and liquid chromatography-mass spectrometry analysis of donepezil degradation products
T1  - Analiza degradacionih proizvoda donepezila primenom tečne hromatografije i tečne hromatografije-masene spektrometrije
EP  - 455
IS  - 3
SP  - 447
VL  - 21
DO  - 10.2298/CICEQ141023047M
ER  - 

@article{
author = "Mladenović, Aleksandar R. and Jadranin, Milka and Pavlović, Aleksandar D. and Petrović, Slobodan and Drmanić, Saša and Avramov-Ivić, Milka and Mijin, Dušan",
year = "2015",
abstract = "This study describes the investigation of degradation products of donepezil (DP) using a stability-indicating RP-HPLC method for determination of donepezil, which is a centrally acting reversible acetyl cholinesterase inhibitor. In order to investigate the stability of the drug and formed degradation products, a forced degradation study of the drug sample and finished product under different forced degradation conditions was conducted. Donepezil hydrochloride and donepezil tablets were subjected to stress degradation conditions recommended by the International Conference on Harmonization (ICH). Donepezil hydrochloride solutions were subjected to acid and alkali hydrolysis, chemical oxidation and thermal degradation. Significant degradation was observed under alkali hydrolysis and oxidative degradation conditions. Additional degradation products were observed under the conditions of oxidative degradation. The degradation products observed during forced degradation studies were monitored using the developed high performance liquid chromatography (HPLC) method. The parent method was modified in order to obtain LC-MS compatible method, which was used to identify the degradation products from forced degradation samples using high resolution mass spectrometry. The mass spectrum provided the precise mass from which the molecular formula of the drug substance and formed degradation products was derived, and proved the specificity of the method unambiguously., Proučavanje degradacionih proizvoda donepezila je izvršeno korišćenjem RP-HPLC metode za određivanje stabilnosti donepezila, leka koji pripada grupi reverzibilnih inhibitora acetilholinesteraze. U cilju ispitivanja stabilnosti leka i njegovih degradacionih proizvoda sprovedena je studija forsirane degradacije čiste supstance kao i farmaceutskog proizvoda pod različitim uslovima. Donepezil-hidrohlorid i donepezil tablete su podvrgnuti različitim uslovima degradacije prema preporukama Internacionalne konferencije za harmonizaciju. Rastvori donepezil-hidrohlorida su podvrgnuti kiseloj i baznoj hidrolizi, hemijskoj oksidaciji i termalnoj degradaciji. Pri baznoj hidrolizi i hemijskoj oksidaciji uočena je značajna degradacija polaznog molekula. Oksidativnom degradacijom nastaju i proizvodi koji nisu uočeni kod ostalih postupaka forsirane degradacije. Nastali proizvodi analizirani su novorazvijenom HPLC metodom. Osnovna metoda je modifikovana u cilju dobijanja LC-MS kompatibilne metode kako bi se identifikovali nastali degradacioni proizvodi. Na osnovu resultata dobijenih masenom spektrometrijom dobijene su tačne mase proizvoda degradacije, čime je omogućeno određivanje njihovih molekulskih formula.",
publisher = "Association of the Chemical Engineers of Serbia",
journal = "Chemical Industry & Chemical Engineering Quarterly",
title = "Liquid chromatography and liquid chromatography-mass spectrometry analysis of donepezil degradation products, Analiza degradacionih proizvoda donepezila primenom tečne hromatografije i tečne hromatografije-masene spektrometrije",
pages = "455-447",
number = "3",
volume = "21",
doi = "10.2298/CICEQ141023047M"
}

Mladenović, A. R., Jadranin, M., Pavlović, A. D., Petrović, S., Drmanić, S., Avramov-Ivić, M.,& Mijin, D.. (2015). Liquid chromatography and liquid chromatography-mass spectrometry analysis of donepezil degradation products. in Chemical Industry & Chemical Engineering Quarterly
Association of the Chemical Engineers of Serbia., 21(3), 447-455.
https://doi.org/10.2298/CICEQ141023047M

Mladenović AR, Jadranin M, Pavlović AD, Petrović S, Drmanić S, Avramov-Ivić M, Mijin D. Liquid chromatography and liquid chromatography-mass spectrometry analysis of donepezil degradation products. in Chemical Industry & Chemical Engineering Quarterly. 2015;21(3):447-455.
doi:10.2298/CICEQ141023047M .

Mladenović, Aleksandar R., Jadranin, Milka, Pavlović, Aleksandar D., Petrović, Slobodan, Drmanić, Saša, Avramov-Ivić, Milka, Mijin, Dušan, "Liquid chromatography and liquid chromatography-mass spectrometry analysis of donepezil degradation products" in Chemical Industry & Chemical Engineering Quarterly, 21, no. 3 (2015):447-455,
https://doi.org/10.2298/CICEQ141023047M . .

TY  - JOUR
AU  - Pavlović, Aleksandar D.
AU  - Ignjatović, Ljubiša M.
AU  - Popov, Saša Z.
AU  - Mladenović, Aleksandar R.
AU  - Stanković, Igor N.
PY  - 2014
UR  - http://TechnoRep.tmf.bg.ac.rs/handle/123456789/5761
AB  - A direct-injection, split-mode capillary gas chromatographic procedure with flame ionization detection was developed for the analysis of eight solvents used in the synthesis and purification of the anti-thrombotic drug clopidogrel bisulfate. The solvents analyzed were methanol, acetone, dichloromethane (DCM), 2-butanol, cyclohexane, toluene, acetic acid and N, N-dimethylformamide (DMF). In addition, because of dehydration of 2-butanol during the drying process, significant amounts of 2-butanol dehydration products (1-butene, cis- and trans-isomers of 2-butene, 2,2-oxybis[butane] and 1-(1- -methylpropoxy)butane) may be detected in clopidogrel bisulfate samples. The content of each of these volatile products can be evaluated using the same gaschromatographic method, with quantification based on the response factor established for the chromatographic peak of 2-butanol. Based on a large number of result sets, retrospectively, from many different batches analyzed, conclusions were made about process variations and reliability and a lack of consistency was identified in the quality of the active substance from a particular producer source. Multivariate analysis was used as the statistical technique to classify the samples. From the analyzed set of 11 solvents, 6 of them were preselected based upon their occurrence in the samples and both Principal Component Analysis (PCA) and Hierarchical Cluster Analysis (HCA) were performed.
PB  - Serbian Chemical Society
T2  - Journal of the Serbian Chemical Society
T1  - Application of gas chromatography analysis to quality control of residual organic solvents in clopidogrel bisulfate
EP  - 1293
IS  - 10
SP  - 1279
VL  - 79
DO  - 10.2298/JSC131120013P
ER  - 

@article{
author = "Pavlović, Aleksandar D. and Ignjatović, Ljubiša M. and Popov, Saša Z. and Mladenović, Aleksandar R. and Stanković, Igor N.",
year = "2014",
abstract = "A direct-injection, split-mode capillary gas chromatographic procedure with flame ionization detection was developed for the analysis of eight solvents used in the synthesis and purification of the anti-thrombotic drug clopidogrel bisulfate. The solvents analyzed were methanol, acetone, dichloromethane (DCM), 2-butanol, cyclohexane, toluene, acetic acid and N, N-dimethylformamide (DMF). In addition, because of dehydration of 2-butanol during the drying process, significant amounts of 2-butanol dehydration products (1-butene, cis- and trans-isomers of 2-butene, 2,2-oxybis[butane] and 1-(1- -methylpropoxy)butane) may be detected in clopidogrel bisulfate samples. The content of each of these volatile products can be evaluated using the same gaschromatographic method, with quantification based on the response factor established for the chromatographic peak of 2-butanol. Based on a large number of result sets, retrospectively, from many different batches analyzed, conclusions were made about process variations and reliability and a lack of consistency was identified in the quality of the active substance from a particular producer source. Multivariate analysis was used as the statistical technique to classify the samples. From the analyzed set of 11 solvents, 6 of them were preselected based upon their occurrence in the samples and both Principal Component Analysis (PCA) and Hierarchical Cluster Analysis (HCA) were performed.",
publisher = "Serbian Chemical Society",
journal = "Journal of the Serbian Chemical Society",
title = "Application of gas chromatography analysis to quality control of residual organic solvents in clopidogrel bisulfate",
pages = "1293-1279",
number = "10",
volume = "79",
doi = "10.2298/JSC131120013P"
}

Pavlović, A. D., Ignjatović, L. M., Popov, S. Z., Mladenović, A. R.,& Stanković, I. N.. (2014). Application of gas chromatography analysis to quality control of residual organic solvents in clopidogrel bisulfate. in Journal of the Serbian Chemical Society
Serbian Chemical Society., 79(10), 1279-1293.
https://doi.org/10.2298/JSC131120013P

Pavlović AD, Ignjatović LM, Popov SZ, Mladenović AR, Stanković IN. Application of gas chromatography analysis to quality control of residual organic solvents in clopidogrel bisulfate. in Journal of the Serbian Chemical Society. 2014;79(10):1279-1293.
doi:10.2298/JSC131120013P .

Pavlović, Aleksandar D., Ignjatović, Ljubiša M., Popov, Saša Z., Mladenović, Aleksandar R., Stanković, Igor N., "Application of gas chromatography analysis to quality control of residual organic solvents in clopidogrel bisulfate" in Journal of the Serbian Chemical Society, 79, no. 10 (2014):1279-1293,
https://doi.org/10.2298/JSC131120013P . .