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Four new degradation products of doxorubicin: An application of forced degradation study and hyphenated chromatographic techniques.

ABSTRACT: Forced degradation study on doxorubicin (DOX) was carried out under hydrolytic condition in acidic, alkaline and neutral media at varied temperatures, as well as under peroxide, thermal and photolytic conditions in accordance with International Conference on Harmonization (ICH) guidelines Q1(R2). It was found extremely unstable to alkaline hydrolysis even at room temperature, unstable to acid hydrolysis at 80 °C, and to oxidation at room temperature. It degraded to four products (O-I-O-IV) in oxidative condition, and to single product (A-I) in acid hydrolytic condition. These products were resolved on a C8 (150 mm×4.6 mm, 5 µm) column with isocratic elution using mobile phase consisting of HCOONH4 (10 mM, pH 2.5), acetonitrile and methanol (65:15:20, v/v/v). Liquid chromatography-photodiode array (LC-PDA) technique was used to ascertain the purity of the products noted in LC-UV chromatogram. For their characterization, a six stage mass fragmentation (MS6) pattern of DOX was outlined through mass spectral studies in positive mode of electrospray ionization (+ESI) as well as through accurate mass spectral data of DOX and the products generated through liquid chromatography-time of flight mass spectrometry (LC-MS-TOF) on degraded drug solutions. Based on it, O-I-O-IV were characterized as 3-hydroxy-9-desacetyldoxorubicin-9-hydroperoxide, 1-hydroxy-9-desacetyldoxorubicin-9-hydroperoxide, 9-desacetyldoxorubicin-9-hydroperoxide and 9-desacetyldoxorubicin, respectively, whereas A-I was characterized as deglucosaminyl doxorubicin. While A-I was found to be a pharmacopoeial impurity, all oxidative products were found to be new degradation impurities. The mechanisms and pathways of degradation of doxorubicin were outlined and discussed.

SUBMITTER: Kaushik D

PROVIDER: S-EPMC5762242 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Four new degradation products of doxorubicin: An application of forced degradation study and hyphenated chromatographic techniques.

Kaushik Dheeraj D Bansal Gulshan G

Journal of pharmaceutical analysis 20150523 5

Forced degradation study on doxorubicin (DOX) was carried out under hydrolytic condition in acidic, alkaline and neutral media at varied temperatures, as well as under peroxide, thermal and photolytic conditions in accordance with International Conference on Harmonization (ICH) guidelines Q1(R2). It was found extremely unstable to alkaline hydrolysis even at room temperature, unstable to acid hydrolysis at 80 °C, and to oxidation at room temperature. It degraded to four products (O-I-O-IV) in ox ...[more]

PMID: 29403942

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Project description:Blueberry (Vaccinium spp.) fruit consumption has increased over the last 5 years, becoming the second most important soft fruit species after strawberry. Despite the possible economic and sensory impact, the blueberry volatile organic compound (VOC) composition has been poorly investigated. Thus, the great impact of the aroma on fruit marketability stimulates the need to step forward in the understanding of this quality trait. Beside the strong effect of ripening, blueberry aroma profile also varies due to the broad genetic differences among Vaccinium species that have been differently introgressed in modern commercial cultivars through breeding activity. In the present study, divided into two different activities, the complexity of blueberry aroma was explored by an exhaustive untargeted VOC analysis, performed by two complementary methods: SPME-GC-MS (solid phase microextraction- gas chromatography-mass spectrometry) and PTR-ToF-MS (proton transfer reaction-time of flight-mass spectrometry). The first experiment was aimed at determining the VOC modifications during blueberry ripening for five commercially representative cultivars ("Biloxi," "Brigitta Blue," "Centurion," "Chandler," and "Ozark Blue") harvested at four ripening stages (green, pink, ripe, and over-ripe) to outline VOCs dynamic during fruit development. The objective of the second experiment was to confirm the analytical capability of PTR-ToF-MS to profile blueberry genotypes and to identify the most characterizing VOCs. In this case, 11 accessions belonging to different Vaccinium species were employed: V. corymbosum L. ("Brigitta," "Chandler," "Liberty," and "Ozark Blue"), V. virgatum Aiton ("Centurion," "Powder Blue," and "Sky Blue"), V. myrtillus L. (three wild genotypes of different mountain locations), and one accession of V. cylindraceum Smith. This comprehensive characterization of blueberry aroma allowed the identification of a wide pull of VOCs, for the most aldehydes, alcohols, terpenoids, and esters that can be used as putative biomarkers to rapidly evaluate the blueberry aroma variations related to ripening and/or senescence as well as to genetic background differences. Moreover, the obtained results demonstrated the complementarity between chromatographic and direct-injection mass spectrometric techniques to study the blueberry aroma.

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Four new degradation products of doxorubicin: An application of forced degradation study and hyphenated chromatographic techniques.

Publications

Four new degradation products of doxorubicin: An application of forced degradation study and hyphenated chromatographic techniques.

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