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Identification and simultaneous quantification of potential genotoxic impurities in first-line HIV drug dolutegravir sodium using fast ultrasonication-assisted extraction method coupled with GC-MS and in-silico toxicity assessment.
Sambandan, Elumalai; Thenmozhi, Kathavarayan; Santosh, G; Wang, Chun-Chi; Tsai, Pei-Chien; Gurrani, Swapnil; Senthilkumar, Sellappan; Chen, Yi-Hsun; Ponnusamy, Vinoth Kumar.
Afiliación
  • Sambandan E; Department of Chemistry, School of Advanced Sciences, Vellore Institute of Technology (VIT), Vellore 632014, India.
  • Thenmozhi K; Department of Chemistry, School of Advanced Sciences, Vellore Institute of Technology (VIT), Vellore 632014, India.
  • Santosh G; Department of Chemistry, School of Advanced Sciences, Vellore Institute of Technology (VIT), Chennai 600127, India.
  • Wang CC; School of Pharmacy, Kaohsiung Medical University, Kaohsiung City 807, Taiwan.
  • Tsai PC; Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung City 807, Taiwan; Department of Computational Biology, Institute of Bioinformatics, Saveetha School of Engineering, Saveetha Institute of Medical and Technical Sciences, Chennai 602105, Tamil Nadu, India.
  • Gurrani S; Department of Applied Science and Humanities, Invertis University, Bareilly, Uttar Pradesh, India.
  • Senthilkumar S; Department of Chemistry, School of Advanced Sciences, Vellore Institute of Technology (VIT), Vellore 632014, India. Electronic address: senthilkumar.s@vit.ac.in.
  • Chen YH; Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung City 807, Taiwan. Electronic address: jayshung1985@gmail.com.
  • Ponnusamy VK; Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung City 807, Taiwan; Research Center for Precision Environmental Medicine, Kaohsiung Medical University, Kaohsiung City 807, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Ci
J Chromatogr B Analyt Technol Biomed Life Sci ; 1245: 124275, 2024 Sep 15.
Article en En | MEDLINE | ID: mdl-39178609
ABSTRACT
Dolutegravir (DLG) has become a distinctive first-line antiretroviral therapy for the treatment of HIV in most countries due to its affordability, high efficacy, and low drug-drug interactions. However, the evaluation of genotoxic impurities (GTIs) in DLG and their toxicity assessment has not been explored thoroughly. Thus, in this study, a simple, fast, and selective analytical methodology was developed for the identification and determination of 7 GTIs in the comprehensive, explicit route of synthesis for the dolutegravir sodium (DLG-Na) drug. A facile, fast ultrasonication-assisted liquid-liquid extraction procedure was adapted to isolate the GTIs in DLG-Na and then analyzed using the gas chromatography (GC)-electron impact (EI)/mass spectrometer (MS) quantification (using selective ion monitoring mode) technique. This EI-GC/MS method was validated as per the current requirements of ICH Q2 (R1) guidelines. Under optimal method conditions, excellent linearities were achieved with R between 0.9959 and 0.9995, and high sensitivity was obtained in terms of detection limits (LOD) between 0.15 to 0.63 µg/g, and quantification limits (LOQ) between 0.45 to 1.66 µg/g for the seven GTIs in DLG. The obtained recoveries ranged from 98.2 to 104.3 % at LOQ, 15 µg/g, and 18 µg/g concentration levels (maximum daily dose of 100 mg). This developed and validated method is rapid, easy to adopt, specific, sensitive, and accurate in estimating the seven GTIs in a relatively complex sodium matrix of the DLG-Na drug moiety. As a method application, two different manufactured samples of DLG-Na drug substances were analyzed for the fate of the GTIs and drug safety for the intended dosage applications. Moreover, an in-silico QSAR toxicity prediction assessment was carried out to prove scientifically the potential GTI nature of each impurity from the alerting functional groups.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oxazinas / Piperazinas / Piridonas / Contaminación de Medicamentos / Límite de Detección / Compuestos Heterocíclicos con 3 Anillos / Cromatografía de Gases y Espectrometría de Masas Límite: Humans Idioma: En Revista: J Chromatogr B Analyt Technol Biomed Life Sci Asunto de la revista: ENGENHARIA BIOMEDICA Año: 2024 Tipo del documento: Article País de afiliación: India Pais de publicación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oxazinas / Piperazinas / Piridonas / Contaminación de Medicamentos / Límite de Detección / Compuestos Heterocíclicos con 3 Anillos / Cromatografía de Gases y Espectrometría de Masas Límite: Humans Idioma: En Revista: J Chromatogr B Analyt Technol Biomed Life Sci Asunto de la revista: ENGENHARIA BIOMEDICA Año: 2024 Tipo del documento: Article País de afiliación: India Pais de publicación: Países Bajos