title: Characterization of forced degradation products and in silico toxicity prediction of Sofosbuvir: A novel HCV NS5B polymerase inhibitor.
abstract: Sofosbuvir is a direct acting antiviral medication used to treat Hepatitis C viral infection. The present study focuses on the degradation behavior of the drug under various stress conditions (hydrolysis, oxidative, thermal and photolytic) as per International Conference on Harmonization (ICH Q1A (R2)) guidelines. A high performance liquid chromatographic system (HPLC) was used to develop a selective, precise and accurate method for separating all the degradation products. The separation was achieved on a Sunfire™ C18 (150mm×4.6mm×5μm) stationary phase with a mobile phase of 10mM ammonium acetate (pH 5.0) buffer and acetonitrile in gradient elution mode. A quadrupole-time of flight mass analyzer equipped with an electrospray ionization technique was used to propose the structural information based on the MS/MS and accurate mass measurements. Seven degradation products were identified and characterised by LC-ESI-QTOF-MS/MS. In silico toxicity of the drug and its degradation products was determined using TOPKAT and DEREK toxicity prediction softwares. The proposed method was validated as per the ICH Q2 guidelines.
authors.affiliation: National Institute of Pharmaceutical Education and Research [NIPER], Balanagar, Hyderabad, Telangana, India.
authors.forename: Debasish
authors.initials: D
authors.lastname: Swain
authors.affiliation: National Institute of Pharmaceutical Education and Research [NIPER], Balanagar, Hyderabad, Telangana, India. Electronic address: gana@niperhyd.ac.in.
authors.forename: Gananadhamu
authors.initials: G
authors.lastname: Samanthula
authors.affiliation: National Institute of Pharmaceutical Education and Research [NIPER], SAS Nagar, Mohali, Punjab, India.
authors.forename: Shweta
authors.initials: S
authors.lastname: Bhagat
authors.affiliation: National Institute of Pharmaceutical Education and Research [NIPER], SAS Nagar, Mohali, Punjab, India.
authors.forename: P V
authors.initials: PV
authors.lastname: Bharatam
authors.affiliation: Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology [BIT], Mesra (Ranchi), Jharkhand, India.
authors.forename: Venkatakrishna
authors.initials: V
authors.lastname: Akula
authors.affiliation: Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology [BIT], Mesra (Ranchi), Jharkhand, India.
authors.forename: Barij N
authors.initials: BN
authors.lastname: Sinha
mesh_terms: D000818:Animals; D003198:Computer Simulation; D005544:Forecasting; D008297:Male; D051379:Mice; D051381:Rats; D000069474:Sofosbuvir / Q000378:metabolism* / Q000633:toxicity*; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000069474:Sofosbuvir; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: Degradation behavior; In silico toxicity; LC-ESI-QTOF–MS/MS; Sofosbuvir