Article

A Validated Stability Indicating RP-HPLC Method for Valganciclovir, Identification and Characterization of Forced Degradation Products of Valganciclovir Using LC-MS/MS

Authors:
  • Smt. Kashibai Navale College of Pharmacy Kondhwa Pune
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Abstract

The objective of the present study was to report the stability of novel antiviral drug, valganciclovir based on the information obtained from forced degradation studies. Valganciclovir was subjected to forced hydrolytic (acidic, alkaline and neutral), oxidative, photolytic and thermal stress in accordance with the ICH guideline Q1A (R2). The drug showed labiality under only acidic and photoacidic conditions while it was stable to other stress conditions. Resolution of the drug and degradation products was achieved on a Hypersil Gold C-18 column (4.6 × 250 mm, 5 μm) utilizing acetonitrile (A) and potassium dihydrogen ortho phosphate buffer (pH 5.0; 0.01M) in the ratio of 5:95 (v/v) at a flow rate of 0.6 ml/min and at the detection wavelength 252 nm. The major acidic stress degradation product was characterized by LC-MS/MS and its fragmentation pathway was proposed. Validation of the LC-DAD method was carried out in accordance with ICH guideline. The method met all required criteria and was applied for analysis of commercially available tablets.

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... The various methods have been used for the quantitative determination of antiviral drugs such as UV, capillary electrophoresis, and Different chromatographic methods likes GC and HPLC, LC-MS, GC-MS. In this review, authors concentrate on stability, suggesting HPLC /RP-HPLC methods for the accurately and effective development and validation of selected antiviral drugs such as, Atazanavir sulfate [35][36], Abacavir [37][38], Acyclovir [39], Adefovir Dipivoxil [41], Boceprevir [42], Baloxavir marboxil [43],Cobicistat [44], Darunavir ethanolate [45][46], Dolutegravir sodium [47][48], Didanosin [49], Efavirenz [50][51][52], Emtricitabine [53], Etravirine [54][55], Famciclovir [56][57][58], Foscarnet [59], Ganciclovir [60], Imiquimod [61], Lamivudine [62], Oseltamivir [63], Ribavirin [64][65], Simeprevir [66][67], Tenofovir [68], Valganciclovir [69][70][71][72], Zanamivir [73] and Zidovudine [74].The selective stability indicating RP-HPLC/ HPLC approaches for different antiviral drugs is summaries in Table.2 ...
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A protein precipitation, liquid chromatography/tandem mass spectrometry (LC/MS/MS) method has been developed and validated for the simultaneous determination of valganciclovir and its active metabolite ganciclovir in human plasma. The solvent system also served as a protein precipitation reagent. The chromatographic separation was achieved on an Aquasil C18 column (50 mm x 2.1mm, 5 microm). A linear gradient mobile phase between 0.02% formic acid and methanol was used. Detection was by positive ion electrospray tandem mass spectrometry on a Sciex API3000. The standard curves, which ranged from 4 to 512 ng/mL for valganciclovir and from 0.1 to 12.8 microg/mL for ganciclovir, were fitted to a 1/x weighted quadratic regression model. The method was proved to be accurate, specific and sensitive enough and was successfully applied to a pharmacokinetic study.
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We compared the efficacy and safety of valganciclovir with those of oral ganciclovir in preventing cytomegalovirus (CMV) disease in high-risk seronegative solid organ transplant (SOT) recipients of organs from seropositive donors (D+/R-). In this randomised, prospective, double-blind, double-dummy study, 364 CMV D+/R- patients received valganciclovir 900 mg once daily or oral ganciclovir 1000 mg three times a day (tid) within 10 days of transplant and continued through 100 days. CMV disease, plasma viremia, acute graft rejection, graft loss and safety were analyzed up to 6 and 12 months post-transplant. Endpoint committee-defined CMV disease developed in 12.1% and 15.2% of valganciclovir and ganciclovir patients, respectively, by 6 months, though with a difference in the relative efficacy of valganciclovir and ganciclovir between organs (i.e. an organ type-treatment interaction). By 12 months, respective incidences were 17.2% and 18.4%, and the incidence of investigator-treated CMV disease events was comparable in the valganciclovir (30.5%) and ganciclovir (28.0%) arms. CMV viremia during prophylaxis was significantly lower with valganciclovir (2.9% vs. 10.4%; p=0.001), but was comparable by 12 months (48.5% valganciclovir vs 48.8% ganciclovir). Time-to-onset of CMV disease and to viremia were delayed with valganciclovir; rates of acute allograft rejection were generally lower with valganciclovir. Except for a higher incidence of neutropenia with valganciclovir (8.2%, vs 3.2% ganciclovir) the safety profile was similar for both drugs. Overall, once-daily oral valganciclovir was as clinically effective and well-tolerated as oral ganciclovir tid for CMV prevention in high-risk SOT recipients.
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