Abstract
Objective: Development of a stability-indicating reverse phase liquid chromatographic (RP-HPLC) method for the simultaneous quantification of 11 impurities in the combined dosage forms of lamivudine and tenofovir disoproxil fumarate drug substances.Methods: Efficient chromatographic separation of all analytes was achieved on a Waters X-terra RP18 column (150 x 4.6 mm, 3.5 mm) using mobile phase A (ammonium acetate buffer, pH adjusted to 5.0±0.05 with dilute orthophosphoric acid) and mobile phase B (mixture of methanol and ammonium acetate buffer in the ratio of 20:80) with the flow rate of 1.0 ml/min in gradient elution mode at 260 nm.Results: The method was validated in terms of the limit of detection, limit of quantification, linearity, accuracy, precision and robustness according to the international conference on harmonisation (ICH Q2R1). Regression analysis showed that the correlation coefficient (r2) is greater than 0.997 for individual active drug substances as well as their related substances. The method has proven very accurate (94.6 % to 108.2 % with % RSD not more than 4.9), highly precise (% RSD of the Intra-day and the inter-day study was not more than 8.9) and robust enough to deliver accurate results, when the chromatographic conditions were altered intentionally. Forced degradation studies were conducted in acidic, basic, thermal, photolytic, humid and peroxide stress conditions, where all the degradation peaks were monitored. Highest degradation of lamivudine was observed under oxidative stress condition and tenofovir was more susceptible to degradation under acidic and alkaline conditions.Conclusion: The present method is able to separate all the related compounds with each other and with the main drug substances with the resolution more than 2.0. The test solution was found to be stable in diluent up to 24 h. The mass balance of forced degradation of formulations, close to 99 %, made this method as a stability indicating method.
Highlights
Tenofovir disoproxil fumarate {9-[(R)-2-[[bis [[isopropoxycarbonyl] oxy] methoxy] phosphonyl] methoxy] popyl] adenine fumarate} is a nucleotide analog reverse transcriptase inhibitor (NRTI) and is used for treating HIV infection in adults in combination with other antiretroviral agents
Lamivudine {4-amino-1-[(2R, 5S)-2-(hydroxyl methyl)-1,3-oxathiolan-5-yl]-1,2-dihydro pyrimidin-2-one} is an another NRTI used in the treatment of HIV infection and chronic hepatitis B virus (HBV) [1,2]
In order to maintain the quality of these drug substances, degradation study of combined dosage forms is of prime importance for the determination of the various degraded impurities
Summary
Tenofovir disoproxil fumarate {9-[(R)-2-[[bis [[isopropoxycarbonyl] oxy] methoxy] phosphonyl] methoxy] popyl] adenine fumarate} is a nucleotide analog reverse transcriptase inhibitor (NRTI) and is used for treating HIV infection in adults in combination with other antiretroviral agents. Lamivudine {4-amino-1-[(2R, 5S)-2-(hydroxyl methyl)-1,3-oxathiolan-5-yl]-1,2-dihydro pyrimidin-2-one} is an another NRTI used in the treatment of HIV infection and chronic hepatitis B virus (HBV) [1,2]. The combination of these two drugs is available in the market with brand names of Forstavir 30s tablet, Tavin 30s tablet, Ricovir 30s tablet, Tenolam 30s tablet, Envir 30s tablet with 300 mg strength of each rugs substance. As per the USP monograph, the specification limits for tenofovir monoester and tenofovir isopropyl impurities are 1.0 % and 0.3 %, respectively. In order to maintain the quality of these drug substances, degradation study of combined dosage forms is of prime importance for the determination of the various degraded impurities
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