Background Tuberculosis is an infection that has high mortality rate in human as well as in animals if it remains unattained for long time. Scientists are always desirous to discover new molecules against Mycobacterium tuberculosis; one of them is bedaquiline which was recently approved to treat multidrug resistance TB. During the clinical study of new molecule stability and impurity are the key aspects to develop formulation. Stability issues in bulk drug are dangerous to drug safety and needs careful attention in formulation development. Bedaquiline stability study was completed with reversed-phase high-performance liquid chromatography (HPLC) and utilized in degradation kinetic study of bedaquiline in aqueous condition under different pH, temperature, and concentrations of degradant. Results Linearity was obtained in 50.0-250.0μg/ml, correlation coefficient, and regression line equation were 0.998 and Y=18528x + 7E+06 respectively. Intraday, inter day precision, and repeatability RSD were less than 2.0%. Average recovery in accuracy study was more than 98.0% showed that good recovery was obtained. Degradation kinetics parameters like activation energy (Ea), half-life (t50), rate constant (k), and shelf life (t90) were calculated under different condition for bedaquiline. Entropy and enthalpy of reaction was studied to gather knowledge about energy of system. Conclusion The result explained that bedaquiline degradation was pH-dependant, as increase in concentration of degradant and temperature, there was increase in degradation rate of bedaquiline. Bedaquiline was stable in neutral aqueous condition and at lower temperatures, shows that drug is hydrophobic in nature. Kinetic data showed that bedaquiline followed first order kinetics in acidic and alkaline pH.
Bedaquiline (BDQ) is a new drug approved by United States Food and Drug Administration (USFDA) in 2012 for the treatment of drug-resistant tuberculosis, which has become a major threat globally. The manuscript presents the development of three liquid chromatography (LC) based analytical methods. The first is a stability indicating RP-HPLC (reverse phase-high performance liquid chromatography) method to analyze the BDQ in presence of its degradation products. Another UPLC/ESI–MS (ultra-performance liquid chromatography/electron spray ionization–mass spectrometry) method was developed for the identification of different degradation based and process related impurities and the third, preparative HPLC method was developed for the isolation of major degradation products. Eleven degradation products and one process related impurity were identified using UPLC/ESI–MS whereas preparative HPLC was used to isolate two degradation products and their chemical structure was elucidated using nuclear magnetic resonance, mass and infra-red spectral data.
Objective: The objective of the present study was to investigate the stability of TRZ against different stressors and to prepare impurity profile for potential impurities and degradation products (DPs) formed under stress degradation of TRZ bulk drug and formulation. Methods: Three analytical methods were developed; the stability-indicating method that was developed using HPLC instrument with 0.01M ammonium acetate buffer (pH 4.0 using glacial acetic acid (GAA)) and acetonitrile in gradient program. The second method was a UPLC/ESI-MS method using 0.1 % Formic acid in Milli Q water (pH= 2.70) and 0.1%Formic acid in Milli Q water: Acetonitrile (10:90) in gradient program for identification of TRZ and DPs while the third, preparative HPLC method was used for isolation of impurities using (A) 0.05% ammonia (NH3) in water and (B) Acetonitrile+20% mobile phase A in gradient sequence. Gradient sequences are described in the main text. Results: The analytical method for stability study was developed and validated using ICH (Q2) R1 guidelines. The result of stability study by stress degradation showed that TRZ was susceptible to degradation in acid (7 DPs), alkaline, neutral (9 DPs) and oxidative conditions (10 DPs); major DPs were identified (where it was possible) and the chemical structure was elucidated by combining the data of ESI/MS, NMR and/or Tandem MS. The Impurity profiling was completed by reporting all the DPs, either major or minor for TRZ bulk drug and formulation. Conclusion: The complete Impurity profiling for TRZ is reported for the first time in literature. The study data would be add-on for formulation storage condition and further development.
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