scholarly journals A SELECTIVE AND SENSITIVE LC-MS/MS METHOD FOR QUANTIFICATION OF FOUR POTENTIAL GENOTOXIC IMPURITIES IN ATAZANAVIR SULFATE DRUG SUBSTANCE IN TRACE LEVEL

2021 ◽  
pp. 137-144
Author(s):  
SIVA JYOTHI N. ◽  
VENKATNARAYANA MUVVALA
Keyword(s):  
Mobile Phase ◽  
Multiple Reaction Monitoring ◽  
Research Work ◽  
Active Pharmaceutical Ingredient ◽  
Drug Substance ◽  
Genotoxic Impurities ◽  
Liquid Chromatography Tandem Mass ◽  
Short Run ◽  
Acquity Uplc ◽  
Atazanavir Sulfate

Objective: The main objective of current research work is to develop and validate a rapid, sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the trace analysis of four potential genotoxic impurities in Atazanavir Sulfate drug substance. Methods: LC-MS/MS analysis of four potential genotoxic impurities was done on Acquity UPLC CSH C18 (100 mm × 2.1 mm, 1.7 μm) column. In this method, mobile phase A (10 mM ammonium acetate) mobile phase B (methanol: acetonitrile (90:10, v/v) with gradient run with the flow rate of 0.2 ml/min. The method was developed with the short run time of 13 min. Triple quadrupole mass detector coupled with positive electrospray ionization was used for the quantification of genotoxic impurities in multiple reaction monitoring (MRM) mode. Results: The method was linear in the range of 0.3 ppm to 4.5 ppm for BOC Hydrazine Acid impurity, BOC Epoxide and Keto impurity with a correlation coefficient not less than 0.9994. The accuracy of the method was in the range of 99.26% to 105.71% for all four potential genotoxic impurities (PGIs). No impurities were identified in the Atazanavir Sulfate active pharmaceutical ingredient sample. Conclusion: The proposed method is specific, linear, precise, accurate, robust and stable for the quantification of the four genotoxic impurities at very low levels.

scholarly journals A Simple and Sensitive LC-MS/MS Method for Determination and Quantification of Potential Genotoxic Impurities in the Vismodegib Active Pharmaceutical Ingredient

2021 ◽  
pp. 88-102
Author(s):  
Rayala Rama Rao ◽  
Gundapaneni Ravi Kumar ◽  
Vadde Megha Vardhan ◽  
Veeraswami Boddu
Keyword(s):  
Mobile Phase ◽  
Multiple Reaction Monitoring ◽  
Active Pharmaceutical Ingredient ◽  
Mass Detection ◽  
Nitrobenzoic Acid ◽  
Genotoxic Impurities ◽  
Drug Sample ◽  
Multiple Reaction Monitoring Mode ◽  
Short Run ◽  
Gradient Mode

A rapid and sensitive LC-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantitative analysis of four potential genotoxic impurities Imp-A (2-chloro-5-nitroaniline), Imp-B (1-chloro-2-iodo-4-nitrobenzene), Imp-C (1-(2-chloro-5-nitrophenyl)ethan-1-one) and Imp-D (2-chloro-5-nitrobenzoic acid) in Vismodegib API drug sample. This trace analysis was achieved on CSH C18, 15.0 cm x 3.0 mm, 1.7 micron column maintained at 45°C. Optimal mobile phase consisted of 0.05% formic acid in water was used as mobile phase A and acetonitrile used as mobile phase B in gradient mode with the flow rate of 0.5 mL/min. The developed method had the short run time of 12 minutes. Quantification of four potential genotoxic impurities were carried out using mass detection with electrospray ionization in multiple reaction monitoring mode. The method was linear in the range of 0.03 ppm to 1.50 ppm for four potential genotoxic impurities with a correlation coefficient not less than 0.999. The recoveries were found satisfactory over the range between 96.67 and 106.90% for all selected impurities. The developed method was able to quantitate all four PGIs at a concentration level of 0.03 ppm (0.03 ppm with respect to 20 mg /mL Vismodegib).

scholarly journals An efficient HILIC-MS/MS method for the trace level determination of three potential genotoxic impurities in aripiprazole active drug substance

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sumanth Mullangi ◽  
Kunta Ravindhranath ◽  
Ravi Kiran Panchakarla
Keyword(s):  
Mobile Phase ◽  
Active Drug ◽  
Gradient Elution ◽  
Drug Substance ◽  
Hydrophilic Interaction ◽  
Chromatography Tandem Mass Spectrometry ◽  
Genotoxic Impurities ◽  
Liquid Chromatography Tandem Mass ◽  
Gradient Elution Mode

AbstractA sensitive and selective hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS) method was developed and validated for trace analysis of potential genotoxic impurities (PGIs): 2,3-dichloroaniline (PGI-1), bis(2-chloroethyl) amine (PGI-2), and 2-chloroethylamine (PGI-3), in aripiprazole (APZ) active drug substance. Separation of analytes was achieved on ACE HILIC–N Column (HILN-5-1046U, 100 × 4.6 mm, 5 μm) in gradient elution mode with mobile phase A [acetonitrile:ammonium formate buffer (95:5 v/v)] and mobile phase B [acetonitrile:ammonium formate buffer (50:50 v/v)] at a flow rate of 0.8 mL/min. Developed method was linear in the concentration range of 8–100 ppm for PGI-1, 11–100 ppm for PGI-2, and 12.5–100ppm for PGI-3 with R2 > 0.996. The developed method was accurate for quantification of each PGI with percent recoveries greater than 96% and RSD (%) not more than 5%. The developed method was precise for quantification of PGIs in aripiprazole with RSD (%) of not more than 4% for any of the PGIs. There was no interference of diluent peaks at the retention time of the PGIs and APZ in the method. All the PGIs and sample solutions were found to be stable at ambient laboratory temperature (25 ± 5 °C) and refrigerated condition (2–8 °C) for a period of 48 h. The developed HILIC-MS/MS method can be used for trace quantification of PGIs in aripiprazole drug in quality control laboratories of the pharmaceutical industry.

scholarly journals P63 UPLC/MS/MS assay for the simultaneous determination of seven antibiotics in human serum – application to pediatric studies

2019 ◽  
Vol 104 (6) ◽  
pp. e43.2-e43
Author(s):  
S Magreault ◽  
O Chaussenery-Lorentz ◽  
T Storme ◽  
E Jacqz-Aigrain
Keyword(s):  
Multiple Reaction Monitoring ◽  
Internal Standard ◽  
Ultra Performance Liquid Chromatography ◽  
Routine Activity ◽  
Therapeutic Drug ◽  
Pharmacokinetic Studies ◽  
Pediatric Dose ◽  
Liquid Chromatography Tandem Mass ◽  
Sampling Volume ◽  
Acquity Uplc

BackgroundAntimicrobials are widely used in children but pediatric dose regimens are not always validated, and PK studies, required to validate dosage, are difficult to conduct in children. Low sampling volume limits the number of PK samples drawn per patient and analytical methods adapted to small volumes are not always available. Due to the wide inter-patient pharmacokinetic (PK) variability in children, particularly neonates, therapeutic drug monitoring is required to adapt dosage to individual patients. In such clinical and analytical context, our aim was to develop a unique, rapid and highly sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) assay to quantify 7 antibiotics (amoxicillin, azithromycin, cefotaxime, ciprofloxacin, meropenem, metronidazole and piperacillin) in low sample volumes (50 µL) for both routine monitoring and pharmacokinetic studies.MethodsAfter protein precipitation by acetonitrile, the antibiotics and their associated deuterated internal standard were separated on a Waters Acquity UPLC HSS T3 (100 mm x 2.1 mm; 1.8 µm). The mobile phases consisted of a gradient of ammonium acetate (pH 2.4; 5mM) and acetonitrile acidified with 0.1% (v/v) formic acid (started ratio of 93:7, v/v), run at 0.5 mL/min flow rate (total run time: 2.75 min). Ions were detected in the turbo-ion-spray-positive and multiple-reaction-monitoring modes.ResultsThis method was linear from 0.1–50 µg/mL. Accuracy and precision were evaluated using Quality Control (2, 10, 35 µg/mL). Validation of the method proved that precision, selectivity and stability were all within the recommended limits.ConclusionThis method has the advantage of a unique, efficient and standardized analytical tool for rapid measurement of 7 antibiotics in low blood volume. It has been successfully applied for routine activity and pharmacokinetic studies in children and neonates.Disclosure(s)Nothing to disclose.

A simple and sensitive LC-MS/MS method for determination and quantification of potential genotoxic impurities in the ceritinib active pharmaceutical ingredient

2020 ◽  
Vol 12 (25) ◽  
pp. 3290-3295
Author(s):  
Mia Antolčić ◽  
Mislav Runje ◽  
Nives Galić
Keyword(s):  
Mass Spectrometry ◽  
Liquid Chromatography ◽  
Tandem Mass Spectrometry ◽  
Active Pharmaceutical Ingredient ◽  
Tandem Mass ◽  
Chromatography Tandem Mass Spectrometry ◽  
Genotoxic Impurities ◽  
Liquid Chromatography Tandem Mass

A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was used for quantification of four potential genotoxic impurities (PGIs) in the ceritinib active pharmaceutical ingredient.

scholarly journals DEVELOPMENT AND VALIDATION OF SEVEN PHENYL HYDRAZINE CHLORO ESTER ISOMERS (PGIs) BY RP-HPLC-UV METHOD IN ANTICOAGULANT DRUG SUBSTANCE; APIXABAN

2020 ◽  
pp. 119-123
Author(s):  
SARADHI VENKATA RAMANA V. ◽  
DURGA RAJA K. ◽  
RAGHU BABU K. ◽  
PADMA M. ◽  
JAGADEESH KUMAR V. ◽  
...  
Keyword(s):  
Mobile Phase ◽  
Hplc Method ◽  
Point Of View ◽  
Drug Substance ◽  
Accurate Analysis ◽  
Intermediate Precision ◽  
Chromatography Method ◽  
Rp Hplc ◽  
Genotoxic Impurities ◽  
Anticoagulant Drug

Objective: The objective of this work was to develop and validate a simple and sensitive reverse-phase high-pressure liquid chromatography method for the determination of seven potential genotoxic impurities in Apixaban drug substance. Methods: The optimized separation was achieved by using ACE 3 C18 PFP (150 mm×4.6 mm, 3 µm) HPLC column. The mobile phase-A was a degassed mixture of 0.01M Ammonium acetate buffer(PH adjusted 4.9±0.05 with diluted glacial acetic acid) and mobile phase-B was a degassed mixture of Acetonitrile, Isopropyl alcohol and Buffer PH 4.9 in the ratio of 60:20:20 v/v/v. The gradient program was operated at a flow rate of 1.0 ml/min and UV detection was at 330 nm. Results: The method was superior at linearity for seven impurities and correlation coefficient values were larger than 0.999, moreover, in the separation point of view, this method further achieved no matrix interference through chromatography by better resolution of the other impurities from the Apixaban drug substance and its related impurities for the accurate analysis of seven potential genotoxic impurities. The established limits of detection (LOD), limits of quantification (LOQ) values for the seven mutagenic impurities were each of 5 ppm (0.015µg/ml) and15 ppm (0.045µg/ml) respectively. The developed method was validated as per ICH guidelines and applied as a generic method to determine these seven potential genotoxic impurities for the pharmaceutical process control and drug material release. Conclusion: Validation of this analytical method was carried out including stability, selectivity, linearity, accuracy, system precision, method precision and intermediate precision thus proving that the described RP-HPLC method could be employed for fast and simple analysis of sevenphenyl hydrazine chloro ester isomers in Apixaban drug substance.

Screening of Synthetic Cathinones and Metabolites in Dried Blood Spots by UPLC–MS-MS

2020 ◽  
Author(s):  
Yang Wang ◽  
Yan Shi ◽  
Yingjia Yu ◽  
Lizhu Chen ◽  
Jiebing Jiang ◽  
...  
Keyword(s):  
Multiple Reaction Monitoring ◽  
Dried Blood Spots ◽  
Ultra Performance Liquid Chromatography ◽  
Sample Volume ◽  
Synthetic Cathinones ◽  
Limit Of Quantification ◽  
Blood Spots ◽  
Liquid Chromatography Tandem Mass ◽  
Ionization Mode ◽  
Acquity Uplc

Abstract After its use for decades in clinical screening, dried blood spots (DBS) have recently received considerable attention for their application in various novel psychoactive substances. The goal of this study was to develop and apply a DBS-based assay for 37 synthetic cathinones and their metabolites. Thirty microliters of whole blood sample after administration was spotted onto Whatman FTA classical cards, dried and extracted, and then analyzed by ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS-MS). The samples were chromatographed on a Waters Acquity UPLC®HSS T3 column (1.8 μm, 2.1 × 100 mm) and then identically packed defender guard cartridges of a Waters Acquity UPLC®HSS T3 column (1.8 μm, 2.1 × 5 mm, 3/pk). The separation was achieved via solvents of 20 mM ammonium acetate/formic acid 0.1% (A) and acetonitrile (B) at a flow rate of 0.25 mL/min. A tandem MS equipped with positive electrospray ionization mode source was used as the detector. Multiple reaction monitoring with the precursor/product ion combinations was used to quantify each analyte. The linear range of synthetic cathinones in the DBS was 2.0–200 ng/mL, and the lowest limit of quantification was 2.0 ng/mL for some synthetic cathinones and 10 ng/mL for others. The precision and accuracy of the results for the validation samples of the synthetic cathinones were within acceptable criteria. DBS sampling offers the advantages of reduced sample volume and convenient sample storage and shipment. This method can be successfully applied to the quantification of synthetic cathinones.

scholarly journals Development and Validation of a UHPLC-MS/MS Method for the Analysis of Fusarium Mycotoxins in Onion

2021 ◽  
Author(s):  
Sari Rämö ◽  
Minna Haapalainen ◽  
Satu Latvala
Keyword(s):  
High Performance ◽  
Multiple Reaction Monitoring ◽  
Internal Standard ◽  
Gradient Elution ◽  
Fusarium Mycotoxins ◽  
Monitoring Technique ◽  
Liquid Chromatography Tandem Mass ◽  
Serious Disease ◽  
Acquity Uplc ◽  
Development And Validation

AbstractFusarium basal rot (FBR) of onion is a serious disease problem worldwide. The Fusarium species causing FBR can also produce mycotoxins that are potentially harmful to humans and animals. In this study, a multiple reaction monitoring technique with ultra-high-performance liquid chromatography–tandem mass spectrometry (MRM UHPLC-MS/MS) was developed and validated for onion matrix to study Fusarium mycotoxins in the harvested onions. This study was focused on fumonisins B1, B2, and B3 (FB1, FB2, and FB3), beauvericin (BEA), and moniliformin (MON), which are the main mycotoxins produced by Fusarium oxysporum and Fusarium proliferatum. In the in-house validated protocol, the onion samples were extracted with methanol:water (3:1) using magnetic stirring for 15 min. FBs and BEA were determined directly from the filtered extracts, whereas MON required sample concentration prior to analysis. No cleanup of extracts was needed prior to analysis. The target mycotoxins were separated on an Acquity UPLC system BEH C18 column with gradient elution. Mycotoxins were identified and quantified using 13C-FB1 as internal standard. Minor matrix effect was compensated using multi-point matrix-matched calibration curves with uninfected onion sample. For the mycotoxins studied, a good linearity was obtained (R2 ≥ 0.99) and the recoveries were in the range of 67–122%, with the highest standard deviation for MON, 22%. The limits of quantification were from 2.5 to 10 ng g−1 in onion matrix. The method was successfully employed for the analysis of mycotoxins in harvested onions showing FBR symptoms and found to be infected with F. oxysporum and F. proliferatum.

A Sensitive LC–MS/MS Method for the Determination of Afatinib in Human Plasma and Its Application to a Bioequivalence Study

2021 ◽  
Author(s):  
Xi Luo ◽  
Xiu Jin Zhang ◽  
Wen Ling Zhu ◽  
Jin Ling Yi ◽  
Wen Gang Xiong ◽  
...  
Keyword(s):  
Human Plasma ◽  
Mobile Phase ◽  
High Performance ◽  
Multiple Reaction Monitoring ◽  
Internal Standard ◽  
Bioequivalence Study ◽  
Liquid Chromatography Tandem Mass ◽  
Multiple Reaction Monitoring Mode ◽  
Ionization Mode

Abstract A high performance liquid chromatography–tandem mass spectrometry assay for the determination of afatinib (AFT) in human plasma was established. A simple sample preparation of protein precipitation was used and separation was achieved on a C18 column by the gradient mixture of mobile Phase A of water (containing 0.1% ammonia) and the mobile Phase B of acetonitrile and water (V:V = 95:5, containing 0.2% ammonia). The multiple reaction monitoring mode was used to monitor the precursor-to-production transitions of m/z 486.2 → m/z 371.4 for AFT and m/z 492.2 → m/z 371.3 for AFT-d6 (internal standard) at positive ionization mode. The calibration curve ranged from 0.100 to 25.0 ng·mL−1 and the correlation coefficient was greater than 0.99. The intra- and inter-batch precision was less than or equal to 10.0%. Accuracy determined at four concentrations was in the range of 92.3–103.3%. In summary, our method was sensitive, simple and reliable for the quantification of AFT and was successfully applied to a bioequivalence study.

scholarly journals A SELECTIVE AND SENSITIVE METHOD DEVELOPMENT AND VALIDATION BY LC-MS/MS APPROACH FOR TRACE LEVEL QUANTIFICATION OF POTENTIAL GENOTOXIC IMPURITY OF BOC EPOXIDE IN ATAZANAVIR SULPHATE DRUG SUBSTANCE

2017 ◽  
Vol 9 (9) ◽  
pp. 143
Author(s):  
Nelaturi Subbaiah ◽  
Gopireddy Venkata Subba Reddy
Keyword(s):  
Formic Acid ◽  
Method Development ◽  
Limit Of Detection ◽  
Multiple Reaction Monitoring ◽  
Ammonium Hydroxide ◽  
Active Pharmaceutical Ingredient ◽  
Accurate Method ◽  
Drug Substance ◽  
Internal Diameter ◽  
Limit Of Quantification

Objective: To develop and validate a selective, sensitive, rapid and accurate method using LC-MS/MS technique to achieve efficient separation between active pharmaceutical ingredient (Atazanavir sulphate) and genotoxic impurity (BOC epoxide).Methods: The quantification was carried out using the column puro sphere star RP 18 e (length 150 mm, internal diameter 4.6 mm, particle size 3.0 µm) with electrospray ionization in multiple reaction monitoring (MRM) detection mode. Eluent-A was 0.1% formic acid in water and eluent-B was 0.1% formic acid and 0.1% ammonium hydroxide solution (25%) in acetonitrile. The isocratic mode of elution was carried out for the elution of impurity with the shorter run time of 6 min. The flow rate was 1.0 ml/min and column oven temperature was maintained 25 °C.Results: The method was validated as per ICH guidelines and arrived the limit of detection and limit of quantification for the potential genotoxic impurity and found to be 0.2 ppm and 0.5 ppm. The developed method was found linear in the concentration range of 0.5 ppm to 6 ppm and accuracy results were within the range. Conclusion: The developed short span method found to be selective, sensitive, precise and accurate for the quantification of the BOC epoxide genotoxic impurity in atazanavir sulphate drug substance.

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