Acetamide is a potential genotoxic impurity; it should control in drug substance based on daily dosage level. It forms from base-contaminated acetonitrile and by-product of some drug substances. The available methods for acetamide in drug substance and water samples were determined by GC-MS using internal standard with critical procedures. These developed and validated methods can assist in evaluating the reaction between acetonitrile and different bases and also determine trace level acetamide in drug substances. The method development was initiated with DB-624, 30 m, 0.32 width and 1.0-μm column. The column was used to validate at the 600 ppm TTC value. Similarly, the CP-SIL 5CB, 60 m, 0.32 width, the 5-μm column was used for the remaining TTC values. The validation study was performed for all TTC limits. The % RSD for precision at 600, 60, 20, 10 and 2.5 ppm was <15%. The % recovery at all TTC level was in between the 70 and 130%. Solution stability study was performed up to the 24 h. At 2.5 ppm, the results were <15% variation from the initial value. The linearities from the 50 to 150% concerning TTC values were more than limit of 0.98 correlation coefficient. The limit of detection and limit of quantitation values were 0.4 to the 1.3 ppm, respectively, for 2.5 ppm TTC limit method.

During the oxidative (10% H2O2) degradation of suvorexant drug substance, around 1.0% of one impurity and less than 1.0% four impurities were found by a new high-performance liquid chromatography (HPLC) assay and related substance method. The mass numbers of 1.0% impurity was 469 [M + H]+, remaining four impurities were 172 [M + H]+, 467 [M + H]+, 483 [M + H]+ and 485 [M + H]+. The 469 [M + H]+, 485[M + H] and 172 [M + H]+ impurities were characterized by using the LC-MS/MS, HR-MS and 1D, 2D NMR spectroscopic data. The 172 [M + H]+ impurity was prepared synthetically and co-injected in HPLC. The retention time of synthesized 172 [M + H]+ impurity was matching with the unknown degradation impurity in HPLC. The developed mass compatible HPLC and ultra performance liquid chromatography methods were validated for drug substance and process impurities by following ICH Q2 (R1) guidelines.

A highly sensitive gas chromatography‐mass spectrometry quantitative method was developed for 3,3‐dimethylallyl bromide genotoxic impurity in the tazarotene drug substance. The method was validated by following the International conference for harmonization Q2 (R1) guideline for the limit test of 3,3‐dimethylallyl bromide genotoxic impurity in the tazarotene drug substance. The 148 m/z, 150 m/z, and 69 m/z ions were selected to get a response in mass spectrometry for 3,3‐dimethylallyl bromide. DB‐1 (30 mm × 0.25 × 1.0 µm) column was used for the separation of 3,3‐dimethylallyl bromide from the sample matrix. The limit of detection and limit of quantitation for 3,3‐dimethylallyl bromide in this method was 0.7 and 2.1 ppm, respectively. The method was precise and accurate at limit of quantitation level, 1.7% RSD was observed at limit of quantitation precision and 100.9% recovery observed at limit of quantitation accuracy, it was linear from the 5 to 20 µg/L, the correlation coefficient (r) was 0.9996.

Background: Aza sugars are organi c sugars having nitrogen containing polyhydroxyl sugar molecules. These molecules are active pharmaceutical ingredients; these are not well separated and eluted early in the HPLC and UPLC columns due to high polar nature. Aza sugars are having high conductivity hence the ion chromatography validated method has been established for the castanospermin and celgosivir along with its degradation studies (impurities). Methods: An ion chromatography with conductivity detector-cation column was used to determine the assay of castanospermin and celgosivir as in the form of bulk active pharmaceutical ingredients. The degradation impurities were identified and characterized by using the UPLC-TOF and the LCMS/MS techniques. Results: An ion chromatography method was developed and determined the assay for castanospermin and celgosivir as in the form of bulk active pharmaceutical ingredients with the specificity of the miglitol and 1-deoxynojirimycin. Validation was performed for assay of the castanospermin and celgosivir. The method precision %RSD results at 0.25 mg/mL concentration of castanospermin and celgosivir were 1.1 and 0.7 respectively. The linearity was performed from 25 to 200% (w.r.t 0.25 mg/mL); the results were 1.000 and 0.999 coefficient for the castanospermin and celgosivir respectively. The recovery studies, robustness, ruggedness, and solution stability results were within the acceptance limits of the ICHQ2 (R1) guidelines. The stress study for the castanospermin and celgosivir active pharmaceutical ingredients was performed by using 0.5N HCl solution, 0.5N NaOH solution, 3.0% H202 solution, UV-visible and the thermal conditions. The castanospermin was degraded as 20.8% of noxide impurity, and celgosivir was degraded as 10.0% n-oxide impurity under 3.0% H202 solution. In base degradation, the celgosivir was back converted completely to castanospermin. These n-oxide impurities were identified and characterized by using UPLC-TOF and LCMS/MS techniques after collection from the ion chromatography. Castanospermin and celgosivir are stable in remaining stress conditions. Conclusions: From the present study, it was found that robust analytical ion chromatography technique is used for the determination of assay in Aza sugar, especially assay for the castanospermin and celgosivir with minimum usage of test sample 0.25 mg/mL and used green chemistry solvents. The study also explains that the unique degradation of castanospermin and celgosivir under oxidative and base hydrolysis, Oxidative degradation impurities were identified and characterized as n-oxides of its respective castanospermin and celgosivir active pharmaceutical ingredients by using HRMS and LC-MS/MS.

DOI: http://doi.org/10.1002/sscp.202000050 The cover picture shows an orthogonal approach for method development and validation of three potential halo alkyl alcohol genotoxic impurities in miglitol drug substance by fast gas chromatography–mass spectrometry. The chloro ethanol/bromo ethanol/iodo ethanol is a key starting material (KSM) in miglitol drug substance synthesis. As per ICH M7, it is a potential genotoxic impurity (PGI), it should show cut‐off in miglitol drug substance. The developed and validated FGC‐MS quantitative method for chloro ethanol, bromo ethanol and iodo ethanol in miglitol drug substance are specific, accurate, precise, linear, robust and rugged at 2.0 ppm limit quantitation level and they can be detected up to 0.7 ppm.