Characterization of Five Oxidative Degradation Impurities and One Process Impurity of Suvorexant Drug Substance by LC-MS/MS, HR-MS and 1D, 2D NMR: Validation of Suvorexant Drug Substance and Process Impurities by HPLC and UPLC.

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.

An Orthogonal Approach for Determination of Acetamide Content in Pharmaceutical Drug Substance and Base-Contaminated Acetonitrile by GC and GC-MS External Method.

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.

Development and Validation of Miglitol and Its Impurities by RP-HPLC and Characterization Using Mass Spectrometry Techniques.

Alpha glucoside inhibitors used to treat type-2 diabetes mellitus (DM) are likely to be safe and effective. These agents are most effective for postprandial hyperglycemia. Miglitol is a type of drug used to treat type-2 DM. A simple, selective, linear, precise and accurate reversed-phase high-performance liquid chromatography (RP-HPLC) method was developed and validated for a related substance of miglitol and its identification, and characterization was done by different mass spectrometry techniques. The gradient method at a flow rate of 1.0 mL/min was employed on a prevail carbohydrate ES column (250 × 4.6 mm, 5 µm particle size) at a temperature of 35 °C. Mobile phase A consisted of 10 mM dipotassium hydrogen orthophosphate adjusted to pH 8.0 using concentrated phosphoric acid and mobile phase B consisted of acetonitrile. The ultraviolet detection wavelength was 210 nm and 20 µL of the sample were injected. The retention time for miglitol was about 24.0 min. Forced degradation of the miglitol sample was conducted in accordance with the International Conference on Harmonisation (ICH) guidelines. Acidic, basic, neutral, and oxidative hydrolysis, thermal stress, and photolytic degradation were used to assess the stability-indicating the power of the method. Substantial degradation was observed during oxidative hydrolysis. No degradation was observed under the other stress conditions. The method was optimized using samples generated by forced degradation and sample solutions spiked with impurities and epimers. Good resolution of the analyte peak from peaks, corresponding to process-related impurities, epimers and degradation products, was achieved and the method was validated as per the ICH guidelines. The method can successfully be applied for routine analysis of miglitol.