No abstract

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.

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.

Nitrosamine impurities are potential carcinogens, which are forming from the synthesis of drug substance as byproduct and also forming in presence of NaNO2/HNO3 and secondary amines (e.g., dimethyl amines, diethyl amine etc.,), which should be controlled in the medication of the human beings. Hence, robust and sensitive analytical method is required to control the nitroso amine impurities in drugs. The object of this method is to quantify the N-Nitrosodimethylamine (NDMA) impurity at 0.01 ppm level in ranitidine drug substance (form-1 and form-2) and drug product (tablets and capsules) of different geography. The source of NDMA impurity is also from the dimethyl amine as a key starting material using the ranitidine synthetic process. NDMA is forming when dimethyl amine is reacting with nitrous acid. The optimized LC method conditions were ACE C18-AR 3 µm, 150 × 4.6 mm column, mobile phase A as 0.1% formic acid in water, mobile phase B as 100% methanol, 0.8 ml/minute flow with gradient (time/%mobile phase B): 0/3, 3/3, 15/15, 15.1/100, 17/100, 17.1/3, 22/3, column temperature: 40°C, injection volume 50 µl, and total run time as 22 minutes. The final response achieved with multiple reaction monitoring (MRM) type: MRM [Q1 Mass (Da):75 Q3:58.2 Time (msecond)] in atmospheric chemical ionization positive mode. The optimized method was validated against the International Council for Harmonisation Q2 (R1) and United States of Pharmacopeia general chapter for compendial method validations 1225. This method can detect up to 0.01 ppm and quantify up to 0.03 ppm, the method shows linearity from 0.03 to 20 ppm.