Quantitation of 8 Nitrosamines in Thiocolchicoside API by LCMS-8045 system

User Benefits

- A simple and robust LC/MS method for the determination of nitrosamines in Thiocolchicoside API - Simultaneous analysis of eight nitrosamines without the need of complex sample pre-treatment

Introduction

Thiocolchicoside: Thiocolchicoside is a muscle relaxant that is commonly used to treat back pain and other pains caused by vertebral column or spinal cord disorders, as well as to relieve pain after surgery. It is a natural derivated product from colchicine and a semi-synthetic derivative of colchicoside. This medication functions by interacting with specific receptors in the central nervous system. Overview : The Drug Regulatory Authorities first noticed the presence of the nitrosamine (NSA) impurity, N- nitrosodimethylamine (NDMA) in products containing valsartan in July 2018. The discovery of nitrosamines in some types of drug products led the authorities to consider their existence in other APIs and drug products due to use of vulnerable processes and materials that may produce nitrosamine impurities. Therefore, the FDA published a guidance for industry; the recommendations in which apply to all chemically synthesized APIs. Occurrence of Nitrosamines: Formation of nitrosamines is possible in the presence of secondary, tertiary, or quaternary amines and nitrite salts under acidic reaction conditions. Under these conditions, nitrite salts may form nitrous acid, which can react with an amine to form a nitrosamine. Apart from these there are other routes such as; vendor-sourced starting materials and raw materials; recovered solvents, catalysts and reagents; cross contamination from common manufacturing facility; quenching process using nitrous acid; and packing/storage; which may result in nitrosamines formation or contamination. Toxicity/ Regulation/ Methods: NDMA and N- nitrosodiethylamine (NDEA) have been classified as probable human carcinogens. Hence, United state Food and Drug Administration (USFDA) recommends the following acceptable intake (AI) limits for NDMA, N-nitroso-N-methyl- 4-aminobutyric acid (NMBA), NDEA, N-nitrosoethyl isopropylamine (NEIPA), N-nitrosomethyl phenylamine (NMPA) and N-nitrosodiisopropylamine (NDIPA). These limits are applicable only if a drug product contains a single nitrosamine, and lowest of which is 0.03 ppm for drug substances with Maximum daily dose (MDD) of 880 mg/day. If more than one nitrosamine impurity is identified in the same drug substance the limit for total nitrosamines listed in table 1 is still not more than 26.5 ng/day or 0.03 ppm. Hence, it is imperative to detect above mentioned nitrosamines with Limit of Quantitation (LOQ) as low as possible to be sure that not just single nitrosamine impurity is below 0.03 ppm, but also total nitrosamine impurities are below 0.03 ppm.

May 23, 2022 GMT