Quantitation of Varenicline Nitroso-Drug Substance Related Impurity (VNDSRI) in Varenicline API by GC-MS/MS

User Benefits

- A GC-MS/MS method for the trace level determination of VNDSRI in Varenicline API

Introduction

Varenicline is a prescription medication used to treat smoking addiction. It is a high-affinity partial agonist for the α4β2 nicotinic acetylcholine receptor subtype (nACh) and has the capacity to reduce cravings and withdrawal symptoms. It is estimated that varenicline successfully helps, one of every eleven people who smoke; to remain abstinent from tobacco for six months. It is on the World Health Organization's List of Essential Medicines and is available as a generic medication. Varenicline Nitroso-Drug Substance Related Impurity (VNDSRI) is also known as N-nitroso varenicline. USFDA has identified higher levels of this impurity in some Varenicline finished drugs to be above FDA’s acceptable intake limit in some samples of Varenicline finished drugs. To ensure the safety and quality of varenicline tartrate drug product and drug substance, the USFDA has developed and validated a method to determine the presence or absence of VNDSRI. Toxicity/ Regulation/ Methods: Consumption of VNDSRI up to the acceptable intake limit of 37 nanograms per day is considered reasonably safe for humans, based on lifetime exposure. VNDSRI may increase the risk of cancer if people are exposed to it above the acceptable intake limit and over a long period of time, but a person taking a drug that contains VNDSRI at-or-below the acceptable intake limit every day for 70 years is not expected to have an increased risk of cancer. Agency scientists have evaluated the risk of exposure to VNDSRI at interim acceptable intake levels up to 185 ng per day (92.5 ppm) and have determined that it presents a minimal additional cancer risk when compared to a lifetime of exposure to VNDSRI at the 37 ng per day (18.5 ppm) level. N-nitroso varenicline is a solid with boiling point reported as 400.6±40.0°C at 760 mmHg. Due to such high boiling nature, LC-MS/MS has been the preferred analytical choice. The USFDA has published an HRMS method for the determination of VNDSRI in Varenicline tablets. However, an attempt was made to develop an application where selective extraction of VNDSRI is done by using liquid-liquid extraction technique which minimize the high boiling API matrix. Similarly, with the help of high temperature compatible column & advanced GC features unwanted traces of impurity is removed thus reducing any possibility of carryover. This application note describes a GC-MS/MS method for the determination of VNDSRI in Varenicline API using GCMS-TQ8040 NX with AOC-20i+s Plus system.

January 24, 2023 GMT