Microwave-induced Oxygen Combustion (MIC) for Determination of Elemental Impurities in Pure Tricyclic Active Pharmaceutical Ingredients (APIs)

Introduction

Tricyclic antidepressants are used as active pharmaceutical ingredients to treat depression, bipolar disorder, anxiety, obsessive-compulsive disorder and other mood disorders. They are also effective as analgesics so are used to treat chronic pain and used for migraine prophylaxis.

Due to current regulatory requirements (ICH Guideline Q3D, USP <232> and <233>, as well as Ph.Eur. 5.20) the consideration of elemental impurities has been mandatory for all pharmaceutical products, drug substances (APIs) and excipients since 2018. In this context a specific focus is set on Cd, Pb, As and Hg, the so called "big four". Due to their high toxicological relevancy the regulatories stated the lowest permitted daily exposure values (PDE) for these elements.

Microwave-induced oxygen combustion (MIC) allows the digestion of 0.5 g of different tricyclic APIs with residual carbon content lower than 1% using diluted nitric acid as absorbing solution. The achieved recoveries lie between 94% and 103% for the evaluated elements. The low residual carbon content and acidity of digests makes MIC an alternative sample preparation method for pure tricyclic APIs if concentrated acids apart from nitric acid want to be avoided.