Due to current regulatory requirements (ICH Guideline Q3D, USP <232> and <233>, as well as Ph.Eur. 5.20) the consideration of elemental impurities is mandatory for all pharmaceutical products, drug substances (APIs) and excipients as of January 2018. In this context a specific focus is set on cadmium (Cd), mercury (Hg), lead (Pb) and arsenic (As), the so called "big four". Due to their high toxicological relevancy, the regulatories stated the lowest permitted daily exposure values (PDE) for these elements. These regulations have established a need for the testing of these elements and correct sample preparation is crucial. Within the sample preparation section of USP <233> closed vessel digestion is stated as an appropriate method.
Determination of the Best Digestion Method
Closed vessel digestion can be performed by several different digestion methods. In an experiment focusing on the tricyclic antidepressants, amitriptyline hydrochloride, carbamazepine and imipramine hydrochloride, it was determined the best method of closed vessel digestion is by microwave-induced oxygen combustion (MIC). MIC digests organic samples in oxygen pressurized closed quartz vessels. During combustion in an oxygen atmosphere, samples are converted into gases or solids (e.g. halides, oxides). Non-metal elements can be collected in weak alkaline absorption solutions and metals are usually absorbed directly in diluted acids. Favorable results for MIC have been achieved thanks to the high temperatures reached during the combustion process (higher than 1000°C), allowing the complete destruction of most organic matrices. As a result, the low RCC ensures the avoidance of carbon matrix interferences. In addition, to prevent contaminations, the MIC process uses only oxygen with high purity.