Determination of toxic elements in tricyclic active pharmaceutical ingredients by ICP-MS: a critical study of digestion methods

Abstract

The determination of As, Cd, Hg and Pb in tricyclic active pharmaceutical ingredients (APIs) was performed by ICP-MS after digestion by both combustion and wet digestion methods. Carbamazepine was digested using the dry ashing method recommended in United States Pharmacopeia 35th edition and significant losses of analytes were observed in recovery tests (38.0 ± 8.9, 99.5 ± 7.1, and 89.4 ± 6.3% of recovery for As, Cd and Pb, respectively). Mercury was completely lost by volatilization during digestion. The digestion of carbamazepine, amitriptyline hydrochloride and imipramine hydrochloride by microwave-assisted wet digestion in closed vessels (MW-AD) was not effective and a yellow-orange solid residue was observed for all substances. ¹H NMR of the carbamazepine residue indicated the nitration of carbamazepine aromatic rings forming stable nitro compounds. High pressure asher digestion systems were also used and solid residues were observed for carbamazepine and amitriptyline hydrochloride even under drastic digestion conditions (280 °C, 120 min). A complete digestion of all substances was obtained only by the use of high temperature and long time of digestion and reduction of sample mass to 0.08 g (320 °C, 180 min). The microwave-induced combustion (MIC) method for digestion of tricyclic APIs allowed the digestion of 0.5 g of all substances with high efficiency (RCC lower than 1%) using diluted nitric acid as absorbing solution (7 mol l⁻¹). The recoveries using this method were between 94 and 103% for the evaluated elements. The low RCC and acidity of digests obtained using MIC allowed the compatibility with ICP-MS and makes MIC a promising alternative as a sample preparation method for subsequent determination of toxic elements in APIs by ICP-MS.