Controlled Strategies and Estimation of Trace Toxic Solvents 1,2-Dichloroetane and Carbon Tetrachloride in Pharmaceuticals

Pharmaceutical residual solvents are volatile organic substances that are utilized in the production of drug substances and finished drugs. Solvents are an important part of the synthesis of active pharmaceutical ingredients (APIs) and drug products, where their correct choice can enhance the efficiency of reactions and affect key characteristics such as crystal structure, purity, and solubility. Since solvents and the associated impurities are part and parcel of the manufacturing process, they might not be completely removed during the processing and could be left in the final product. As a result, controlling residual solvents is a critical aspect of pharmaceutical development and manufacturing. Residual solvents tests are not usually described in single monographs since the nature of solvents can vary across manufacturers. Such solvents may be dangerous to the environment and also to patient safety in case of excessive levels. Thus, the ICH guideline Q3C (R9) provides acceptable limits of residual solvents. This guideline classifies solvents that are left behind into three categories depending on their possible risk to the human health with consideration of toxicity data and environmental issues. Pharmaceutical manufacturing should not use Class 1 solvents such as benzene (2 ppm), carbon tetrachloride (4 ppm), 1, 2- dichloroethane (5 ppm), 1, 1- dichloroethane (8 ppm) and 1, 1- trichloroethane (1500 ppm), as they are known human carcinog However, the small traces of these solvents can still be found as impurities in other solvents commonly used. E.g., benzene can be present in ethanol, methanol, acetone, and isopropyl alcohol whereas 1,1-dichloroethane and 1,1-trichloroethane can be present in dichloromethane. As such, special care and close-up regulation is required to keep the levels of these dangerous solvents in the solvents utilized in the manufacturing of pharmaceuticals at a minimal level.