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A case of contaminated paracetamol

10 July 2020 - Pharma

News item in the Netherlands: newspaper NRC and investigative TV program Zembla have uncovered contaminated paracetamol for sale to consumers (NRC piece). The contaminant is 4-chloroaniline, a compound that is listed at the European Food Safety Authority (EFSA) as a genotoxic carcinogen. The levels found (6 mg per kilo) are 18 times the level considered safe. Other national health authorities interviewed for the news report were less alarmed. They do not see a need for a product recall.
The paracetamol raw material was produced in China and currently in high demand due to the corona pandemic. The synthesis method is not one listed on the Wikipedia page but a method starting from chlorobenzene. It is permitted to use this method since 2002, widely used in the world not just China and considered a cheaper production method. Drug manufacturers in Europe are not always required to disclose their raw-material producers, in the Netherlands it is a trade secret but in Italy it is public information.

But what is the synthesis method of not one of the classics? A Quora page has one answer: chlorobenzene is nitrated to 4-nitrochlorobenzene, then nucleophilic aromatic substitution with sodium hydroxide and HCl workup gives 4-nitrophenol, reduction with hydrogen and platinum gives 4-aminophenol and finally acylation with acetic acid gives the paracetamol (N-(4-hydroxyphenyl)acetamide). Still does not explain the chloroaniline. My best guess is incomplete removal of 4-nitrochlorobenzene starting material in the 4-nitrophenol synthesis. Preventable because the solubility of reactant and product are very dissimilar.

But is there reason for concern? It does not help that the European ESFA has way lower safety limits than national authorities, companies conduct their own quality checks on Chinese imports, establish that raw paracetamol meets expectations then proceed to formulate and sell. NRC news does not have a scoop.