Potential contamination of medicinal products by mesilate esters and related compounds

Regulatory authorities have shown recent concern over possible contamination of medicinal products by mesilate esters and related compounds where the active substances are mesilates, (di)isetionates, tosilates or besilates.

Preclinical studies with certain mesilate esters have revealed that their DNA alkylation action can induce mutagenic, carcinogenic and teratogenic effects. This has been reported for methyl and ethyl mesilate and it is not unreasonable to suspect that similar toxic effects may exist in alkyl esters of other low molecular weight sulfonic acids, e.g. tosilates. Although there are no data showing the toxic effect of such esters in humans, there is nevertheless a potential risk that genotoxic substances as described above may be present as impurities in medicinal products containing active substances in the form of sulfonic acid esters.

Sulfonic acids are widely used in synthetic processes to manufacture drug substances (in the form of catalyst e.g. tosic acid, and are also formed as a by-product of their use as leaving groups) and in salt formation; sulfonic acids are widely used as they form very effective (highly crystalline) and safe salts.  Elimination of the use of sulfonic acids is highly undesirable either from a synthetic process or salt formation perspective. 

Sulfonate esters can potentially be formed through the interaction of sulphonic acids and alcohols. The problem of formation could be eliminated by the avoidance of alcoholic solvents.   However in many instances substituting alcohols for other solvents is either impractical, impacts upon the quality of drug substance, and could have environmental consequences. 

Intertek ASG can provide a range of analytical techniques to address this problem:

• LC-MS methods developed and optimised for quantification of mesilate impurities in a customers product
• GC-MS methods developed and optmised to quantify impurities such as methane sulphonates
• HS-GC methods developed to monitor the levels of Methanol and ethanol (and other residual solvents) in the free base
• HS-GC and GCMS to determine volatile genotoxic compounds

If you would like to find out more about these services or Intertek's pharmaceutical analysis capabilities then please contact pharma-europe@intertek.com for an information pack.