Identification and analysis of an impurity inducing clinical adverse effect in anti-adhesion carboxymethyl chitosan products.

Controlling and minimizing the adverse effects of drugs are the key issues in ensuring the safety of drug therapy. Carboxymethyl chitosan has been widely used as an anti-adhesion material. However, recently in China there have been several reported instances of conjunctival hyperemia associated with the use of carboxymethyl chitosan containing products. Through MS, FTIR, and GC analysis, an impurity, diglycolic acid, was discovered in carboxylmethyl chitosan products. Pharmacological tests further indicated diglycolic acid has antithrombogenicity properties and induces vasodilation, both of which can cause conjunctival hyperemia. Thus, through these tests it was ascertained that diglycolic acid was the culprit responsible for the adverse clinical effects. Next, emphasis shifted to trying to discover the mechanism responsible for generating the diglycolic acid. Under strong basic conditions, chloroacetic acid can generate glycolic acid, which, upon etherification, can become diglycolic acid. In order to avoid future adverse effects, we have established an HPLC method to detect and determine diglycolic acid in carboxymethyl chitosan products. This method is specific, accurate, and precise, and can be easily implemented into routine monitoring practice. Concurrently, a refined method has also been established in order to eliminate diglycolic acid from carboxymethyl chitosan.