The Determination and Control of Genotoxic Impurities in APIs - Pharmaceutical Technology

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The Determination and Control of Genotoxic Impurities in APIs
The authors provide an overview of methods for the quantitative determination of genotoxic impurities (GTIs) in active pharmaceutical ingredients.

Pharmaceutical Technology
Volume 35, pp. s24-s30

Control of selected GTIs in APIs

GTIs can be well controlled by the process, without affecting quality, by modifying the route of synthesis. Methods for controlling sulfonates and alkylating agents are described below.

Sulfonates. Sulfonate ester formation is dramatically reduced at low amounts of water, or when acid is partially neutralized by substoichiometric concentrations of the weak base, 2,6 lutidine, to mimic conversion of a basic API to a salt. In the presence of a slight excess of base, ester formation was drastically reduced. These findings, particularly those involving an excess of base, are compelling and provide a scientific understanding to allow for the design of process conditions to minimize and control sulfonate formation (19).

Alkylating agents. Effective control of the alkylation process was possible because dimethyl sulfonate reagents barely reacted with nylon at room temperature (i.e., 25 C). At 100 C, the reaction could be stopped rapidly by immersing the tube in an ice bath. The optimum incubation times for alkylation with dimethyl sulfonate and diethyl sulfonate were 3 and 10 min, respectively. Dimethyl sulfonate, a less toxic reagent than dimethyl sulfonate, caused less damage to the nylon tubes and produced more chemically stable O-alkylated derivatives (20).


Identification and control of genotoxins in a synthetic process are challenging because of GTIs' evolving nature and variable points of entry. Hence, synthetic routes should be screened for the identification of structural elements that cause genotoxicity. Based on EMA guidelines, the TTC value of GTIs is 1.5 μg/day, but the value varies according to daily dose and length of use. Bearing in mind the sensitivity requirements of respective impurities, the authors developed an analytical matrix using GC methods. The analytical methods described here fulfilled the regulatory guidelines.

V. Gangadhar* is an executive in the Analytical Research Department, Y. Pardha Saradhi is a manager in the Analytical Research Department, and R. Rajavikram is a project trainee, all at Neuland Laboratories, Temple St., Bonthapalli Village, Jinnaram Mandal, Medak District 502 313 (A.P.), India, tel. +91 08458 392629,

*To whom all correspondence should be addressed.


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