Evaluation of different injection techniques in the gas chromatographic determination of thermolabile trace impurities in a drug substance.

Thermodegradation of labile compounds in the hot injection port of a gas chromatograph causes many problems and can lead to ambiguous, poorly reproducible results. Splitless injection used in trace analysis in order to achieve a lower detection limit may even enhance the difficulties due to the longer residence time of the volatized sample in the injection port. Different techniques were tested to avoid thermodegradation of an epoxide and its corresponding chlorohydrin in a drug substance: variation of the injector temperature, high inlet flow rate during injection by electronic pressure programming, and cool on-column injection. The results showed that on-column injection was superior to splitless injection. The chlorohydrin formed epoxide by release of HCl upon splitless injection. A more detailed investigation of the factors that affect epoxide formation indicates that active sites within the injector are responsible for the degradation and that the reaction is temperature dependent. However, results equivalent to those obtained by on-column injection were obtained for splitless injection when inert materials were used in the injector.