An on-column methylation technique (OCMT) is described for the simultaneous, gas chromatographic determination in blood of ethosuximide (ES), phenobarbital (PB), primidone (PD), phenytoin (DPH), and 5-ethyl-5-phenylhydantoin (EPH). Multiple internal standards are employed in the OCMT, in order to eliminate or to minimize greatly error sources common to the technology of gas chromatography and to compensate for the different chemical dispositions of the antiepileptic drugs in an OCMT. The internal standards used in the OCMT were as follows: alpha,alpha,beta-trimethylsuccinimide (TMS) was used for the determination of ES; 5-ethyl-5-para-tolylbarbituric acid (MPB), for PB; 5-ethyl-5-(para-tolyl) hexahydropyrimidine-4,6-dione (MPD), for PD; and 5-(para-tolyl)-5-phenylhydantoin (MPPH), for EPH and DPH. The use of ether, the buffering of the plasma sample at pH 7.6, and the use of dilute (0.30-0.35 M) trimethyl-phenylammonium hydroxide (TMPAH) contributed to the specificity of the extraction scheme of the OCMT. The precision and accuracy of the OCMT was attributed to the use of appropriate, multiple internal standards. A method is described for the preparation of standard solutions of drugs in blank plasma (biological matrix) and for the use of the standards in calibration and daily intra-laboratory control of the OCMT.

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A number of reagents have been examined for effecting the conversion of an optically pure 2‐phenylhydantoic acid to an optically active 5‐phenylhydantoin. Trifluoroacetic anhydride (TFAA method) and dilute hydrochloric acid (acid‐catalysis method) proved to be the reagents of choice. The dependence of the kinetics of racemization of the 5‐phenylhydantoin system on temperature has been studied in dilute hydrochloric acid solution to support the conclusion that 5‐phenylhydantoins prepared by the acid‐catalysis method are nearly, if not entirely, optically uniform.

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