Confirmatory Analysis of Barbiturates and Benzodiazepines

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Both barbiturates and benzodiazepines can be identified by using GC-MS methodologies, although each drug class requires a different pre-treatment routine prior to analysis. It should also be remembered, as with all chromatographic analyses, that blanks should be run between each sample under investigation and check standards analysed as required by the quality assurance (QA) procedures in place in the laboratory.

9.2.4.1 GC-MS Analysis of Barbiturates

Due to their highly polar nature, barbiturates require derivatization prior to analysis by GC-MS. In such cases, the sample is dissolved in methanol, centrifuged, the supernatant recovered and placed in a derivatizing vial and is then 'blown down' under nitrogen. The derivatization procedure, using 0.2 M trimethylanilin-ium hydroxide in methanol, is, in principle, the same as that used for other pre-column derivatizations. However, with this system the reaction does not occur immediately because insufficient activation energy is available at ambient temperature for this to take place. Direct transfer of the reaction mixture onto the heated injection block of the gas chromatograph overcomes this problem and the derivatization reaction can then proceed. Such a reaction, an example of 'flash alkylation' is illustrated in Scheme 9.1.

MeOH

Scheme 9.1 N-methylation of a generalized barbiturate.

Table 9.2 GC operating conditions and parameters used for the GC-MS analysis of barbiturate derivatives

System/parameter

Description/conditions

Column

Injection temperature Column oven temperature programme Carrier gas Split ratio Detector

Mass spectrometric, temperature and settings as required

300 600 900 1200 Retention time (s)

I I I | I I I | I I I | I I I | I I I | I 200 400 600 800 1000 Retention time (s)

I I I | I I I | I I I | I I I | I I I | I 200 400 600 800 1000 Retention time (s)

m/z mrr

j ffTpTT 100

WTTtt|WWTTtTF

Figure 9.1 GC-MS data obtained for laboratory standard and casework samples of phenobarbitone, derivatized with trimethylanilinium hydroxide: (a) gas chromatogram of standard (tr, 166 s); (b) gas chromatogram of casework sample (tr, 164 s); (c) mass spectrum of standard; (d) mass spectrum of casework sample.

Having derivatized the sample, it can then be analysed by GC-MS, using the operating conditions shown in Table 9.2.

By employing this system, it is possible to analyse and identify barbiturates in casework samples, as illustrated in Figure 9.1 for the analysis of phenobarbitone. If the retention time and mass spectral data obtained for the standard and the components of the drugs sample are the same (as shown in this case), then an identification can be called.

The mass spectrum of the N-methylated derivative of phenobarbitone (5) is shown below in Figure 9.2. Explain this spectrum as fully as you can, considering the major ions with m/z > 110.

Answer

The major ions may arise as follows:

9.2.4.2 GC-MS Analysis of Benzodiazepines

Benzodiazepines can be conveniently identified by GC-MS analysis. This class of compounds does not require derivatization and thus can be analysed directly

Figure 9.2 Mass spectrum of the N-methylated derivative of phenobarbitone (DQ 9.3).

Table 9.3 GC operating conditions and parameters used for the GC-MS analysis of benzodiazepines

System/parameter Description/conditions

Injection temperature 275°C

Column oven temperature 250°Ca

Carrier gas He, at a flow rate of 1 ml min-1

Split ratio 20:1

Detector Mass spectrometric, temperature and settings as required a Isothermal.

from a solid-free methanol extract of the drug sample, by using the (typical) operating conditions shown in Table 9.3.

Again, if the retention time and mass spectral data obtained for the standard and the casework sample are the same, then an identification can be called.

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