II.3.6 Barbiturates by Masaru Terada and Ritsuko Watanabe

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II.3.6 Barbiturates by Masaru Terada and Ritsuko Watanabe 3.6 II.3.6 Barbiturates by Masaru Terada and Ritsuko Watanabe Introduction Barbiturates are being widely used as antiepileptics, hypnotics and anaesthetics (> Figure 6.1 and > Table 6.1). Th e incidence of barbiturate poisoning cases tends to increase in Japan ( > Figure 6.2) [1]. A majority of the barbiturate drugs is being controlled by the Narcotics ⊡ Figure 6.1 Structures of barbiturates. © Springer-Verlag Berlin Heidelberg 2005 302 Barbiturates ⊡ Figure 6.2 Incidence of fatal barbiturate poisoning cases. Since fatal cases due to Vegetamin® tablets containing phenobarbital are many, its incidence rate is also shown in this figure. and Psychotropics Control Law in Japan; thus they are also important drugs in view of forensic toxicology. Th e analysis of barbiturates in human specimens is being made by GC [2–6], GC/ MS [3, 6, 7–9], HPLC [10–13], LC/MS/MS [14], capillary electrophoresis [15] and immu- noassays [16, 17]. In this chapter, usual methods for analysis of barbiturates by GC and HPLC are presented. ⊡ Table 6.1 Properties and doses of barbiturates Action type Compound Route Therapeutic Maximum dose (g) dose (g) long-acting barbital oral 0.3 0.5 phenobarbital oral 0.03–0.2 0.25 phenobarbital sodium suppository 0.015–0.03 0.2 metharbital oral 0.1 Intermediate amobarbital oral 0.1–0.3 0.5 acting amobarbital sodium i.v./i. m. 0.25–0.5 short-acting pentobarbital calcium oral 0.05–0.1 0.5 pentobarbital sodium i.v. 0.1 0.5 secobarbital sodium i.v. 0.1–0.2 hexobarbital oral 0.1–0.4 0.5 ultrashort-acting thiopental sodium i.v. 0.3–0.5 (anaesthetic) thiamylal sodium i.v. 0.3–0.5 1.0 GC analysis 303 ⊡ Figure 6.3 Methylation reaction of phenobarbital with TMAH. GC analysis [3, 6] Reagents and their preparation • Barbital, phenobarbital sodium, amobarbital sodium, pentobarbital sodium, secobarbital sodium, hexobarbital, thiopental sodium and thiamylal can be purchased from Sigma (St. Louis, MO, USA); pure powder of metharbital was donated by Dainippon Pharmaceu- tical Co., Ltd., Osaka, Japan. • Each barbiturate is dissolved in methanol to prepare 1 mg/mL stock standard solution and stored at –20 °C. • An on-column methylation reagent, 0.2 M trimethylanilium hydroxide (TMAH) (Pierce, Rockford, IL, USA), is diluted with methanol to prepare 4 mM TMAH or 0.4 mM TMAH solution to be used as an on-column methylation reagent (> Figure 6.3)a. • Diethyl ether b used is of a special grade as pure as that used for analysis of the autoxidation value (AV) and peroxide value (POV) (Dojin Laboratories, Kumamoto, Japan). Other organic solvents are of the highest purity commercially available. • For calibration curves, various concentrations (4–200 ng/mL) of each barbiturate are pre- pared by diluting each 1 mg/mL solution with methanol, and a 10-µL each is evaporated to dryness under a stream of nitrogen, followed by addition of 0.2 mL serum. GC conditions Instrument: a Shimadzu GC-14A gas chromatograph (Shimadzu Corp., Kyoto, Japan). Column: a methylsilicone fused silica wide-bore capillary columnc ( DB-1, 15 m × 0.53 mm i. d., fi lm thickness 1 µm, J & W Scientifi c, Folsom, CA, USA). Column temperature: 60 °C → 8 °C/min → 250 °C; injection temperature: 250 °C d; carrier gas (fl ow rate): He (15 mL/min); make-up gas (fl ow rate): He (30 mL/min); detectors: an FID and a nitrogen-phosphorus detector ( NPD). 304 Barbiturates Procedure i. A 0.2-mL volume of serume, 1.3 mL distilled water, 1.0 mL of 0.2 M sodium acetate/acetic acid buff er solution (pH 6.0) and 6.0 mL of ethyl acetate/diethyl ether (1:1, v/v)f are placed in a glass centrifuge tube with a ground-in stopper. ii. Th e tube is shaken vigorously for 5 min. iii. It is centrifuged at 800 g for 5 min, and the organic layer is transferred to a glass vial with a conical bottom. iv. Th e organic extract is evaporated to dryness under a stream of nitrogen with warming at 40 °C; the residue is dissolved in 0.4 mL of 0.4 mM TMAH methanolic solution. v. A 1–2 µL aliquot of it is injected into GC; in this method, external calibration method is used. An external calibration curveg is constructed by spiking various concentrations of a barbiturate into serum. Th e peak area of a peak obtained from a test specimen is applied to the calibration curve to obtain its concentration in a specimen. For identifi cation by GC/ MS, mass spectra are presented in > Table 6.2. ⊡ Table 6.2 Mass spectra of free forms and methyl derivatives of barbiturates Compound M. W. CI mode EI mode Other fragment ions (isobutane) base peak MH+ metharbital 198 155 170, 112, 169 methylmetharbital 212 213 169 184, 126, 112 allobarbital 208 167 124, 80, 141, 106, 53 methylallobarbital 236 237 195 138, 194, 110, 221 amobarbital 226 156 141, 157, 55, 98 methylamobarbital 254 255 169 184, 112, 126 pentobarbital 226 141 156, 157, 55, 98 methylpentobarbital 254 255 169 184, 112, 126 secobarbital 238 167 168, 97, 124, 55 methylsecobarbital 266 267 196 195, 181, 138, 223 hexobarbital 236 221 81, 157, 80, 79, 155, 108, 53 methylhexobarbital 250 251 235 81, 79, 169 mephobarbital 246 218 117,118,146,103 methylmephobarbital 260 261 232 117, 146, 175, 77 phenobarbital 232 204 117, 146, 161, 77, 115 methylphenobarbital 260 261 232 117, 146, 175, 77 cyclobarbital 236 207 141, 81, 79, 67 methylcyclobarbital 264 265 235 169, 79 thiamylal 254 184 168, 167 thiopental 242 172 157, 173, 97, 69 Instrument: a Shimadzu QP-1000EX GC/MS instrument: column: DB-1 (15 m × 0.25 mm i.d., film thickness 0.25 µm); column temperature: 60° C (3 min) → 8° C/min → 290° C; injection temperature: 250° C; carrier gas (flow rate): He (1 mL/min); electron energy: 70 eV (EI), 200 eV (CI); reagent gas: isobutane. GC analysis 305 Assessment and some comments on the method Th e GC analysis of barbiturates without any derivatization gives very low sensitivities, even if a non-polar fused silica wide-bore capillary column (DB-1) is used, except for metharbital and hexobarbital. Th e sensitivities of most barbiturates are enhanced several-fold to several ten-fold by the methyl-derivatization (> Figs. 6.4 and 6.5, and > Table 6.3). Th e on-column methylation is very rapid and simple. Th e detection limits of the methyl-derivatives of barbiturates were 60–90 pg on-column with an NPD and 14–19 ng on-column with an FID. Methylmephobarbital is identical with methylphenobarbital; this means that discrimination ⊡ Figure 6.4 Gas chromatograms of free forms (A) and methyl-derivatives (B) of barbiturates using an NPD. Amounts of barbiturates used for the free and derivatized forms were 2 and 1 ng on-column, respectively. 1: metharbital; 2: allobarbital; 3: amobarbital; 4: pentobarbital; 5: secobarbital; 6: hexobarbital; 7: phenobarbital. 306 Barbiturates ⊡ Figure 6.5 Gas chromatograms for methyl derivatives of barbiturates spiked into distilled water (A) and human serum (B), and for blank human serum (C) using an NPD. The amount of each barbiturate spiked into distilled water or 0.2 mL plasma was 0.5 µg. The peak numbers are the same as specified in > Figure 6.4. between mephobarbital and phenobarbital becomes impossible aft er methylation of these compounds. It should be cautioned that the peak of thiopental overlaps that of methylcyclo- barbital. HPLC analysis [10] Reagents and their preparation • Each barbiturate is dissolved in methanol to prepare 10 µg/mL standard solution and stored at –20 °C. • As internal standard (IS) solution, 5-(4-methylphenyl)-5-phenylhydantoin (Sigma) is dis- solved in methanol to prepare 10 µg/mL solution. HPLC analysis 307 ⊡ Table 6.3 Retention times and detection limits for main barbiturates and their methyl derivatives measured by GC-NPD Compound Retention time Detection limit (min) (pg/on-column) metharbital 6.86 139 methylmetharbital 6.30 52 allobarbital 9.13 667 methylallobarbital 7.61 46 amobarbital 10.7 667 methylamobarbital 9.27 61 pentobarbital 11.0 667 methylpentobarbital 9.61 60 secobarbital 11.6 435 methylsecobarbital 10.2 48 hexobarbital 12.3 169 methylhexobarbital 11.9 52 mephobarbital 12.8 306 methylmephobarbital 12.2 57 phenobarbital 13.5 1,670 methylphenobarbital 12.2 57 cyclobarbital 13.7 1,360 methylcyclobarbital 12.4 89 thiopental 12.4 80 • Calibration curves: 10, 25, 50, 100, 500 and 1,000 µL of the standard solution of each bar- biturate were separately placed in glass centrifuge tubes together with 50 µL of IS solution, and evaporated to dryness under a stream of nitrogen, followed by addition of 0.5 mL se- rum each. HPLC conditions Column: a reversed phase columnh ( ODS-80 Ts, 10 cm × 4.6 mm i.d., particle diameter 2 µm, Toso, Tokyo, Japan). Mobile phase: 8 mM phosphoric acid solution/acetonitrile (3:7, v/v). Detection wavelength: 215 nm; fl ow rate: 0.4 mL/min; temperature: room temperature. Procedure i. A 0.5-mL volume of blood (urine)i, 50 µL IS solution, 0.5 mL distilled water, 0.1 mL of 0.2 acetic acid/sodium acetate buff er solution (pH 6.0) and 3 mL of ethyl acetate/diethyl ether (1:1, v/v) are placed in a 10-mL volume glass centrifuge tube with a ground-in stopper. 308 Barbiturates ii. Th e tube is well voltex-mixed or shaken for 2 min.
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