II.4.1 Diphenylmethane Antihistaminics by Yoko Hieda and Kojiro Kimura

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II.4.1 Diphenylmethane Antihistaminics by Yoko Hieda and Kojiro Kimura 4.1 II.4.1 Diphenylmethane antihistaminics by Yoko Hieda and Kojiro Kimura Introduction Diphenylmethane antihistaminics are being widely used for treatments of allergy, motion (travel) sickness and cold. Th ey are also being sold as over-the-counter drugs. Th e structures of principal drugs of this group are shown in > Figure 1.1. Th ey are being analyzed by GC [1–6] and HPLC [7–13]. In this chapter, a GC method for simultaneous analysis of diphenylmethane antihistaminics and also HPLC methods for some representative drugs of this group are pre- sented. Simultaneous analysis by GC [4] Reagents and their preparation • Diphenhydramine hydrochloride, diphenylpyraline hydrochloride, phenyltoloxamine citrate, orphenadrine hydrochloride, benactyzine hydrochloride, doxylamine succinate, carbinoxamine maleate, chlorpheniramine maleate, triprolidine hydrochloride, homo- chlorcyclizine dihydrochloride, hydroxyzine dihydrochloride, clemastine fumarate and meclizine dihydrochloride can be purchased from Sigma (St. Louis, MO, USA). Pure powder of terodiline hydrochloride and piperilate hydrochloride was donated by Kissei Pharmaceutical Co., Ltd., Nagano, Japan and Nippon Shinyaku Co., Ltd., Kyoto, Japan, respectively. Sep-Pak C18 cartridges (classic type) were purchased from Waters (Milford, MA, USA). Other common chemicals were of the highest purity commercially available. • Care should be taken for that all of the above 15 kinds of drugs are in the salt forms. All compounds (5-mg each as the weight of its free base) are altogether dissolved in methanol to prepare 10 mL solution; a 10-µL volume of the mixture solution is spiked into 1 mL of whole blood or urine. One of the 15 drugs is selected for use as internal standard (IS). • Chloroform/methanol (9:1) and distilled water, 100–200 mL each, are prepared. • 0.5 M NaHCO3 solution: a 4.2-g aliquot of NaHCO3 is dissolved in distilled water to pre- pare 100 mL solution. GC conditions GC columna: DB-1 (15 m × 0.32mm i. d., fi lm thickness 1.0 µm), DB-17 (15 m × 0.32mm i. d., fi lm thickness 0.25 µm) both obtained from J & W Scientifi c (Folsom, CA, USA). © Springer-Verlag Berlin Heidelberg 2005 316 Diphenylmethane antihistaminics ⊡ Figure 1.1 Structures of principal diphenylmethane antihistaminics. GC conditions: an HP 5890 Series II gas chromatographb (Agilent Technologies, Palo Alto, CA, USA); detector: FID; column temperatures: 160 °C (1 min) →5 °C/min →290 °C for the DB-1 column, and 160 °C (1 min) →5 °C/min →280 °C for the DB-17 column; injection tem- perature: 240 °C; detection temperature: 280 °C; carrier gas: He; its fl ow rate: 3 mL/min; a 1-µL aliquot of sample solution is injected into GC in the splitless mode (1 min), followed by the split mode at 160 °C of oven temperature. Simultaneous analysis by GC 317 Procedure i. A 10-mL volume of methanol and 10 mL distilled water are passed through a Sep-Pak C18 cartridge c for its activation. ii. A 10-µL aliquot of methanolic solution of a suitable ISd (in case of simultaneous analysis of spiked drugs, 5 µg each in the 10 µL solution) is added to 1 mL whole blood, and mixed well with 9 mL distilled water for complete hemolysis. To this mixture, 5 mL of 0.5 M NaH- CO3 solution is added to make it slightly alkaline. To 1-mL volume of a urine specimen, a µ 10- L aliquot of the IS solution, 4 mL distilled water and 5 mL of 0.5 M NaHCO3 solution are added. iii. Either mixture of whole blood or urine specimen is poured e into the activated cartridge with a fl ow rate not faster than 5 mL/min using a 10-mL volume glass syringe. iv. Th e cartridge is washed with 10 mL distilled water, and the target compounds are slowly eluted with 3 mL of chloroform/methanol (9:1) into 4-mL volume glass vial. v. A small amount of the upper aqueous phase of the eluate is carefully removed with a Pas- teur pipette; the lower organic phase is evaporated to dryness under a stream of nitrogen. Th e residue is dissolved in 100 µL methanol, and a 1-µL aliquot of it is injected into GC. For quantitation, the peak area ratio of a target compound to IS is obtained. vi. For quantitative analysis, a 10-µL of IS solution and one of various concentrations of a target compound are added to 1 mL of blank whole blood or urine obtained from healthy subjects; at least 4 vials containing diff erent concentrations of the compound should be prepared. Th ese vials are processed according to the above procedure and analyzed by GC. Th e calibration curve consists of peak area ratio of a target compound to IS on the vertical axis and the concentration of a target compound on the horizontal axis. Th e peak area ratio obtained at the step v is applied to the calibration curve to obtain the concentration. Assessment and some comments on the method > Figure 1.2 shows gas chromatograms for the authentic diphenylmethane antihistaminics and for extracts of whole blood and urine in the presence and absence of 5 µg each of drugs per 1 mL obtained by the present method using a DB-1 capillary column. Many compounds ap- peared as sharp peaks. With an intermediately polar DB-17 capillary column, sharp peaks also appeared. By using both DB-1 and DB-17 columns, most compounds can be separated with sharp peaks; however phenyltoloxamine and orphenadrine (peaks 3 and 4) could not be sepa- rated with either column. With the DB-1 column, the peak of triprolidine (peak 9) overlapped an impurity peak of whole blood and urine extracts, and the peak of chlorpheniramine (peak 6) overlapped a small impurity peak of the whole blood extract. Th ese problems could be over- come by using the DB-17 column. Th e recoveries of the drugs from human whole blood were not lower than 90 % except for meclizine; the latter shows 49.4 % recovery. Th e recoveries of the drugs from urine were also not lower than 90 % except benactyzine, piperilate and meclizine; those of the latter drugs were 64.6, 72.2 and 79.8 %, respectively. Th e detection limits for diphenylmethane antihistaminics using the capillary GC method are 0.2–0.5 µg/mL. To enhance sensitivity and specifi city, GC/MS can be used; however, for most compounds, molecular or quasi-molecular peaks are missing in the positive EI mode [4] 318 antihistaminics Diphenylmethane ⊡ Figure 1.2 Capillary gas chromatograms for diphenylmethane antihistaminics extracted from whole blood and urine [4]. HPLC analysis of diphenyhydramine in blood and urine 319 except for terolidine and triprolidine. For the latter compounds, relatively intense molecular ions appear to be used for sensitive detection. In the positive and negative CI modes, intense quasi-molecular ions appear for most drugs, which can be used for sensitive quantitation. HPLC analysis of diphenyhydramine in blood and urine [7] Diphenhydramine is one of the most popular drugs in this group, and its poisoning cases are many. In this section, one of the most common method by HPLC for diphenyldramine is described. Reagents and their preparation • Diphenhydramine hydrochloride and imipramine hydrochloride can be obtained from Sigma. • IS: imipramine hydrochloride is dissolved in distilled water to prepare 0.5 µg/mL solu- tion. • Extraction solutions: hexane/isopropanol (98:2, v/v), saturated potassium carbonate aque- ous solution and 0.5 % (v/v) phosphoric acid solution. HPLC conditions An HPLC system includes a usual conveying pump, an injector and a UV detector. Column: reversed phase ODS-1 Spherisorb (15 cm × 0.46cm i. d., particle diameter 5 µm); mobile phase: acetonitrile/distilled water/1 M sodium dihydrogenphosphate solution (11:7:2, v/v); its fl ow rate: 1.8 mL/min: detection wavelength: 205 nm. Procedure i. To 1 mL of serum or urine, 100 µL of IS solution and 200 µL of saturated potassium car- bonate solution are added and extracted with hexane/isopropanol (98:2, v/v) by shaking. ii. To the organic phase, 100 µL of phosphoric acid solution for back-extraction of the com- pounds. An aliquot of the aqueous phase is injected into HPLC. Assessment of the method Th e retention times of diphenyhydramine and IS were 4.6 and 6.4 min, respectively. Linearity could be obtained in the range of 1–100 ng/mL; the detection limit was reported to be 1 ng/mL. 320 Diphenylmethane antihistaminics HPLC analysis of chlorpheniramine and its metabolites in blood and urine [8] Chlorpheniramine is one of the most popular antihistaminics, and has been being used for over 50 years. In this section, HPLC analysis of chlorpheniramine and its metabolites didemethyl- chlorpheniramine and demethylchlorpheniramine is described. Reagents and their preparation • Chlorpheniramine maleate and brompheniramine maleate are obtainable from Sigma. • IS: brompheniramine maleate is dissolved in distilled water to prepare 1 µg/mL solution. • Solutions to be used for extraction: 5 % KOH and 0.5 % phosphoric acid solutions. HPLC conditions An HPLC system to be used includes a usual conveying pump, an injector and a UV detector. µ Column: a reversed phase C18 column (30 cm × 0.39 cm i. d., particle diameter 5 m); mobile phase: acetonitrile/75 mM phosphate buff er solution (pH 2.5) (25:75, v/v); its fl ow rate: 2 mL/ min; detection wavelength: 254 nm. Procedure i. To 1 mL of serum or urine, 100 µL of IS solution and 250 µL of 5 % KOH solution were added and extracted with 5 mL ethyl ether. ii. Th e target compounds are back-extracted from the organic phase by adding 0.5 mL of 0.5 % phosphoric acid solution.
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