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Technical Note

Hydroxyzine: An Analytical Profile

Norman G. Odeneal II,* John F. Casale, and Heidi L. Wojno
 U.S. Department of Justice
Drug Enforcement Administration
Special Testing and Research Laboratory
22624 Dulles Summit Court
Dulles, VA 20166
[email: norm1fc -at- yahoo.com]

ABSTRACT: Hydroxyzine, an anxiolytic and antihistamine, was identified as an adulterant in several large shipments of illicit cocaine. Analytical data (gas chromatography, infrared spectroscopy, mass spectrometry, and proton nuclear magnetic resonance spectroscopy) are presented.

KEYWORDS: Hydroxyzine, Anxiolytic, Antihistamine, Cocaine, Forensic Chemistry


Figure 1: Structure of Hydroxyzine

Introduction

This laboratory recently received samples from several multi-kilogram seizures of cocaine hydrochloride containing varying amounts of hydroxyzine (2 - 20 %) (1). The full chemical name for hydroxyzine is 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]ethanol. Hydroxyzine is marketed as an anxiolytic (used in treatment of anxiety), antihistamine (allergy), and as a mild tranquilizer (2,3). It is sold in tablet form. Federal law restricts this drug to prescription use only. Herein, we provide analytical data for hydroxyzine (4).

Experimental

Hydroxyzine: C21H27ClN2O2     374.91 amu

Source
 Sigma, Inc. (Atlanta, Georgia); Lot #083K0522

Gas Chromatography  
Instrument Agilent 6890N with a flame ionization detector
Column HP-1, 30 m x 0.25 mm x 0.25 µm film thickness
Injector Temperature 280° C
Oven Temperature 250° C Isothermal
Carrier Gas Hydrogen at 1.1 mL/min, split ratio = 25:1

Utilizing the above experimental parameters, the retention time for hydroxyzine is 10.63 minutes. The retention time relative to cocaine is 2.85.

Infrared Spectroscopy
Infrared spectra were obtained on a Nexus 670 FT-IR equipped with a single bounce attenuated total reflectance (ATR) accessory (Figure 2).

Mass Spectrometry  
Instrument Agilent 6890 interfaced with an Agilent 5973 MSD
Column DB-1, 30 m x 0.25 mm x 0.25 µm film thickness
Injector Temperature 280° C
Oven Temperature 90° C for 2 min, 14° C/min to 300° C
Carrier Gas Helium with split ratio = 25:1
Scan Range 34 - 550 amu
Electron Ionization 70 eV

The Total Ion Chromatogram (TIC) for hydroxyzine is shown in Figure 3. The fragmentation pattern shows a molecular ion at m/z 374 and a base peak of m/z 201 (Figure 4). Hydroxyzine may also be further characterized by GC/MS after derivatization. Hydroxyzine (5 mg) was reacted with a mixture of 250 µL of N-methyl-N-trimethylsilyltrifluoroacetamide (MSTFA) in 250 µL of chloroform at 80° C for 30 minutes. The mass spectrum of the resulting trimethylsilyl (TMS) derivative gives a molecule ion at m/z 446 (Figure 5).

Nuclear Magnetic Resonance Spectroscopy
 One dimensional proton NMR analyses were performed on a Varian Mercury 400 MHz NMR using a 5 mm Nalorac Indirect Detection probe. The sample was prepared at 10-30 mg/mL in deuterium oxide (D2O) containing TSP (3-(trimethylsilyl)propionic-2,2,3,3-d4 acid, sodium salt) as the reference at 0 ppm (Aldrich Chemical Co., Milwaukee, Wisconsin). Maleic acid was used as the internal (quantitation) standard. The proton spectrum of the standard was obtained with 8 scans using a 45 second delay, 90° pulse, 5 second acquisition time, and oversampling of 4 (Figure 6).

Results and Discussion

The referenced exhibits appear to be the first identified to contain hydroxyzine. Based on cocaine signature analysis, it appears that the hydroxyzine was added to the cocaine hydrochloride and physically mixed prior to pressing into kilogram bricks.

The purpose for adulterating illicit cocaine with such an unusual (and relatively expensive) compound is unclear. A (brief) review of several websites dedicated to drug abuse does not suggest any synergistic/desirable or pseudo-therapeutic effects to co-administration of hydroxyzine with cocaine. Therefore, it is most likely that it was used merely as a “cut of convenience”.

Acknowledgements

The author wishes to thank Senior Research Chemist Patrick A. Hays (this laboratory) for his time and expertise in interpreting the NMR spectrum of hydroxyzine.

References

  1. Anonymous. Diltiazem, hydroxyzine, and methylephedrine identified in separate shipments of cocaine. Microgram Bulletin 2004;37(8):137.

  2. Merck Index. 13th Edition; Whitehouse Station, Merck Research Laboratories: 1996, p. 563.

  3. http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a682866.html

  4. See also: Terry Mills III and J. Conrad Roberson, Instrumental Data for Drug Analysis, 2nd Ed., Vol. 2, pp.1182 - 1183; Elsevier, New York: 1987 (includes UV, MS, NMR, and FTIR data).

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figure 2
Figure 2: FTIR-ATR Spectrum of Hydroxyzine Hydrochloride

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figure 3
Figure 3: Total Ion Chromatogram of Hydroxyzine

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figure 4
Figure 4: Electron Ionization Mass Spectrum of Hydroxyzine

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figure 5
Figure 5: Electron Ionization Mass Spectrum of the Trimethylsilyl Derivative of Hydroxyzine

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figure 6
Figure 6: 400 MHz Proton NMR Spectrum of Hydroxyzine in D2O

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