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Technical Note

Diltiazem HCl: An Analytical Profile

DeMia E. Peters
U.S. Department of Justice
Drug Enforcement Administration
Special Testing and Research Laboratory
22624 Dulles Summit Court
Dulles, VA 20166
[email: demia -at- lycos.com]

ABSTRACT: Diltiazem, a potent vasodilator that is used in a wide variety of heart medications, 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: Diltiazem, Benzothiazepine, Calcium Channel Blocker, Vasodilator, Cocaine, Forensic Chemistry

Figure 1: Structure of Diltiazem Hydrochloride

Introduction

This laboratory recently received samples from several multi-kilogram seizures of cocaine hydrochloride (ranging from 71 - 85 % cocaine HCl) containing varying amounts of diltiazem hydrochloride (8 - 20 %) (1,2). The full chemical name for diltiazem is (2S-cis)-3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (3) [Figure 1]. It is prescribed as a calcium channel blocker, and has potent vasodilating activity (4,5). This vasodilation is accomplished without additional oxygen consumption by the heart (6). These therapeutic properties have made diltiazem hydrochloride an important constituent in a myriad of heart medications which are widely prescribed for effects in combating angina, hypertension, and/or irregular heartbeats (7). Herein, we provide analytical data for diltiazem hydrochloride (8).

Experimental

Diltiazem: C₂₂H₂₆N₂O₄S 414.53 amu

Source of Diltiazem
Sigma-Aldrich, Inc. (St. Louis, Missouri); Lot #123K0968, 99 %

Utilizing the above experimental parameters, the retention time for diltiazem HCl is 17.64 minutes. The retention time relative to cocaine is 1.52. A screening run utilizing the above parameters will detect the presence of diltiazem and allow for correct quantitation parameters to be selected.

Data was obtained by the use of an attenuated total reflectance (ATR) attachment on FTIR. The data was not ATR corrected [Figure 2]. In addition, spectral data was obtained with a KBr dispersion technique on FTIR [Figure 3]. The principal peaks are at 1680 cm^-1 and 1250 cm^-1.

Electron impact mass spectrometry data shows a molecular ion at 414 amu and a base ion of 58 amu [Figure 4A]. When the ion abundance of this spectrum is enhanced 10x, the ions are more easily viewed [Figure 4B].

Nuclear Magnetic Resonance Spectroscopy
Analyses were performed on a Varian Mercury 400 MHz NMR. The sample was prepared at 22.4 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 and maleic acid as the internal standard. The maleic acid forms a singlet at 6.4 ppm. 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 5].

Results and Discussion

The referenced exhibits appear to be the first identified to contain diltiazem. Based on cocaine signature analysis, it appears that the diltiazem was added to the cocaine during one of the final processing stages; either: A) the base was added to cocaine base and the two were co-precipitated as hydrochloride salts; or B) the hydrochloride was added to 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 diltiazem 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 John F. Casale and Senior Forensic Chemist Pamela R. Smith (this laboratory) for their assistance. The author would also like to acknowledge Senior Research Chemist Patrick A. Hays (this laboratory) for his time and expertise in interpreting the NMR spectrum of diltiazem hydrochloride.

References

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

2. See also: Anonymous. Cocaine containing diltiazem on the west coast. Microgram Bulletin 2005;38(1):2.

3. Clarke’s Analysis of Drugs and Poisons (electronic version); London, The Pharmaceutical Press: 2004.

4. Gil-Agusti M, Carda-Broch S, Garcia-Alvarez-Coque MC, Esteve-Romero J. Use of micellar mobile phases for the chromatographic determination of clorazepate, diazepam and diltiazem in pharmaceuticals. Journal of Chromatographic Science 2000;38:521-527.

5. http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a684027.html

6. Nagao T, Sato M, Nakajima H, Kiyomoto A. Studies on a new 1,5-benzothiazepine derivative (CRD-401). IV. Coronary vasodilating effect and structure-activity relationship. Chemical and Pharmaceutical Bulletin 1973;21(1):92-97.

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

8. See also: Terry Mills III and J. Conrad Roberson, Instrumental Data for Drug Analysis, 2nd Ed., Vol. 1, pp.708 - 709; Elsevier, New York: 1987 (includes UV, MS, NMR, and FTIR data).

[Figures 2 through 5 follow on the next three pages.]

Figure 2: Uncorrected FTIR-ATR Spectrum of Diltiazem Hydrochloride

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Figure 3: KBr Dispersion FTIR Spectrum of Diltiazem Hydrochloride

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Figure 4a: Electron Impact Mass Spectrum of Diltiazem

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Figure 4b: Electron Impact Mass Spectrum of Diltiazem (Enhanced 10x)

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Figure 5: 400 MHz Proton NMR Spectrum of Diltiazem Hydrochloride in D₂O

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