Elsevier

Journal of Chromatography A

Volume 1217, Issue 48, 26 November 2010, Pages 7547-7555
Journal of Chromatography A

Identification of amino-tadalafil and rimonabant in electronic cigarette products using high pressure liquid chromatography with diode array and tandem mass spectrometric detection

https://doi.org/10.1016/j.chroma.2010.10.018Get rights and content

Abstract

A high-pressure liquid chromatography-diode array detection and multi-mode ionization tandem mass spectrometry (HPLC-DAD–MMI-MS/MS) method was used to identify amino-tadalafil and rimonabant in electronic cigarette (e-cigarette) cartridges. Amino-tadalafil is a drug analogue of the commercially approved Cialis™ (i.e. tadalafil). Rimonabant is a drug that was, at one time, approved for weight loss in Europe (although approval has been retracted), but not in the United States. In addition, poor quality control over the e-cigarette products analyzed here is shown by the presence of nicotine in products labeled as containing no nicotine or by the presence of significant amounts of rimonabant oxidative degradant in e-cigarette products containing rimonabant. Identification was accomplished by comparing the retention time of relevant peaks in the sample with those of standard compounds, in addition to comparison of the UV spectra, mass spectra and/or product ion mass spectra.

Introduction

Adulteration of products such as dietary and herbal supplements with drugs is a practice which can lead to potentially serious health consequences. Numerous reports exist in the literature of various matrices (e.g. herbal supplements, dietary supplements, pills, etc.) being adulterated with various drug compounds [1], [2], [3], [4], [5], [6]. Safety issues are complex and include possible toxicity of natural constituents, presence of contaminants or adulterants, and potential interactions between natural constituents, adulterant compounds and any prescription drugs a user may be taking. For example, tadalafil which is used for treatment of erectile dysfunction (ED), has been found as an adulterant in a variety of products [2], [5]. It is known that this drug can drastically lower blood pressure when taken in conjunction with certain nitrate containing drugs creating the possibility of a serious life-threatening event [7].

Electronic cigarettes are new devices being marketed as a way to enjoy the benefits of smoking without the serious health hazards associated with it. E-cigarette devices are designed to be refilled by purchasing either replacement liquids which are then used to refill existing delivery cartridges or new cartridges containing the desired flavor blend. Two basic designs of e-cigarettes currently exist, and their design differs in how the flavor solution is contained and heated. Both designs are based on the same principle: inhalation on the mouth piece activates a heater element. The heater element then aerosolizes the flavor solution which can consist of various combinations of propylene glycol, nicotine, tobacco extracts, flavorants and/or adulterants.

A thorough review of the legal status of e-cigarettes is beyond the scope of this publication, however, regulations concerning the distribution and/or sales of e-cigarettes are quite variable depending on the region. For example, e-cigarettes cannot be sold in Australia, Brazil, Canada, Panama, Singapore or Switzerland, but their sale is authorized in Britain, China, Denmark, Italy, the Netherlands and New Zealand. However, in Denmark and New Zealand, electronic cigarettes are considered medical devices and their sale is contingent on approval of the government or prescription by a medical authority [8], [9]. Within the United States, the sale of e-cigarette products is legal, however, the importation of e-cigarette products is currently prohibited. Further, the classification of e-cigarettes either as a tobacco product or as a drug delivery device is currently being contested [10].

Amino-tadalafil is a structural analogue of tadalafil, (6R,12aR)-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-pyrazino [10,20:1,6] pyrido[3,4-b]indole-1,4-dione, the active pharmaceutical ingredient in Cialis™, a prescription drug approved in the US for treatment of ED. The structures of tadalafil and amino-tadalafil are shown in Fig. 1(a) and (b), respectively. It has been reported that ED drugs such as tadalafil, have been added to other, unapproved, matrices ostensibly to treat ED [2]. Similarly, there have also been reports of herbal or dietary supplements being adulterated with designer ED analogues such as amino-tadalafil [5].

Rimonabant, 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide (trade name Zimulti™), was approved for the treatment of obesity in Europe, however its marketing authorization was withdrawn by the European Medicines Agency in 2009. Approval by the US FDA has been withheld due to unresolved issues between rimonabant therapy and increased frequencies of psychiatric adverse events, including suicide and an ill-defined constellation of neurological symptoms and seizures [11]. The structures of rimonabant and its oxidative impurity are shown in Fig. 1(c) and (d) respectively.

The purpose of this communication is to show the presence of an unapproved active pharmaceutical ingredient (API), rimonabant, and an ED drug analogue, amino-tadalafil in e-cigarette products. We will show that the contents of e-cigarette cartridges or refill solutions are poorly controlled as evidenced by the presence of compounds where they should not be (e.g. nicotine present in products advertised as containing no nicotine) or by the undisclosed degradation of advertised ingredients. Finally, we will show that e-cigarette products can now be included in the array of products which can be adulterated with active pharmaceutical ingredients or their analogues.

Section snippets

Chemicals and reagents

Rimonabant HCl (99%) was purchased from AK Scientific (Mountain View, Ca, USA). Tadalafil (99.7%, commercial name Cialis™) was supplied by Eli Lilly. Amino-tadalafil was purchased from Toronto Research Chemicals (North York, Ontario, Canada). Acetonitrile (Optima LC/MS grade) and water (Optima LC/MS grade) were purchased from Fisher Scientific (Pittsburgh, PA, USA). Ammonium acetate was purchased from Sigma Chemicals (St. Louis, MO, USA). A HALO C18 (2.1 mm × 100 mm, 2.7 μm) column was purchased

Results and discussion

A gradient eluent program was used to screen the various e-cigarette products. Standard solutions of tadalafil, amino-tadalafil and rimonabant were prepared at approximately 10 μg/mL and analyzed to determine their retention times, UV spectra, mass spectra and product ion mass spectra. The initial selection of standard compounds was dictated by the label information provided on the e-cigarette product package.

Sample extracts were analyzed using both diode array and mass detection with the mass

Conclusion

Two forms of e-cigarette products (refill solution and replacement cartridges) advertised as containing either E-Cialis or E-rimonabant were analyzed. E-cigarette products advertised as containing E-Cialis did not contain tadalafil (i.e. Cialis™), rather they contained amino-tadalafil. E-cigarette products advertised as containing rimonabant, did contain rimonabant and a significant amount of an oxidative impurity of rimonabant. Finally, of the samples analyzed, E-cigarette products advertised

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The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination or policy.

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