Chemical Profile of Ecstasy Tablets – a Review

Ecstasy is a popular name of a substance called 3,4methylenedioxymethamphetamine (MDMA). Pharmacologically it displays effects related to amphetamine-type drugs like restlessness, well-being, and others. The Ecstasy is seized as tablets with a large variety of symbols and colors and an extremely diverse content. Also MDMA, other psychoactive compounds may be present, with or instead of, LSD, amphetamine, heroin, cocaine, and others. Considering the illicit production of ecstasy tablets, the raw materials used can be contaminated with several impurities and, multiple synthesis routes can be used generating a great variety number of sub-products and contaminants. The goal of this article is to evaluate the different methods of analysis described in the literature commonly used to determine the chemical profile of ecstasy tablets and use the analysis as a strategy to produce a database of ecstasy tablets seized at Rio de Janeiro State that will provide additional information for drug traffic repression. The interchange with others databases in Brazil and outside will evaluate the origin of these ecstasy tablets.


Introduction
In 1985, the amphetamines derivatives methylenedioxy and methoxy were placed in the Class 1 of the restricted substances' list from USA 8  Ecstasy is illicitly sold in tablet form, and typically prepared in a professional manner with a great variability of colors and symbols. Like all the abuse drugs illegally commercialized, the contents of this tablets are much diversified.
Also MDMA others psychoactive compounds may be presents, with or instead of like LSD, amphetamine, heroine, ketamine, cocaine and others. As a drug produced in illicit labs, it may be used, in their synthesis, impure precursors. Furthermore, a great number of synthetic routes may be used generating a large number of products, sub-products and contaminants. These contaminants are usually organic substances and result from the secondary reactions in the synthetic route, or from the precursor's contaminations, or even from inefficient purification methods and also may be presents in contaminated packets 9 .
Characterization studies of drugs may supply useful information to police authorities for combating drug dealing. Chemical connections between amounts may be established and materials from different seizures may be allocated in groups of similar characteristics. Furthermore, connections can be established between users and suppliers, a drug distribution pattern could be identified, and the different routes used by drug trafficking and the production sources, including the geographical origin may become clear 10 .
In 1976, GOMM et al compared amphetamine tablets and LSD blotters based only in the dimensions and in the microscopic exam. Nowadays, a reliable chemical profile of the illicit drugs combines physical, chemical, and statistical techniques to establish connections between different seizures 11 .
The complete chemical profile of Ecstasy tablets requires five main analytical tools: physical characterization of the tablets, which characterizes the samples by size, color, logotype and shape; active substance analysis to verify the presence of MDMA in the tablets and to determine the presence of others psychoactive substances (illicit or not) in the tablets; organic impurities analysis, evaluating the presence of sub-product routes; metallic traces which help in the identification of the synthetic route when they are used as catalysts in MDMA synthesis; excipients analysis which helps in the identification of similarity in the compression process of the tablets (same relation drug:exciepient) 9 .
The goal of this paper is to describe the different tools used to trace physical and chemical profiles of ecstasy tablets and to evaluate the advantages and disadvantages of these tools; this will aid police in creating a database of ecstasy tablets seized at Rio de Janeiro State, wich will permit provide additional information for drug traffic repression. The interchange with others databases in Brazil and outside will evaluate the origin of these ecstasy tablets.

Methodology
The electronic search was made using "Medline/PubMed" databases. There were used strategically words like "MDMA", "Ecstasy", "Chemical Profile", "Separation Methods", Impurities Profiles" and "Synthetic Routes". An initial analysis was achieved verifying the paper titles and their abstracts. After this trial, all the papers selected were obtained and reviewed.

Physical Aspects of the Tablets
Among abuse drugs, ecstasy tablets are known for their extremely variable physical aspects. It's common to find variable physical patterns in different ecstasy manufactures; these characteristics could be used in tablets individualizations. On the other hand, the unique information of similar physical aspects doesn't imply that tablets are part of the same batch or producer. Different physical aspects could be found on tablets with similar chemical aspects, since the same producer can use different dyes and labels in tablets production. Cheng

Analysis of the active compounds present in ecstasy
The term ecstasy is a generic one, since tablets sold as ecstasy may not present the Depending of the technique additional reference materials could be necessary. In the absence of reference materials, the MS detector can be used to elucidate the chemistry structure of the unknown compounds.

Organic impurities analysis
The organic impurities analysis can be used to help in the linkage of different seizures originated from the same laboratory and, possible, from the same batch of the illicit drug 9 .
The impurities can either be found in the precursors or can be produced during the MDMA synthesis, besides the ones present in the additives and in the diluents that could appear during the tablet production 9 . The impurities analysis is not restricted to the detection of the synthesis reaction byproducts, but the possibility of the byproducts react themselves generating further byproducts must be considered.
So it is important to develop a broad method that allows the identification of these residues.
In Ecstasy tablets, MDMA is considered the main illicit compound. Pathways of MDMA synthesis involve the use of isosafrole, safrole, piperonal and 3,4-MDP-2-P as precursors 11 . The two main routes are the Leuckart reaction and the reductive amination 11,14 .
In common impurities that participate in two or more synthesis route. It was important to identify the tablets from the same batch that exhibited the same impurity profile. The primary MDMA precursor found was safrole, probably obtained from sassafras oil.
Amphetamine and methamphetamine was found as impurities due to bottles used in synthesis process contaminations.

Elemental analysis (metals)
Metal residues could be found in ecstasy pills as a result of their use as catalysts and reducing agents or as components of the dyes used in the tablets, as well as contaminants of the materials used as additives and excipients during tablets that Pt was the main reducing agent in Holland MDMA production.

Excipients analysis
BELL et al (2000) have demonstrated that the excipients used in ecstasy tablets, the relation of drug:excipient, and even the hydration level of the illicit compounds, especially MDMA, could be used to discriminate different batches from the same seizing or to determinate the routes of drug trafficking. The spectroscopic techniques are the most used in these analyses, since the spectrum generate could serve as a "fingerprint" of drug samples 20 .

E. A. Alves & B. D. Sabino
The most used technique with the "fingerprint" intention is Raman Spectroscopy. This technique provides a spectrum with plenty of information without sample preparation, allowing the use in tablets, powders and liquids analyses 20 .
When it is associated with a statistical treatment it may to differentiate excipients compositions in ecstasy tablets 21 . The Raman spectrum is ideal because it can be subtracted from the excipients spectrum, generating unquestionable information in samples identifications 20 .

N isotopic ratio analysis in MDMA
The Isotope Ratio Mass Spectrometer (IRMS) is an analytical tool that exhibits a wide application in forensic science 22,23 . In this analysis, the sample is firstly converted in gas, for example, CO 2 , N 2 , CO, H 2 and SO 2 these gases are analyzed in a mass spectrometry at the same time that a reference material is analyzed. The IRMS are instruments with a unique magnetic focus where the isotopes are continuously and simultaneously detected by a multi-collector beam. The stable isotopes measurements are expressed as delta values () according to the formula: where R 13 = C/ C 12 13 . The greatest carbon isotope abundance ( 13 C) is 11.000ppm (0,011) in relation to its principal isotope ( 12 C). Others abundance values are: 2 H/ 1 H = 158ppm, 15 N/ 14 N = 3.700ppm, 18 Tablets   Table 1 summarizes the advantages and disadvantages of all the methods used to trace chemical profile of Ecstasy tablets.

Discussion
In the linkage of different seized samples by using chemical analysis of the drug, it's important to consider the complex pathway traversed by the drug before it gets into the user's hands. Synthetic drugs are especially rich in chemical information due to the singular characteristics provided in each chain stage.
Physical aspects of the tablets do not give precise information, as laboratories use different dyes and labels of logos to produce ecstasy pills with diverse physical patterns using the same bulk batches 13 . Physical analyses help with the characterization, but relevant additional information that can be obtained from others analyses. There is value in these analyses, as they are the only ones that could provide information about the compression machines used in the tablets. In the case of a repetitive and outstanding defect in the pills, it could be related to a physical or mechanical defect in the machine 10 .
The organic impurities are directly related to the synthesis process since they generally originated from drug synthesis 10  Metals could also give important information over the synthesis method, but it could also give data about the dyes added after the bulk production. These dyes could be added to the same batch during the bulk production or to different batches after their production. So, data about organic impurities and metal composition must crossover to give more precise information over the synthesis of MDMA. The

Conclusions
Synthetic drugs, like Ecstasy, have altered the illicit drug market. The portability and effiveness of facilities stimulate their trafficking and complicate their identification by the police.
The elucidation of the chemical profile of Ecstasy tablets in a region would be enable the construction of a detailed database that could be linked to others databases in others regions. Partnerships between these regions could highlight the drug traffic routes, as well origins of drug production. This database could also be used to connect the seized drugs with specific regions of origin. However, to obtain correct information regarding the differences and similarities between the chemical profiles analyzed, it is necessary to seek a deep knowledge of the chemical production of synthetic drugs. MDMA synthesis has common intermediate compounds, which makes the knowledge of impurities formation and its stabilities in reaction medium vital. the significance of some impurities in the synthetic route identification and, mainly, the interchangeability between impurities from distinct routes is of particular importance. It is therefore necessary to obtain new precursors as chemical markers to begin an ecstasy chemical profile study.
The use of equipment with sufficient sensibility and precision is vital to the impurities identification process, particularly if additional reference materials are unavailable. The use of gaseous or liquid chromatographs coupled to mass spectrometers is recommended and are indispensable in these studies. In metals analysis, it will be necessary the use of particulars equipments, such as: the atomic absorption spectrometer with flame ionization. Others techniques could provide additional data and could be useful in the characterization, such as: Raman Spectroscopy, near Infrared Spectroscopy, and others.
The chemical profile analysis of ecstasy tablets as a tool in the investigative intelligence is actuallt routine in European countries and in USA. In Brazil, and other developing countries, the forensics analyses of ecstasy tablets are restricted to the identification of the prohibited substances. Observing the strategic importance of these analyses, this new approach to drug analysis will be a reality in all the Forensic Laboratories around the world.