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The characterization of counterfeit Captagon tablets
SCIENTIFIC & TECHNICAL
The characterization of counterfeit Captagon tablets N AL-GHARABLY and A-R AL-OBAID Department of Pharmacology and Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia Journal of the Forensic Science Society 1994; 34: 165-167 Received 4 December 1992; accepted 15September 1993
Captagon (fenethylline) has been banned in Saudi Arabia since 1986. Despite this, it remains popular with problem drug users and is in widespread illicit production. Of 667 batches of seized "Captagon" tablets subjected to physical and chemical tests, 84% were found to be illicitly-produced fenethylline from a common source, and 16% were found to be fake tablets, consisting of a mixture of quinine and caffeine, also presumed to have a common origin. Fenethylline was synthesised by a modification of the German patented method.
Captagon (Fenetyllin) is in Saudi Arabien seit 1986 nicht mehr zugelassen. Trotzdem bleibt die Substanz bei Drogenkonsumenten sehr popular und wird weit verbreitet gesetzwidrig produziert. Aufgrund der physikalischen und chemischen Tests von 667 untersuchten Chargen sichergestellter CaptagonTabletten, stammen 84% des unrechtmassig-produzierten Fenetyllins aus einer gleichen Quelle. Bei den restlichen 16% handelt es sich um falsche Tabletten, bestehend aus einer Mischung aus Chinin und Coffein, vermutlich auch aus gleicher Produktion stammend. Zur Synthetisierung des Fenetyllins gelangte eine Modifikation des in Deutschland patentierten Vorgehens zur Anwendung.
Le "Captagon" (fenethylline) est interdit en Arabie Saoudite depuis 1986. MalgrC cela, c'est tojours une drogue populaire avec les toxicomanes et sa production illicite est Ctendue. De 667 lots de tablettes de "Captagon" saisies, suite 2 des tests physiques et chimiques, 84% s'av6rent Ctre de la fenethylline produite illkgalement d'une source commune et 16% sont des tablettes fausses constituCes d'un mClange de quinine et de cafkine dont on presume une origine commune. La fenethylline est synthetisee par une modification de la mCthode allemande patentee.
El Captagon (Fenetilina) esti prohibido en Arabia Saudita desde 1986. A pesar de ello sigue siendo popular su uso entre la poblaci6n drogadicta y su producci6n ilicita esta bastante extendida. De 10s 667 lotes de comprimidos de Captagon aprehendidos, sometidos a analisis fisicos y pruebas quimicas, el 84% dieron como resultado que se trataba de Fenetilina ilicita procedente de un origen comlin. El restante 16% resultaron ser falsos y consistian en una mezcla de quinina y cafeina, tambien de origen ilicito. La Fenetilina habia sido sintetizada mediante una modificaci6n del sistema patentado aleman.
Key Words: Drugs of abuse; Fenethylline; Captagon; Synthesis; Fake tablets JFSS 1994; 34(3): 165-167
Introduction Captagon (fenethylline hydrochloride) is one of the most widely abused stimulants in the Middle East, and in the Gulf states in particular, and its consumption is soaring [I]. Many heroin users, if unable to obtain heroin, substitute fenethylline, although its effects are different from those of amphetamine [Z]. Captagon has been banned in Saudi Arabia since 1986, and is no longer in clinical use, and there is therefore widespread illicit production of tablets and counterfeit tablets (fakes). Generally the illicit tablets are similar in formulation to that used for tablets manufactured in the pharmaceutical industry, but not every active ingredient will necessarily be present and, if present, the amount and purity may vary. In this work the physical and chemical characteristics of illicit Captagon tablets were examined. Because it is no longer available commercially, analytical standards of fenethylline were prepared by a modification of the German patent method [3]. Experimental Synthesis The synthesis of basically substituted alkylxanthine derivatives, including fenethylline (7-[2-[amethylphenyl) amino]-ethyl]-theophylline) has been reported [3]. Fenethylline was obtained by the condensation of the precursor 7-(8ch1oroethyl)theophylline with amphetamine under reflux using toluene for 4-6 h and subsequent treatment with iso-propyl alcohol and acidification with hydrochloric acid. This synthesis was unsuccessful and we therefore prepared fenethylline using a modification of the original method.
Amphetamine and theophylline were obtained from Merck AG, Darmstadt, Germany and 1,2dibromoethane was obtained from BDH Ltd, Poole, England. An alternative precursor, 7-(8bromoethyl)theophylline, which was prepared from theophylline by refluxing with 1,2-dibromoethane, was refluxed with amphetamine for 18 h. The crude fenethylline product was purified through a flash silica gel column to give a 64% yield of the hydrochloride. Fenethylline and its salt were characterized by TLC, mp, IR, UV, 'HNMR and 13CNMR analysis and elemental analysis. All data were identical to those reported in the literature [4]. Materials and methods Batches of seized illicit Captagon tablets were obtained from the General Directorate of Drug Control in Riyadh and 8 tablets from each of the 667
batches were subjected to physical and chemical analysis. The tablet thickness, diameter, marks and groove width were determined using a Reichert stereomicroscope. Thin layer chromatography was carried out on glass plates coated with Silica Gel G, 250 mm thick, and air dried, using a developing system consisting of strong ammonia solution and methanol (1.5 :100). The absorption spectra were determined between the wave length 200 and 400nm on a UV-Vis LKB 4054 spectrophotometer using a 1cm path length cell. Fenethylline, caffeine and quinine were extracted by organic solvent from aqueous alkaline solution and dissolved in 0.1 N H2S04 or 0.1 N NaOH for use as standards. Results and discussion Physical examination showed that some of the seized samples (about 16%) were thicker, had a narrower groove, and bilunar inversions nearer to the edge (Figure 1 and Table 1).
FIGURE 1 Grooves on the two sides of Captagon (left) and counterfeit (right) tablets.
The Rf values and the absorption maxima for the seized tablets are shown in Table 2. The majority of the tablets contained fenethylline, but about 16% of the total were fakes, and were shown by TLC and UV-Vis spectrophotometry to contain a mixture of caffeine and quinine with no trace of fenethylline. The forensic scientist may be able to help law enforcement officers to locate the sources of supply JFSS 1994; 34(3): 165- 167
and manufacture of illicit drugs by providing information which relates seizures of different batches with features of the tablets, manufacturing defects, patterns, residual components, and counterfeiting. In this instance, examination of 667 seized batches of Captagon tablets showed that 84%, containing fenethylline, had the same physical and chemical characteristics. They were therefore presumed to be illicitly-produced, to have come from the same illicit source and to have found their way onto the black market through illegal smuggling. However, 16% of the seized batches were shown to be fakes, with different physical characteristics, and containing only caffeine and quinine. Since they, too, were similar, they were also presumed to have a common origin. TABLE 1 Physical differences between illicit Captagon and counterfeit Captagon tablets Captagon
Counterfeit
(mm)
(mm)
TABLE 2 Chemical differences between illicit Captagon and counterfeit Captagon tablets UV absorption maxima ( n m ) in aqueous solution
Captagon tablets Counterfeit tablets Fenethylline Caffeine Quinine
Acidic
Alkaline
TLC Rf value
275 250,273 317,346 275 273 250 317,346
No shift 280 330 No shift No shift 280 330
0.56 0.52-0.63 0.56 0.63 0.52
Acknowledgements This work was supported by CPRC41 grant, of the Research Centre, College of Pharmacy, King Saud University, Riyadh.
References 1. Keup W. Use, indication and distribution in different countries of the stimulant and hallucinogenic amphetamine derivatives under consideration by WHO. Drug and Alcohol Dependence 1986; 17: 169-192. 2. Nickel B, Niebch G , Peter G , Vonschlichtegroll A and Tibes U. Fenethylline: New results on pharmacology, metabolism and kinetics. Drug and Alcohol Dependence 1986; 17: 235-257. 3. Kholstaedt E and Klinger KH. Basically substituted alkylxanthine derivatives. German Patent 1962; 1: 123, 329. 4. Moffat AC. Clarke's Isolation and Identification of Drugs, 2nd edition. London: The Pharmaceutical Press, 1986: 613-614.
JFSS 1994; 34(3): 165-167
The characterization of counterfeit Captagon tablets N AL-GHARABLY and A-R AL-OBAID Department of Pharmacology and Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia Journal of the Forensic Science Society 1994; 34: 165-167 Received 4 December 1992; accepted 15September 1993
Captagon (fenethylline) has been banned in Saudi Arabia since 1986. Despite this, it remains popular with problem drug users and is in widespread illicit production. Of 667 batches of seized "Captagon" tablets subjected to physical and chemical tests, 84% were found to be illicitly-produced fenethylline from a common source, and 16% were found to be fake tablets, consisting of a mixture of quinine and caffeine, also presumed to have a common origin. Fenethylline was synthesised by a modification of the German patented method.
Captagon (Fenetyllin) is in Saudi Arabien seit 1986 nicht mehr zugelassen. Trotzdem bleibt die Substanz bei Drogenkonsumenten sehr popular und wird weit verbreitet gesetzwidrig produziert. Aufgrund der physikalischen und chemischen Tests von 667 untersuchten Chargen sichergestellter CaptagonTabletten, stammen 84% des unrechtmassig-produzierten Fenetyllins aus einer gleichen Quelle. Bei den restlichen 16% handelt es sich um falsche Tabletten, bestehend aus einer Mischung aus Chinin und Coffein, vermutlich auch aus gleicher Produktion stammend. Zur Synthetisierung des Fenetyllins gelangte eine Modifikation des in Deutschland patentierten Vorgehens zur Anwendung.
Le "Captagon" (fenethylline) est interdit en Arabie Saoudite depuis 1986. MalgrC cela, c'est tojours une drogue populaire avec les toxicomanes et sa production illicite est Ctendue. De 667 lots de tablettes de "Captagon" saisies, suite 2 des tests physiques et chimiques, 84% s'av6rent Ctre de la fenethylline produite illkgalement d'une source commune et 16% sont des tablettes fausses constituCes d'un mClange de quinine et de cafkine dont on presume une origine commune. La fenethylline est synthetisee par une modification de la mCthode allemande patentee.
El Captagon (Fenetilina) esti prohibido en Arabia Saudita desde 1986. A pesar de ello sigue siendo popular su uso entre la poblaci6n drogadicta y su producci6n ilicita esta bastante extendida. De 10s 667 lotes de comprimidos de Captagon aprehendidos, sometidos a analisis fisicos y pruebas quimicas, el 84% dieron como resultado que se trataba de Fenetilina ilicita procedente de un origen comlin. El restante 16% resultaron ser falsos y consistian en una mezcla de quinina y cafeina, tambien de origen ilicito. La Fenetilina habia sido sintetizada mediante una modificaci6n del sistema patentado aleman.
Key Words: Drugs of abuse; Fenethylline; Captagon; Synthesis; Fake tablets JFSS 1994; 34(3): 165-167
Introduction Captagon (fenethylline hydrochloride) is one of the most widely abused stimulants in the Middle East, and in the Gulf states in particular, and its consumption is soaring [I]. Many heroin users, if unable to obtain heroin, substitute fenethylline, although its effects are different from those of amphetamine [Z]. Captagon has been banned in Saudi Arabia since 1986, and is no longer in clinical use, and there is therefore widespread illicit production of tablets and counterfeit tablets (fakes). Generally the illicit tablets are similar in formulation to that used for tablets manufactured in the pharmaceutical industry, but not every active ingredient will necessarily be present and, if present, the amount and purity may vary. In this work the physical and chemical characteristics of illicit Captagon tablets were examined. Because it is no longer available commercially, analytical standards of fenethylline were prepared by a modification of the German patent method [3]. Experimental Synthesis The synthesis of basically substituted alkylxanthine derivatives, including fenethylline (7-[2-[amethylphenyl) amino]-ethyl]-theophylline) has been reported [3]. Fenethylline was obtained by the condensation of the precursor 7-(8ch1oroethyl)theophylline with amphetamine under reflux using toluene for 4-6 h and subsequent treatment with iso-propyl alcohol and acidification with hydrochloric acid. This synthesis was unsuccessful and we therefore prepared fenethylline using a modification of the original method.
Amphetamine and theophylline were obtained from Merck AG, Darmstadt, Germany and 1,2dibromoethane was obtained from BDH Ltd, Poole, England. An alternative precursor, 7-(8bromoethyl)theophylline, which was prepared from theophylline by refluxing with 1,2-dibromoethane, was refluxed with amphetamine for 18 h. The crude fenethylline product was purified through a flash silica gel column to give a 64% yield of the hydrochloride. Fenethylline and its salt were characterized by TLC, mp, IR, UV, 'HNMR and 13CNMR analysis and elemental analysis. All data were identical to those reported in the literature [4]. Materials and methods Batches of seized illicit Captagon tablets were obtained from the General Directorate of Drug Control in Riyadh and 8 tablets from each of the 667
batches were subjected to physical and chemical analysis. The tablet thickness, diameter, marks and groove width were determined using a Reichert stereomicroscope. Thin layer chromatography was carried out on glass plates coated with Silica Gel G, 250 mm thick, and air dried, using a developing system consisting of strong ammonia solution and methanol (1.5 :100). The absorption spectra were determined between the wave length 200 and 400nm on a UV-Vis LKB 4054 spectrophotometer using a 1cm path length cell. Fenethylline, caffeine and quinine were extracted by organic solvent from aqueous alkaline solution and dissolved in 0.1 N H2S04 or 0.1 N NaOH for use as standards. Results and discussion Physical examination showed that some of the seized samples (about 16%) were thicker, had a narrower groove, and bilunar inversions nearer to the edge (Figure 1 and Table 1).
FIGURE 1 Grooves on the two sides of Captagon (left) and counterfeit (right) tablets.
The Rf values and the absorption maxima for the seized tablets are shown in Table 2. The majority of the tablets contained fenethylline, but about 16% of the total were fakes, and were shown by TLC and UV-Vis spectrophotometry to contain a mixture of caffeine and quinine with no trace of fenethylline. The forensic scientist may be able to help law enforcement officers to locate the sources of supply JFSS 1994; 34(3): 165- 167
and manufacture of illicit drugs by providing information which relates seizures of different batches with features of the tablets, manufacturing defects, patterns, residual components, and counterfeiting. In this instance, examination of 667 seized batches of Captagon tablets showed that 84%, containing fenethylline, had the same physical and chemical characteristics. They were therefore presumed to be illicitly-produced, to have come from the same illicit source and to have found their way onto the black market through illegal smuggling. However, 16% of the seized batches were shown to be fakes, with different physical characteristics, and containing only caffeine and quinine. Since they, too, were similar, they were also presumed to have a common origin. TABLE 1 Physical differences between illicit Captagon and counterfeit Captagon tablets Captagon
Counterfeit
(mm)
(mm)
TABLE 2 Chemical differences between illicit Captagon and counterfeit Captagon tablets UV absorption maxima ( n m ) in aqueous solution
Captagon tablets Counterfeit tablets Fenethylline Caffeine Quinine
Acidic
Alkaline
TLC Rf value
275 250,273 317,346 275 273 250 317,346
No shift 280 330 No shift No shift 280 330
0.56 0.52-0.63 0.56 0.63 0.52
Acknowledgements This work was supported by CPRC41 grant, of the Research Centre, College of Pharmacy, King Saud University, Riyadh.
References 1. Keup W. Use, indication and distribution in different countries of the stimulant and hallucinogenic amphetamine derivatives under consideration by WHO. Drug and Alcohol Dependence 1986; 17: 169-192. 2. Nickel B, Niebch G , Peter G , Vonschlichtegroll A and Tibes U. Fenethylline: New results on pharmacology, metabolism and kinetics. Drug and Alcohol Dependence 1986; 17: 235-257. 3. Kholstaedt E and Klinger KH. Basically substituted alkylxanthine derivatives. German Patent 1962; 1: 123, 329. 4. Moffat AC. Clarke's Isolation and Identification of Drugs, 2nd edition. London: The Pharmaceutical Press, 1986: 613-614.
JFSS 1994; 34(3): 165-167