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Analysis of pharmaceutical impurities in the methamphetamine crystals seized for drug trafficking in Korea
Forensic Science International 227 (2013) 48–51
Contents lists available at SciVerse ScienceDirect
Forensic Science International journal homepage: www.elsevier.com/locate/forsciint
Analysis of pharmaceutical impurities in the methamphetamine crystals seized for drug trafficking in Korea§ Sanggil Choe, Sewoong Heo, Hyeyoung Choi, Eunmi Kim, Heesun Chung, Jaesin Lee * National Forensic Service, Seoul 158-707, Republic of Korea
A R T I C L E I N F O
A B S T R A C T
Article history: Available online 30 November 2012
Some methamphetamine (MA) crystals contain pharmaceutical impurities. They often come from the co-ingredients of cold drugs used for extracting ephedrine or pseudoephedrine. Though these impurities are not so commonly encountered, they reflect the trends in precursor chemicals and manufacturing sources. As a result of monitoring impurities in the MA crystals seized in Korea during 2006–2011, 10 species of pharmaceutical impurities were identified by gas chromatography–flame ionization detection and gas chromatography–mass spectrometry. They may be co-ingredients of the legal drugs used as a source of ephedrine or pseudoephedrine. In contrast, some of them are presumed to be adulterants added during or after clandestine synthesis. It is interesting that some of these have been identified in the MA crystals seized in other countries in the same year. Species of pharmaceutical impurities in the MA crystals increased particularly in 2010, indicating a change in precursor chemicals and/or manufacturing sources. ß 2012 Elsevier Ireland Ltd. All rights reserved.
Keywords: Methamphetamine (MA) Pharmaceutical impurity Cold drug Trend analysis
1. Introduction Methamphetamine (MA) is one of the most highly addictive drugs and is strongly controlled in most countries. The supply of MA can be reduced by systematic control of smuggling routes, precursors, and other chemicals used for clandestine synthesis. Impurities in MA can provide valuable information for efficient narcotics control. Thus, many attempts have been made to obtain useful information from the impurities in MA [1–5]. MA is synthesized mainly from ephedrine or pseudoephedrine, and the MA crystals can contain impurities that originate from the ingredients of precursor chemicals or reagents. MA crystals may contain methylephedrine, methylpseudoephedrine, or dimethylamphetamine when the MA is synthesized from ephedrine compounds extracted from Ephedra herb [6]. In contrast, when MA crystals are manufactured from legal drugs that contain ephedrine or psuedoephedrine, the products often contain pharmaceutical co-ingredients of the precursors. It has been reported that the co-ingredients include acetaminophen, brompheniramine, chlorpheniramine, dextromethorphan, diphenhydramine, doxyla-
§ This paper is part of the special issue entitled ‘‘The 50th Annual Meeting of the International Association of Forensic Toxicologists (TIAFT)’’. June 3–8, 2012, Hamamatsu, Japan. Guest edited by Adjunct Professor Einosuke Tanaka and Associate Professor Masaru Terada. * Corresponding author at: Narcotics Analysis Division, National Forensic Service, 139 Jiyang-ro, Yangcheon-gu, Seoul 158-707, Republic of Korea. Tel.: +82 2 2600 4940; fax: +82 2 2600 4939. E-mail address: [email protected] (J. Lee).
0379-0738/$ – see front matter ß 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.forsciint.2012.11.007
mine, guaifenesin, and triprolidine [7]. MA crystals containing pharmaceutical impurities are not common among MA seizures. For this reason, reports about these impurities are limited and rare compared to those about the impurities produced as by-products during MA synthesis. But, the pharmaceutical impurities can supply useful information about the trends in precursor chemicals, identity of the seized materials, and smuggling patterns. Thus, we report on identifying and monitoring the pharmaceutical impurities in MA crystals seized in Korea and what they mean. The results may help to monitor clandestine synthesis and smuggling trends of MA crystals. 2. Experimental 2.1. Chemicals and standards MA crystal samples were selected from those seized for drug trafficking and/or abuse in Korea during 2006–2011 mainly by the National Police Agency. The samples were involved with 609 criminal cases and were sent to National Forensic Service for forensic identification. Four internal standards (n-decane (C10), npentadecane (C15), n-eicosane (C20), and n-octacosane (C28)) and 8 of the pharmaceutical standards (phenacetin, acetaminophen, desloratadine, dimethyl sulfone, barbital, ambroxol, chlorpheniramine, and procaine) were purchased from Sigma–Aldrich (St. Louis, MO, USA). Ketamine was purchased from Cerilliant (Round Rock, TX, USA), and caffeine was supplied by Hanil pharmaceutical industries (Seoul, Korea). Ethyl acetate was purchased from Yakuri Pure Chemicals (Osaka, Japan), and was used as the extraction solvent. 2.2. Instruments An Agilent 6890N gas chromatography–flame ionization detector (GC–FID) system equipped with a DB-5 capillary column (30 m 0.32 mm 1.0 mm film thickness) (Agilent Technologies, Santa Clara, CA, USA) was used to analyze the impurities. The identifications were confirmed using a gas chromatography–mass spectrometry (GC–MS) system. GC–MS analysis was carried out on an Agilent
S. Choe et al. / Forensic Science International 227 (2013) 48–51 5975C mass selective detector (MSD) equipped with a 7890A gas chromatograph and an HP-5MS capillary column (30 m 0.25 mm i.d. 0.25 mm film thickness). The MSD was operated in electron ionization (EI) mode at 70 eV. Acquisition was carried out in scan mode, and the mass range was set at m/z 50–400. Oven temperature of GC–FID and GC–MS was programmed as follows: 50 8C for 1 min, 10 8C/min to 300 8C, and then held for 10 min. The injector and detector (transfer line) temperatures were set at 240 8C and 300 8C, respectively. Helium of high purity was used as the carrier gas at a constant column flow rate of 2 mL/min for GC–FID and 1 mL/min for GC–MS. Injections were carried out in splitless mode for 1 min, and then purged.
49
methods, but there may have been some correlation between the MA seizures. Acetaminophen is an analgesic used to relieve cold symptoms and was identified in the MA crystal seized also in 2010. It has been reported that desloratadine is produced as a byproduct when a cold drug extract containing loratadine is reduced with hydroiodic acid and red phosphorus [7]. Desloratadine was found in the MA seized in 2011. Phenacetin was identified in the MA seized in 2010 and 2011. This analgesic is not permitted in many countries including South Korea due to its adverse effects. But, it is still being sold in some countries as an ingredient of analgesic drugs. Ambroxol is an expectorant used to treat colds and was identified in the MA seized in 2010. It may have been a co-ingredient in the cold drug used as a source of ephedrine or pseudoephedrine. Dimethyl sulfone is a sulfurbased dietary supplement that is frequently used as a MA adulterant [10]. Ephedra herb extracts are used as a dietary supplement for weight reduction or as a traditional cold medicine in East Asia, and dimethyl sulfone can be a coingredient of these dietary supplements containing ephedrine or pseudoephedrine used to synthesize MA. We have reported previously that the MA crystals containing dimethyl sulfone seized in Korea in 1996 and 2003 may have had some correlation to those seized in the US in the same year [11–13]. Furthermore, dimethyl sulfone was first identified in the Australian ‘ice’ seized during 1998–2002 [4]. Dimethyl sulfone was not as frequently observed in MA crystals until the early 2000s and could be a chemical marker for the similarity test between different MA seizures. But, dimethyl sulfone has become a frequently encountered ingredient in MA crystals since then. It has been reported that 32.3% of the MA crystals (41 of 127 samples) seized in Japan during 2006–2007 contained dimethyl sulfone [14], indicating that quantitative analyses should be conducted to compare MA seizures containing dimethyl sulfone. Dimethyl sulfone was identified additionally in the MA crystals seized in Korea in 2007 and 2009, and a study concerning identification of dimethyl sulfone in the MA crystals seized in the US in 2007 has been reported [15]. But, additional chemical information is required to compare the MA seizures. Barbital and ketamine have been known as adulterants added to increase psychoactivity. But,
2.3. Extraction of impurities Impurities in the MA crystals were extracted and analyzed by GC–FID and GC– MS following the established analytical method [8]. Following the method, 50 mg of MA sample was dissolved in 1 mL of buffer solution (four parts 0.1 M phosphate buffer [pH 7.0] and one part 10% [w/v] Na2CO3). The solution was extracted by vortexing for 10 min with 0.5 mL ethyl acetate containing four ISs (n-decane (C10, IS1), n-pentadecane (C15, IS2), n-eicosane (C20, IS3), n-octacosane (C28, IS4) at 20 mg/L). After centrifuging the solution for 3 min at 3,000 rpm, the organic layer was transferred to the glass insert of a GC microvial for automatic sampling, and 1 mL was injected into the GC–FID. The organic layer was diluted 5 times with ethylacetate, and 1 mL was injected into the GC–MS. GC–MS analysis was carried out to identify the impurities detected by GC–FID, and the identifications were reconfirmed by comparing GC retention times and MS spectral data with those of the impurity standards.
3. Results and discussion We identified 10 species of pharmaceutical impurities in 19 of 609 MA crystal samples seized in Korea during 2006–2011 (Fig. 1), and Fig. 2 shows the GC–FID chromatograms of the MA crystals containing the pharmaceutical impurities. The pharmaceutical impurities are not only characteristic, but they are stable and in relatively high amounts compared with those of the by-product impurities. Thus, pharmaceutical impurities can be used to compare MA crystals seized in different countries. Chlorpheniramine is an antihistamine frequently used as a co-ingredient of over-the-counter cold drugs containing ephedrine or pseudoephedrine, and it was identified as an impurity in the MA crystal seized in 2010. It is interesting that the same compound has been identified in the MA seized in Iran in the same year [9]. It was difficult to compare the both data due to different analytical
Br
H N
N
N
O
HO
H N
O N
N
O
O
Acetaminophen
H N
O HO
Phenacetin
Caffeine
Br NH2
Ambroxol
H N
Cl N
O
O
Cl
N
HN
N
NH
NH
Cl
O
Barbital
Desloratadine
Chlorpheniramine
O
Ketamine
O
O
O N
H2N
Procaine
S
O
Dimethylsulfone
Fig. 1. Pharmaceutical impurities identified in the methamphetamine (MA) crystals seized in Korea.
50
S. Choe et al. / Forensic Science International 227 (2013) 48–51
Fig. 2. Gas chromatography–flame ionization detection (GC–FID) chromatograms of the methamphetamine (MA) crystals containing pharmaceutical impurities. P1, acetaminophen; P2, caffeine; P3, ambroxol; P4, chlorpheniramine; P5, desloratadine; P6, phenacetin; P7, barbital; P8, ketamine; P9, procaine; P10, dimethyl sulfone; 1, benzaldehyde; 2, cis-1,2-dimethyl-3-phenylaziridine; 3, N-ethylamphetamine; 4, unidentified compound-1; 5, unidentified compound-2; 6, 3,4-dimethyl-5phenyloxazolidine; 7, N,N-dimethylamphetamine; 8, unidentified compound-3.
barbital is often used as a co-ingredient of analgesics that can be used with ephedrine or pseudoephedrine, and it may be the same with ketamine. Barbital was identified in the MA crystals seized in 2010, and ketamine in those seized in 2007 and 2011. Diphenhydramine is one of the most frequently used coingredients of ephedrine tablets. It has been identified in the MA crystals seized in 2002 and 2003 [2], and it was also identified in the MA seized in Japan [16]. But, it was not identified in the MA crystals used in this study. Identifying pharmaceutical impurities may be useful not only for a similarity analysis but for monitoring changes in precursor chemicals or manufacturing sources. In the present study, we found that species of pharmaceutical impurities in MA crystals have increased particularly since 2010 (Table 1). A previous study showed that only dimethyl sulfone, diphenhydramine and procaine were occasionally identified in the MA crystals seized during 1996–2005 [2], and this had been true until 2009. A rapid
increase of pharmaceutical impurities indicates some changes in smuggling patterns and synthetic conditions of the MA crystals seized in Korea, and it may be the same with the neighboring East Asian countries. We have reported previously that there may have been significant changes in MA precursor chemicals seized in Korea around 2002–2003, and it might have been influenced by reinforced domestic regulations and/or international factors such as the sea blockade enforced around North Korea [11]. In contrast, recent changes around 2010 may be mainly due to the reinforced regulations on drug trafficking in Asian countries, which may have made it difficult for clandestine MA manufacturers to obtain pure ephedrine or pseudoephedrine powders. This means that reinforcing the regulations has short-term effects on the clandestine manufacture and trade of MA crystals flowing into Korea. But, drug trafficking has been globalized, and local regulations cannot be a long-term solution to decrease drug trafficking.
S. Choe et al. / Forensic Science International 227 (2013) 48–51
51
Table 1 Identification of the pharmaceutical impurities in the MA crystals seized in 609 cases. Identified impurities
Seized year (No. of the total cases) 2006 (86)
Phenacetin Ambroxol Acetaminophen + caffeine Chlorpheniramine Desloratadine Barbital Procaine Ketamine Dimethyl sulfone
2007 (151)
2008 (55)
2009 (69)
2010 (107)
2011 (141)
1 1 2 1
1
1 3 4 1 1
Past migration of clandestine labs between East Asian countries may be a good example of the ‘‘balloon effect’’. First widespread use of MA in the East Asia can be traced back to Japan after the Second World War. A rapid increase in MA abusers was a social problem in the 1960s, and the Japan government reinforced regulations on the clandestine manufacture of MA. Resultantly, clandestine labs almost disappeared in Japan, but they migrated to neighboring countries such as Korea. This resulted in social problems again in Korea in the 1980s, and regulations were reinforced by the Korean government. As a result of the regulations, clandestine labs have almost disappeared in Korea since 1990s, but they may have migrated to neighboring countries once again. Despite the regulations reinforced by local governments, clandestine manufacturing has not been exterminated, and MA abuse still remains as a problem in many countries. Migration of clandestine labs had been restricted to the neighboring countries until the 1990s. But it may have been globalized due to increase of international mail and personal exchange since the 2000s. Globalization has become a new trend of clandestine MA production [17]. It indicates that MA smuggling can be reduced only by the cooperative regulations worldwide. Chemical trend observed in this study may not be restricted to the MA crystals seized in Korea. Change of smuggling pattern may be reflected in the chemical properties of MA crystals, and the chemical information will help efficient regulation of MA smuggling. For this reason, analytical method used for impurity profiling should be standardized, and chemical trends should be shared. This may include sharing information concerning the identifications of characteristic impurities in the MA crystals seized for drug trafficking. 4. Conclusion Rareness of the pharmaceutical impurities enables comparisons between MA crystals seized in different countries. The pharmaceutical impurities can also be used to investigate manufacturing sources, because some of them are approved only in some limited countries. Monitoring of the pharmaceutical impurities can also supply useful information concerning recent trends in clandestine manufacture and drug trafficking, which will contribute to reducing worldwide MA trafficking and abuse. Acknowledgements This study was supported by funding from the National R&D program of the Ministry of Education, Science and
1 1 1
Technology (2012-0009836) and the National Forensic Service of Korea. References [1] K. Kuwayama, H. Inoue, J. Phorachata, K. Kongpatnitiroj, V. Puthaviriyakorn, K. Tsujikawa, H. Miyaguchi, T. Kannamori, Y.T. Iwata, N. Kamo, T. Kishi, Comparison and classification of methamphetamine seized in Japan and Thailand using gas chromatography with liquid–liquid extraction and solid-phase microextraction, Forensic Sci. Int. 175 (2008) 85–92. [2] J.S. Lee, H.S. Chung, K. Kuwayama, H. Inoue, M.Y. Lee, J.H. Park, Determination of impurities in illicit methamphetamine seized in Korea and Japan, Anal. Chim. Acta 619 (2008) 20–25. [3] F.M. Dayrit, M.C. Dumlao, Impurity profiling of methamphetamine hydrochloride drugs seized in the Philippines, Forensic Sci. Int. 144 (2004) 29–36. [4] Y. Qi, I.D. Evans, A. McCluskey, Australian Federal Police seizures of illicit crystalline methamphetamine (‘ice’) 1998–2002: impurity analysis, Forensic Sci. Int. 164 (2006) 201–210. [5] J.X. Zhang, D.M. Zhang, X.G. Han, Identification of impurities and statistical classification of methamphetamine hydrochloride drugs seized in China, Forensic Sci. Int. 182 (2008) 13–19. [6] W.D. Barker, U. Antia, A study of the use of Ephedra in the manufacture of methamphetamine, Forensic Sci. Int. 166 (2007) 102–109. [7] S.C. DiPari, J.A. Bordelon, H.F. Skinner, Desloratadine: the reaction byproduct of the reduction of cold tablets containing loratadine with hydriodic acid/red phosphorus, Microgram J. 3 (2005) 69–77. [8] H. Inoue, T. Kanamori, Y.T. Iwata, Y. Ohmae, K. Tsujikawa, S. Saitoh, T. Kishi, Methamphetamine impurity profiling using a 0.32 mm i.d. nonpolar capillary column, Forensic Sci. Int. 135 (2003) 42–47. [9] A.R. Khajeamiri, M. Faizi, F. Sohani, T. Baheri, F. Kobarfard, Determination of impurities in illicit methamphetamine samples seized in Iran, Forensic Sci. Int. 217 (2012) 204–206. [10] D.T. Vu, SPME/GC–MS characterization of volatiles associated with methamphetamine: toward the development of a pseudomethamphetamine training material, J. Forensic Sci. 46 (2001) 1014–1024. [11] J.S. Lee, W.K. Yang, E.Y. Han, S.Y. Lee, Y.H. Park, M.A. Lim, H.S. Chung, J.H. Park, Monitoring precursor chemicals of methamphetamine through enantiomer profiling, Forensic Sci. Int. 173 (2007) 68–72. [12] Methamphetamine ‘‘ice’’ with dimethyl sulfone in Hawai, Microgram 29 (1996) 196–197 (published by the Drug Enforcement Administration Office of Forensic Sciences). [13] Unusual methamphetamine exhibits in Stow, Ohaio, Microgram Bull. 36 (2003) 49 (published by the Drug Enforcement Administration Office of Forensic Sciences). [14] H. Inoue, K. Kuwayama, Y.T. Iwata, T. Kanamori, K. Tsujikawa, H. Miyaguchi, Simple and simultaneous detection of methamphetamine and dimethyl sulfone in crystalline methamphetamine seizures by fast gas chromatography, Forensic Toxicol. 26 (2008) 19–22. [15] ‘‘Ice’’ methamphetamine concealed in a (presumed child’s) mini-purse/keychain in New York city, Microgram Bull. 40 (2007) 88 (published by the Drug Enforcement Administration Office of Forensic Sciences). [16] Y.T. Iwata, H. Inoue, K. Kuwayama, T. Kanamori, K. Tsujikawa, H. Miyaguchi, T. Kishi, Forensic application of chiral separation of amphetamine-type stimulants to impurity analysis of seized methamphetamine by capillary electrophoresis, Forensic Sci. Int. 161 (2006) 92–96. [17] World Drug Report 2011, United Nations Office of Drugs and Crime (UNODC), Vienna, June 2011.
Contents lists available at SciVerse ScienceDirect
Forensic Science International journal homepage: www.elsevier.com/locate/forsciint
Analysis of pharmaceutical impurities in the methamphetamine crystals seized for drug trafficking in Korea§ Sanggil Choe, Sewoong Heo, Hyeyoung Choi, Eunmi Kim, Heesun Chung, Jaesin Lee * National Forensic Service, Seoul 158-707, Republic of Korea
A R T I C L E I N F O
A B S T R A C T
Article history: Available online 30 November 2012
Some methamphetamine (MA) crystals contain pharmaceutical impurities. They often come from the co-ingredients of cold drugs used for extracting ephedrine or pseudoephedrine. Though these impurities are not so commonly encountered, they reflect the trends in precursor chemicals and manufacturing sources. As a result of monitoring impurities in the MA crystals seized in Korea during 2006–2011, 10 species of pharmaceutical impurities were identified by gas chromatography–flame ionization detection and gas chromatography–mass spectrometry. They may be co-ingredients of the legal drugs used as a source of ephedrine or pseudoephedrine. In contrast, some of them are presumed to be adulterants added during or after clandestine synthesis. It is interesting that some of these have been identified in the MA crystals seized in other countries in the same year. Species of pharmaceutical impurities in the MA crystals increased particularly in 2010, indicating a change in precursor chemicals and/or manufacturing sources. ß 2012 Elsevier Ireland Ltd. All rights reserved.
Keywords: Methamphetamine (MA) Pharmaceutical impurity Cold drug Trend analysis
1. Introduction Methamphetamine (MA) is one of the most highly addictive drugs and is strongly controlled in most countries. The supply of MA can be reduced by systematic control of smuggling routes, precursors, and other chemicals used for clandestine synthesis. Impurities in MA can provide valuable information for efficient narcotics control. Thus, many attempts have been made to obtain useful information from the impurities in MA [1–5]. MA is synthesized mainly from ephedrine or pseudoephedrine, and the MA crystals can contain impurities that originate from the ingredients of precursor chemicals or reagents. MA crystals may contain methylephedrine, methylpseudoephedrine, or dimethylamphetamine when the MA is synthesized from ephedrine compounds extracted from Ephedra herb [6]. In contrast, when MA crystals are manufactured from legal drugs that contain ephedrine or psuedoephedrine, the products often contain pharmaceutical co-ingredients of the precursors. It has been reported that the co-ingredients include acetaminophen, brompheniramine, chlorpheniramine, dextromethorphan, diphenhydramine, doxyla-
§ This paper is part of the special issue entitled ‘‘The 50th Annual Meeting of the International Association of Forensic Toxicologists (TIAFT)’’. June 3–8, 2012, Hamamatsu, Japan. Guest edited by Adjunct Professor Einosuke Tanaka and Associate Professor Masaru Terada. * Corresponding author at: Narcotics Analysis Division, National Forensic Service, 139 Jiyang-ro, Yangcheon-gu, Seoul 158-707, Republic of Korea. Tel.: +82 2 2600 4940; fax: +82 2 2600 4939. E-mail address: [email protected] (J. Lee).
0379-0738/$ – see front matter ß 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.forsciint.2012.11.007
mine, guaifenesin, and triprolidine [7]. MA crystals containing pharmaceutical impurities are not common among MA seizures. For this reason, reports about these impurities are limited and rare compared to those about the impurities produced as by-products during MA synthesis. But, the pharmaceutical impurities can supply useful information about the trends in precursor chemicals, identity of the seized materials, and smuggling patterns. Thus, we report on identifying and monitoring the pharmaceutical impurities in MA crystals seized in Korea and what they mean. The results may help to monitor clandestine synthesis and smuggling trends of MA crystals. 2. Experimental 2.1. Chemicals and standards MA crystal samples were selected from those seized for drug trafficking and/or abuse in Korea during 2006–2011 mainly by the National Police Agency. The samples were involved with 609 criminal cases and were sent to National Forensic Service for forensic identification. Four internal standards (n-decane (C10), npentadecane (C15), n-eicosane (C20), and n-octacosane (C28)) and 8 of the pharmaceutical standards (phenacetin, acetaminophen, desloratadine, dimethyl sulfone, barbital, ambroxol, chlorpheniramine, and procaine) were purchased from Sigma–Aldrich (St. Louis, MO, USA). Ketamine was purchased from Cerilliant (Round Rock, TX, USA), and caffeine was supplied by Hanil pharmaceutical industries (Seoul, Korea). Ethyl acetate was purchased from Yakuri Pure Chemicals (Osaka, Japan), and was used as the extraction solvent. 2.2. Instruments An Agilent 6890N gas chromatography–flame ionization detector (GC–FID) system equipped with a DB-5 capillary column (30 m 0.32 mm 1.0 mm film thickness) (Agilent Technologies, Santa Clara, CA, USA) was used to analyze the impurities. The identifications were confirmed using a gas chromatography–mass spectrometry (GC–MS) system. GC–MS analysis was carried out on an Agilent
S. Choe et al. / Forensic Science International 227 (2013) 48–51 5975C mass selective detector (MSD) equipped with a 7890A gas chromatograph and an HP-5MS capillary column (30 m 0.25 mm i.d. 0.25 mm film thickness). The MSD was operated in electron ionization (EI) mode at 70 eV. Acquisition was carried out in scan mode, and the mass range was set at m/z 50–400. Oven temperature of GC–FID and GC–MS was programmed as follows: 50 8C for 1 min, 10 8C/min to 300 8C, and then held for 10 min. The injector and detector (transfer line) temperatures were set at 240 8C and 300 8C, respectively. Helium of high purity was used as the carrier gas at a constant column flow rate of 2 mL/min for GC–FID and 1 mL/min for GC–MS. Injections were carried out in splitless mode for 1 min, and then purged.
49
methods, but there may have been some correlation between the MA seizures. Acetaminophen is an analgesic used to relieve cold symptoms and was identified in the MA crystal seized also in 2010. It has been reported that desloratadine is produced as a byproduct when a cold drug extract containing loratadine is reduced with hydroiodic acid and red phosphorus [7]. Desloratadine was found in the MA seized in 2011. Phenacetin was identified in the MA seized in 2010 and 2011. This analgesic is not permitted in many countries including South Korea due to its adverse effects. But, it is still being sold in some countries as an ingredient of analgesic drugs. Ambroxol is an expectorant used to treat colds and was identified in the MA seized in 2010. It may have been a co-ingredient in the cold drug used as a source of ephedrine or pseudoephedrine. Dimethyl sulfone is a sulfurbased dietary supplement that is frequently used as a MA adulterant [10]. Ephedra herb extracts are used as a dietary supplement for weight reduction or as a traditional cold medicine in East Asia, and dimethyl sulfone can be a coingredient of these dietary supplements containing ephedrine or pseudoephedrine used to synthesize MA. We have reported previously that the MA crystals containing dimethyl sulfone seized in Korea in 1996 and 2003 may have had some correlation to those seized in the US in the same year [11–13]. Furthermore, dimethyl sulfone was first identified in the Australian ‘ice’ seized during 1998–2002 [4]. Dimethyl sulfone was not as frequently observed in MA crystals until the early 2000s and could be a chemical marker for the similarity test between different MA seizures. But, dimethyl sulfone has become a frequently encountered ingredient in MA crystals since then. It has been reported that 32.3% of the MA crystals (41 of 127 samples) seized in Japan during 2006–2007 contained dimethyl sulfone [14], indicating that quantitative analyses should be conducted to compare MA seizures containing dimethyl sulfone. Dimethyl sulfone was identified additionally in the MA crystals seized in Korea in 2007 and 2009, and a study concerning identification of dimethyl sulfone in the MA crystals seized in the US in 2007 has been reported [15]. But, additional chemical information is required to compare the MA seizures. Barbital and ketamine have been known as adulterants added to increase psychoactivity. But,
2.3. Extraction of impurities Impurities in the MA crystals were extracted and analyzed by GC–FID and GC– MS following the established analytical method [8]. Following the method, 50 mg of MA sample was dissolved in 1 mL of buffer solution (four parts 0.1 M phosphate buffer [pH 7.0] and one part 10% [w/v] Na2CO3). The solution was extracted by vortexing for 10 min with 0.5 mL ethyl acetate containing four ISs (n-decane (C10, IS1), n-pentadecane (C15, IS2), n-eicosane (C20, IS3), n-octacosane (C28, IS4) at 20 mg/L). After centrifuging the solution for 3 min at 3,000 rpm, the organic layer was transferred to the glass insert of a GC microvial for automatic sampling, and 1 mL was injected into the GC–FID. The organic layer was diluted 5 times with ethylacetate, and 1 mL was injected into the GC–MS. GC–MS analysis was carried out to identify the impurities detected by GC–FID, and the identifications were reconfirmed by comparing GC retention times and MS spectral data with those of the impurity standards.
3. Results and discussion We identified 10 species of pharmaceutical impurities in 19 of 609 MA crystal samples seized in Korea during 2006–2011 (Fig. 1), and Fig. 2 shows the GC–FID chromatograms of the MA crystals containing the pharmaceutical impurities. The pharmaceutical impurities are not only characteristic, but they are stable and in relatively high amounts compared with those of the by-product impurities. Thus, pharmaceutical impurities can be used to compare MA crystals seized in different countries. Chlorpheniramine is an antihistamine frequently used as a co-ingredient of over-the-counter cold drugs containing ephedrine or pseudoephedrine, and it was identified as an impurity in the MA crystal seized in 2010. It is interesting that the same compound has been identified in the MA seized in Iran in the same year [9]. It was difficult to compare the both data due to different analytical
Br
H N
N
N
O
HO
H N
O N
N
O
O
Acetaminophen
H N
O HO
Phenacetin
Caffeine
Br NH2
Ambroxol
H N
Cl N
O
O
Cl
N
HN
N
NH
NH
Cl
O
Barbital
Desloratadine
Chlorpheniramine
O
Ketamine
O
O
O N
H2N
Procaine
S
O
Dimethylsulfone
Fig. 1. Pharmaceutical impurities identified in the methamphetamine (MA) crystals seized in Korea.
50
S. Choe et al. / Forensic Science International 227 (2013) 48–51
Fig. 2. Gas chromatography–flame ionization detection (GC–FID) chromatograms of the methamphetamine (MA) crystals containing pharmaceutical impurities. P1, acetaminophen; P2, caffeine; P3, ambroxol; P4, chlorpheniramine; P5, desloratadine; P6, phenacetin; P7, barbital; P8, ketamine; P9, procaine; P10, dimethyl sulfone; 1, benzaldehyde; 2, cis-1,2-dimethyl-3-phenylaziridine; 3, N-ethylamphetamine; 4, unidentified compound-1; 5, unidentified compound-2; 6, 3,4-dimethyl-5phenyloxazolidine; 7, N,N-dimethylamphetamine; 8, unidentified compound-3.
barbital is often used as a co-ingredient of analgesics that can be used with ephedrine or pseudoephedrine, and it may be the same with ketamine. Barbital was identified in the MA crystals seized in 2010, and ketamine in those seized in 2007 and 2011. Diphenhydramine is one of the most frequently used coingredients of ephedrine tablets. It has been identified in the MA crystals seized in 2002 and 2003 [2], and it was also identified in the MA seized in Japan [16]. But, it was not identified in the MA crystals used in this study. Identifying pharmaceutical impurities may be useful not only for a similarity analysis but for monitoring changes in precursor chemicals or manufacturing sources. In the present study, we found that species of pharmaceutical impurities in MA crystals have increased particularly since 2010 (Table 1). A previous study showed that only dimethyl sulfone, diphenhydramine and procaine were occasionally identified in the MA crystals seized during 1996–2005 [2], and this had been true until 2009. A rapid
increase of pharmaceutical impurities indicates some changes in smuggling patterns and synthetic conditions of the MA crystals seized in Korea, and it may be the same with the neighboring East Asian countries. We have reported previously that there may have been significant changes in MA precursor chemicals seized in Korea around 2002–2003, and it might have been influenced by reinforced domestic regulations and/or international factors such as the sea blockade enforced around North Korea [11]. In contrast, recent changes around 2010 may be mainly due to the reinforced regulations on drug trafficking in Asian countries, which may have made it difficult for clandestine MA manufacturers to obtain pure ephedrine or pseudoephedrine powders. This means that reinforcing the regulations has short-term effects on the clandestine manufacture and trade of MA crystals flowing into Korea. But, drug trafficking has been globalized, and local regulations cannot be a long-term solution to decrease drug trafficking.
S. Choe et al. / Forensic Science International 227 (2013) 48–51
51
Table 1 Identification of the pharmaceutical impurities in the MA crystals seized in 609 cases. Identified impurities
Seized year (No. of the total cases) 2006 (86)
Phenacetin Ambroxol Acetaminophen + caffeine Chlorpheniramine Desloratadine Barbital Procaine Ketamine Dimethyl sulfone
2007 (151)
2008 (55)
2009 (69)
2010 (107)
2011 (141)
1 1 2 1
1
1 3 4 1 1
Past migration of clandestine labs between East Asian countries may be a good example of the ‘‘balloon effect’’. First widespread use of MA in the East Asia can be traced back to Japan after the Second World War. A rapid increase in MA abusers was a social problem in the 1960s, and the Japan government reinforced regulations on the clandestine manufacture of MA. Resultantly, clandestine labs almost disappeared in Japan, but they migrated to neighboring countries such as Korea. This resulted in social problems again in Korea in the 1980s, and regulations were reinforced by the Korean government. As a result of the regulations, clandestine labs have almost disappeared in Korea since 1990s, but they may have migrated to neighboring countries once again. Despite the regulations reinforced by local governments, clandestine manufacturing has not been exterminated, and MA abuse still remains as a problem in many countries. Migration of clandestine labs had been restricted to the neighboring countries until the 1990s. But it may have been globalized due to increase of international mail and personal exchange since the 2000s. Globalization has become a new trend of clandestine MA production [17]. It indicates that MA smuggling can be reduced only by the cooperative regulations worldwide. Chemical trend observed in this study may not be restricted to the MA crystals seized in Korea. Change of smuggling pattern may be reflected in the chemical properties of MA crystals, and the chemical information will help efficient regulation of MA smuggling. For this reason, analytical method used for impurity profiling should be standardized, and chemical trends should be shared. This may include sharing information concerning the identifications of characteristic impurities in the MA crystals seized for drug trafficking. 4. Conclusion Rareness of the pharmaceutical impurities enables comparisons between MA crystals seized in different countries. The pharmaceutical impurities can also be used to investigate manufacturing sources, because some of them are approved only in some limited countries. Monitoring of the pharmaceutical impurities can also supply useful information concerning recent trends in clandestine manufacture and drug trafficking, which will contribute to reducing worldwide MA trafficking and abuse. Acknowledgements This study was supported by funding from the National R&D program of the Ministry of Education, Science and
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Technology (2012-0009836) and the National Forensic Service of Korea. References [1] K. Kuwayama, H. Inoue, J. Phorachata, K. Kongpatnitiroj, V. Puthaviriyakorn, K. Tsujikawa, H. Miyaguchi, T. Kannamori, Y.T. Iwata, N. Kamo, T. Kishi, Comparison and classification of methamphetamine seized in Japan and Thailand using gas chromatography with liquid–liquid extraction and solid-phase microextraction, Forensic Sci. Int. 175 (2008) 85–92. [2] J.S. Lee, H.S. Chung, K. Kuwayama, H. Inoue, M.Y. Lee, J.H. Park, Determination of impurities in illicit methamphetamine seized in Korea and Japan, Anal. Chim. Acta 619 (2008) 20–25. [3] F.M. Dayrit, M.C. Dumlao, Impurity profiling of methamphetamine hydrochloride drugs seized in the Philippines, Forensic Sci. Int. 144 (2004) 29–36. [4] Y. Qi, I.D. Evans, A. McCluskey, Australian Federal Police seizures of illicit crystalline methamphetamine (‘ice’) 1998–2002: impurity analysis, Forensic Sci. Int. 164 (2006) 201–210. [5] J.X. Zhang, D.M. Zhang, X.G. Han, Identification of impurities and statistical classification of methamphetamine hydrochloride drugs seized in China, Forensic Sci. Int. 182 (2008) 13–19. [6] W.D. Barker, U. Antia, A study of the use of Ephedra in the manufacture of methamphetamine, Forensic Sci. Int. 166 (2007) 102–109. [7] S.C. DiPari, J.A. Bordelon, H.F. Skinner, Desloratadine: the reaction byproduct of the reduction of cold tablets containing loratadine with hydriodic acid/red phosphorus, Microgram J. 3 (2005) 69–77. [8] H. Inoue, T. Kanamori, Y.T. Iwata, Y. Ohmae, K. Tsujikawa, S. Saitoh, T. Kishi, Methamphetamine impurity profiling using a 0.32 mm i.d. nonpolar capillary column, Forensic Sci. Int. 135 (2003) 42–47. [9] A.R. Khajeamiri, M. Faizi, F. Sohani, T. Baheri, F. Kobarfard, Determination of impurities in illicit methamphetamine samples seized in Iran, Forensic Sci. Int. 217 (2012) 204–206. [10] D.T. Vu, SPME/GC–MS characterization of volatiles associated with methamphetamine: toward the development of a pseudomethamphetamine training material, J. Forensic Sci. 46 (2001) 1014–1024. [11] J.S. Lee, W.K. Yang, E.Y. Han, S.Y. Lee, Y.H. Park, M.A. Lim, H.S. Chung, J.H. Park, Monitoring precursor chemicals of methamphetamine through enantiomer profiling, Forensic Sci. Int. 173 (2007) 68–72. [12] Methamphetamine ‘‘ice’’ with dimethyl sulfone in Hawai, Microgram 29 (1996) 196–197 (published by the Drug Enforcement Administration Office of Forensic Sciences). [13] Unusual methamphetamine exhibits in Stow, Ohaio, Microgram Bull. 36 (2003) 49 (published by the Drug Enforcement Administration Office of Forensic Sciences). [14] H. Inoue, K. Kuwayama, Y.T. Iwata, T. Kanamori, K. Tsujikawa, H. Miyaguchi, Simple and simultaneous detection of methamphetamine and dimethyl sulfone in crystalline methamphetamine seizures by fast gas chromatography, Forensic Toxicol. 26 (2008) 19–22. [15] ‘‘Ice’’ methamphetamine concealed in a (presumed child’s) mini-purse/keychain in New York city, Microgram Bull. 40 (2007) 88 (published by the Drug Enforcement Administration Office of Forensic Sciences). [16] Y.T. Iwata, H. Inoue, K. Kuwayama, T. Kanamori, K. Tsujikawa, H. Miyaguchi, T. Kishi, Forensic application of chiral separation of amphetamine-type stimulants to impurity analysis of seized methamphetamine by capillary electrophoresis, Forensic Sci. Int. 161 (2006) 92–96. [17] World Drug Report 2011, United Nations Office of Drugs and Crime (UNODC), Vienna, June 2011.