As narcotic analgesics, fentanyl compounds have been commonly produced and widely used during surgical procedures. The residual and waste of fentanyl compounds have potential harmful impacts on the environment and human health. The oxidative degradation of fentanyl compounds by sodium bromate mixed systems was studied. Factors influencing the oxidation reaction, including molar ratio of NaBrO3/H+/SO32−, molar ratio of NaBrO3/fentanyl and pH, were investigated. Fentanyl, carfentanil and 3-methylfentanyl were able to be completely degraded in 30 minutes by a NaBrO3 mixed system under optimum conditions, the molar ratio of NaBrO3/H+/SO32− equal to 20:3:10, the molar ratio of NaBrO3:fentanyl compounds 50:1 and pH = 4. Sufentanil was only able to be degraded by 74% under the same conditions. The degradation products of the fentanyl compounds detected and identified by gas chromatography/mass spectrometry suggested several possible degradation pathways.

INTRODUCTION

Fentanyl compounds have been used widely as narcotic analgesics during surgical procedures (Stanlety & Weberster 1978). The fentanyl family compounds including carfentanil, sufentanil and 3-methylfentanyl (Figure S1, available online at http://www.iwaponline.com/wst/072/185.pdf) have the characteristic propionyl aniline and piperidine groups, which determine their toxicities. The human body may exhibit symptoms such as insufficient lung ventilation, hypotension or deep coma and may even die when the fentanyl concentration exceeds a certain level in plasma (Newshan 1998; Woodall et al. 2008). Several studies (Gourlay et al. 1988; Martin et al. 2006; Santos et al. 2013) concluded that fentanyl pollution in the ecological environment was dangerous to human health. Therefore, the fentanyl compounds pollution in water should be degraded by a highly efficient method.

Fentanyl was experimentally found to be degraded possibly by thermal decomposition at 350 °C with a high efficiency and yet was difficult to degrade in solution by H2O2 at room temperature or HCl at 70 °C with a low conversion of 30%, whereas no degradation was observed in sodium hydroxide solution or under ultraviolet irradiation (Garg et al. 2010). Qi et al. (2011) found that the fentanyl compounds may be degraded in solution, by such oxidants as H2O2, peracetic acid (CH3CO3H), trichloroisocyanuric acid (C3O3N3Cl3) and sodium percarbonate/N,N,N,N-tetraacetylethylene diamino, into N-phenylpropanamide, benzaldehyde, benzonitrile, chlorobenzaldehyde and propanil, and that the degradation of C3O3N3Cl3 and sodium percarbonate/N,N,N,N-tetraacetylethylene diamine had better oxidative degradation abilities.

NaBrO3 has been used as an oxidant for preparation of bromine chemicals in many applications. For example, primary alcohol could be oxidized and esterified (Takase et al. 1995), and olefins hydroxylated (Ohta et al. 1990; Masuda et al. 1994), to produce bromine chemicals with a system of NaBrO3/NaHSO3, which generated HOBr and delivered Br-radicals in aqueous solution (Beckwith et al. 1996; Metsger et al. 2000; Khan et al. 2003). It was shown that Br-radicals created in the NaBrO3/NaHSO3 system had an oxidative capability. Therefore, the NaBrO3 system could be used to treat the residual of the fentanyl compounds in wastewater.

This study reports the oxidative degradation of fentanyl compounds by the NaBrO3 mixed system, for which the optimum conditions have been investigated by varying such factors as the molar ratio of NaBrO3/H+/, the pH of solution and the dosage of the NaBrO3 mixed system. The resulting products from fentanyl degradation have been detected and identified by gas chromatography/mass spectrometry (GC/MS) to suggest their possible degradation pathways and to ascertain how the degradation products are formed.

MATERIALS AND METHODS

Materials

Sodium bromate, sodium hydrogen sulphite, sodium sulphite, sodium hydroxide and sodium thiosulphate, of chemical grade, and dichloromethane of analytic grade were purchased from Beijing Chemical Reagent Company. The fentanyl compounds were synthesised with a purity >99% according to the procedure described by Janssen (1962). Dipotassium hydrogen phosphate was used as a buffer to prepare 1 mol/L solutions of NaBrO3, Na2SO3, NaHSO3 and H2SO4. Sodium bromate mixed systems (, H+ and ) were prepared by mixing corresponding solutions well before use. Sulphuric acid (1 mol/L) was added to adjust the pH in the solution of the mixed system, which was measured by a pH meter (PHSJ-4A) before the reaction.

Degradation of fentanyl compounds

The fentanyl in dichloromethane solution (0.2 mL; 5.3 × 10−2mol/mL) was added into a 10 mL tube. After the dichloromethane was volatilised by nitrogen purging in a laboratory hood at room temperature, a certain volume of the aqueous solution (NaBrO3, H+ and ) was added into the tube. The degradation reaction was initiated by stirring at a rate of 1,200 rev/min at room temperature. After the degradation reaction had proceeded for 5, 15 and 30 minutes, sodium sulphite solution (1.0 mol/L), to act as a reducing agent, was added dropwise to end the reaction.

Determination of the residual concentration of fentanyl compounds

The residual fentanyl compounds in the mixed system were extracted by 5 mL dichloromethane. To optimize the extraction of fentanyl, the pH was adjusted to be 12 with 5.0 mol/L sodium hydroxide solution. The extracted fentanyl compounds were quantitatively determined by gas chromatography (Agilent 6890) with a flame ionization detector (Raikos et al. 2009 ) with a HP capillary column (25 m × 0.25 mm × 0.25 μm) using splitless injection mode at a temperature of 230 °C. The flow velocity of the carrier gas was 1 mL/min. The column temperature was kept at 70 °C for 1 minute and then raised to 200 °C at a rate of 20 °C/min. Under these conditions, the retention times of fentanyl, carfentanil, sufentanil and 3-methylfentanyl were 7.2 minutes, 7.6 minutes, 8.0 minutes and 7.1 minutes, respectively. The ratio of the measured concentration to the initial concentration was defined as a degradation ratio by the formula: , where R is degradation ratio, C0 the initial concentration of fentanyl compounds and Ct the residual concentration of fentanyl compounds after ending the reaction.

Analysis of degradation products

The degradation products of fentanyl compounds in the extractive phase were analysed by GC/MS (Agilent 6890/5973) (Goromaru et al. 1984; Sachs et al. 1996) with a HP capillary column (30 m × 0.25 mm × 0.25 μm). During GC separation, the temperature was increased from 40 to 280 °C at a rate of 20 °C/min with a solvent delay of 2 minutes. GC/MS analysis was performed with a Trio-1 bench-top instrument under electron impact operating conditions (emission, 0.15 mA; electron energy, 70 eV; and source temperature, 200 °C). Full scanning MS data were acquired with unit resolution (50% valley definition) at 1 s/scan over a 50–500 μmass range.

RESULTS AND DISCUSSION

Oxidative degradation of fentanyl by NaBrO3 mixed system

The fentanyl degradation efficiencies of the solutions of NaBrO3, NaBrO3/H+, NaBrO3/Na2SO3, NaBrO3/Na2SO3/H+ and NaBrO3/NaHSO3 with different pH ranges were investigated. Figure 1 shows that no marked degradation was observed in the solutions of NaBrO3, NaBrO3/H+ and NaBrO3/Na2SO3, while a notable oxidative treatment of fentanyl by the NaBrO3 mixed system, strongly depending upon both reducing agent () and pH, was observed.

Figure 1

Degradation of fentanyl in mixed sodium bromate systems under the experimental conditions of 1 mol/L NaBrO3, Na2SO3, NaHSO3, molar ratio NaBrO3/SO32− = 1:1 and molar ratio NaBrO3/fentanyl = 50:1.

Figure 1

Degradation of fentanyl in mixed sodium bromate systems under the experimental conditions of 1 mol/L NaBrO3, Na2SO3, NaHSO3, molar ratio NaBrO3/SO32− = 1:1 and molar ratio NaBrO3/fentanyl = 50:1.

The mixed solution of NaBrO3 and Na2SO3 had colours indicative of differing degradation activity (Table 1, first three rows). The darker colour was likely associated with a higher oxidative capacity of the mixed sodium bromate system. It was reported that the Br-radicals delivered from HOBr generated in this system made the reaction solution dark and have oxidation capability (Beckwith et al. 1996; Metsger et al. 2000; Khan et al. 2003). The more oxidative Br-radicals the mixed sodium bromate system generated, the darker colour the solution showed. Therefore, the colour of the solution system was a proper indicator of oxidation activity.

Table 1

The relationship between the colour of NaBrO3/NaHSO3 and the degradation capability

Mixed solution pH Colour Degradation ratio (%) in 30 minutes 
NaBrO3/ Na2SO3 6.8 Hyaline 1.3 
NaBrO3/H2SO4/ Na2SO3 3.2 Salmon 79.2 
NaBrO3/ NaHSO3 0.5 Salmon >99.9 
NaBrO3/ NaHSO3 0.5 ↓ adjust 6.8 Salmon ↓ Hyaline  
Mixed solution pH Colour Degradation ratio (%) in 30 minutes 
NaBrO3/ Na2SO3 6.8 Hyaline 1.3 
NaBrO3/H2SO4/ Na2SO3 3.2 Salmon 79.2 
NaBrO3/ NaHSO3 0.5 Salmon >99.9 
NaBrO3/ NaHSO3 0.5 ↓ adjust 6.8 Salmon ↓ Hyaline  

Moreover, when the pH of the mixed solution was increased from 0.5 to 6.8, the solution colour changed from salmon to hyaline (Table 1, last row). This suggested that the concentration of Br-radicals, as highly active intermediate substances, in the NaBrO3/NaHSO3 mixed solution might be strongly dependent upon pH (i.e., the concentration of H+), being illustrated by such reactions as ; (Bierenstiel et al. 2005).

Factors influencing fentanyl degradation with mixed NaBrO3/Na2SO3

The effects of such factors as molar ratio of to NaBrO3, molar ratio of NaBrO3 to fentanyl and pH on degradation were investigated to identify the optimal degradation formula, as shown in Figure 2. The experimental results (Figure 2(a)) indicated that the optimal ratio of NaBrO3/ was in the range of 0.50–1.25. Figure 2(b) shows the influence of pH on the oxidative degradation ratio of fentanyl. Low pH was highly advantageous to the degradation of fentanyl. The degradation ratio of fentanyl was distinctly reduced by an increase of the pH over 4. Figure 2(c) shows the degradation capability (i.e., the molar ratio of NaBrO3 to fentanyl). An increase in dosage of sodium bromate improved the degradation efficiency of fentanyl, which may enable us to identify the corresponding optimal conditions for the complete degradation of fentanyl in different reaction times. The degradation ratio of fentanyl was able to reach 99.9% in 30 minutes with the molar ratio of NaBrO3 to fentanyl over 50:1. Moreover, the molar ratio of NaBrO3 to fentanyl was larger than 70:1, which resulted in a degradation ratio of above 99.9% in 5 minutes (Figure 2(c)).

Figure 2

Factors influencing fentanyl degradation with mixed NaBrO3/Na2SO3: (a) molar ratio of NaBrO3 to Na2SO3, (b) pH ranging from 3 to 6.5, (c) molar ratio of NaBrO3 to fentanyl.

Figure 2

Factors influencing fentanyl degradation with mixed NaBrO3/Na2SO3: (a) molar ratio of NaBrO3 to Na2SO3, (b) pH ranging from 3 to 6.5, (c) molar ratio of NaBrO3 to fentanyl.

In summary, the degradation efficiency during the reaction process was influenced by such factors as molar ratio of to NaBrO3, molar ratio of reactant to fentanyl and pH. The optimal conditions for degradation of fentanyl were the molar ratio of NaBrO3/H+/Na2SO3 approximately equal to 1.0:0.15:0.5 (i.e., 20:3:10) and pH = 4. For a degradation ratio above 99.9% in 30 minutes, the molar ratio of NaBrO3 to fentanyl should be higher than 50:1.

Oxidative degradation of fentanyl compounds in a NaBrO3/NaHSO3/Na2SO3 mixed system

To avoid using sulphuric acid, NaHSO3 and Na2SO3 reagents were chosen to produce H+ and . Under the optimized conditions, the degradation formula of NaBrO3/NaHSO3/Na2SO3 = 20:3:7 with a pH of 4 was used to degrade fentanyl compounds. The initial concentration of fentanyl compounds was 5.3 × 10−2mol mL−1. Figure S2 (available online at http://www.iwaponline.com/wst/072/185.pdf) indicates that the degradation ratios of fentanyl, 3-methylfentanyl and carfentanil all reached above 99.9% in 30 minutes. The degradation ratio of sufentanil was only 74% in 30 minutes because the thiophene ring in the structure of sufentanil was brominated by the active oxidative intermediates. The molar ratio of NaBrO3 to sufentanil was above 65:1, which resulted in a nearly complete degradation in 30 minutes.

Degradation products and possible degradation pathways for fentanyl compounds

Based on the GC/MS spectrum with total ion chromatography presented in Figure S3 (online at http://www.iwaponline.com/wst/072/185.pdf), the possible structural formulas were determined and identified (Table 2). The degradation products of carfentanil, 3-methylfentanyl and sufentanil were similar to those of fentanyl (Table S1, online at http://www.iwaponline.com/wst/072/185.pdf). This indicated that the identified products were mainly derived from the cleavage of the C=N bonds in the piperidine ring and the C=C bond next to the C=N bond in the oxidant solution.

Table 2

Products of oxidative degradation of fentanyl using sodium bromate system

Serial number Name Structures Main mass fragments 
2-dibromo-ethylbenzene  65,91(100),171,263(261:263:265 = 1:2:1) 
1-bromethyl-4-bromobenzene  51,65,90,171 (100),206,250(247:249:251 = 1:2:1) 
N-phenyl-propionamide  57,77,93(100),149 
N-phenyl-2-bropropionamide  51,98(100),120,227(227:229 = 1:1) 
3,4-dibromoaniline  63,90,125,143,170,250(248:250:252 = 1:2:1)(100) 
2,4,6-tribromoaniline  62,90,125,143,170,223,251,328(326:328:330:334 = 1:3:3:1)(100) 
4-bromoaniline  65,91,129(100),170(170:172 = 1:1) 
UC UC 57,77,105,132,176,203,217(100),259,308,364 
Serial number Name Structures Main mass fragments 
2-dibromo-ethylbenzene  65,91(100),171,263(261:263:265 = 1:2:1) 
1-bromethyl-4-bromobenzene  51,65,90,171 (100),206,250(247:249:251 = 1:2:1) 
N-phenyl-propionamide  57,77,93(100),149 
N-phenyl-2-bropropionamide  51,98(100),120,227(227:229 = 1:1) 
3,4-dibromoaniline  63,90,125,143,170,250(248:250:252 = 1:2:1)(100) 
2,4,6-tribromoaniline  62,90,125,143,170,223,251,328(326:328:330:334 = 1:3:3:1)(100) 
4-bromoaniline  65,91,129(100),170(170:172 = 1:1) 
UC UC 57,77,105,132,176,203,217(100),259,308,364 

UC: unknown chemical.

According to the detected and identified degradation products, possible degradation pathways for fentanyl in the Na2BrO3/NaHSO3/Na2SO3 mixed solution with a pH of 4 are proposed in Figure 3. The pathways were mainly composed of the following four pathways: (1) the oxidation of N-dealkylation at the piperidine ring, (2) the oxidation of the carbon atom next to the nitrogen at the piperidine ring, (3) the oxidation of the α-C next to the benzene ring, and (4) the further hydrolysis of amide and bromination reaction. This proposition was similar to those reported by others (Qi et al. 2011). Probably, the other fentanyl compounds underwent similar degradation pathways.

Figure 3

Possible degradation pathways of fentanyl by the sodium bromate mixed solution.

Figure 3

Possible degradation pathways of fentanyl by the sodium bromate mixed solution.

CONCLUSION

The oxidative degradation of such fentanyl compounds as fentanyl, 3-methylfentanyl, sufentanil and carfentanil in aqueous solutions containing NaBrO3, NaHSO3 and Na2SO3 was examined. The experimental results showed that in acidic conditions, the reaction between and ions produced some highly active intermediates able to degrade fentanyl compounds through oxidation reactions. When the molar ratio of NaBrO3/NaHSO3/Na2SO3 was equal to 20:3:7 and pH = 4, the degradation ratios of fentanyl, 3-methylfentanyl, and carfentanil were above 99.9% in 30 minutes with the molar ratio of NaBrO3 to fentanyl compounds larger than 50:1, while the molar ratio of NaBrO3 to sufentanil needed to be higher than 65:1 for a complete degradation in 30 minutes. The degradation products identified by GC/MS suggested the possible pathways of the cleavages of C–N and C–C in the structures of fentanyl compounds. The C–N bonds were cleaved by oxidative N-dealkylation reactions at the piperidine ring and amide sites as well as oxidative C–C bond cleavage between the α-C and β-C next to the benzene ring.

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Supplementary data