A surface-enhanced raman nanoparticle and a detection method of fentanyl substances

Abstract

The present application relates to a kind of surface enhanced raman nanoparticles and fentanyl substance detection method, belong to the field of drug safety detection.The surface enhanced raman nanoparticles is noble metal nanoparticle, the noble metal nanoparticle is preferably gold nanobiscake.The fentanyl substance detection method uses the surface enhanced raman nanoparticles of the present application to carry out raman detection.The surface enhanced raman nanoparticles and fentanyl substance detection method can quickly, non-destructively detect trace fentanyl substance in the sample to be measured, and has very good application prospect in public safety detection.

Description

Technical Field

[0001] This invention relates to the field of drug safety testing, specifically to a method for detecting surface-enhanced Raman spectroscopy nanoparticle sols and fentanyl-like substances. Background Technology

[0002] Fentanyl is a potent synthetic opioid and a highly effective synthetic anesthetic, belonging to the opioid class of drugs. In recent years, fentanyl has been illegally produced and sold, and its abuse and proliferation have become a major public health problem worldwide. Many countries have strengthened their control and crackdown efforts on fentanyl.

[0003] As the first line of defense at a nation's borders, the customs system is responsible for the comprehensive and accurate inspection and screening of import and export goods and parcels to prevent the inflow or outflow of illicit items. Fentanyl, a highly dangerous drug, poses a significant threat to society and the public if not detected and intercepted promptly and quickly. More importantly, non-destructive testing of mail and parcels is crucial for detecting fentanyl. Due to the large volume of mail and parcels, manual inspection is time-consuming, labor-intensive, and prone to damage. Non-destructive testing technologies not only improve the speed and efficiency of inspections but also reduce damage to mail and parcels, lowering postal operating costs and enhancing customs' inspection capabilities.

[0004] However, due to the relatively complex chemical structure of fentanyl and its numerous derivatives, traditional methods such as mass spectrometry require specialized instruments and technicians, resulting in high costs and long processing times. Drug detection strips and dog sniffing are susceptible to spoofing and false positives, and the characteristics of suspicious substances can be easily imitated, leading to misjudgments. X-ray imaging technology has limited detection capabilities for novel fentanyl derivatives.

[0005] Therefore, it is crucial to develop a simple and convenient technical means to quickly and non-destructively detect fentanyl-like substances in mail and packages. Summary of the Invention Invention Overview

[0007] To address the problems of complex operation, low efficiency, high cost, need to destroy the coating, low accuracy, poor sensitivity, and incomplete detection in existing technologies for detecting fentanyl-related substances, this invention provides surface-enhanced Raman nanoparticles, a surface-enhanced Raman nanoparticle sol, and a method for detecting fentanyl-related substances.

[0008] In a first aspect, the present invention provides a surface-enhanced Raman nanoparticle, which preferably adopts a gold nanoparticle structure. The surface-enhanced Raman nanoparticle can detect fentanyl-related substances rapidly, easily, with high accuracy, high sensitivity, low cost, and non-destructively, and can detect a wide variety of fentanyl-related substances, thus exhibiting excellent technical effects.

[0009] Secondly, the present invention provides a surface-enhanced Raman nanoparticle sol, wherein the surface-enhanced Raman nanoparticle sol contains the surface-enhanced Raman nanoparticles described in the first aspect, which can quickly, easily, with high accuracy, high sensitivity, low cost, and non-destructively detect fentanyl-related substances, and can detect a wide variety of fentanyl-related substances, thus exhibiting excellent technical effects.

[0010] Thirdly, the present invention provides a method for detecting fentanyl-related substances. The detection method uses the surface-enhanced Raman spectroscopy of nanoparticles as described in the second aspect for detection, preferably with the addition of an agglomerating agent, and more preferably with potassium iodide as an agglomerating agent. The detection method can detect a variety of fentanyl-related substances rapidly, simply, with high accuracy, high sensitivity, low cost, and non-destructively, and has excellent technical effects. Invention Details

[0012] To address the aforementioned technical problems, the present invention provides the following technical solutions.

[0013] In a first aspect, the present invention provides surface-enhanced Raman nanoparticles.

[0014] A surface-enhanced Raman nanoparticle, wherein the surface-enhanced Raman nanoparticle is a noble metal nanoparticle, the particle size of the noble metal nanoparticle is 20 nm to 200 nm, and the noble metal in the noble metal nanoparticle includes gold or silver; the noble metal nanoparticle is one of gold nanospheres, gold nanocakes, gold nanorods, gold core-shell structures, silver nanospheres, and silver cubic particles.

[0015] In some preferred embodiments, the noble metal nanoparticles are gold nanoparticles.

[0016] In some preferred embodiments, the noble metal nanoparticles are gold nanopatties with a diameter of 40-100 nanometers and a thickness of 15-35 nanometers. In some even more preferred embodiments, the noble metal nanoparticles are gold nanopatties with a diameter of 60-90 nanometers and a thickness of 20-35 nanometers.

[0017] In some preferred embodiments, the noble metal nanoparticles are gold nanopatties with a diameter of 80 nm ± 10 nm and a thickness of 30 nm ± 5 nm.

[0018] Secondly, the present invention provides a surface-enhanced Raman nanoparticle sol.

[0019] A surface-enhanced Raman nanoparticle sol comprising the surface-enhanced Raman nanoparticles described in the first aspect and a solvent.

[0020] In some embodiments, the solvent includes at least one of water, ethanol, and methanol.

[0021] In some embodiments, the structure of the surface-enhanced Raman nanoparticles is a gold nanoparticle cake.

[0022] In some embodiments, the preparation method of the surface-enhanced Raman nanoparticle sol includes: mixing a noble metal precursor solution with a protective agent solution, adding ethanol (to adjust the morphology of the particles), reacting to obtain a noble metal nanoparticle solution, centrifuging to obtain precipitate 1, washing precipitate 1, centrifuging to obtain precipitate 2, mixing precipitate 2 with water to obtain the surface-enhanced Raman nanoparticle sol.

[0023] In some embodiments, the noble metal precursor in the noble metal precursor solution includes tetrachloroauric acid (HAuCl4).

[0024] In some embodiments, the noble metal precursor solution is heated to 90°C-105°C before being mixed with the protective agent solution. In some embodiments, the noble metal precursor solution is heated at 90°C-105°C for 20-35 minutes before being mixed with the protective agent solution. The morphology of the particles is affected by temperature, and heating at the temperatures provided by this invention is beneficial for obtaining excellent particle morphology.

[0025] In some embodiments, the protective agent in the protective agent solution includes at least one selected from sodium citrate, polyvinylpyrrolidone (PVP), hexadecyltrimethylamine bromide (CTAB), hexadecyltrimethylamine chloroform (CTAC), and hexadecyltrimethylamine iodoformide (CTAI).

[0026] In some embodiments, the noble metal precursor solution and the protective agent solution are mixed within 2 seconds.

[0027] In some embodiments, the amount of ethanol added is 10uL-100uL. In some embodiments, the amount of ethanol added is 10uL, 20uL, 30uL, 40uL, 50uL, 60uL, 70uL, 80uL, 90uL, or 100uL.

[0028] In some embodiments, the reaction temperature is 90°C-105°C. In some embodiments, the reaction temperature is 90°C, 91°C, 92°C, 93°C, 94°C, 95°C, 96°C, 97°C, 98°C, 99°C, 100°C, 101°C, 102°C, 103°C, 104°C, or 105°C. In some embodiments, the reaction temperature is 100°C.

[0029] In some embodiments, the reaction time is 20 min to 60 min. In some embodiments, the reaction time is 20 min, 25 min, 30 min, 35 min, 40 min, 45 min, 50 min, 55 min, or 60 min. In some embodiments, the reaction time is 25 min to 35 min. In some embodiments, the reaction time is 30 min.

[0030] In some embodiments, the solvent of the noble metal precursor solution includes water.

[0031] In some embodiments, the mass ratio of the noble metal precursor in the noble metal precursor solution to the protective agent in the protective agent solution is 10.0:3.0-10.0:1.0. In some embodiments, the mass ratio of the noble metal precursor in the noble metal precursor solution to the protective agent in the protective agent solution is 10.0:3.0, 10.0:2.5, 10.0:2.0, 10.0:1.5, or 10.0:1.0. In some embodiments, the mass ratio of the noble metal precursor in the noble metal precursor solution to the protective agent in the protective agent solution is 10.0:3.0.

[0032] In some embodiments, the concentration of the noble metal precursor in the noble metal precursor solution is 0.001 wt% to 1.000 wt%. In some embodiments, the concentration of the noble metal precursor in the noble metal precursor solution is 0.001 wt%, 0.005 wt%, 0.010 wt%, 0.020 wt%, 0.030 wt%, 0.040 wt%, 0.050 wt%, 0.060 wt%, 0.070 wt%, 0.080 wt%, 0.090 wt%, 0.100 wt%, 0.200 wt%, 0.300 wt%, 0.400 wt%, 0.500 wt%, or 1.000 wt%. In some embodiments, the concentration of the noble metal precursor in the noble metal precursor solution is 0.010 wt% to 0.050 wt%. In some embodiments, the concentration of the noble metal precursor in the noble metal precursor solution is 0.050 wt%.

[0033] In some embodiments, the concentration of the protective agent in the protective agent solution is 0.5 wt%-2.0 wt%. In some embodiments, the concentration of the protective agent in the protective agent solution is 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1.0 wt%, 1.1 wt%, 1.2 wt%, 1.3 wt%, 1.4 wt%, 1.5 wt%, 1.6 wt%, 1.7 wt%, 1.8 wt%, 1.9 wt%, or 2.0 wt%. In some embodiments, the concentration of the protective agent in the protective agent solution is 0.8 wt%-1.2 wt%. In some embodiments, the concentration of the protective agent in the protective agent solution is 1.0 wt%.

[0034] In some embodiments, the solvent of the protective agent solution includes water.

[0035] In some embodiments, the cleaning is performed using at least one of ethanol, methanol, and water. In some embodiments, the cleaning is performed 1-5 times. In some embodiments, the cleaning is performed 1, 2, 3, 4, or 5 times.

[0036] In some embodiments, the concentration of noble metal nanoparticles in the surface-enhanced Raman nanoparticle sol is 6 × 10⁻⁶. 11 6 x 10 units / ml 13 The concentration of noble metal nanoparticles in the surface-enhanced Raman nanoparticle sol is 6 × 10⁻⁶ / ml. In some embodiments, the concentration of noble metal nanoparticles in the surface-enhanced Raman nanoparticle sol is 6 × 10⁻⁶ / ml. 12 per ml.

[0037] In some embodiments, the structure of the surface-enhanced Raman nanoparticles is a gold nanopatty. The preparation method of the surface-enhanced Raman nanoparticle sol includes: heating a noble metal precursor solution to 90℃-105℃ or 100℃ for 20min-35min; mixing the noble metal precursor solution with a protective agent solution; completing the mixing of the noble metal precursor solution and the protective agent solution within 2 seconds; adding ethanol (to adjust the morphology of the particles), wherein the amount of ethanol added is 10uL; reacting at 90℃-105℃ for 20min-60min; cooling to room temperature to obtain a noble metal nanoparticle solution; and centrifuging. Precipitate 1 was obtained, precipitate 1 was washed, centrifuged, and precipitate 2 was obtained. Precipitate 2 was mixed with water to obtain the surface-enhanced Raman nanoparticle sol. The noble metal precursor in the noble metal precursor solution includes tetrachloroauric acid (HAuCl4); the concentration of the noble metal precursor in the noble metal precursor solution is 0.05 wt%; the concentration of the protective agent in the protective agent solution is 1.0 wt%; the solvent of the noble metal precursor solution includes water; the solvent of the protective agent solution includes water; the number of washing cycles is 1-5; the concentration of noble metal nanoparticles in the surface-enhanced Raman nanoparticle sol is 6 × 10⁻⁶.11 6 x 10 units / ml 13 per ml.

[0038] Thirdly, the present invention provides a method for detecting fentanyl-like substances.

[0039] A method for detecting fentanyl-related substances, comprising the following steps:

[0040] (1) Extraction: Take the liquid sample to be tested or wipe the solid sample to be tested with a wiping solvent;

[0041] (2) Raman spectroscopy detection: The liquid sample to be tested or the wiping solvent after wiping is transferred into the surface-enhanced Raman nanoparticle sol described in the second aspect, and then Raman spectroscopy with laser wavelengths of 785nm, 633nm, 532nm and / or 1064nm is used for detection to obtain the Raman frequency shift spectrum data of the liquid sample to be tested.

[0042] (3) Result Interpretation: Raman shift spectral data within 832±6cm -1 1000±6cm -1 1030±6cm -1 and 1200±6cm -1 The liquid sample to be tested contains fentanyl-like substances if it has peaks at at least 1, 2, 3, or 4 wavenumbers; or if its Raman shift spectral data are within 1000 ± 6 cm⁻¹. -1 1030±6cm -1 and 1200±6cm -1 The solid or liquid sample to be tested contains fentanyl-like substances and has peaks at at least 1, 2, or 3 wavenumbers; the Raman shift spectral data are within 832 ± 6 cm⁻¹. -1 1000±6cm -1 1030±6cm -1 and 1200±6cm -1 The solid or liquid sample to be tested, which has no peaks at any wavenumber, does not contain fentanyl-related substances.

[0043] In some embodiments, the Raman spectroscopy detection in step (2) further includes adding an agglomerating agent solution after transferring the liquid sample to be tested or the wiping solvent after wiping to the surface-enhanced Raman nanoparticle sol described in the second aspect, and before performing Raman spectroscopy detection.

[0044] In some embodiments, the flocculant in the flocculant solution includes at least one selected from KCl, KBr, KI, MgSO4, MgCl2, NaBr, and NaCl. In some preferred embodiments, the flocculant in the flocculant solution is KI.

[0045] In some embodiments, the concentration of the flocculant in the flocculant solution is 0.01 mol / L to 5.00 mol / L. In some embodiments, the concentration of the flocculant in the flocculant solution is 0.01 mol / L, 0.05 mol / L, 0.10 mol / L, 0.50 mol / L, 0.60 mol / L, 0.70 mol / L, 0.80 mol / L, 0.90 mol / L, 1.00 mol / L, 1.10 mol / L, 1.20 mol / L, 1.30 mol / L, 1.40 mol / L, 1.50 mol / L, 2.00 mol / L, 2.50 mol / L, 3.00 mol / L, 3.50 mol / L, 4.00 mol / L, 4.50 mol / L, or 5.00 mol / L. In some embodiments, the concentration of the flocculant in the flocculant solution is 1.00 mol / L.

[0046] In some embodiments, the agglomerant solution uses at least one of water, methanol, and ethanol as a solvent.

[0047] In some embodiments, the excitation power of the Raman spectrum is 10mW to 500mW. In some embodiments, the excitation power of the Raman spectrum is 10mW, 50mW, 100mW, 150mW, 200mW, 250mW, 300mW, 350mW, 400mW, 450mW, or 500mW.

[0048] In some embodiments, the wiping solvent is at least one of methanol, acetone, ethanol, or diethyl ether.

[0049] In some embodiments, wiping the solid sample to be tested with a wiping solvent includes wiping the solid sample to be tested with a cotton swab moistened with a wiping solvent.

[0050] In some embodiments, the volume of the wiping solvent is 0.1 mL to 1.0 mL. In some embodiments, the volume of the wiping solvent is 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, or 1.0 mL.

[0051] In some embodiments, the wiping is performed 1 to 5 times. In some embodiments, the wiping is performed 1, 2, 3, 4, or 5 times.

[0052] In some embodiments, the wiping time is 1 to 10 seconds. In some embodiments, the wiping time is 1 second, 2 seconds, 3 seconds, 4 seconds, 5 seconds, 6 seconds, 7 seconds, 8 seconds, 9 seconds, or 10 seconds.

[0053] In some embodiments, the transfer includes transfer by immersion, dripping, or pressing.

[0054] In some embodiments, the volume ratio of the liquid test sample or wiping solvent to the surface-enhanced Raman spectroscopy nanoparticle sol is 1:10 to 1:1. In some embodiments, the volume ratio of the liquid test sample or wiping solvent to the surface-enhanced Raman spectroscopy nanoparticle sol is 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, or 1:1. In some embodiments, the volume ratio of the liquid test sample or wiping solvent to the surface-enhanced Raman spectroscopy nanoparticle sol is 1:2.

[0055] In some embodiments, the volume ratio of the agglomerating agent solution to the surface-enhanced Raman spectroscopy (SERS) nanoparticle sol is 1:10 to 1:1. In some embodiments, the volume ratio of the agglomerating agent solution to the SERS nanoparticle sol is 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, or 1:1. In some embodiments, the volume ratio of the agglomerating agent solution to the SERS nanoparticle sol is 1:4.

[0056] In some embodiments, the solid sample to be tested may be made of metal, ceramic, glass, plastic, stone, wood, or skin.

[0057] In some embodiments, the solid sample to be tested includes mail, parcels, boxes, bags, appliances, furniture, containers, or skin.

[0058] In some embodiments, the Raman spectroscopy includes detection using a portable Raman spectrometer or a handheld Raman spectrometer.

[0059] Fourthly, the present invention provides an application of the surface-enhanced Raman nanoparticles of the first aspect, the surface-enhanced Raman nanoparticle sol of the second aspect, or the detection method of the third aspect.

[0060] Applications of a first aspect of surface-enhanced Raman nanoparticles, a second aspect of surface-enhanced Raman nanoparticle sol, or a third aspect of the detection method in the detection of fentanyl-related substances, in the rapid detection of trace fentanyl-related substances, in the rapid detection of trace fentanyl-related substances on the surface of mail or packages, or in the rapid non-destructive detection of trace fentanyl-related substances on the surface of mail or packages.

[0061] In some embodiments, the fentanyl compounds include 4-fluorobutyryl fentanyl, 4-fluoroisobutyryl fentanyl, butyryl fentanyl, isobutyryl fentanyl or its salts, furanyl fentanyl or its salts, valerate fentanyl or its salts, β-hydroxythiofentanyl, cis-3-methylfentanyl or its salts, oxfentanyl, p-fluorofentanyl, sufentanyl citrate, acetylfentanyl, β-hydroxy-3-methylfentanyl, 4-anilino-N-phenylethylpiperidine, remifentanyl or its salts, α-methylfentanyl or its salts, N-phenylethyl-4-piperidinone, carfentanyl, β-hydroxyfentanyl, 3-methylthiofentanyl or its salts, alfentanyl, fentanyl, acetylalfamethylfentanyl, acryloylfentanyl or its salts, thiofentanyl or its salts, and alfamethylthiofentanyl. Fentanyl or its salts, tetrahydrofuran fentanyl, 2-thiophenecarboxyl fentanyl or its salts, chloroacetyl fentanyl or its salts, benzoyl fentanyl or its salts, (2-fluorobenzoyl)fentanyl or its salts, (3-fluorobenzoyl)fentanyl or its salts, (2-chlorobenzoyl)fentanyl or its salts, (4-fluorobenzoyl)fentanyl or its salts, p-chlorofuranoyl fentanyl or its salts, p-chloromethoxyacetyl fentanyl or its salts, p-chlorothiophenecarboxyl fentanyl or its salts, p-chlorobenzoyl fentanyl or its salts, p-chlorocyclopropionyl fentanyl or its salts, p-chloroacetyl fentanyl or its salts, cyclopentyl fentanyl or its salts, cyclobutyl fentanyl or its salts, heptyl fentanyl or its salts, ethoxyacetyl fentanyl or its salts, phenylpropionyl fentanyl or its salts, butyryl α-methyl fentanyl or its salts, cyclo Butylformylfentanyl or its salts, isovalerylfentanyl or its salts, N-benzylbutyrylfentanyl or its salts, N-benzylcyclopropylfentanyl or its salts, N-benzylvalerylfentanyl or its salts, N-benzylacetylfentanyl or its salts, N-benzylhexanoylfentanyl or its salts, alfamethylfentanyl or its salts, betahydroxy-3-methylfentanyl or its salts, betahydroxyfentanyl or its salts, betahydroxyisobutyrylfentanyl or its salts, betahydroxyvalerylfentanyl or its salts, thiofentanyl or its salts, ethoxyacetylfentanyl or its salts, cyclopentylformylfentanyl or its salts, p-methylbutyrylfentanyl or its salts, o-methylfentanyl or its salts, p-methoxyacrylfentanyl or its salts, N-benzylfentanyl or its salts, N-benzyl-p-fluorofentanyl or its salts, norcarfentanyl Fentanyl or its salts, N-(4-methylphenethyl)-isobutyryl fentanyl or its salts, phenylpropionyl fentanyl or its salts, heptayl fentanyl or its salts, 2-thiophenecarboxyl fentanyl or its salts, chloroacetyl fentanyl or its salts, benzoyl fentanyl or its salts, cyclobutylcarboxyl fentanyl or its salts, (2-fluorobenzoyl)fentanyl or its salts, (3-fluorobenzoyl)fentanyl or its salts, isovaleryl fentanyl or its salts, (2-chlorobenzoyl)fentanyl or its salts, (4-fluorobenzoyl)fentanyl or its salts, p-fluoroacetyl fentanyl or its salts, p-fluorotetrahydrofuranoyl or its salts, p-fluorobenzoyl fentanyl or its salts, p-fluorothiophenecarboxyl fentanyl or its salts, p-fluorofuranoyl fentanyl or its salts, p-fluorocyclopentanoyl fentanyl or its salts, p-fluoropentanoyl fentanyl or its saltso-Fluorofentanyl or its salt, o-Fluoroacryloylfentanyl or its salt, o-Fluoroacetylfentanyl or its salt, m-Fluorofentanyl or its salt, m-Fluoromethoxyacetylfentanyl or its salt, m-Fluoroisobutyryloylfentanyl or its salt, m-Fluoroacetylfentanyl or its salt, m-Fluorofuran fentanyl or its salt, m-Fluorobenzoylfentanyl or its salt, p-Chlorofentanyl or its salt, p-Chlorobutyryloylfentanyl or its salt, p-Chlorofuran fentanyl or its salt, p-Chloromethoxyacetylfentanyl or its salt, p-Chlorothiophenecarboxylfentanyl or its salt, p-Chlorobenzoylfentanyl or its salt, p-Chlorocyclopropionylfentanyl or its salt, p-Chloroacetylfentanyl or its salt, p-Methylfentanyl or its salt, p-Methyl-(4-fluorobenzoyl)fentanyl or its salt, p-Methylcyclopentylfentanyl or its salt, p-Methylcyclohexylfentanyl Fentanyl or its salts, p-methyltert-butylcarboxylfentanyl or its salts, p-methylcyclopropylcarboxylfentanyl or its salts, p-methylmethoxyacetylfentanyl or its salts, p-methylthiophenecarboxylfentanyl or its salts, p-methylfuranoylfentanyl or its salts, p-methylbenzoylfentanyl or its salts, p-methylethoxyacetylfentanyl or its salts, p-methyltetrahydrofuranoylfentanyl or its salts, p-methyl-(4-chlorobenzoyl)fentanyl or its salts, o-methylfuranoylfentanyl or its salts, o-methylcyclohexylfentanyl or its salts, o-methylbutyrylfentanyl or its salts, o-methylbenzoylfentanyl or its salts, o-methyl-(4-fluorobenzoyl)fentanyl or its salts, o-methylthiophenecarboxylfentanyl or its salts, o-methylcyclopentylcarboxylfentanyl or its salts, benzoylalfa Methylfentanyl or its salts, hexanoylalfamethylfentanyl or its salts, p-methoxytetrahydrofuran fentanyl or its salts, p-methoxyisobutyryl fentanyl or its salts, p-methoxy-2-methoxyacetylfentanyl or its salts, p-methoxyhexanoyl fentanyl or its salts, thioacetylfentanyl or its salts, N-benzylacetylfentanyl or its salts, N-benzylbutyryl fentanyl or its salts, N-benzyl-(4-chlorobenzoyl)fentanyl or its salts, N-benzylcyclopropylfentanyl or its salts, N-benzylcyclopentylfentanyl or its salts, N-benzylpentylfentanyl or its salts, N-benzylfuran fentanyl or its salts, N-benzylhexanoyl fentanyl or its salts, N-benzyl-p-fluoro-cyclopentylformylfentanyl or its salts, N-benzyl-p-fluoro-cyclohexylformylfentanyl or its salts, N- Benzyl-p-fluoro-furanoyl fentanyl or its salts, N-benzyl-p-fluoro-(3-fluorobenzoyl)fentanyl or its salts, N-benzyl-p-fluoro-acetylfentanyl or its salts, N-benzyl-p-fluoro-thiophenoyl fentanyl or its salts, N-benzyl-p-fluoro-methoxyacetyl fentanyl or its salts, N-benzyl-p-fluoro-isobutyryl fentanyl or its salts, N-benzyl-p-fluoro-butyryl fentanyl or its salts, N-benzyl-p-fluoro-(4-chlorobenzoyl)fentanyl or its salts, N-methylbenzoyl fentanyl or its salts, N-methyl-(4-chlorobenzoyl)fentanyl or its salts, N-methyl-(2-fluorobenzoyl)fentanyl or its salts, N-(4-methylphenylethyl)benzoyl fentanyl or its salts, N-(4-methylphenylethyl)fentanyl or its saltsN-(4-methylphenethyl)-isovalerate fentanyl or its salt, N-(4-methylphenethyl)-n-butyryl fentanyl or its salt, N-cyclopropanoylcyclopropyl fentanyl or its salt, p-fluorofentanyl or its salt, N-(4-methylphenethyl)-(4-chlorobenzoyl)fentanyl or its salt, N-(4-methylphenethyl)-thienocarboxyl fentanyl or its salt, N-(4-nitrophenethyl)fentanyl or its salt, valerate alfamethyl fentanyl or its salt, N-benzylisobutyryl fentanyl or its salt, N-(4-methyl... At least one of the following: (phenylethyl)-cyclohexylformylfentanyl or a salt thereof; N-(4-chlorophenylethyl)fentanyl or a salt thereof; N-(4-methylphenylethyl)-methoxyacetylfentanyl or a salt thereof; N-(4-methylphenylethyl)-acetylfentanyl or a salt thereof; o-methoxybutyryl fentanyl or a salt thereof; o-methoxyvalerate fentanyl or a salt thereof; 3-methylthioacetylfentanyl or a salt thereof; butyryl alfamethylfentanyl or a salt thereof; beta-hydroxy-3-methylbutyryl fentanyl or a salt thereof; and 3-methylthiobutyryl fentanyl or a salt thereof.

[0062] In some embodiments, the fentanyl-like substances include at least one of fentanyl, α-methyl-fentanyl hydrochloride, β-hydroxy-fentanyl hydrochloride, (±)cis-3-methylfentanyl, 3-methylthiofentanyl, p-fluorofentanyl, remifentanyl hydrochloride, sufentanyl citrate, acetylfentanyl, butyryl fentanyl, (±)-β-hydroxythiofentanyl hydrochloride, and 4-fluorobutyryl fentanyl.

[0063] Beneficial effects

[0064] Compared with the prior art, a certain embodiment of the present invention has at least one of the following beneficial technical effects:

[0065] 1. Because the concentration of fentanyl-related substances remaining in mail and packages is very low, direct Raman detection is not possible; furthermore, there are many interfering substances in actual detection, and many methods are difficult to avoid false identification. This invention rapidly extracts and transfers fentanyl-related substances from mail and packages, then transfers the extracted drug molecules to a surface-enhanced Raman nanoparticle sol provided by this invention. Detection is then performed using a portable or handheld Raman spectrometer, achieving ultrasensitive and non-destructive detection of fentanyl-related substances in mail and packages. The detection limit for fentanyl-related substances using this invention is as low as 1 μg / L.

[0066] 2. This invention provides an ultrasensitive, non-destructive detection method for fentanyl-related substances in mail and parcels. Surface-enhanced Raman spectroscopy is used to obtain spectra from mail and parcel samples, allowing for rapid determination of whether the mail or parcel contains fentanyl-related substances. This is highly suitable for customs' rapid detection of fentanyl-related substances in mail and parcels. Conventional methods achieve minute-level detection per sample, while the technical solution of this invention can achieve second-level detection per sample.

[0067] sample.

[0068] 3. The method provided by this invention is simple to operate, low in cost, and fast. It does not require large precision instruments and can realize on-site portable detection of fentanyl-like substances in mail and parcels. It has very low professional requirements for operators, and ordinary people can quickly master and perform the test, which greatly reduces the difficulty of operation. The operation only involves wiping with cotton swabs. It is a "foolproof" operation and saves a lot of labor costs.

[0069] 4. This invention can be applied in the field of public security detection, especially in scenarios such as customs and ports. It provides a rapid and effective screening method that can improve detection efficiency and reduce detection costs. It holds promise for widespread practical application in the rapid and non-destructive detection of fentanyl-related substances, with a very promising application prospect. It is also a key area of ​​national security support. The current technological maturity needs to be improved. The volume of mail and parcels is very large, and the spread and circulation of drugs are very covert and disguised. Trace rapid analysis has a very good application prospect in public security detection.

[0070] 5. Compared with other shapes of surface-enhanced Raman nanoparticles, the present invention preferably uses disc-shaped nanoparticles, and more preferably disc-shaped gold nanoparticles, which is beneficial to improving the detection sensitivity of the surface-enhanced Raman nanoparticles or the surface-enhanced Raman nanoparticle sol of the present invention for fentanyl-like substances.

[0071] 6. Compared with other sizes of surface-enhanced Raman nanoparticles, the present invention preferably uses gold nanoparticle cakes with a diameter of 80 nm and a thickness of 30 nm as surface-enhanced Raman nanoparticles, which is more conducive to improving the detection sensitivity of the surface-enhanced Raman nanoparticles or the surface-enhanced Raman nanoparticle sol of the present invention for fentanyl-related substances.

[0072] 7. The present invention improves the sensitivity of the detection method by adding an agglomerating agent solution when detecting fentanyl-related substances.

[0073] 8. The agglomerating agent in the agglomerating agent solution of the present invention is preferably at least one of KCl, KBr, KI, MgSO4, MgCl2, NaBr, and NaCl, which helps to avoid interference of the agglomerating agent with the detection peak of fentanyl-like substances; wherein the agglomerating agent in the agglomerating agent solution is more preferably KI, which is more conducive to improving the sensitivity of the detection method. Attached Figure Description

[0074] Figure 1 The test results of different types of surface-enhanced Raman nanoparticle sols obtained in Examples 1 and 2 were used to detect fentanyl standard solutions of the same concentration and volume.

[0075] Figure 2This is a test of the ability of different types of agglomerants in Example 4 to enhance the results.

[0076] Figure 3 This is an example of the interference test caused by different types of agglomerating agents in Example 4.

[0077] Figure 4 The scanning electron microscopy characterization of the surface-enhanced Raman nanoparticles after adding different salt solutions as agglomerating agents in Example 5 is shown.

[0078] Figure 5 This is a stability test of KI as an agglomerating agent in Example 6 when testing fentanyl.

[0079] Figure 6 Example 7 illustrates the detection of different types of fentanyl-based standard substances using gold cake nanoparticles.

[0080] Figure 7 Example 7 illustrates the detection of different types of fentanyl-based standard substances using gold cake nanoparticles.

[0081] Terminology definition:

[0082] In this invention, "room temperature" refers to the ambient temperature, which can be 20℃-30℃; in some embodiments, it is 22℃-28℃; in some embodiments, it is 24℃-26℃; and in some embodiments, it is 25℃.

[0083] In the foregoing description of this invention, all figures disclosed herein, whether or not the words “approximately” or “about” are used, are approximate values. Based on the disclosed figures, the value of each figure may vary by less than ±10% or by a difference that is considered reasonable by those skilled in the art, such as ±1%, ±2%, ±3%, ±4%, or ±5%.

[0084] The terms “optional,” “optional,” or “optionally” mean that the event or situation described below may, but is not necessarily, occur. For example, “optional surfactant” means that the surfactant may or may not be present.

[0085] The term “weight percentage” or “percentage by weight” or “wt%” is defined as the weight of a single component in a composition divided by the total weight of all components in the composition and then multiplied by 100.

[0086] The term “and / or” should be understood to mean any one of the options or any combination of two or more of the options.

[0087] The term "wt%" indicates a percentage by mass.

[0088] The term "Raman shift value" refers to the wavenumber at which the elution point of a substance is located in a Raman spectrum.

[0089] In this invention, the “particle size” of a non-spherical particle refers to the width between the two points with the greatest width distance in the non-spherical particle.

[0090] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples. Detailed Implementation

[0091] To enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to provide a more detailed description of the present invention.

[0092] All reagents used in this invention can be purchased commercially or prepared by the methods described in this invention.

[0093] The detection limit described in this invention is the detection limit concentration of fentanyl-like substances in a liquid test sample or in a wiping solvent obtained after wiping a solid test sample with a wiping solvent.

[0094] Example 1: Preparation of surface-enhanced Raman nanoparticle sol with gold nanocakes

[0095] 1. Synthesis of gold nanoparticles: 200 ml of a 0.050% (w / w) HAuCl4 aqueous solution was continuously stirred and heated to boiling (100℃) for 30 min. Then, 3 ml of a 1.0% (w / w) sodium citrate aqueous solution was rapidly injected (completely added within 2 seconds), followed by the addition of 10 μL of ethanol. The mixture was then refluxed (100℃) for another 30 min and cooled to room temperature to obtain an aqueous solution of metal nanoparticles.

[0096] 2. Particle Cleaning and Enrichment: Centrifuge the aqueous solution of metal nanoparticles obtained in step 1 to remove the supernatant, obtaining precipitate 1. Add water to precipitate 1, mix, and centrifuge to obtain precipitate 2. Precipitate 2 is the cleaned metal nanoparticles (the purpose of cleaning is to remove excess protective agent sodium citrate from the particle surface; the synthesized metal nanoparticles need to be cleaned with water, ethanol, or methanol, preferably with water). Then, add an appropriate amount of deionized water to the cleaned metal nanoparticles to achieve a concentration of 6 × 10⁻⁶. 12 cells / ml (can be 6×10) 11 6 x 10 units / ml 13 The surface-enhanced Raman nanoparticle sol was obtained by (particles / ml). The shape and size of the surface-enhanced Raman nanoparticles in the obtained surface-enhanced Raman nanoparticle sol were detected. The surface-enhanced Raman nanoparticles obtained by scanning electron microscopy were disc-shaped with a diameter of 80 nm and a thickness of 30 nm.

[0097] Example 2: Detection of Fentanyl-related Substances

[0098] Extraction of fentanyl-related substances: The cotton swab is moistened with ethanol (or at least one of methanol or ethanol, with a volume ratio of methanol to ethanol of 1:0, 0:1, or 1:1) and wiped on the surface of the sample containing fentanyl-related substances to extract the fentanyl-related substances. The wiping is performed twice, and the total wiping time is 5 seconds.

[0099] Transfer and detection of fentanyl-related substances: Known fentanyl standard samples were directly used for detection to test the sensitivity of surface-enhanced Raman nanoparticles to fentanyl samples. In the practical application, fentanyl-related substances were extracted using cotton swabs and then immersed in the surface-enhanced Raman nanoparticle sol obtained in step (1), thereby transferring fentanyl-related substances into the surface-enhanced Raman sol. The total immersion time was 10 s. Then, Raman spectrometry was used for detection. Detection conditions: laser wavelength was 785 nm, excitation power was 100 mW, integration time was automatic, the instrument detection and recognition process usually did not exceed 20 s, and the number of integrations was 1. The Raman instrument model was SHINS-P785V, Xiamen SHINS Technology Co., Ltd.

[0100] Example 3: Performance evaluation of fentanyl detection using sol-gels with different surface-reinforced Raman nanoparticles

[0101] 1. Preparation of different types of surface-reinforced Raman nanoparticle sols

[0102] 1) Preparation of Au spheres (55 nm particle size) sol: 200 ml of 0.010% HAuCl4 aqueous solution was continuously stirred and heated to boiling (100℃) for 30 min. Then, 1.5 ml of 1.0% sodium citrate solution was rapidly injected (completely added within 2 seconds). The mixture was then boiled under reflux for another 30 min and cooled to room temperature to obtain an aqueous solution of metal nanoparticles. The obtained aqueous solution of metal nanoparticles was centrifuged to remove the supernatant, yielding precipitate 1. Precipitate 1 was then mixed with water and centrifuged again to obtain precipitate 2. Precipitate 2 is the washed metal nanoparticles. Then, an appropriate amount of deionized water was added to the washed metal nanoparticles to achieve a concentration of 6 × 10⁻⁶. 12 The surface-enhanced Raman spectroscopy (SERS) nanoparticle sol was obtained by measuring particles per ml. The shape and size of the SERS nanoparticles in the obtained SERS nanoparticle sol were detected. The SERS nanoparticles were found to be spherical with a particle size of 55 nm by scanning electron microscopy. The prepared SERS nanoparticle sol was named Au sphere (55 nm particle size) sol.

[0103] 2) Preparation of Au spheres (30 nm particle size) sol: 200 ml of a 0.010% HAuCl4 aqueous solution was continuously stirred and heated to boiling (100℃) for 30 min. Then, 3 ml of a 1.0% sodium citrate aqueous solution was added within 2 seconds. The mixture was then boiled and refluxed for another 30 min, followed by cooling to room temperature to obtain an aqueous solution of metal nanoparticles. The obtained aqueous solution of metal nanoparticles was centrifuged to remove the supernatant, yielding precipitate 1. Precipitate 1 was then mixed with water and centrifuged again to obtain precipitate 2. Precipitate 2 is the washed metal nanoparticles. Then, an appropriate amount of deionized water was added to the washed metal nanoparticles to achieve a concentration of 6 × 10⁻⁶. 12 The surface-enhanced Raman spectroscopy (SERS) nanoparticles were obtained by sampling at a density of 1 particle per ml. The shape and size of the SERS nanoparticles in the obtained SERS nanoparticle sol were detected. The SERS nanoparticles were found to be spherical with a particle size of 30 nm by scanning electron microscopy. The prepared SERS nanoparticle sol was named Au sphere (30 nm particle size) sol.

[0104] 3) Preparation of Ag sphere (different particle sizes) sol (taking 100nm as an example):

[0105] (1) First, place 10ml of 45nm Au seeds in a 100ml flask, then add 58ml of ultrapure water;

[0106] (2) Then, transfer 0.84 ml of 1 wt% sodium citrate aqueous solution and 0.84 ml of 1 wt% ascorbic acid aqueous solution to the Au seed solution and stir evenly for 5 min;

[0107] (3) Finally, 9.6 ml (1.344 ml of 20 mM AgNO3 diluted to 9.6 ml) of AgNO3 solution was added to the round-bottom flask at a certain dropping rate using a syringe.

[0108] (4) The addition was completed in approximately 45 minutes, followed by centrifugation and characterization. The amounts of each substance required for the synthesis of Ag particles of different sizes are shown in the table below:

[0109]

[0110] 4) Preparation of Ag cubes (80nm particle size) sol: Take a clean, dried round-bottom flask, add 20ml of 1,5-pentanediol, and incubate at 195°C for 10min. Then, take two syringes, draw in appropriate amounts of AgNO3 solution and polyvinylpyrrolidone solution, and then begin to add AgNO3 solution and polyvinylpyrrolidone solution dropwise to the incubated pentanediol. Observe the solution color change from colorless to grayish-green, then 80nm Ag cubes can be obtained.

[0111] 5) Preparation of 55nm Au@3nm MOF sol: Au@3nm MOF structures were synthesized by adding the organic ligand dimethylimidazole to a 55nm Au solution. During the synthesis of Au@3nm MOF, particles with different shell thicknesses could be precisely prepared by slightly adjusting the amounts of Zn ions and added 2-methylimidazole, with the Zn ion to 2-methylimidazole ratio maintained at 1:3.

[0112] 6) The 55nm Au@4nm ZrO2 sol and 55nm Au@2nm TiO2 sol were purchased from Xiamen SHINS Technology Co., Ltd.

[0113] 2. Sensitivity assessment of different types of surface-reinforced Raman spectroscopy nanoparticle sols:

[0114] 200 μL of different types of surface-enhanced Raman nanoparticle sols were added to the test tubes, followed by 100 μL of 0.1 mg / L fentanyl ethanol solution and 50 μL of 1 mol / L KI solution, respectively. The mixture was then used as the sensitivity test solution, and Raman spectroscopy was used for detection. The Raman spectroscopy detection conditions were the same as in Example 2.

[0115] result: Figure 1 Detection of 100 μL 0.1 mg / L fentanyl standard solution by different types of surface-reinforced Raman spectroscopy nanoparticle sols. Figure 1 It can be clearly seen in the spectrum of a 0.1 mg / L fentanyl ethanol solution that at 832 ± 6 cm⁻¹ -1 1000±6cm-1 1030±6cm -1 and 1200±6cm -1 There are at least two peaks at the displacement point. Among them, the peak intensity of the gold nanoparticle is the strongest at the characteristic peak of fentanyl. Therefore, the gold nanoparticle has the strongest surface Raman enhancement ability.

[0116] Example 4: Optimization of the detection method for fentanyl-related substances using gold cake nanoparticles

[0117] Preparation of salt solutions of different types of agglomerating agents: Dissolve different types of agglomerating agents KCl, KBr, KI, MgSO4, MgCl2, Na2SO4, NaBr, and NaCl in water to a concentration of 1.00 mol / L to obtain salt solutions of different types of agglomerating agents.

[0118] Sensitivity assessment of different types of agglomerating agents: 200 μL of the surface-enhanced Raman nanoparticle sol obtained in Example 1 was added to different test tubes, followed by 100 μL of 0.1 mg / L fentanyl ethanol solution and 50 μL of 1.00 mol / L salt solutions of different types of agglomerating agents. The mixture was then analyzed using a Raman spectrometer. The Raman spectrometer detection conditions were the same as in Example 2.

[0119] Sensitivity assessment without agglomerating agent: 200 μL of the surface-enhanced Raman nanoparticle sol obtained in Example 1 was added to different test tubes, followed by 100 μL of 0.1 mg / L fentanyl ethanol solution and 50 μL of water. The mixture was then analyzed using a Raman spectrometer. The Raman spectrometer detection conditions were the same as in Example 2.

[0120] Blank interference test of different types of agglomerating agents: 200 μL of the surface-enhanced Raman nanoparticle sol obtained in Example 1 was added to different test tubes, followed by 100 μL of ethanol and 50 μL of 1.00 mol / L salt solutions of different types of agglomerating agents. The mixture was then detected using a Raman spectrometer. The Raman spectrometer detection conditions were the same as in Example 2.

[0121] Result: See Figure 2 and Figure 3 .

[0122] Figure 2 To account for the effects of different types of agglomerating agents, surface-enhanced Raman nanoparticle sols with the same volume (200 μL) and fentanyl standard solutions with the same volume (100 μL) were used. Figure 2It is evident that when no other flocculants are added, only the same volume of water is added, the characteristic peak signal of fentanyl is weak. Adding flocculants significantly enhances the characteristic peak signal of fentanyl, indicating that flocculants accelerate particle aggregation, thus resulting in a higher intensity signal. In the spectra testing the effect of different types of flocculants on the signal of fentanyl-like substances, the peak signal at 832±6 cm⁻¹ is significantly stronger. -1 1000±6cm -1 1030±6cm -1 and 1200±6cm -1 There are at least two peaks at the displacement point. Among them, the signal intensity is strongest when KI (potassium iodide) is used as the agglomerant. Therefore, KI is preferred as the agglomerant.

[0123] Figure 3 To investigate whether the addition of different types of agglomerating agents interfered with the test results, since the test solution did not contain fentanyl standard, from Figure 3 It is evident from the data that during the test, when Na2SO4 was used as an agglomerating agent, it affected the agglomerates at a density of 1000±6 cm. -1 1030±6cm -1 Interference exists at the displacement point, while other salts do not interfere with the detection of the blank sample.

[0124] Example 5: Mechanism study of different salt solutions as agglomerating agents

[0125] To investigate the mechanism of different types of agglomerating agent salt solutions as agglomerating agents, 200 μL of surface-enhanced Raman nanoparticle sol obtained in Example 1 was added to a test tube, followed by 100 μL of 0.1 mg / L fentanyl ethanol solution and 50 μL of 1.00 mol / L salt solutions of different types of agglomerating agents (the preparation methods of different types of agglomerating agent salt solutions are described in "(1) Optimization of the types of salt solutions as agglomerating agents" in Example 2), mixed, and then detected by Raman spectroscopy; the Raman spectroscopy detection conditions were the same as in Example 2.

[0126] The purpose of adding an agglomerating agent is to accelerate the aggregation of surface-enhanced Raman spectroscopy (SERS) nanoparticles, bringing the particles closer together and thus enhancing their reinforcing ability. Electron microscopy characterization of SERS nanoparticles with different salt solutions as agglomerating agents revealed that, under the same conditions, KI resulted in the most compact particle aggregation.

[0127] Result: See Figure 4 .

[0128] Figure 4 Characterized by scanning electron microscopy. Figure 4 a represents the characterization of gold nanorods. Figure 4b- Figure 4 f represents the scanning electron microscopy characterization of gold nanoparticles and their addition with different agglomerating agents.

[0129] Example 6: Stability test of KI as an agglomerating agent

[0130] Stability test of KI as an agglomerating agent: To investigate the stability of KI as an agglomerating agent, 200 μL of the surface-enhanced Raman nanoparticle sol obtained in Example 1 was added to a test tube, followed by 100 μL of 0.1 mg / L fentanyl ethanol solution and 50 μL of 1 mol / L KI aqueous solution. The mixture was then analyzed using Raman spectroscopy at different time points after mixing. The Raman spectroscopy detection conditions were the same as in Example 2, and the results are shown in [Figure 2]. Figure 5 .

[0131] Results Analysis: The test signal changes over time. A stable system is crucial for detection; therefore, the stability of the signal after adding the agglomerant was measured. Figure 5 For stability performance testing. Statistical analysis was conducted at 1000±6cm. -1 The signal intensity at the displacement point changes over time. It can be seen that the Raman signal intensity of fentanyl in this system is basically stable within 300 s, and the average RSD of three parallel measurements is 3.28%. This result reflects the good stability of KI as a flocculant.

[0132] Example 7: Detection of different types of fentanyl-based standard substances by gold cake nanoparticles

[0133] Ethanol solutions of different types of fentanyl compounds (fentanyl, α-methylfentanyl hydrochloride, β-hydroxyfentanyl hydrochloride, (±)cis-3-methylfentanyl, 3-methylthiofentanyl, p-fluorofentanyl, remifentanyl hydrochloride, sufentanil citrate, acetylfentanyl, butyryl fentanyl, (±)-β-hydroxythiofentanyl hydrochloride, 4-fluorobutyryl fentanyl) at different concentrations (1 μg / L, 10 μg / L, 100 μg / L, 1000 μg / L) and a blank solvent (ethanol) without fentanyl compounds were added to the surface-enhanced Raman nanoparticle sol of gold nanopatterns prepared according to Example 1. The volume of the surface-enhanced Raman nanoparticle sol of gold nanopatterns was 200 μL, and the amount of fentanyl ethanol solution or blank solvent (ethanol) without fentanyl compounds added was 100 μL. Then, 50 μL of 1 mol / L ethanol solution was added. The KI aqueous solution was mixed and then detected using a Raman spectrometer; the Raman spectrometer detection conditions were the same as in Example 2, and the results were as follows. Figure 6 and Figure 7 As shown.

[0134] Results analysis: From Figure 6 and Figure 7 It can be clearly seen in the spectrum of the blank solvent, which does not contain fentanyl-like substances, that the concentration is around 832±6 cm⁻¹. -1 1000±6cm -1 1030±6cm -1 and 1200±6cm -1 There was no peak at the shift point, but in the spectra of fentanyl ethanol solutions of 1 μg / L, 10 μg / L, 100 μg / L, or 1000 μg / L, a peak was observed at 832 ± 2 cm⁻¹. -1 1000±2cm -1 1030±2cm -1 and 1200±2cm -1 At least two peaks were observed at the displacement point. The surface-enhanced Raman nanoparticles (or surface-enhanced Raman nanoparticle sol) and detection method provided by this invention were used for detection. The results show that the detection limits for fentanyl and α-methyl-fentanyl hydrochloride are as low as 1 ug / L, and the detection limits for other fentanyl-related substances are as low as 10 ug / L.

[0135] Conclusion: This invention optimizes the morphology of metal nanoparticles, studies the most suitable nanoparticles for detecting fentanyl-related substances, and develops a rapid method for extracting fentanyl-related substances from samples such as mail or parcels. The detection method of this invention differs from other methods. Mass spectrometry requires specialized equipment and technicians and is time-consuming. Chromatography requires large-scale equipment, has specific requirements for experimental sites and environments, is expensive, and requires specialized technicians. X-ray imaging technology has limited detection capabilities for novel fentanyl derivatives. This invention's method is based on surface-enhanced Raman spectroscopy for rapid, non-destructive detection of fentanyl-related substances in samples such as mail or parcels. This method offers convenient pretreatment, low cost, speed, and non-destructive operation; portable Raman spectrometers can also be used, making it a simple method ideal for rapid on-site detection.

[0136] The method of this invention has been described through preferred embodiments. Those skilled in the art will readily be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and context of this invention to implement and apply the technology of this invention. Those skilled in the art can refer to the content herein to appropriately improve process parameters. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of this invention.

Claims

1. A method for detecting fentanyl-like substances, characterized in that, Includes the following steps: (1) Extraction: Take the liquid sample to be tested or wipe the solid sample to be tested with a wiping solvent; (2) Raman spectroscopy detection: The liquid sample to be tested or the wiping solvent after wiping is transferred to the surface-enhanced Raman nanoparticle sol, and an agglomerating agent solution is added, wherein the agglomerating agent in the agglomerating agent solution is KI; then Raman spectroscopy with laser wavelengths of 785 nm, 633 nm, 532 nm and / or 1064 nm is used for detection to obtain the Raman frequency shift spectrum data of the liquid sample to be tested; wherein, the surface-enhanced Raman nanoparticle sol includes surface-enhanced Raman nanoparticles and solvent; the surface-enhanced Raman nanoparticles are noble metal nanoparticles, wherein the noble metal nanoparticles are gold nanocakes with a diameter of 40 nm-100 nm and a thickness of 15 nm-35 nm; (3) Result interpretation: Raman shift spectral data within 832±6 cm -1 1000±6 cm -1 1030 ±6cm -1 and 1200±6 cm -1 The liquid sample to be tested contains fentanyl-like substances if it has peaks at at least 1, 2, 3, or 4 wavenumbers; or if its Raman shift spectral data are within 1000 ± 6 cm⁻¹. -1 1030 ±6cm -1 and 1200±6 cm -1 The solid or liquid sample to be tested contains fentanyl-like substances and has peaks at at least 1, 2, or 3 wavenumbers; the Raman shift spectral data are within 832 ± 6 cm⁻¹. -1 1000±6 cm -1 1030 ±6cm -1 and 1200±6 cm -1 The solid or liquid sample to be tested, which has no peaks at any wavenumber, does not contain fentanyl-related substances.

2. According to the detection method of claim 1, the noble metal nanoparticles are gold nanoparticle cakes with a diameter of 80 nanometers ± 10 nanometers and a thickness of 30 nanometers ± 5 nanometers.

3. The detection method according to claim 1, wherein the concentration of the agglomerant in the agglomerant solution is 0.01 mol / L - 5.00 mol / L; and / or The agglomerating agent solution uses at least one of water, methanol, and ethanol as a solvent; and / or The excitation power of the Raman spectrum is 10mW~500mW; and / or The wiping solvent is at least one of methanol, acetone, ethanol, or diethyl ether; and / or The process of wiping the solid sample with a wiping solvent includes wiping the solid sample with a cotton swab moistened with a wiping solvent; and / or The volume of the wiping solvent is 0.1 mL - 1.0 mL; and / or The wiping is performed 1-5 times; and / or The wiping time is 1 second to 10 seconds; and / or The transfer includes transfer by immersion, dripping, or pressing; and / or The volume ratio of the liquid sample to be tested or the wiping solvent to the surface-enhanced Raman nanoparticle sol is 1:10 to 1:1; and / or The volume ratio of the agglomerating agent solution to the surface-enhanced Raman nanoparticle sol is 1:10 to 1:

1.

4. The detection method according to claim 1, wherein the concentration of the agglomerant in the agglomerant solution is 1.00 mol / L; and / or The wiping is performed twice; and / or The volume ratio of the liquid sample to be tested or the wiping solvent to the surface-enhanced Raman nanoparticle sol is 1:2; and / or The volume ratio of the agglomerating agent solution to the surface-enhanced Raman nanoparticle sol is 1:

4.

5. The detection method according to claim 1, wherein the material of the solid sample to be tested includes metal, ceramic, glass, plastic, stone, wood or skin.

6. The detection method according to claim 1, wherein the solid sample to be tested includes mail, parcels, packaging boxes, packaging bags, electrical appliances, furniture, containers or skin.

7. The detection method according to claim 1, wherein the Raman spectroscopy includes detection using a portable Raman spectrometer or a handheld Raman spectrometer.

8. The detection method according to claim 1, wherein the solvent comprises at least one of water, ethanol and methanol.

9. The detection method according to claim 1, wherein the preparation method of the surface-enhanced Raman nanoparticle sol comprises: Mix the noble metal precursor solution with the protective agent solution, and then add ethanol; After the reaction, a solution of noble metal nanoparticles was obtained. After centrifugation, precipitate 1 was obtained. Precipitate 1 was washed and centrifuged again to obtain precipitate 2. Precipitate 2 was mixed with water to obtain the surface-enhanced Raman nanoparticle sol.

10. The detection method according to claim 9, wherein the noble metal precursor solution is heated to 90°C-105°C before being mixed with the protective agent solution.

11. The detection method according to claim 9, wherein the noble metal precursor solution is heated at 90°C-105°C for 20 min-35 min before being mixed with the protective agent solution.

12. The detection method according to claim 9, wherein the noble metal precursor in the noble metal precursor solution comprises tetrachloroauric acid; and / or The protective agent in the protective agent solution includes at least one of sodium citrate, polyvinylpyrrolidone, hexadecyltrimethylamine bromide, hexadecyltrimethylamine chlorohydrate, and hexadecyltrimethylamine iodo; and / or The noble metal precursor solution and the protective agent solution are mixed within 2 seconds; The reaction temperature is 90℃-105℃; and / or The reaction time is 20 min-60 min; and / or The amount of ethanol added is 10 μL-100 μL; and / or The solvent for the noble metal precursor solution includes water; and / or The mass ratio of the precious metal precursor in the precious metal precursor solution to the protective agent in the protective agent solution is (10.0:3.0) - (10.0:1.0); and / or The concentration of the noble metal precursor in the noble metal precursor solution is 0.001 wt%-1.000 wt%; and / or The concentration of the protective agent in the protective agent solution is 0.5wt%-2.0wt%; and / or The cleaning is performed using at least one of ethanol, methanol, and water; and / or The cleaning is performed 1-5 times; and / or The concentration of noble metal nanoparticles in the surface-enhanced Raman nanoparticle sol is 6 × 10⁻⁶. 11 6 x 10 cells / ml 13 per ml.

13. The detection method according to claim 9, wherein the reaction temperature is 100°C; and / or The reaction time is 25 min - 35 min; and / or The concentration of the noble metal precursor in the noble metal precursor solution is 0.050 wt%; and / or The concentration of the protective agent in the protective agent solution is 1.0 wt%; and / or The concentration of noble metal nanoparticles in the surface-enhanced Raman nanoparticle sol is 6 × 10⁻⁶. 12 per ml.

14. The detection method according to claim 9, wherein the reaction time is 30 min.

15. The detection method according to claim 1, wherein the structure of the surface-enhanced Raman nanoparticles is a gold nanopatty, and the preparation method of the surface-enhanced Raman nanoparticle sol includes: Heat the noble metal precursor solution to 90℃-105℃ for 20 min-35 min. Mix the noble metal precursor solution with the protective agent solution; The noble metal precursor solution and the protective agent solution are mixed within 2 seconds, and then ethanol is added. The amount of ethanol added is 10 μL. The reaction is carried out at 90℃-105℃ for 20 min-60 min. After cooling to room temperature, a noble metal nanoparticle solution is obtained. After centrifugation, precipitate 1 is obtained. Precipitate 1 is washed and centrifuged again to obtain precipitate 2. Precipitate 2 is mixed with water to obtain the surface-enhanced Raman nanoparticle sol. The noble metal precursor solution contains tetrachloroauric acid as the noble metal precursor; the concentration of the noble metal precursor in the noble metal precursor solution is 0.05 wt%; the concentration of the protective agent in the protective agent solution is 1.0 wt%; the solvent of the noble metal precursor solution includes water; the solvent of the protective agent solution includes water; the number of washing cycles is 1-5; the concentration of noble metal nanoparticles in the surface-enhanced Raman nanoparticle sol is 6 × 10⁻⁶. 11 6 x 10 cells / ml 13 per ml.

16. The detection method according to claim 15, wherein the heating in the preparation method of the surface-enhanced Raman nanoparticle sol is to heat the noble metal precursor solution to 100°C.

17. The detection method according to any one of claims 1-16, wherein the fentanyl-related substances include 4-fluorobutyryl fentanyl, 4-fluoroisobutyryl fentanyl, butyryl fentanyl, isobutyryl fentanyl or its salts, furanyl fentanyl or its salts, valerate fentanyl or its salts, β-hydroxythiofentanyl, cis-3-methylfentanyl or its salts, oxfentanyl, p-fluorofentanyl, sufentanyl citrate, acetylfentanyl, β-hydroxy-3-methylfentanyl, 4-anilino-N-phenylethylpiperidine, remifentanyl or its salts, α-methylfentanyl or its salts, and N-phenylethyl-4-piperidinone. Carfentanil, β-hydroxyfentanil, 3-methylthiofentanil or its salts, alfentanil, fentanyl, acetylalfamethylfentanil, acryloylfentanil or its salts, thiofentanil or its salts, alfamethylthiofentanil or its salts, tetrahydrofuran fentanil, 2-thienocarbamoyl fentanil or its salts, chloroacetylfentanil or its salts, benzoylfentanil or its salts, (2-fluorobenzoyl)fentanil or its salts, (3-fluorobenzoyl)fentanil or its salts, (2-chlorobenzoyl)fentanil or its salts, (4-fluorobenzoyl)fentanil or its salts, p-chlorofuranoyl ... Chloromethoxyacetylfentanyl or its salts, p-chlorothiophenecarboxylfentanyl or its salts, p-chlorobenzoylfentanyl or its salts, p-chlorocyclopropionylfentanyl or its salts, p-chloroacetylfentanyl or its salts, cyclopentylfentanyl or its salts, cyclobutylfentanyl or its salts, heptafentanyl or its salts, ethoxyacetylfentanyl or its salts, phenylpropionylfentanyl or its salts, butyroyl α-methylfentanyl or its salts, cyclobutylfentanyl or its salts, isovalerylfentanyl or its salts, N-benzylbutyroylfentanyl or its salts, N-benzylcyclopropylfentanyl or its salts, N-benzylpentylfentanyl or its salts, N-benzyl... Fitanil or its salts, N-benzylhexanoyl fentanyl or its salts, alfamethyl fentanyl or its salts, beta-hydroxy-3-methyl fentanyl or its salts, beta-hydroxy fentanyl or its salts, beta-hydroxyisobutyryl fentanyl or its salts, beta-hydroxypentanoyl fentanyl or its salts, thiofentanyl or its salts, ethoxyacetyl fentanyl or its salts, cyclopentylformyl fentanyl or its salts, p-methylbutyryl fentanyl or its salts, o-methyl fentanyl or its salts, p-methoxyacryl fentanyl or its salts, N-benzyl fentanyl or its salts, N-benzyl-p-fluorofentanyl or its salts, norcarfentanyl or its salts, N-(4-methylphenethyl)- Isobutyryl fentanyl or its salt, phenylpropionyl fentanyl or its salt, heptayl fentanyl or its salt, 2-thiophenecarboxyl fentanyl or its salt, chloroacetyl fentanyl or its salt, benzoyl fentanyl or its salt, cyclobutylcarboxyl fentanyl or its salt, (2-fluorobenzoyl)fentanyl or its salt, (3-fluorobenzoyl)fentanyl or its salt, isovaleryl fentanyl or its salt, (2-chlorobenzoyl)fentanyl or its salt, (4-fluorobenzoyl)fentanyl or its salt, p-fluoroacetyl fentanyl or its salt, p-fluorotetrahydrofuranyl or its salt, p-fluorobenzoyl fentanyl or its salt, p-fluorothiophenecarboxyl fentanyl or its salt, p-fluorofuranyl fentanyl or its salt, p-fluorocyclopentyl fentanyl or its salt 1. Fentanyl valerate or its salt, 2. o-Fluorofentanyl or its salt, 2. o-Fluoroacryloylfentanyl or its salt, 2. o-Fluoroacetylfentanyl or its salt, 3. m-Fluorofentanyl or its salt, 3. m-Fluoromethoxyacetylfentanyl or its salt, 3. m-Fluorofuran fentanyl or its salt, 3. m-Fluorobenzoylfentanyl or its salt, 4. p-Chlorofentanyl or its salt, 4. p-Chlorobutyryloylfentanyl or its salt, 4. p-Chlorofuran fentanyl or its salt, 4. p-Chloromethoxyacetylfentanyl or its salt, 4. p-Chlorothiophenecarboxylfentanyl or its salt, 4. p-Chlorobenzoylfentanyl or its salt, 4. p-Chlorocyclopropionylfentanyl or its salt, 4. p-Chloroacetylfentanyl or its salt, 4. p-Methylfentanyl or its salt, 4. p-Methyl- (4-fluorobenzoyl)fentanyl or its salt, p-methylcyclopentyl fentanyl or its salt, p-methylcyclohexyl fentanyl or its salt, p-methyltert-butyl fentanyl or its salt, p-methylcyclopropyl fentanyl or its salt, p-methylmethoxyacetyl fentanyl or its salt, p-methylthiophene fentanyl or its salt, p-methylfuranoyl fentanyl or its salt, p-methylbenzoyl fentanyl or its salt, p-methylethoxyacetyl fentanyl or its salt, p-methyltetrahydrofuranoyl fentanyl or its salt, p-methyl-(4-chlorobenzoyl)fentanyl or its salt, o-methylfuranoyl fentanyl or its salt, o-methylcyclohexyl fentanyl or its salt, o-methylbutyryl fentanyl or its salt, o-methylbenzoyl fentanyl or its salt, o-methyl- (4-Fluorobenzoyl)fentanyl or its salt, o-methylthiophenecarboxylfentanyl or its salt, o-methylcyclopentylfentanyl or its salt, benzoylalfamethylfentanyl or its salt, hexanoylalfamethylfentanyl or its salt, p-methoxytetrahydrofuran fentanyl or its salt, p-methoxyisobutyryl fentanyl or its salt, p-methoxy-2-methoxyacetylfentanyl or its salt, p-methoxyhexanoylfentanyl or its salt, thioacetylfentanyl or its salt, N-benzylacetylfentanyl or its salt, N-benzylbutyryl fentanyl or its salt, N-benzyl-(4-Chlorobenzoyl)fentanyl or its salt, N-benzylcyclopropylfentanyl or its salt, N-benzylcyclopentylfentanyl or its salt, N-benzylpentylfentanyl or its salt, N-benzylfuran fentanyl or its salt, N-benzylhexanoylfentanyl or its salt, N-benzyl-p-fluorocyclopentylfentanyl or its salt, N-benzyl-p-fluorocyclohexanoylfentanyl or its salt, N-benzyl-p-fluorofuran fentanyl or its salt, N-benzyl-p-fluoro-(3-fluorobenzoyl)fentanyl or its salt, N-benzyl-p-fluoro-acetylfentanyl or its salt, N-benzyl-p-fluoro-thiophene fentanyl or its salt, N-benzyl-p-fluoro-methoxyacetylfentanyl or its salt, N-benzyl-p-fluoro-isobutyryl fentanyl or its salt, N-benzyl-p-fluoro-butyryl fentanyl or its salt, N-benzyl-p-fluoro- (4-Chlorobenzoyl)fentanyl or its salt, N-methylbenzoylfentanyl or its salt, N-methyl-(4-chlorobenzoyl)fentanyl or its salt, N-methyl-(2-fluorobenzoyl)fentanyl or its salt, N-(4-methylphenethyl)-benzoylfentanyl or its salt, N-(4-methylphenethyl)fentanyl or its salt, N-(4-methylphenethyl)-isovalerylfentanyl or its salt, N-(4-methylphenethyl)-n-butyrylfentanyl or its salt, N-cyclopropionylcyclopropylfentanyl or its salt, p-fluorofentanyl or its salt, N-(4-methylphenethyl)-(4-chlorobenzoyl)fentanyl or its salt, N-(4-methylphenethyl)-thiophenecarboxylfentanyl or its salt, N- At least one of the following: (4-nitrophenylethyl)fentanyl or a salt thereof, alfamethyl fentanyl valerate or a salt thereof, N-benzylisobutyryl fentanyl or a salt thereof, N-(4-methylphenylethyl)-cyclohexylformyl fentanyl or a salt thereof, N-(4-chlorophenylethyl)fentanyl or a salt thereof, N-(4-methylphenylethyl)-methoxyacetyl fentanyl or a salt thereof, N-(4-methylphenylethyl)-acetyl fentanyl or a salt thereof, o-methoxybutyryl fentanyl or a salt thereof, o-methoxyvalerate fentanyl or a salt thereof, 3-methylthioacetyl fentanyl or a salt thereof, alfamethyl butyryl fentanyl or a salt thereof, betahydroxy-3-methylbutyryl fentanyl or a salt thereof, and 3-methylthiobutyryl fentanyl or a salt thereof.

18. The detection method according to any one of claims 1-16, wherein the fentanyl-related substances include at least one of fentanyl, α-methyl-fentanyl hydrochloride, β-hydroxy-fentanyl hydrochloride, (±)cis-3-methylfentanyl, 3-methylthiofentanyl, p-fluorofentanyl, remifentanyl hydrochloride, sufentanyl citrate, acetylfentanyl, butyryl fentanyl, (±)-β-hydroxythiofentanyl hydrochloride, and 4-fluorobutyryl fentanyl.

19. The application of the detection method according to any one of claims 1-16 in the detection of fentanyl-related substances, in the rapid detection of trace fentanyl-related substances, in the rapid detection of trace fentanyl-related substances on the surface of mail or parcels, or in the rapid non-destructive detection of trace fentanyl-related substances on the surface of mail or parcels.

20. The application according to claim 19, wherein the fentanyl compound comprises 4-fluorobutyryl fentanyl, 4-fluoroisobutyryl fentanyl, butyryl fentanyl, isobutyryl fentanyl or a salt thereof, furanyl fentanyl or a salt thereof, valerate fentanyl or a salt thereof, β-hydroxythiofentanyl, cis-3-methylfentanyl or a salt thereof, oxfentanyl, p-fluorofentanyl, sufentanyl citrate, acetylfentanyl, β-hydroxy-3-methylfentanyl, 4-anilino-N-phenylethylpiperidine, remifentanyl or a salt thereof, α-methylfentanyl or a salt thereof, N-phenylethyl-4-piperidinone, carfentanyl β-hydroxyfentanyl, 3-methylthiofentanyl or its salt, alfentanyl, fentanyl, acetylalfamethylfentanyl, acryloylfentanyl or its salt, thiofentanyl or its salt, alfamethylthiofentanyl or its salt, tetrahydrofuran fentanyl, 2-thienocarbamoyl fentanyl or its salt, chloroacetylfentanyl or its salt, benzoylfentanyl or its salt, (2-fluorobenzoyl)fentanyl or its salt, (3-fluorobenzoyl)fentanyl or its salt, (2-chlorobenzoyl)fentanyl or its salt, (4-fluorobenzoyl)fentanyl or its salt, p-chlorofuranoylfentanyl or its salt, p-chloromethoxy Acetylfentanyl or its salts, p-chlorothiophenecarboxylfentanyl or its salts, p-chlorobenzoylfentanyl or its salts, p-chlorocyclopropionylfentanyl or its salts, p-chloroacetylfentanyl or its salts, cyclopentylfentanyl or its salts, cyclobutylfentanyl or its salts, heptafentanyl or its salts, ethoxyacetylfentanyl or its salts, phenylpropionylfentanyl or its salts, butyroyl α-methylfentanyl or its salts, cyclobutylfentanyl or its salts, isovalerylfentanyl or its salts, N-benzylbutyroylfentanyl or its salts, N-benzylcyclopropylfentanyl or its salts, N-benzylpentylfentanyl or its salts, N-benzyl Acetylfentanyl or its salts, N-benzylhexanoylfentanyl or its salts, alfamethylfentanyl or its salts, beta-hydroxy-3-methylfentanyl or its salts, beta-hydroxyfentanyl or its salts, beta-hydroxyisobutyryl fentanyl or its salts, beta-hydroxypentanoyl fentanyl or its salts, thiofentanyl or its salts, ethoxyacetylfentanyl or its salts, cyclopentylformylfentanyl or its salts, p-methylbutyryl fentanyl or its salts, o-methylfentanyl or its salts, p-methoxyacryl fentanyl or its salts, N-benzylfentanyl or its salts, N-benzyl-p-fluorofentanyl or its salts, norcarfentanyl or its salts, N-(4-methylphenylethyl)- Isobutyryl fentanyl or its salt, phenylpropionyl fentanyl or its salt, heptayl fentanyl or its salt, 2-thiophenecarboxyl fentanyl or its salt, chloroacetyl fentanyl or its salt, benzoyl fentanyl or its salt, cyclobutylcarboxyl fentanyl or its salt, (2-fluorobenzoyl)fentanyl or its salt, (3-fluorobenzoyl)fentanyl or its salt, isovaleryl fentanyl or its salt, (2-chlorobenzoyl)fentanyl or its salt, (4-fluorobenzoyl)fentanyl or its salt, p-fluoroacetyl fentanyl or its salt, p-fluorotetrahydrofuranyl or its salt, p-fluorobenzoyl fentanyl or its salt, p-fluorothiophenecarboxyl fentanyl or its salt, p-fluorofuranyl fentanyl or its salt, p-fluorocyclopentyl fentanyl or its salt 1. Fentanyl valerate or its salt, 2. o-Fluorofentanyl or its salt, 2. o-Fluoroacryloylfentanyl or its salt, 2. o-Fluoroacetylfentanyl or its salt, 3. m-Fluorofentanyl or its salt, 3. m-Fluoromethoxyacetylfentanyl or its salt, 3. m-Fluorofuran fentanyl or its salt, 3. m-Fluorobenzoylfentanyl or its salt, 4. p-Chlorofentanyl or its salt, 4. p-Chlorobutyryloylfentanyl or its salt, 4. p-Chlorofuran fentanyl or its salt, 4. p-Chloromethoxyacetylfentanyl or its salt, 4. p-Chlorothiophenecarboxylfentanyl or its salt, 4. p-Chlorobenzoylfentanyl or its salt, 4. p-Chlorocyclopropionylfentanyl or its salt, 4. p-Chloroacetylfentanyl or its salt, 4. p-Methylfentanyl or its salt, 4. p-Methyl- (4-fluorobenzoyl)fentanyl or its salt, p-methylcyclopentyl fentanyl or its salt, p-methylcyclohexyl fentanyl or its salt, p-methyltert-butyl fentanyl or its salt, p-methylcyclopropyl fentanyl or its salt, p-methylmethoxyacetyl fentanyl or its salt, p-methylthiophene fentanyl or its salt, p-methylfuranoyl fentanyl or its salt, p-methylbenzoyl fentanyl or its salt, p-methylethoxyacetyl fentanyl or its salt, p-methyltetrahydrofuranoyl fentanyl or its salt, p-methyl-(4-chlorobenzoyl)fentanyl or its salt, o-methylfuranoyl fentanyl or its salt, o-methylcyclohexyl fentanyl or its salt, o-methylbutyryl fentanyl or its salt, o-methylbenzoyl fentanyl or its salt, o-methyl- (4-Fluorobenzoyl)fentanyl or its salt, o-methylthiophenecarboxylfentanyl or its salt, o-methylcyclopentylfentanyl or its salt, benzoylalfamethylfentanyl or its salt, hexanoylalfamethylfentanyl or its salt, p-methoxytetrahydrofuran fentanyl or its salt, p-methoxyisobutyryl fentanyl or its salt, p-methoxy-2-methoxyacetylfentanyl or its salt, p-methoxyhexanoylfentanyl or its salt, thioacetylfentanyl or its salt, N-benzylacetylfentanyl or its salt, N-benzylbutyryl fentanyl or its salt, N-benzyl-(4-Chlorobenzoyl)fentanyl or its salt, N-benzylcyclopropylfentanyl or its salt, N-benzylcyclopentylfentanyl or its salt, N-benzylpentylfentanyl or its salt, N-benzylfuran fentanyl or its salt, N-benzylhexanoylfentanyl or its salt, N-benzyl-p-fluorocyclopentylfentanyl or its salt, N-benzyl-p-fluorocyclohexanoylfentanyl or its salt, N-benzyl-p-fluorofuran fentanyl or its salt, N-benzyl-p-fluoro-(3-fluorobenzoyl)fentanyl or its salt, N-benzyl-p-fluoro-acetylfentanyl or its salt, N-benzyl-p-fluoro-thiophene fentanyl or its salt, N-benzyl-p-fluoro-methoxyacetylfentanyl or its salt, N-benzyl-p-fluoro-isobutyryl fentanyl or its salt, N-benzyl-p-fluoro-butyryl fentanyl or its salt, N-benzyl-p-fluoro- (4-Chlorobenzoyl)fentanyl or its salt, N-methylbenzoylfentanyl or its salt, N-methyl-(4-chlorobenzoyl)fentanyl or its salt, N-methyl-(2-fluorobenzoyl)fentanyl or its salt, N-(4-methylphenethyl)-benzoylfentanyl or its salt, N-(4-methylphenethyl)fentanyl or its salt, N-(4-methylphenethyl)-isovalerylfentanyl or its salt, N-(4-methylphenethyl)-n-butyrylfentanyl or its salt, N-cyclopropionylcyclopropylfentanyl or its salt, p-fluorofentanyl or its salt, N-(4-methylphenethyl)-(4-chlorobenzoyl)fentanyl or its salt, N-(4-methylphenethyl)-thiophenecarboxylfentanyl or its salt, N- At least one of the following: (4-nitrophenylethyl)fentanyl or a salt thereof, alfamethyl fentanyl valerate or a salt thereof, N-benzylisobutyryl fentanyl or a salt thereof, N-(4-methylphenylethyl)-cyclohexylformyl fentanyl or a salt thereof, N-(4-chlorophenylethyl)fentanyl or a salt thereof, N-(4-methylphenylethyl)-methoxyacetyl fentanyl or a salt thereof, N-(4-methylphenylethyl)-acetyl fentanyl or a salt thereof, o-methoxybutyryl fentanyl or a salt thereof, o-methoxyvalerate fentanyl or a salt thereof, 3-methylthioacetyl fentanyl or a salt thereof, alfamethyl butyryl fentanyl or a salt thereof, betahydroxy-3-methylbutyryl fentanyl or a salt thereof, and 3-methylthiobutyryl fentanyl or a salt thereof.

21. The application according to claim 19, wherein the fentanyl-like substance comprises at least one of fentanyl, α-methyl-fentanyl hydrochloride, β-hydroxy-fentanyl hydrochloride, (±)cis-3-methylfentanyl, 3-methylthiofentanyl, p-fluorofentanyl, remifentanyl hydrochloride, sufentanyl citrate, acetylfentanyl, butyryl fentanyl, (±)-β-hydroxythiofentanyl hydrochloride, and 4-fluorobutyryl fentanyl.

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