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Non-Steroidal Anti-Inflammatory Drugs (Nsaids)

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Non-Steroidal Anti-Inflammatory Drugs (Nsaids) NON-STEROIDAL ANTI-INFLAMMATORY DRUGS ANALYSIS IN MILK BY QUECHERS AND LC-MS: LOW AND HIGH RESOLUTION DETECTION AND CONFIRMATION APPROACHES A. Rúbies1, L. Guo2, I. Beguiristain1, F. Centrich1, M. Granados2 1. Laboratori Agència de Salut Pública de Barcelona, 2. Departament de Química Analítica - Universitat de Barcelona. * INTRODUCTION NON-STEROIDAL ANTI-INFLAMATORY DRUGS (NSAIDs) Non-steroidal anti-inflammatory drugs (NSAIDs) are used as anti-inflammatory, analgesic and OXICAMS ANTHRANILIC ACID DERIVATIVES ACETIC ACID antipyretic drugs in medicine and veterinary. Their action mechanism is based on the blocking of PROPIONIC ACID DERIVATIVES DERIVATIVES the biosynthesis of prostaglandins. NSAIDs are highly effective and extensively used, but they have some adverse side effects, such as hepatotoxicity, renal disorders or allergic reactions. In the European Union, to assure food safety and protect consumers, maximum residue limits have been established for some authorised NSAIDs in food products. Therefore, high throughput and reliable analytical methodology is required for the effective control of NSAIDs in food from animal Flufenamic acid origin. Liquid chromatography (LC) coupled to mass spectrometry (MS) is currently the technique of choice in confirmatory analysis of NSAIDs residues. We present a new method for the determination of representative NSAIDs in milk based on QuEChERS methodology, LC-MS/MS and UHPLC-HRMS. Meloxicam Ketoprofen Diclofenac EU Maximum Residue Limits (MRLs) Recommended NSAIDs concentrations for NSAIDs in milk. to be monitored according to NICOTINIC ACID DERIVATIVES PYRAZOLONES Community Reference Laboratory Meclofenamic acid MRL Concentration NSAID NSAID -1 (µg kg-1) (µg kg ) Flunixin 5-hydroxyflunixin 40 Phenylbutazone Oxyphenbutazone 5 Flunixin 40 Diclofenac Phenylbutazone Diclofenac 0.1 Ibuprofen Tolfenamic acid 50 Naproxen 10 Oxyphenylbutazone Mefenamic acid 5-Hydroxyflunixin Meloxicam 15 Niflumic acid NSAIDs IN MILK: EXTRACTION AND CLEAN-UP HPLC – MS/MS (QqQ) NSAIDs have quite different chemical structures and different functional groups. LC Conditions for NSAIDs Conditions for NSAIDs MS/MS (QqQ) Optimisation of sample treatment for a NSAIDs multiresidue method is a complex issue. Column: Biphenyl, Phenomenex (2.1x100)mm, 2.6 µm Fragmentor Precursor Collision Product Analyte ESI Column temperature: 40ºC Energy (V) ion (m/z) Energy (V) ions* (m/z) QuEChERS PROPOSED METHOD Mobile phases: A: water (0.1% formic acid) 25 295 B: ACN (0.1% formic acid) 5-OH-flunixin + 110 313 35 280 Diclofenac - 90 294 10 250 Phenyl- 10 279 Milk + Na2SO4 + ammonium acetate - 150 307 butazone 15 131 15 251 Flunixin - 70 295 35 209 Extraction with 5% acetic acid in ACN Flufenamic 15 237 - 130 281 acid 25 216 15 105 -1 Ketoprofen + 130 255 Addition of ascorbic acid Flow rate: 0.4 mL min 50 77 Meclofenamic 12 279 Injection volume: 20 µL + 110 297 Quantification: Matrix matched surrogate standards method acid 15 264 15 237 13 Niflumic acid - 130 281 Clean-up by d-SPE C18 Internal standards: Meloxicam-D3, Phenylbutazone- C, Niflumic 35 177 13 13 acid- C, Flufenamic- C. Oxyphen- 15 295 - 130 323 LOQ = 2,5 µg/kg butazone 25 134 25 141 Addition of Na2SO4 Working range: 2,5-40 µg/Kg. Ionisation: ESI+ and ESI- Meloxicam + 130 352 15 115 The method is straightforward, reliable, Flufenamic + 110 288 15 270 acid 13C and well suited for high throughput 6 Evaporation and filtration Meloxicam confirmatory analysis of NSAIDS in milk + 130 355 15 115 D3 samples Niflumic acid 13 + 130 288 35 250 C6 Phenyl- butazone + 130 321 25 166 13C UHPLC-HRMS/MS (Q-Orbitrap) 12 In bold quantification transition. UHPLC conditions: LC-MS equipment: Agilent 1290 UHPLC coupled to Agilent 6460 Column: Kinetex, Phenomenex (2.1x100)mm, 1.7 µm triple quadrupole (QqQ) mass spectrometer with electrospray Column temperature: 40ºC ionization source. Mobile phases: A: water containing 0.1% formic acid B: ACN MRM chromatogram of a spiked sample at 1.5 µg kg-1 Validation results (HPLC-QqQ) Gradient: 70/30 (0’), 45/55 (10’). Flow rate: 300 µL min-1 Injection volume: 5 µL CCα (µg·kg-1) Level Extraction Precision Analyte Trueness (%) Quantification: Matrix matched surrogate standards method (µg·kg-1) Recovery (%) (RSD%) CCβ (µg·kg-1) 13 Internal standards: Meloxicam-D3, Phenylbutazone- C12, 2.5 92.9 10.3 97.6 1.5 13 13 5.0 90.2 13.5 94.6 Flunixin 1.9 Niflumic acid- C6, Flufenamic- C6. 10.0 95.2 7.9 105.1 Working mode: PRM with intermediate Collision Energy UHPLC-MS/HRMS instrumentation: Thermo 25.0 89.3 10.8 102.3 No MRL 2.5 89.7 14.3 91.2 Ionisation: HESI+ and HESI- Accela coupled to a Q-Exactive mass 1.1 5.0 87.1 9.7 103.8 1.5 spectrometer with heated electrospray 5-OH-Flunixin 10.0 88.2 11.5 85.7 MRL= 40 µg·kg-1 25.0 88.2 10.0 101.1 Milk samples were spiked in decreasing concentracions 41.2 ionization source (HESI). 40.0 88.3 1.7 101.9 and extracted to check performance of the instrument: 42.3 0.4 -1 -1 -1 -1, -1 2.5 78.1 16.9 98.8 1 µg·kg , 0.7 µg·kg , 0.5 µg·kg , 0.3 µg·kg 0.1 µg·kg Phenylbu- 5.0 89.1 12.6 101.8 0.8 Precursor ions were detected at all concentrations. NSAIDs HRMS parameters tazone 10.0 95.3 11.8 99.1 25.0 86.1 14.9 88.9 Neutralized 2.5 94.7 11.7 103.2 0.9 Precursor Product ion Analyte HESI Collision Oxyphen- 5.0 89.3 13.1 94.6 ion (m/z) (m/z) 1.3 Chromatogram of an extract from a milk sample (0.5 µg·kg-1 ): Energy (V) butazone 10.0 91.1 12.2 98.8 25.0 85.6 13.7 100.7 5-OH- Flunixin - 311.0650 267.0750 20 Precursor ions 2.5 93.4 9.2 108.4 1.0 RT: 0.00 - 12.01 RT: 0.00 - 12.01 5.0 90.6 7.8 107.4 RT: 4.37 NL: 5.27E4 RT: 8.36 NL: 3.51E5 Ketoprofen + 255.1012 209.0948 20 Niflumic acid 1.4 AA: 261978 m/z= 311.0634-311.0666 F: FTMS - p AA: 2843522 m/z= 281.0529-281.0557 F: FTMS - p ESI 10.0 93.4 10.1 94 BP: 311.0650 ESI Full ms2 [email protected] BP: 281.0543 100 100 Full msx ms2 [email protected] [50.00-650.00] MS ICIS 15102038 [email protected] [email protected] - 323.1402 295.1448 32 25.0 93.9 10.1 100.8 [50.00-620.00] MS ICIS 15102038 50 50 Niflumic acid RT: 6.66 RT: 8.81 0.8 5-OH-flunixin AA: 8255 AA: 5534 2.5 96.0 10.3 108.8 BP: 281.0544 BP: 281.0545 Flunixin - 295.0700 251.0798 25 0 0 RT: 5.12 NL: 8.62E4 RT: 8.54 NL: 8.83E3 Flufenamic 5.0 90.9 7.9 108 AA: 485442 m/z= 255.0999-255.1025 F: FTMS + p AA: 22981 m/z= 294.0081-294.0111 F: FTMS - p ESI 1.2 BP: 255.1013 ESI Full msx ms2 [email protected] BP: 294.0085 acid 10.0 96.5 8.3 95.5 100 100 Full msx ms2 [email protected] + 352.0420 141.0110 15 [email protected] [50.00-740.00] MS [email protected] [email protected] ICIS 15102038 [50.00-620.00] MS ICIS 15102038 25.0 91.9 9.4 101.2 50 RT: 6.33 Ketoprofen 50 Diclofenac AA: 18071 Niflumic acid - 281.0543 237.0642 20 2.5 92.3 9.2 92.4 1.5 BP: 255.1015 0 0 RT: 5.37 NL: 8.18E4 RT: 9.44 NL: 5.66E4 5.0 91.0 8.8 100.0 AA: 394403 m/z= 323.1386-323.1418 F: FTMS - p AA: 560494 m/z= 307.1437-307.1467Diclofenac F: FTMS - p ESI - 294.0096 250.0191 10 Diclofenac 1.9 BP: 323.1403 ESI Full msx ms2 [email protected] BP: 307.1453 100 100 Full msx ms2 [email protected] 10.0 97.1 12.8 102.0 [email protected] [email protected] [email protected] [email protected] [50.00-740.00] MS ICIS 15102038 [email protected] [50.00-675.00] MS ICIS - 307.1452 280.1524 15 25.0 90.9 12.2 90.8 50 Oxyfenbutazone 50 RT: 9.82 15102038 Phenylbutazone AA: 47178 0.4 BP: 307.1453 2.5 81.0 10.4 87.6 0 0 RT: 5.55 NL: 3.79E5 RT: 10.64 NL: 7.75E4 Flufenamic acid - 280.0591 236.0683 28 5.0 95.6 12.0 97.8 AA: 2643895 m/z= 295.0685-295.0715 F: FTMS - p AA: 598493 m/z= 280.0577-280.0605 F: FTMS - p ESI BP: 295.0696 ESI Full msx ms2 [email protected] BP: 280.0590 Ketoprofen 0.8 100 100 Full msx ms2 [email protected] 10.0 92.2 10.7 98.8 [email protected] [email protected] [email protected] [email protected] acid - 294.0096 258.0324 10 [50.00-740.00] MS ICIS 15102038 [email protected] [50.00-675.00] MS ICIS 25.0 87.5 8.6 103.1 50 Flunixin 50 15102038 Flufenamic acid Meloxicam D + 355.0587 --- 10 No MRL 0 0 3 2.5 94.4 15.2 98.0 RT: 5.54 NL: 4.47E5 RT: 10.79 NL: 2.09E4 1.0 AA: 2871771 m/z= 352.0402-352.0438 F: FTMS + p AA: 143350 m/z= 294.0081-294.0111 F: FTMS - p ESI BP: 352.0417 ESI Full msx ms2 [email protected] BP: 294.0095 5.0 92.5 9.0 102.8 100 100 Full msx ms2 [email protected] acid C - 286.0793 --- 10 1.4 [email protected] [50.00-740.00] MS [email protected] [email protected] 13 Meloxicam 10.0 92.0 7.8 102.0 Meloxicam ICIS 15102038 [email protected] [50.00-675.00] MS ICIS MRL= 15 µg·kg-1 50 50 Meclofenamic acid 15102038 15.0 91.2 Phenylbutazone C13 - 319.1862 --- 10 15.8 0 0 25.0 90.5 12.2 104.3 0 1 2 3 4 5 6 7 8 9 10 11 12 0 1 2 3 4 5 6 7 8 9 10 11 12 16.5 Time (min) Niflumic acid C - 287.0752 --- 10 Time (min) 13 0.5 C:\TraceFinderData\...\Data\15102816 10/28/15 19:50:29 ME5 2.5 91.2 10.8 105.6 C:5 Inj Vol 10.000000 Mass Tolerance 10.0 ppm Meclofenamic 5.0 90.4 10.4 102.8 C:\TraceFinderData\32\Projects\Aines\151028_2\Methods\Aines_FULLMS\AINES_FULL MS.meth 0.9 Chromatogram of an extract RT:from0.00 - 12.02 a milk sample (0.1 µg·kg-1 ) acid 10.0 93.3 10.4 84.1 RT: 5.56 NL: 8.01E5 25.0 95.3 12.2 94.1 AA: 5253126 m/z= 115.0309-115.0333 F: FTMS + p ESI Full msx ms2 BP: 115.0326 100 [email protected] [email protected] [50.00-740.00] (precursorC:\TraceFinderData\...\Data\15102816 ions,10/28/15 19:50:29left, productME5 ions right) RT: 6.27 MS ICIS 15102816 C:5 Inj Vol 10.000000 Mass Tolerance 5.0 ppm 50 AA: 11883 C:\TraceFinderData\32\Projects\Aines\151028_2\Methods\Aines_FULLMS\AINES_FULL MS.meth BP: 115.0327 RT: 0.00 - 12.02 0 RT: 8.32 NL: 3.98E5 RT: 8.30 NL: 4.61E5 AA: 3584190 m/z=
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