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Multi-Residue Automated Turbulent Flow Online LC-MS/MS Method for the Determination of Antibiotics in Milk

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Multi-Residue Automated Turbulent Flow Online LC-MS/MS Method for the Determination of Antibiotics in Milk Multi-residue Automated Turbulent Flow 63551 Method: Online LC-MS/MS Method for the Determination of Antibiotics in Milk Katerina Bousova, Klaus Mittendorf, Thermo Fisher Scientific Food Safety Response Center, Dreieich, Germany Key Words Transcend TLX, TSQ Quantum Access MAX, Antibiotics, Food Safety, Milk, TurboFlow Technology 1. Schematic of Method Sample Shaking 1. Weigh 500 mg of shaken milk into 2 mL centrifuge tube Sample 500 mg + IS 2. Add 450 µL acetonitrile and 50 µL working IS solution 3. Vortex sample for 5 minutes Extraction 4. Centrifuge sample with 12,000 rpm for 5 minutes For fast screening of antibiotics, microbiological or bioassay techniques are widely used. These techniques 5. Filter sample through 0.45 µm nylon microfilter are not able to distinguish between the different types of antibiotics and provide only a semi-quantitative result Centrifugation and Filtration for the total amount of drug residues. The big drawback is the incidence of false-negative or false-positive results 6. Inject into TLX-LC-MS/MS because of low sensitivity and specificity. However, these screening assays are still very popular and widely used Turbulent Flow LC-MS/MS because of their cost-effectiveness and speed of analysis. For quantitative analysis it is necessary to use instrumental techniques such as LC-MS/MS. This 2. Introduction technique can also be used for screening, and provides Antibiotics are a group of chemicals that are widely used much higher sensitivity and greater specificity. The in animal husbandry primarily for protection of animals use of LC-MS/MS for screening was described in a from disease but also as growth promoters. The European validated multi-residue screening method to monitor Union (EU) has set maximum residue limits (MRL) for 58 antibiotics in milk1. a variety of antibiotics in animal tissues, milk and eggs; suitable methods are required to be capable of detecting these residues at regulated levels. For the last decade laboratories have been using methods only for one class of antibiotics. However, an increasing number of multi-residue methods covering different classes of drugs are being developed as more efficient and cost- effective procedures. 2 This note describes a multi-residue confirmatory 6. Calibration Standards method for the quantitative determination of antibiotics ® in milk using turbulent flow chromatography coupled 6.1 Kanamycin Sigma-Aldrich to LC-MS/MS. This method fulfills the increasing need 6.2 Amikacin Sigma-Aldrich for a cost-effective and fast method by employing 6.3 Dihydrostreptomycin Sigma-Aldrich Thermo Scientific TurboFlow technology (via the 6.4 Streptomycin Sigma-Aldrich Thermo Scientific Transcend TLX) for online sample 6.5 Lincomycin hydrochloride Sigma-Aldrich cleanup. This approach has already been applied in the monohydrate development of a screening method for antibiotics in 6.6 Clindamycin hydrochloride Sigma-Aldrich milk2. The method in this note is different due to the 6.7 Trimethoprim Sigma-Aldrich increased number of antibiotics detected as well as the inclusion of quantitative results. 6.8 Josamycin Sigma-Aldrich 6.9 Spiramycin Sigma-Aldrich 3. Scope and Application 6.10 Tilmicosin Sigma-Aldrich This online TLX-LC-MS/MS method can be applied 6.11 Tylosin tartrate Sigma-Aldrich to detect and quantify the presence of 36 compounds 6.12 Clarithromycin Sigma-Aldrich from 7 different classes of antibiotics (aminoglycosides, sulfonamides, macrolides, quinolones, tetracyclines, 6.13 Erythromycin A dihydrate Sigma-Aldrich lincosamides and trimethoprim) in milk. This 6.14 Oleandomycin phosphate Dr. Ehrenstorfer multi-residue method fulfills legislative requirements dehydrate described in the EU Commission Decision 2002/657/EC3. 6.15 Tylvalosin tartrate FarmKemi® 6.16 Sulfadimethoxine Sigma-Aldrich 4. Principle 6.17 Sulfadoxin Sigma-Aldrich This method uses turbulent flow chromatography for 6.18 Sulfaquinoxaline Sigma-Aldrich online cleanup of the sample. Sample concentration, cleanup and analytical separation are carried out in a 6.19 Sulfachlorpyridazine Sigma-Aldrich single run using a TurboFlow™ column connected to an 6.20 Sulfaclozine sodium Dr. Ehrenstorfer analytical LC column. Macromolecules are removed 6.21 Oxytetracycline hydrochloride Sigma-Aldrich from the sample extract with high efficiency, while target 6.22 Doxycycline hyclate Sigma-Aldrich analytes are retained on the column based on different 6.23 Marbofloxacin Sigma-Aldrich chemical interactions. After application of a wash step, 6.24 Ciprofloxacin Sigma-Aldrich the trapped compounds are transferred onto the analytical LC column and separated conventionally. Before applying 6.25 Danofloxacin Sigma-Aldrich the sample extract onto the TurboFlow column, the 6.26 Enrofloxacin Sigma-Aldrich sample is thoroughly mixed to evenly distribute the fat 6.27 Difloxacin Sigma-Aldrich and then fortified with an internal standard, extracted 6.28 Oxolinic acid Sigma-Aldrich with acetonitrile and centrifuged. Cleanup using the 6.29 Flumequine Sigma-Aldrich TLX system was optimized for maximum recovery 6.30 Nalidixic acid Sigma-Aldrich of targeted compounds and minimal injection of co-extractives into the mass spectrometer. Identification 6.31 Enoxacin Sigma-Aldrich of antibiotics is based on retention time, ion-ratios using 6.32 Ofloxacin Sigma-Aldrich multiple reaction monitoring (MRM) of characteristic 6.33 Lomefloxacin hydrochloride Sigma-Aldrich transition ions, and quantification using matrix matched 6.34 Norfloxacin Sigma-Aldrich standards of one of the selected MRM ions. 6.35 Sarafloxacin hydrochloride Sigma-Aldrich trihydrate 5. Reagent List Part Number 6.36 Cinoxacin Sigma-Aldrich 5.1 Purified Water – D 13321 Internal Standard Thermo Scientific Barnstead EASYpure II water system 6.37 Sulfaphenazole Sigma-Aldrich 5.2 Methanol Fisher Scientific Optima, 10767665 LC-MS grade 5.3 Water, LC-MS grade 10777404 5.4 Acetonitrile Optima® LC-MS grade 10001334 5.5 Isopropanol, HPLC grade 10674732 5.6 Acetone, HPLC grade 10131560 5.7 Formic acid, extra pure, >98% 10375990 5.8 Heptafluorobutyric acid, 99% 172800250 5.9 Ammonia, extra pure, 35% 10305170 3 7. Standards Preparation 9. Consumables Part Number 7.1 Stock Standard Solutions of Veterinary Drugs 9.1 Thermo Scientific TurboFlow CH-953289 Stock standard solutions (1000 µg/mL) are prepared Cyclone P (50 × 0.5 mm) column individually by dissolving the analytes in methanol 9.2 Thermo Scientific BetaSil (lincosamides, macrolides, sulfonamides, tetracyclines phenyl-hexyl (50 × 2.1 mm, 3 µm) 73003-052130 and trimethoprim), in water (aminoglycosides) and in column methanol with 2% 2M NH4OH (quinolones). Solutions 9.3 LC vials 3205111 are stored at -20 °C. 9.4 LC caps 3151266 7.2 Working Standard Solution 9.5 Thermo Scientific Pipette 3214535 The working calibration standard solution containing Finnpipette 100–1000 µL 1000 µg/L is prepared by dilution of individual stock 9.6 Pipette Finnpipette™ 20–200 µL 3214534 standard solutions with acetonitrile. Solution should 9.7 Pipette Finnpipette 10–100 µL 3166472 be prepared fresh every time before using. 9.8 Pipette Finnpipette 500–5000 µL 3166473 7.3 Stock Solution of Internal Standard 9.9 Pipette Finnpipette 1000–10,000 µL 3214536 Stock standard solution of the internal standard 9.10 Pipette holder 3651211 (1000 µg/mL) is prepared by dilution of sulfaphenazole 9.11 Pipette tips 0.5–250 µL, 500/box 3270399 in methanol. Solution is stored at -20 °C. 9.12 Pipette tips 1–5 mL, 75/box 3270420 7.4 Working Standard Solution of Internal Standard 9.13 Pipette tips 100–1000 µL, 200/box 3270410 The working standard solution of the internal standard 9.14 Pipette tips 20,000–10,000 µL, 3270425 (2000 µg/L) was prepared by dilution of stock standard 40/box solution (sulfaphenazole) with acetonitrile. Solution 9.15 Pipette Pasteur soda lime glass, FB50251 should be prepared fresh every time before using. 150 mm 9.16 Pipette suction device 3120891 8. Aparatus Part Number 9.17 Spatula, 18/10 steel 3458179 8.1 Turbulent flow chromatograph 9.18 Spatula, nylon 3047217 Transcend™ TLX-1 system 9.19 1 mL Single-use syringes 1066-4161 8.2 Thermo Scientific TSQ Quantum 9.20 17 mm nylon syringe filter, 0.45 µm F2513-1 Access MAX triple quadrupole 9.21 Vial rack (2 mL) 12211001 mass spectrometer 9.22 Centrifuge plastic tube (2 mL) 3150968 8.3 Fisher Science Education™ 02225102 precision balance 9.23 Rack for 50, 15, 2 and 0.5 mL tubes 10321031 8.4 Sartorius analytical balance 14557812 9.24 Pipette tips 20,000–10,000 µL, 3270425 40/box 8.5 Barnstead™ EASYpure™ II D 13321 water system 9.25 Pipette Pasteur soda lime glass, FB50251 150 mm 8.6 Vortex shaker 14505141 8.7 Vortex universal cap 3205029 Glassware Part Number 8.8 Accu-jet® pipettor 3140246 9.26 Beaker, 50 mL 10527211 8.9 Thermo Scientific Heraeus Fresco 208590 9.27 Beaker, 100 mL 10769541 17 micro centrifuge 9.28 Beaker, 25 mL 10683771 9.29 Volumetric flask, 25 mL 10107901 9.30 Volumetric flask, 10 mL 10406681 9.31 Volumetric flask, 5 mL 10770803 9.32 Volumetric flask, 100 mL 10675731 9.33 5 mL glass pipette 10179522 4 10. Procedure • Filling strokes [steps]: 1 10.1 Sample Preparation • Injection port: LC Vlv1 (TX channel) • Injection speed [µL/s]: 100 The sample of milk is shaken vigorously by hand. The • Pre inject delay [ms]: 500 sample (500 mg) is then weighed into a 2 mL polypropylene • Post inject delay [ms]: 500 tube. Working internal standard solution (50 µL) and • Post clean with solvent 1 [steps]: 5 acetonitrile (450 µL) are added to the sample. The • Post clean with solvent 2 [steps]: 5 sample is shaken for 5 min on the vortex and then • Valve clean with solvent 1 [steps]: 5 centrifuged at 12000 rpm for 5 min for removal of • Valve clean with solvent 2 [steps]: 5 protein. The supernatant is filtered through a nylon • Injection volume: 25 µL micro filter (0.45 µm pore size) directly into the LC vial and the sample is analyzed by TLX-LC-MS/MS.
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