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RapidFire Mass Spectrometry with Enhanced Throughput as an Alternative to Liquid-Liquid Salt Assisted Extraction and LC/MS Analysis for Sulfonamides in Honey Brian T. Veach, Thilak K. Mudalige, and Peter Rye Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.6b04889 • Publication Date (Web): 20 Feb 2017 Downloaded from http://pubs.acs.org on March 1, 2017
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Analytical Chemistry
RapidFireTM Mass Spectrometry with Enhanced Throughput as an Alternative to Liquid-Liquid Salt Assisted Extraction and LC/MS Analysis for Sulfonamides in Honey Brian T. Veach, †* Thilak K. Mudalige, † and Peter Rye§ †Office of Regulatory Affairs, Arkansas Regional Laboratory, U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, Arkansas 72079, United States §Agilent Technologies, Life Sciences & Diagnostics Group, 121 Hartwell Avenue, Lexington, MA 02421, United States ABSTRACT: The use of veterinary drugs in honey bees for the prevention of infectious disease is ever increasing due to the spread of colony collapse disorder around the world. The United States Food and Drug Administration is concerned about the presence of these drugs residues in honey as they often lead to health concerns or potential antibiotic resistance. Currently there is a need for a rapid screening method for the detection of veterinary drugs in honey. Herein is a method that utilizes automated solid-phase extraction that is directly coupled to a mass spectrometer for the quantitative screening of 12 different regulated sulfonamides in honey. Identification of the residues was performed using MS/MS with a triple quadrupole mass spectrometer. The acquisition method developed for this analysis can extract with the automated solid-phase extraction system and analyze a single sample on the mass spectrometer in approximately 20 seconds, with minimal sample preparation. A target testing limit of 10 ng/g in honey for the sulfonamides was used based upon action limits set for other food commodities regulated by the United States Food and Drug Administration. A complete method validation procedure was conducted to evaluate the effectiveness of this quantitative screening method.
In October 2006, beekeepers in the United States began reporting losses of 30–90% of their colonies due to infection 1. Most of the infected colonies exhibited symptoms inconsistent with any previously known cause of honeybee deaths; however, the catastrophic losses were not confined to the United States 2 . Drastic declines in bee populations were witnessed globally 2,3. This epidemic became known as Colony Collapse Disorder (CCD) 1-4. Several investigators have offered insight into the reasons for the decline of honey bees; however, the combination of stressors that have been identified have made it difficult in determining a single feature for CCD 3. CCD is significant because the commercial production of many specialty crops like almonds and other tree nuts, berries, fruits, and vegetables are dependent on pollination by honey bees. It is estimated that bee pollination (via honey bees) is responsible for more than $15 billion in increased crop value each year 5. Annually, honey bees produce more than 140 million pounds of honey in the United States. Thus, maintaining a large and healthy honey bee population has colossal economic ramifications. With the monetary significance directly associated with the health of the honey bee colonies, the probability of veterinary drugs being administered to treat and prevent infectious diseases/illnesses is extremely high. The use of these drugs can become a potential health risk for consumers because these drugs are often transferred to the honey. Sulfonamides are a commonly used and inexpensive class of antibacterial drugs which have been used for many decades as a veterinary drug 6. Although there are numerous analytical methods for the analysis of sulfonamides in honey; these methods require an extensive amount of sample cleanup followed by analysis using high performance liquid chromatog-
raphy and mass spectrometry (LC/MS) 7-10. While these methods are effective, they are also extremely labor intensive and require a substantial amount of time to complete. Within the regulatory field of analysis, there is a dire need for a high throughput, quick screening method that can be performed with minimal effort by an analyst. The RapidFireTM system, which conducts high speed solid phase extraction (sampling, loading, washing, and injection) through multiple pumps running in concert, can potentially replace high performance liquid chromatography in MS-based analyses 11-14. As a result, the labor and time required for extraction and analysis can be drastically reduced or eliminated. Herein, we report a validated quantitative screening methodology which uses a RapidFireTM automated solid-phase extraction system directly coupled to a mass spectrometer (RFMS) for the analysis of 12 different targeted sulfonamides in honey. The extraction and analysis can be performed unattended, and completed in 20 seconds per sample. To the best of our knowledge, this is the first time that such an application of RFMS has been reported regarding veterinary drugs in a food matrix. Experimental section Materials and reagents Standards of sulfamerazine (SMR), sulfadiazine (SDZ), sulfachloropyridazine (SCP), sulfathiazole (STZ), sulfaquinoxaline (SQX), sulfamethazine (SMZ), sulfadimethoxine (SDM), sulfadoxine (SDX), sulfaethoxypyridazine (SEP), sulfamethoxypridazine (SMP), sulfamethoxazole (SMX), and sulfapyridine (SPD) were purchased from SPEX CertiPrep Laboratories (St. Louis, MO). The internal standard sulfamethazine
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13C6 was purchased from Cambridge Isotopes (Andover, MA). LC/MS grade acetonitrile, LC/MS grade formic acid, residue grade glacial acetic acid, and HPLC grade methanol was purchased from Fisher Scientific (Houston, TX). Ultra-pure water (18 MΩ·cm) obtained from a Thermo Scientific Barnstead Nanopure System (Waltham, MA) was utilized for extraction and analysis. Control honey products were obtained from commercially available sources for the demonstration of negative controls and spike recoveries. Standards Preparation A 10.0 ng/g matrix standard was prepared by fortifying 2.00 grams (+/- 0.03g) of residue free control honey with 50.0 µL of a 400 ng/g analytical standard solution. The 10.0 ng/g matrix standard was then further prepared as described in the sample preparation section. Sample Preparation The internal standard solution (sulfamethazine 13C6) was added to 2.00 grams (+/- .03g) of residue free control matrix in a 50 mL polypropylene centrifuge tube to provide a concentration of 40.0 ng/g. Approximately 40.0 mL of 0.1% formic acid in water was added to each 50 mL centrifuge tube, and the tube was shaken for approximately 60 seconds or until the sample is dissolved thoroughly into solution. A volume of 1.00 mL of glacial acetic acid was added to each tube, and the tube was shaken for approximately 30 seconds. The samples were then transferred to a 96 position well plate for analysis. Analysis of Reference Materials and Commercial Products Reference materials were obtained from commercially available sources and were prepared as described in the sample preparation section. As there are numerous types and colors of honey, it was of utmost importance to analyze representative types of honey that are commonly found. Those chosen for analysis were a raw unprocessed honey, an amber honey, and a white honey. The validation procedure was conducted over three nonconsecutive days. Three separate matrices were compared against the matrix standard to demonstrate the ruggedness of the method. Each sample batch consisted of multiple matrix blanks and laboratory fortified blanks. Laboratory fortified blanks were spiked with the intermediate fortification standard at concentrations of 10.0 ng/g, 20.0 ng/g, and 40.0 ng/g. Automated Solid-Phase Extraction and Mass Spectrometry An Agilent RapidFire 365 automated extraction system with three HPLC quaternary pumps was coupled to an Agilent 6490 triple quadrupole mass spectrometer (Agilent, Santa Clara, CA) equipped with an electrospray ionization (ESI) interface source. Agilent RapidFire 4.0 and Agilent MassHunter B.07.00 software were employed for instrument acquisition and data processing. The RFMS system was equipped with a reusable RapidFire C18 Type C solid-phase extraction (SPE) cartridge (G9203-80105). Solvent A, used for sample loading and washing, was water containing 0.1% (v/v) formic acid. Solvent B, used for sample elution, was 90% acetonitrile (v/v) containing 0.1% (v/v) formic acid. Samples were sequentially analyzed by aspirating 10 µL onto the collection loop under vacuum directly from multi-well plates (state 1). While 600 msec. was defined as
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the maximum aspiration time, the average time to fill the sample loop was approximately 200 msec. The 10 µL of sample was loaded onto the C18 cartridge and washed, by quaternary pump 1, using solvent A at a flow rate of 1.50 mL/min for 3000 msec. (state 2). The retained analytes were then eluted to the mass spectrometer by quaternary pump 3, using solvent B at a flow rate of 1.00 mL/min for 6000 msec. (state 4). The system was re-equilibrated by quaternary pump 1, using solvent A at a flow rate of 1.5 mL/min for 6000 msec. (state 5). No extra wash (state 3) was needed for the optimized method. Therefore, the main function of quaternary pump 2 in this method was to wash the sample collection loop with solvent B at a flow rate of 1.25 mL/min for 6000 msec. concurrent with sample elution (state 4). The entire sampling cycle was approximately 20 sec per well enabling the analysis of a 96-well plate in approximately 32 min. Table 1. RapidFire operating parameters State 1 State 2 State 3 State 4 State 5
Aspirate Sample load/wash Extra Wash Sample Elute Re-equilibrate
600 msec. 3000 msec. 0 msec. 6000 msec. 6000 msec.
The triple quadrupole mass spectrometer was equipped with an electrospray ionization (ESI) source. In order to provide optimal sensitivity for this screening method, the mass spectrometer was operated in multiple reaction monitoring (MRM) mode with Q1 resolution set to unit, and Q3 resolution set to wide (precursor ions and product ions are listed in Figures 1– 3). The gas temperature, gas flow, sheath gas temperature, and sheath gas flow were set to 290 °C, 20 L/min, 400 °C, and 12 L/min respectively. Electrical voltages were optimized for the capillary voltage at + 2000 volts, nebulizer voltage at + 500 volts, cell accelerator voltage of + 4 volts, and a fragmentor voltage of 380 volts. The positive high pressure RF was set to 150 volts and the low pressure RF was set to 75 volts. The collision energies for each MRM transition are provided in Figures 1–3. The instrument was tuned and calibrated in positive ionization mode using the manufacturer’s calibration solution. Data Analysis Quantitative analysis was performed for each analyte of interest by calculating the ratio of the area of the most abundant ion with respect to the area of the internal standard. Each representative ratio was plotted against the concentration of a 10 ng/g matrix fortified standard. Because the sample is directly injected onto the mass spectrometer from the RFMS system, there are not any chromatographic retention times. As a result, it is impossible to differentiate any isobars with this method. Therefore; any presumptive positive detected would necessitate further analysis with a confirmatory method. Presumptive positive criteria for samples at or above the target testing limit of 10 ng/g was based on the presence of both product ions having a response ≥ ½ the product ion area counts of the 10 ng/g matrix standard. Additionally, the product ion of the internal standard must exhibit ≥ ½ the product ion area counts of the 10 ng/g matrix standard in order to demonstrate method efficiency. Results and Discussion Method Optimization
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Analytical Chemistry
Method optimization consisted of a two-fold process. The first step was to maximize the performance of the RFMS system with respect to SPE phases, load times, wash times, elution times, solvent choices, solvent compositions, and flow rates. Subsequently, upon completion of the RFMS optimization the mass spectrometer needed tuning for each targeted compound in respect to response and peak shape. The RFMS system in conjunction with a triple quadrupole mass spectrometer does have a limitation on the number of MRM transitions which can be acquired during the analysis due to scan speed. Because of this, two separate acquisitions were created in order to encompass all the drug residues of interest. All mass spectrometer parameters initially used to optimize the RFMS system were imported from previously published literature with respects to MRM transitions, temperatures, voltages, and gasses 7-10,15-28. These values although not optimal for this system, served as a basis for optimizing the RFMS system. All initial experiments for method development with the RFMS system were conducted using 40.0 ng/g fortified reagent blanks in 10 mL of 0.1% formic acid in water, so that all data derived from our research work would be directly correlated to the method performance and not that of a matrix issue. The SPE cartridge phases which were readily available to evaluate were limited to phenyl, C4, C8, C18, and HILIC. All of these cartridges evaluated are specifically designed for a RapidFire instrument and were obtained from Agilent. Multiple injections of a high level standard (40.0 ng/g) with identical RFMS conditions were evaluated in order to select the optimal SPE cartridge phase with regards to mass spectral response and peak shape. Results conclusively demonstrated that the C18 SPE phase was the optimal phase choice for this method. Most of the analytes of interest were not retained at all, or minimally retained with the HILIC, phenyl, C4, or C8 in comparison to the C18 phase. Further research was conducted using various solvents, various compositions of those solvents, and different flow rates in order to maximize the RFMS system with respects to time and instrument response. Studies showed that any extra wash of the SPE cartridge resulted in a loss of instrument response of ≥ 50%, despite the choice of flow or solvent used; thus, any additional washing of the cartridge was avoided. Each tunable mass spectral parameter was later optimized through direct injection of a laboratory fortified reagent blank via the RFMS system. Solvent blanks were also evaluated directly after the analysis of standards to ascertain if any residual carryover was present. Through all method optimization and validation efforts, no visible carryover was observed; this is most likely due to the 6000 msec. elution and 6000 msec. equilibration times. Although these times could most likely be cut in half, they help eliminate the possibility of carryover from sample to sample. Upon completion of instrument optimization, laboratory fortified matrix blanks and laboratory matrix blanks were analyzed in comparison to the laboratory fortified reagent blanks. Studies demonstrated that up to 1 order of magnitude of matrix suppression for some analytes took place for a 10 ng/g fortified honey matrix in 10 mL of 0.1% formic acid in water. Additionally, there was such a substantial amount of background for the matrix blanks that the likelihood of generating a high percentage false positives based off of area counts was a major concern. Furthermore, many of the product ions for a
10 ng/g fortified matrix standard exhibited a signal to noise ratio (S/N) of only slightly > 3:1. In hopes of minimizing matrix effects, and improving signal to noise, further sample dilutions were evaluated. All studies performed were at a sample concentration of 10.0 ng/g. Sample dilutions of 2.00 grams into 10.0 mL, 2.00 grams into 20.0 mL, and 2.00 grams into 40.0 mL were examined. Additionally, varying pH levels of the sample were also evaluated. Each of the sample dilutions were compared to each other with respects to background noise. The 20.0 mL dilution showed on average 20–30% less background noise than the 10.0 mL dilution; however, the 40.0 mL dilution exhibited approximately 50% less background for most of residues than the 10.0 mL dilution. Furthermore, the loss of analyte sensitivity was minimal in the 40.0 mL dilution compared to that of the 10.0 mL and 20.0 mL dilutions. It was also discovered that lowering the pH of the sample with the addition of 1.00 mL of glacial acetic acid enhanced instrument response. As a result, all of the validation efforts were performed using a 2.00 gram dilution of sample in 40.0 mL of 0.1% formic acid with further acidification using glacial acetic acid.
Figure 1. Mass spectra of 6 different targeted sulfacetamide drug residues from a 10 ng/g laboratory fortified blank honey sample. Two MRM transition for each drug residue are illustrated along with suggested collision energy which is located directly above the MRM transition. Method Validation All of the control honey matrices were evaluated prior to validation efforts using an approved FDA method to demonstrate the absence of any of the targeted sulfonamides 10. Twenty-one spikes were fortified at the target testing limit, 9 were fortified at 2 times the target testing limit, and 9 were fortified at 4 times the target testing limit. Furthermore, an incurred honey residue sample which contained sulfathiazole at > 20 ng/g was also analyzed. Mass spectral data for a 10
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ng/g matrix spike is listed in Figures 1–3. The method validation study occurred over three non-consecutive days and consisted of a total of 39 fortified matrix spikes, 30 matrix blanks, and one incurred sample 3,10,29,30. Sulfaquinoxaline Sulfadimethoxine Sulfamethazine Sulfachloropyridazine Sulfadiazine Sulfamerazine Sulfamethoxazole Sulfadoxine Sulfaethoxypyridazine Sulfamethoxypridazine Sulfapyridine
111% 121% 98.2% 102% 99.3% 105% 108% 105% 119% 105% 97.3%
14.4% 6.17% 13.1% 16.3% 13.6% 11.7% 12.9% 9.86% 13.1% 8.46% 16.4%
Table 3. 20 ng/g fortified matrix spikes (n = 9) Drug Residue
Figure 2. Mass spectra of the remaining 6 targeted sulfacetamide drug residues from a 10 ng/g laboratory fortified blank honey sample. Two MRM transition for each drug residue are illustrated along with suggested collision energy which is located directly above the MRM transition.
Sulfathiazole Sulfaquinoxaline Sulfadimethoxine Sulfamethazine Sulfachloropyridazine Sulfadiazine Sulfamerazine Sulfamethoxazole Sulfadoxine Sulfaethoxypyridazine Sulfamethoxypridazine Sulfapyridine
Avg. Recovery 86.9% 115% 126% 93.9% 98.9% 96.0% 91.0% 116% 111% 116% 101% 89.3%
RSD 22.3% 17.1% 10.2% 11.7% 15.9% 13.4% 16.2% 13.1% 10.4% 8.50% 7.30% 21.3%
Table 4. 40 ng/g fortified matrix spikes (n = 9) Drug Residue Figure 3. Mass spectra of the internal standard from a blank honey sample fortified at 40 ng/g. The suggested collision energy is provided directly above the MRM transition. The average recoveries and relative standard deviations are provided in Tables 2–4. All 39 assayed laboratory fortified honey samples met the required confirmation criteria for a presumptive positive for each drug residue of interest by exhibiting a response for each MRM at > 50% of the matrix standard. Additionally, the incurred sample confirmed the presence of sulfathiazole. There were also 0% false positives observed in the 30 matrix blanks analyzed. Table 2. 10 ng/g fortified matrix spikes (n = 21) Drug Residue Sulfathiazole
Avg. Recovery 87.1%
RSD 8.58%
Sulfathiazole Sulfaquinoxaline Sulfadimethoxine Sulfamethazine Sulfachloropyridazine Sulfadiazine Sulfamerazine Sulfamethoxazole Sulfadoxine Sulfaethoxypyridazine Sulfamethoxypridazine Sulfapyridine
Avg. Recovery 74.1% 101% 118% 93.0% 86.8% 88.1% 80.9% 112% 107% 123% 101% 88.6%
RSD 22.7% 17.5% 13.5% 13.8% 19.3% 11.9% 13.4% 12.3% 12.0% 11.1% 5.11% 18.3%
Table 5. Comparison of a traditional method verses RapidFire mass spectrometry (herein batch is defined as 20 samples
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Analytical Chemistry
including quality control)
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Liquid-liquid salt assisted extraction
4–6 hours/batch
LC/MS instrument run time
5–10 min/injection
Total Time
5½–9½ hours/batch Versus:
RFMS
~ 20 sec/sample
Total Time
~7 minutes/batch
Conclusion A rapid quantitative screening method for the detection of 12 different sulfonamides in honey matrices was developed with the utilization of RapidFire mass spectrometry. The method not only demonstrated that it is capable of reducing analytical times by >97%, but also exhibited extremely precise results during the three non-consecutive days of method validation where presumptive positive criteria was met for all residues in the 39 fortified honey samples analyzed, and the incurred residue honey analyzed. Furthermore, the method generated no false positives out of the 30 matrix blanks analyzed. This high-throughput and high-capacity method can serve as an optimal quantitative screening method for laboratories performing regulatory analysis.
AUTHOR INFORMATION Corresponding Author * (B.V.) E-mail: Brian.
[email protected]. Phone +1-870-5434085. Fax: +1-870-543-4041., *
Notes The authors declare no competing financial interest.
ACKNOWLEDGMENT The authors would like to thank Dr. Wendy Anderson and Alex Krynitsky for their valuable comments on the draft manuscript. The views expressed in this document are those of the researchers and should not be interpreted as the official opinion or policy of the U.S. Food and Drug Administration, Department of Health and Human Services, or any other agency or component of the U.S. government. The mention of trades names, commercial products, or organizations is for clarification of the methods used and should not be interpreted as an endorsement of a product or a manufacturer.
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Analytical Chemistry
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