©2015 waters corporation 1 identify chemical and herbal components of natural products using lc/ms...
TRANSCRIPT
©2015 Waters Corporation 1
Identify Chemical and Herbal Components of Natural Products Using LC/MS Coupled with
a Novel Informatics Platform
Jimmy Yuk, PhD
Natural Products Research
Waters Corporation
©2015 Waters Corporation 2
Background
The usage and discovery of natural products for herbal remedies, or phytopharmaceuticals are expanding every year worldwide– Global Dietary/Herbal Supplement Market 2014: $61.84 Billion
USD
Herb and plant-based remedies
Traditional Medicines
Personal-care products
Herbal supplements
©2015 Waters Corporation 3
Natural Products = multiple-component mixture!
AlkaloidsTerpenesPhenylpropanoids
Terpenoids
Phenolics
Glucosinolates
Polyketides Can contain >1000s of unique
compounds!
http://www.puremedic.com/images/img-products.jpg?bc_t=7tA9BUifDDKKc3X5mMNtWw
©2015 Waters Corporation 4
Concerns in Natural Products
• NATURAL ≠ SAFE!
• Adulteration is a major concern with natural
products in the market
• Deliberately substituted (financial incentive)
• Increase efficacy
~903 adulterated natural health products that have been detected in the industry! (US FDA)
©2015 Waters Corporation 5
Liquid chromatography coupled with high resolution mass spectrometry
LC-MS screening gained popularity with advent of electrospray ionization
High sensitivity to detect low abundance compounds in extracts (nM sensitivity)
Ability to detect multiple compounds without isolation
Accurate mass screening
Provides information on isotope ratios which can ensure the correct assignment of elemental composition
Enables rapid determination of molecular formula for peak of interest
What is Accurate Mass?
Nominal Mass:
Accurate mass:
CO = 28N2 = 28C2H4 = 28
CO= 27.9949N2= 28.0061C2H4= 28.0313
ID of compounds
©2015 Waters Corporation 6
Obtain elemental composition from
exact mass
Obtain possible structures from various different online databases
Fragment ion confirmation by
checking literature
LC chromatograms and MS spectraManually select each component by extracted ion chromatogram
Structure elucidation procedure for each component chosen
Confirm compound identity and structure
Data Acquisition
Accurate mass screening: Challenges Traditional work flow
C2H4= 28.0313
©2015 Waters Corporation 7
• Fast, robust and reproducible for all of your assays
• Interactive workflow-driven data platform
• Ultra sensitive exact mass MSE
• Optimized for Natural Product LC/MS experiments
Waters Natural ProductsApplication Solution with UNIFI ®
Waters ASR Green Tea Extract
& Catechin in Standard Mix
ACQUITY UPLC® I-Class,ACQUITY UPLC HSS T3 Column
Xevo® G2-XS QTof MS
UNIFI Natural Product Application solution
Ingredient Profiling Application
Synthetic Adulterant Application
• Traditional Medicine Library
• Workflow Template
• Processing/ Acquisition methods
• Reports
• Synthetic Adulterant Library
• Workflow Template
• Processing/ Acquisition methods
• Reports
©2015 Waters Corporation 8
Key Features for Natural Product Screening
Fragment Ion Analysis - MSE 3D Peak Detection and Componentisation
“Snapshot in time”: gather all data possible in one run
Identification tools
• Traditional Medicine Library
• Synthetic Adulterant Library
• MassFragment
1 2
3 4Workflow and Reporting
©2015 Waters Corporation 9
Available Item Tags:– Chinese Name (in Mandarin)
– Classification based on chemical class
– Plant of origin
– Latin Name:o Latin name for the exact
use of the herbo In NP research, Latin Name
is the standard search format for plant of origin
Contains about 600 herbs– All herbs listed in 2010
Chinese PharmacopoeiaClick the plants of interest for
import
Natural Product Application Solution Waters Traditional Medicine Library
©2015 Waters Corporation 10
Compound properties
Chemical formula, Accurate mass, CAS No.
Structure
Plants of origin
Chemical classification
Compound links back to Plant Origin and Chemical class!
Ex: Salviae, Schizonepeta Stem, Herba Glechomae, Organic Esters
Traditional Medicine Library
©2015 Waters Corporation 11
Other names of compound
Item tags (Pharmacological action)
Compound properties Compound structure
Compound identifiers (CAS number, Chemspider ID and PubChem ID )
Synthetic Adulterant Library
©2015 Waters Corporation 12
Diagnostic experimental fragment ions
Synthetic Adulterant Library
©2015 Waters Corporation 13
Custom Natural Product Library
Researchers can import or create their own custom natural products library for component screening
– Easy import format such as excel documents
– A specific library for the researcher’s unique natural product sampleso Saves publications and other detection data
– Simple to curate using online sources such as chemspider
Example: Hoodia standard library (Collaboration project with University of Mississippi, Dr. Bharathi Avula/Dr Yan-Hong Wang)
©2015 Waters Corporation 14
Ginsenoside Rb1
Structure confirmation using MassFragment• MassFragment is an in-
silico fragmentation tool which uses systematic bond disconnection approach to identify possible structures from the parent structure
• Allows higher confidence to identify complex chemical components
• Removes possible false positives in the analysis
12 components for confirmation!
©2015 Waters Corporation 15
Natural Products Workflow (Data to Result)
Ensures data quality
Component identification
Comparison of two samples
Workflow templates What is it?
– Unique data processing and review workflow
– Uses data filters to automatically screen componentised data
– Filters can be saved as a routine workflow.
©2015 Waters Corporation 16
Natural Products Screening workflowCamellia sinensis (Green tea)
Component list
Low CE
High CE
Chromatograph for each component
Workflow templates
Detected fragments
©2015 Waters Corporation 17
Natural Products Screening workflowCamellia sinensis (Green tea)–Binary Compare
Component comparison
Workflow templates Compound
differences
©2015 Waters Corporation 18
Natural Products (NP) Screening study
Ganoderma lucidum
Strychnos nuxvomica(poison nut)
Commiphora mukul(guggul)
Panax Ginseng
Fructus Mume
Euryale Ferox Poria Cocos
Cassia tora L.
Semen Pruni
Dioscoreaopposita
1) Oprah (Weight loss)
2) DaiDaiHua (Weight loss)
3) D.N. Capsule (Pain Relief)
Aurantii fructus immaturus
Picrorhiza kurroa(Kutki)
Place of Origin Ingredients on LabelSample
©2015 Waters Corporation 19
LC conditions
– LC System: Waters® ACQUITY UPLC I-Class
– Column: HSS T3 C18 2.1x100mm, 1.8µm
– Column temp: 40 ºC
– Flow rate: 600 µL/min
– Injection volume: 1 µL
– Mobile phase A: H2O in 0.1% formic acid
– Mobile phase B: ACN
– Gradient: 2-100% B in 14.5 min and 2.5 min 98% A equilibration
MSE conditions
– MS System: Waters Xevo G2-XS QTof
– Ionization: ESI positive and negative
– Capillary voltage: 1.5 kV(+Ve) & 1.5 kV(-Ve)
– Trap CE Ramp 10-40 eV
– Acquisition range: 50-1500 m/z
NP Screening StudyLC/MS method
ACQUITY UPLC I-Class G2-XS QTof MS
©2015 Waters Corporation 20
NP Screening Study Oprah -Screening
Chromatograph for each component
Low CE
Workflow templates
High CE
Components list Item tags
Three fragments identified A comprehensive view using
workflows to identify compounds
©2015 Waters Corporation 21
NP Screening StudyOprah - Results
Ganoderma lucidum Panax Ginseng
Euryale Ferox Poria Cocos
Semen Pruni
Dioscoreaopposita
Overview plot of components
Fructus Mume Cassia tora L.
Ingredients Present Ingredients Absent
Five major compounds were detected from Fructus mume and cassiae tora
• Verified through fragment ions, error limits and isotopic match intensity
©2015 Waters Corporation 22
NP Screening StudyDaidaihua - Results
Chromatograph for each component
Low CE
Workflow templates
High CE
Components listItem tags
One fragments identified
©2015 Waters Corporation 23
NP Screening StudyDaidaihua - ResultsOverview plot of components
Ingredients Present
New Ingredients Present
Adulterants Present
Three adulterants were detected with the highest response. Nine major compounds were detected from Aurantii fructus immaturus and Nelumbinis folium
• Verified through fragment ions, error limits and isotopic match intensity
Aurantii fructus immaturus Nelumbinis folium
Sibutramine Nor-acetildenafil
Cyproterone acetate
©2015 Waters Corporation 24
Low CE
Workflow Templates
Components list
High CE
Four Diagnostic Fragments Matched!
Chromatograph of each
component
Item tags
• Phenylbutazone – Anti-inflammatory drug detected• Strychnine from Strychni Semen was detected
NP Screening StudyD.N Capsule – Screening
©2015 Waters Corporation 25
Chromatograph of Unknown peak
Low CE
No Match high intensity workflow
High intensity peak (not ID)
High CE
One high response unknown peak was found using the “No Match high intensity filter”– “Elucidate” function was used to deduce possible compound
Components list
NP Screening StudyD.N Capsule – Screening
©2015 Waters Corporation 26
Discovery Tools
• Elemental Composition
• Library Search
• Fragment Match
Search hits
Compound information
MS spectrum
Citations
Fragment matches
Two fragments identified
Oxyphenbutazone is an anti-inflammatory drug
NP Screening StudyD.N Capsule – Elucidation
©2015 Waters Corporation 27
Overview plot of components
Ingredients Present
Ingredients Absent
Strychnos nuxvomica
Commiphora mukulPicrorhiza kurroa
Adulterants Present
Phenylbutazone
Oxyphenbutazone
Two adulterants were detected with the highest response. Two major compounds were detected from Strychnos nuxvomica
• Verified through precursor exact mass, fragment ions and isotopic match intensity
Strychnine
NP Screening StudyD.N Capsule – Summary
©2015 Waters Corporation 28
o Factors such as species, geographical location, growth time, etc.
• Any potential markers or patterns that are seen?o Multivariate analysis (MVA) can be used!
Multivariate Analysis – Statistical Modelling
Chemical profiling with UNIFI
Botanical Extract
Botanical chemical fingerprint
Questions:•Is the chemical fingerprint
similar or different?•If different, what changed or
is new?
What about comparison with a group of samples?
Generate Marker matrix using 3D peak signature
LC/MS spectrum
©2015 Waters Corporation 29
Chemical Profiling study:Ginseng comparison study
Ingredients:Panax quinquefoliusRootForm:Capsules
Ingredients:Red Panax ginseng root extract Other: honey, alcohol
Form:Oral Drink
Panaxquinquefolius
Panax notoginseng
Panax ginseng
Reference ginseng products
Commercial ginseng products
Red Panax Ginseng
Wild Harvest: American Ginseng
Prince of Peace: Red Panax Ginseng Extractum
©2015 Waters Corporation 30
LC conditions
– LC System: Waters® ACQUITY UPLC I-Class
– Column: HSS T3 2.1x100mm, 1.8µm
– Column temp: 45 ºC
– Flow rate: 600 µL/min
– Injection volume: 1 µL
– Mobile phase A: H2O in 0.1% formic acid
– Mobile phase B: ACN in 0.1% formic acid
– Gradient: 2-90% B in 18.0 min and 2 min 90% A equilibration
MSE conditions
– MS System: Waters Xevo G2-XS QTof
– Ionization: ESI positive and negative
– Capillary voltage: 6.0 kV(+Ve) & 6.0 kV(-Ve)
– Trap CE Ramp 25-55 eV
– Acquisition range: 100-1500 m/z
Application Example:Ginseng comparison study
©2015 Waters Corporation 31
-2500
-2000
-1500
-1000
-500
0
500
1000
1500
2000
2500
-3000 -2500 -2000 -1500 -1000 -500 0 500 1000 1500 2000 2500 3000
PC
2 (
32.1
% V
aria
nce
)
PC 1 (39.5% Variance)
Authentic vs Commerical Ginseng Products
American GinsengPGPG redPPPQPrince RedPG red
American Ginseng
PG redPGPrince Red
PG
PP
Prince Red
PPPP
PQ
Prince Red
PQ
PG red
American GinsengAmerican Ginseng
PG
PQ
UNIFI 3.0.3 - Ginseng_XevoG2SQTof_POS 2AP2015.usp (M12: PCA-X) - 2015-09-15 15:44:47 (UTC-5)
Panax ginseng
Panax quinquefolius
Panax notoginseng
Red Panax Ginseng
Application Example:Ginseng comparison study – Results
Principal component analysis (PCA) Scores Plot
PCA scores plot displays how different each species of ginseng is but classified the commercial products correctly with the authentic ginseng samples
Prince of Peace
Wild harvest
©2015 Waters Corporation 32
-0.15
-0.10
-0.05
-0.00
0.05
0.10
0.15
0.20
0.25
-0.08 -0.06 -0.04 -0.02 0.00 0.02 0.04 0.06 0.08 0.10 0.12 0.14 0.16 0.18 0.20 0.22 0.24 0.26 0.28 0.30 0.32 0.34
PC
2 L
oad
ing
s
PC1 Loadings
Authentic vs Commerical Ginseng Products
141.95874470.10730
172.97701182.98511
468.17599329.08394473.12574
137.98770392.15445438.19623456.20712 254.16113
361.10971290.11346349.16150276.14393294.15446253.07068271.08116282.11927283.13963342.13910347.09444
158.96135
490.19117384.11448472.18055311.07349646.31668310.12805328.13861484.26463166.08635120.08101342.00315322.21209100.07597
590.24350
428.19130
410.18022127.03926529.20216109.02870225.95589266.98246182.98513284.14932266.13874
281.11269100.07596
306.13304367.14929
363.17712
386.18058370.18539
205.09712188.07075
428.19129
356.17022290.13849338.15946305.98176127.03923315.06428355.10206
410.18023489.19535364.16109888.41408637.42950
655.44020857.48448
439.35579457.36679355.16469332.19648
339.10689147.04409
801.49738200.10718
513.19369522.21702
417.18717
177.05463369.11730
412.22243751.46021
637.42982870.40311839.47414
855.44739
619.41936
381.18731
421.34581765.47667439.35644
374.15911639.44548
382.21192
365.19271619.41907
330.21321564.35822498.25879
621.39905608.38403
839.47368817.49184963.54928985.53130
1016.45983457.36652655.43979439.35607
801.49719
819.50765
386.17031652.41022412.05735208.00540317.05420
319.05008253.00314390.07557573.04959278.02346249.03208419.202751016.46086603.42394
476.21166
985.53167
1131.58880696.43643
1162.51710439.35632405.35078
423.36129441.37169
243.14876476.21161603.424451016.46120765.47631985.53151421.34544339.26778639.44515
955.52137
801.49744
441.37219
423.36176
405.35118
621.43490
226.14621227.15407184.09949823.479391033.46452
459.38273567.40302
573.41420603.42462
585.41393555.40344349.28847952.51394
735.46680
217.19500203.17961854.40835977.57693367.29909775.45865
753.47698978.59128971.49440
692.35696717.45579486.24756866.40910986.45121
1017.49135439.35608785.50267 637.42933421.34558403.33496745.45095583.39838763.46177765.47610619.41920
708.36962
137.98768639.44568801.49738
784.49229
786.52599993.613151440.30302
876.49746776.00577
992.60958
1350.27107493.25518991.59218
985.51061966.52886
969.53728
1079.45197778.483021059.60583
1031.50637
1000.46632
715.47391877.521681005.60693
913.54928895.53864
515.38711820.40349
930.569001075.60133
587.42976
569.41931551.40870
784.51812
533.39790
749.48217
713.46029
731.47103
1260.23990
767.49249
935.53064789.47385
309.117751267.72479805.44778880.42439
1439.802161047.47768929.54435851.44342911.533401225.865421207.854661440.81701661.42713
783.48730
459.38252
1387.91896385.30947482.39824341.28329893.49938
441.37251
367.29913549.39268323.27253692.35650
567.40351464.38774337.28816349.28854
423.36215
405.35137
299.23658281.22608295.24169321.25733313.25232243.21050531.38167585.41407423.42028
335.27288203.17942283.24157297.25715187.14814674.34624365.31946217.19509269.22616189.16363765.47651351.30303423.68832
881.73616
363.30353
603.42534
899.74744
621.43567
381.31452446.37710423.73228
327.26799215.17946423.53358
1061.79895
241.19484271.24171301.25211267.21056161.13256309.25731311.27308273.22108207.17422353.28333255.21061285.22111201.16370383.32993734.36743
1079.80936
441.431551223.85188
644.45044405.40832
259.20562863.72539800.513751492.84440147.11712603.81490747.46591603.49509901.42169
547.362491259.87379621.50538
1241.86236
1456.826781439.93527
805.469581043.78809643.41704
1421.92494
836.398361277.882791205.84293
846.55204854.40920
721.358791034.47233
839.45361
1025.77672
1294.77286
662.46101
823.47998
832.54026
1474.836331220.71659
933.39462895.43521845.53532859.55048820.47159
705.387241229.70370
914.43151440.73950852.41331885.44952100.07596158.96134829.45648
466.26377471.21922708.36978405.35081423.36138909.47981689.42459707.43500
801.49700336.12252302.13799381.21657
765.476181147.58302603.42415
439.35648
421.34569
801.49762
823.47927457.36701783.48665405.35063
708.36899
655.43999684.33741745.44993
403.33484763.46027601.40871793.46865573.41376591.42406308.22165783.48618477.39262423.36127431.31432
441.37174
603.42398
629.43337
315.22046793.46810621.43479655.43987405.35076
865.48967896.41899663.44529645.43476801.49700
603.42449765.47675785.38485291.12249
990.58645
579.14820543.12778561.13848783.48696383.23240619.41900
439.35615423.36128
817.49229
457.36659
643.44908322.22817785.50148277.12762203.09106575.22976
299.11004322.18530444.24994
1136.58163439.356371390.71831407.36595457.36680
938.58135
633.39872651.40908673.39087
639.44519100.07591444.25026
936.56407
384.21636603.42445783.48688805.46818839.45260836.39833621.43485
405.35099367.29865459.38271903.42210
423.36163823.47948441.37196765.47666854.40917867.43795885.44914688.35193275.20021
425.37672443.38669
407.36630891.50452767.49232497.146941241.64788
1263.63139
1223.63896587.42956820.403081279.60435749.481111258.67531
1294.55992605.43965
528.07680640.30267
809.46359
787.48190
769.47114886.39838219.17429264.23198291.12220
920.58105
439.35662457.36709
421.34591655.44036
859.55022801.57535427.70832585.41357
475.37770
839.45247765.47652
783.48709
403.33474
801.49815
947.55507810.01142827.95406493.38798
905.42002637.42966812.48915845.53470
900.41443
885.44935
823.47963
619.41906854.40911603.42447
799.48092441.37161423.36157
1032.63267463.21198
1142.59864
870.40431459.38255824.39980
793.46892753.47653
735.46636
637.42931677.42196439.35576655.44041
457.36666421.34554
425.37568443.38539749.48202754.35670921.51618881.52389605.43940587.42960
1263.63195
899.53373407.36583
1012.46614767.49237929.54427365.10496
1294.56178640.30240
396.03453
423.36163
925.51107
441.37202
389.26791
405.35099
621.43496603.42459356.22166
1046.64851
1146.522891115.59308409.381681110.63852
786.53378747.465141129.572561160.50296
887.49732808.51721
839.40617420.20749
383.16913303.12250400.19566405.15113587.42920605.43964407.36612425.37673443.386821233.621051264.55085498.06617625.29625462.18068460.21220
621.43453327.21361
767.49160
789.47339367.29862569.41847217.19491
807.48412794.01587
796.49294838.41353459.38213823.45945
423.36148
603.42402
405.35082
884.41921
441.37178
820.40297793.46913 869.45377475.37709353.22920
1241.648921223.63858497.14682492.191381294.56100
528.07632
1263.63172
640.30267
749.482051141.069311155.666141151.23602603.781281128.643781322.295941350.75610
1165.52777713.46075583.268051167.66000365.10501
574.28195969.53646
1341.26710533.39799731.471361154.66048396.034491112.61668
738.149881191.86091
789.47414325.11270
1497.45469
551.40876820.40351
285.25738
1133.59560
1120.59480
425.37749
965.00637957.523171415.70289
569.41936649.217761113.57888
407.36695
1131.67864
1147.56245
487.16526
1136.56769
1144.50788
587.43004
885.767091348.75095
1073.58611880.42466
443.38777605.44033360.14971
351.304011371.92460369.314581153.643891047.819451312.78765
929.544881498.46544
911.53431271.24181 1209.87184667.22843
785.50851
515.387461313.29004
947.55577
1486.622621108.62319
1330.307051241.50390
767.492641091.59716
1484.347261160.52311
1348.24941189.163761253.649931138.56996
1222.53908203.17934
1000.46634745.33927784.51881
1128.58171
684.254711497.79268
1131.58987
1475.34304
1109.608631498.13120
1162.51899
1126.63388866.409051493.35429
1136.064741127.13553869.41685
217.194991330.80693807.48451838.41414
1211.532081193.55873805.42271
839.408841046.64861
1405.92744100.07595364.24752
1277.88200
644.450441299.86431
603.42444
661.42687
398.231621423.93814
621.43483
738.36196720.35047723.39664692.35649884.41892
405.35079
423.36147
441.37180
741.44040137.98770158.96145
459.38234824.39807793.46889
1257.521731240.65944
906.40351
1249.021231222.06327464.02403
838.41357
1222.56628891.447271215.10330
1306.19052749.480851230.50772615.75895
1251.52746
1477.74898365.104931246.52371
1214.57842375.09155
947.429571195.60845
551.40847
1233.55917
1177.59623
875.47397
785.50241767.49243
624.764201230.57745325.11252
1248.51936
605.440141015.54423
396.03431
1217.59012
411.11265817.47133
966.42463
853.49265
425.37736
1212.63419
807.48450369.31432
443.38754
1051.00657735.21748997.53353231.04990569.41900587.42946
835.48222
573.16567217.19515
1316.50828
779.41972
870.51909
357.08104
407.36681
952.43360834.47266
360.14961
290.08702673.42913
1306.69241
852.50778821.21731806.13931
393.101961043.52307
870.94322608.27630
617.27982
1308.697571159.585241204.119911263.598301333.149281288.24819
1194.62321533.39796799.46000351.30388428.139281280.623171239.64489851.475851298.70700
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UNIFI 3.0.3 - Ginseng_XevoG2SQTof_POS 2AP2015.usp (M12: PCA-X) - 2015-09-15 15:53:52 (UTC-5)
Panax ginseng
Panax quinquefolius
Panax notoginseng
PCA Loadings Plot
Application Example:Ginseng comparison study – Results
PCA loadings plot displays all the contributing variables (m/z) that explain how different each of the ginseng species are.
Export important markers into structure elucidation tools for identification
©2015 Waters Corporation 33
Discovery Tool
• Elemental Composition
• Library Search
• Fragment Match
Marker List
Search hits
Compound information
MS spectrum
Marker Summary
Fragments identified
Fragment matches
Application Example:Ginseng comparison study – Results
Bring all markers from the PCA loadings and search using the TM library/Chemspider to identify compounds of interest
©2015 Waters Corporation 34
Application Example:Ginseng comparison study – Results
Panax ginseng
Notoginsenoside Fc
Ginsenoside Rf
Ginsenoside Rb2
Panax quinquefolius
Gypenoside X VII
Ginsenoside Rd
Ginsenoside Re
Pseudoginsenoside F11
Panax notoginseng
Notoginsenoside R4
Notoginsenoside R1
Notoginsenoside R2
Notoginsenoside Fa
PCA Loadings Plot UNIFI library searching
Identified Ginseng Markers
©2015 Waters Corporation 35
Summary of UNIFI NP workflowApplication workflows
Sample Prep
UPLC/QTof MSE Data Acquisition
UNIFI Data Processing and Component ID
Identified Components
MS/MS Fragments Verification using MassFragmentTM
Import Components from Waters TM and/or Adulterant Library
Unidentified Components
Structure Elucidation Tool +
Search Internet Libraries
Confirm Component
Identity
Search against Waters TM Library
Structure elucidation and online database
search
Single software (UNIFI) to execute
all the identification steps
MVA of chemical profile
Marker identification +Search Internal/ Internet
Libraries
MVA analysis of chemical profiles of
samples
©2015 Waters Corporation 36
In Summary
There are an increasing number of NPs every year throughout the world – Concerns are increasing due to the
cases of adulteration in NHPs
Natural Products are complex mixtures and require comprehensive analytical technologies identify and confirm chemical components
Natural Products solution with UNIFI is a powerful approach in screening for:– Ingredients in natural health products
– Illegal synthetic adulterants
©2015 Waters Corporation 37
Acknowledgements
Dr. Bharthi AvulaDr. Yan-Hong Wang
Waters Natural Products teamDr. Dhaval Patel Waters SingaporeDr. Lirui (Kevin) Qiao Waters, China
Dr. Giorgis Isaac Waters CorporationDr. Kate Yu Waters Corporation Dr. Kerri Smith Waters CorporationMr. James Traub Waters Corporation
University of Mississippi National Center for Natural Product Research
©2015 Waters Corporation 38
Thank you!!