The Pfizer Institute for Pharmaceutical Materials ScienceUNIVERSITY OF CAMBRIDGE
Antonio Llinàs Martí
ADMET ADMET PredictionPrediction
Fiction or Fiction or Reality?Reality?
Antonio Llinàs MartíThe Pfizer Institute for Pharmaceutical
Materials ScienceUniversity of Cambridge
The Pfizer Institute for Pharmaceutical Materials ScienceUNIVERSITY OF CAMBRIDGE
Antonio Llinàs Martí
Is ADMET important?Is ADMET important?
The Pfizer Institute for Pharmaceutical Materials ScienceUNIVERSITY OF CAMBRIDGE
Antonio Llinàs Martí
Why to predict Physico-Chemical Why to predict Physico-Chemical properties? properties?
The Pfizer Institute for Pharmaceutical Materials ScienceUNIVERSITY OF CAMBRIDGE
Antonio Llinàs Martí
ADMET predictive models ADMET predictive models
●●Linear modelsLinear modelsMLR (MLR (MMultiple ultiple LLinear inear RRegression)egression)PLS (PLS (PPartial artial LLeast east SSquares)quares)PCR (PCR (PPrincipal rincipal CComponents omponents RRegression)egression)
●●Non Linear modelsNon Linear modelsANN (ANN (AArtificial rtificial NNeural eural NNetworks)etworks)RF (RF (RRandom andom FForest)orest)SVM (SVM (SSupport upport VVector ector MMachines)achines)
The Pfizer Institute for Pharmaceutical Materials ScienceUNIVERSITY OF CAMBRIDGE
Antonio Llinàs MartíADMET predictive models ADMET predictive models
Data SetData SetTraining Training SetSet
Test Set (≈30 %)Test Set (≈30 %)
New Data New Data SetSet
Good ModelR2 ≈ 1≈ 1RMSE ≈ 0RMSE ≈ 0BIAS ≈ 0BIAS ≈ 0
R2 = 0.98 0.98RMSE = 0.27RMSE = 0.27BIAS = 0.005BIAS = 0.005
R2 = 0.90 0.90RMSE = 0.68RMSE = 0.68BIAS = 0.01BIAS = 0.01
R2 = 0.78 0.78RMSE = 0.85RMSE = 0.85BIAS = 0.1BIAS = 0.1
Building a Model Building a Model
Cross Cross ValidationValidation
The Pfizer Institute for Pharmaceutical Materials ScienceUNIVERSITY OF CAMBRIDGE
Antonio Llinàs MartíADMET predictive models ADMET predictive models Building Good DataBuilding Good Data
•David Palmer, John Mitchell Unilever Centre For Molecular Informatics, University of Cambridge
The Pfizer Institute for Pharmaceutical Materials ScienceUNIVERSITY OF CAMBRIDGE
Multiple Linear Regression*
Log.S = 0.07nHDon (+/-0.018) - 0.21TPSA (+/-0.033) + 0.11MAXDP (+/-0.022) - 0.22n.Ct (+/-0.019) - 0.29KierFlex (+/-0.032) - 0.59SLOGP (+/0.036) - 0.26ATS2m (+/-0.026) + 0.25RBN (+/-0.033)
R2 RMSE Bias10-fold CV 0.85 0.79 0.00Train 0.87 0.78 0.00Test 0.85 0.82 -0.01
SLOGP Partition coefficient LipophilicityTPSA Polar Surface Area Molecular ChargeMAXDP Maximal Electrotopological positive variation Molecular Chargen.Ct Number of Tertiary Carbons Molecular SizeATS2m "Broto-Moreau Autocorrelation" Molecular Size/PolarizabilityKierFlex Kier Flexibility Index Molecular FlexibilityRBN Number of Rotatable Bonds Molecular FlexibilitynHDon Number of Hydrogen Bond Donors
ADMET predictive models ADMET predictive models Antonio Llinàs Martí
* David Palmer, John Mitchell. Unilever Centre For Molecular Informatics, University of Cambridge
The Pfizer Institute for Pharmaceutical Materials ScienceUNIVERSITY OF CAMBRIDGE
Random Forest*
RMSE(te)=0.69R2(te)=0.89Bias(te)=-0.04
RMSE(tr)=0.27R2(tr)=0.98Bias(tr)=0.005
RMSE(oob)=0.68R2(oob)=0.90Bias(oob)=0.01
ADMET predictive models ADMET predictive models Antonio Llinàs Martí
* David Palmer, John Mitchell. Unilever Centre For Molecular Informatics, University of Cambridge
The Pfizer Institute for Pharmaceutical Materials ScienceUNIVERSITY OF CAMBRIDGE
Antonio Llinàs Martí
Problems with the actual literature data Problems with the actual literature data basesbases
i. i. Egregious errors in reporting data and referencesEgregious errors in reporting data and references
Pontolillo, J. and Eganhouse, P., U.S. Department of Interior. U. S. Geological Survey. Water-Resources Investigations Report 01-4201. Reston. Virginia. 2001
ii. ii. Poor data quality and/or inadequate Poor data quality and/or inadequate documentation proceduresdocumentation procedures
The Pfizer Institute for Pharmaceutical Materials ScienceUNIVERSITY OF CAMBRIDGE
Antonio Llinàs Martí
Problems with the actual literature data Problems with the actual literature data basesbasesi. i. Egregious errors in reporting data and referencesEgregious errors in reporting data and references
* S. E. Adams, J. M. Goodman, R. J. Kidd, A. D. McNaught, P. Murray-Rust, F. R. Norton, J. A. Townsend and C. A. Waudby Org. Biomol. Chem. 2004, 2, 3067-3070.
The Pfizer Institute for Pharmaceutical Materials ScienceUNIVERSITY OF CAMBRIDGE
Antonio Llinàs Martí
Problems with the actual literature data Problems with the actual literature data basesbasesi. i. Egregious errors in reporting data and referencesEgregious errors in reporting data and references
Citation Analysis*
1259. C. Lee, W. Yang, R. G. Parr, C. Lee, W. Yang, R. G. Parr, Phys. Rev. BPhys. Rev. B, 1988, 37, 785, 1988, 37, 785.9 DUPLICATES FOUND:NEAR MATCHES:1382. C. Lee, W. Yang, R. G. Parr, Phys. Rev. B, 1988, 37, 785-789.3008. C. Lee, W. Yang, R. G. Parr, Phys. Rev., 1988, 785-788 .4199. C. Lee, W. Yang, R. Parr, Phys. Rev. B, 1988, 37, 785.6006. C. Lee, W. Yang, R. G. Parr, Phys. Rev. B, 1998, 37, 785. 9038. C. T. Lee, W. T. Yang, R. G. Parr, Phys. Rev. B, 1988, 37, 785.9125. C. Lee, W. Yang, R. G. Parr, Phys. Rev. B, 1993, 37, 785.11481. C. Lee, W. Yang, R. G. Parr, Phys. Rev. B, 1988, 37, 785-789.10742. C. T. Lee, W. T. Yang, R. G. Parr, Phys. Rev. B, 1988, 37, 785-789.
* Bruce Russell, Jonathan Goodman (Unilever Centre For Molecular Informatics, University of Cambridge)
The Pfizer Institute for Pharmaceutical Materials ScienceUNIVERSITY OF CAMBRIDGE
Antonio Llinàs Martí
Problems with the actual literature data Problems with the actual literature data basesbasesi. i. Egregious errors in reporting data and referencesEgregious errors in reporting data and references
Citation Analysis*
1259. C. Lee, W. Yang, R. G. Parr, Phys. Rev. B, 1988, 37, 785.9 DUPLICATES FOUND:NEAR MATCHES:1382. C. Lee, W. Yang, R. G. Parr, Phys. Rev. B, 1988, 37, 785-789.3008. C. Lee, W. Yang, R. G. Parr, Phys. Rev., 1988, 785-788 .4199. C. Lee, W. Yang, R. Parr, Phys. Rev. B, 1988, 37, 785.6006. C. Lee, W. Yang, R. G. Parr, Phys. Rev. B, 1998, 37, 785. 9038. C. T. Lee, W. T. Yang, R. G. Parr, Phys. Rev. B, 1988, 37, 785.9125. C. Lee, W. Yang, R. G. Parr, Phys. Rev. B, 1993, 37, 785.11481. C. Lee, W. Yang, R. G. Parr, Phys. Rev. B, 1988, 37, 785-789.10742. C. T. Lee, W. T. Yang, R. G. Parr, Phys. Rev. B, 1988, 37, 785-789.
* Bruce Russell, Jonathan Goodman (Unilever Centre For Molecular Informatics, University of Cambridge)
The Pfizer Institute for Pharmaceutical Materials ScienceUNIVERSITY OF CAMBRIDGE
Antonio Llinàs Martí
Problems with the actual literature data Problems with the actual literature data basesbasesi. i. Egregious errors in reporting data and referencesEgregious errors in reporting data and references
Pontolillo, J. and Eganhouse, P., U.S. Department of Interior. U. S. Geological Survey. Water-Resources Investigations Report 01-4201. Reston. Virginia. 2001
ia. ia. Multi-level Multi-level referencingreferencing
The Pfizer Institute for Pharmaceutical Materials ScienceUNIVERSITY OF CAMBRIDGE
Antonio Llinàs Martí
Problems with the actual literature data Problems with the actual literature data basesbasesi. i. Egregious errors in reporting data and referencesEgregious errors in reporting data and references
Pontolillo, J. and Eganhouse, P., U.S. Department of Interior. U. S. Geological Survey. Water-Resources Investigations Report 01-4201. Reston. Virginia. 2001
ib. ib. Data errorsData errors
The Pfizer Institute for Pharmaceutical Materials ScienceUNIVERSITY OF CAMBRIDGE
Antonio Llinàs Martí
ii. ii. Poor data quality and/or inadequate Poor data quality and/or inadequate documentation proceduresdocumentation procedures
Temperature Solubility g/l Reference
25
25
2.132
896.2
[1]
[2]N
NN
N
O
O
[1] Oliveri-Mandala, E. (1926), Gazzetta Chimica Italiana 56, 896-901
[2] Ochsner, A. B., Belloto, R. J., and Sokoloski, T. D. (1985), Journal of Pharmaceutical Sciences 74, 132-135
The Pfizer Institute for Pharmaceutical Materials ScienceUNIVERSITY OF CAMBRIDGE
Antonio Llinàs Martí
Solubility: definitionSolubility: definition
Huge range of Huge range of definitionsdefinitions
Kinetic SolubilityKinetic SolubilityThermodynamic SolubilityThermodynamic SolubilityEquilibrium SolubilityEquilibrium SolubilityApparent SolubilityApparent SolubilityIonic SolubilityIonic SolubilitySolubility productSolubility productIntrinsic SolubilityIntrinsic SolubilityAqueous SolubilityAqueous SolubilityStandard SolubilityStandard Solubility......
satiwC
SSww
SSaqaq
SSTT
SS00
S00
**
KK00
KKoo**
KKspsp
The Pfizer Institute for Pharmaceutical Materials ScienceUNIVERSITY OF CAMBRIDGE
Antonio Llinàs Martí
Solubility: definitionSolubility: definition
SolutSolutee
ElectrolyElectrolytete
Non-Non-electrolyteelectrolyte
StronStrongg
WeakWeak
The Pfizer Institute for Pharmaceutical Materials ScienceUNIVERSITY OF CAMBRIDGE
Antonio Llinàs Martí
Solubility: definitionSolubility: definition
Solubility- Concentration of a compound in a saturated solution when excess solid is present
Aqueous Solubility- Concentration of a compound in a saturated solution of pure water when excess solid is present.
Thermodynamic Solubility- Solubility when the compound in solution is at equilibrium with the solid form.
Kinetic Solubility – Solubility at the time when an induced precipitate first appears in a solution
Intrinsic solubility- Of an ionisable compound is the thermodynamic solubility of the free acid or base form (Horter, D, Dressman, J. B., Adv. Drug Deliv. Rev., 1997, 25, 3-14)
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Antonio Llinàs Martí
Process of dissolutionProcess of dissolution
Step Step 11
Step Step 22
Step Step 33
The Pfizer Institute for Pharmaceutical Materials ScienceUNIVERSITY OF CAMBRIDGE
Antonio Llinàs Martí
Factors Influencing SolubilityFactors Influencing Solubility
TemperatureTemperature
SalinitySalinity
pHpH
Dissolved Dissolved
organic matter (DOM)organic matter (DOM)
Co-solventsCo-solvents
CrystallinityCrystallinity
PolymorphismPolymorphism
- In general as T Solubility - In general as T Solubility
- In general as salinity Activity coef Solubility - In general as salinity Activity coef Solubility
- Common ion effect Solubility - Common ion effect Solubility
- - IfIf the solute is subject to acid/base reactions then pH is the solute is subject to acid/base reactions then pH is vital in determining water solubility. vital in determining water solubility.
- DOM Solubility - DOM Solubility
- - ffv v Solubility exponentially Solubility exponentially
The Pfizer Institute for Pharmaceutical Materials ScienceUNIVERSITY OF CAMBRIDGE
Antonio Llinàs Martí
Factors Influencing SolubilityFactors Influencing Solubility
CrystallinityCrystallinity
Crystallinity decreases the apparent solubility
Crystallinity (%) Apparent Solubility M
35 C
88.6
36.7
20.8
3.50 x 10-3
4.39 x 10-3
5.27 x 10-3
N
S
OO
NH2
NH
COOH
The Pfizer Institute for Pharmaceutical Materials ScienceUNIVERSITY OF CAMBRIDGE
Antonio Llinàs Martí
Factors Influencing SolubilityFactors Influencing Solubility
PolymorphismPolymorphism
Crystallising into different crystal forms will result in different melting points and solubilities
Crystalline Form
MP Apparent Solubility M
25 C
I
II
III
68
58
42
5.70 x 10-3
6.30 x 10-3
7.40 x 10-3
O
OH
The Pfizer Institute for Pharmaceutical Materials ScienceUNIVERSITY OF CAMBRIDGE
Antonio Llinàs Martí
Solubility measurementsSolubility measurementsClassical MethodClassical Method
Shake Flask Shake Flask MethodMethod
● Many published variations of this method● With DMSO (normal method in industry) Kinetic Solubility● Equilibria reached?
● Filtering Big errors
● Detection by UV-Vis Chromophores needed
The Pfizer Institute for Pharmaceutical Materials ScienceUNIVERSITY OF CAMBRIDGE
Antonio Llinàs Martí
NH
OCl Cl
ONa NH
OCl Cl
O
Na+
NH
OCl Cl
OH
NH
OCl Cl
OHIn Solution
Powder
DiclofenacDiclofenacAn ExampleAn Example
CheqSol is a new method developed by
The Pfizer Institute for Pharmaceutical Materials ScienceUNIVERSITY OF CAMBRIDGE
Antonio Llinàs Martí
NH
OCl Cl
ONa NH
OCl Cl
O
Na+
NH
OCl Cl
OH
NH
OCl Cl
OHIn Solution
Powder
DiclofenacDiclofenac
Precipitation● As soon as pptate is detected titrant addition stops
● pH keeps going up because AH is removed from solution and A- reacts with H+ to replace the AH lost
● The solution, at this point, is SUPERSATURATEDNOT IN EQUILIBRIUM
The Pfizer Institute for Pharmaceutical Materials ScienceUNIVERSITY OF CAMBRIDGE
Antonio Llinàs Martí
NH
OCl Cl
ONa NH
OCl Cl
O
Na+
NH
OCl Cl
OH
NH
OCl Cl
OHIn Solution
Powder
DiclofenacDiclofenac
Dissolution● After pptation is confirmed an aliquot of base is added
● pH goes down because AH (solid) is brought back in solution, AH (ston), generating A- and H+
● The solution, at this point, is SUBSATURATEDNOT IN EQUILIBRIUM
The Pfizer Institute for Pharmaceutical Materials ScienceUNIVERSITY OF CAMBRIDGE
Antonio Llinàs Martí
NH
OCl Cl
ONa NH
OCl Cl
O
Na+
NH
OCl Cl
OH
NH
OCl Cl
OHIn Solution
Powder
DiclofenacDiclofenac
● We continue “Chasing equilibrium” until a specified number of crossing points have been reached ● A crossing point represents the moment when the solution switches from a saturated solution to a subsaturated solution; no change in pH, gradient zero, no re-dissolving nor precipitating….
SOLUTION IS IN EQUILIBRIUM
Supersaturated Solution
Subsaturated Solution
Si = 1.53 ± 0.15 g/ml
The Pfizer Institute for Pharmaceutical Materials ScienceUNIVERSITY OF CAMBRIDGE
Antonio Llinàs Martí
NH
OCl Cl
ONa NH
OCl Cl
O
Na+
NH
OCl Cl
OH
NH
OCl Cl
OHIn Solution
Powder
DiclofenacDiclofenacCharacterisationCharacterisation
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0 10 20 30 40 50
2 Theta
Co
un
ts
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Co
un
ts
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un
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Co
un
ts
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2 Theta
Co
un
ts
NO MATCH !!!!NO MATCH !!!!
The Pfizer Institute for Pharmaceutical Materials ScienceUNIVERSITY OF CAMBRIDGE
0
2000
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2 Theta
Co
un
ts
Antonio Llinàs Martí
NH
OCl Cl
ONa NH
OCl Cl
O
Na+
NH
OCl Cl
OH
NH
OCl Cl
OHIn Solution
Powder
DiclofenacDiclofenacCharacterisationCharacterisation
0
2000
4000
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0 5 10 15 20 25 30 35 40 45 50
2 Theta
Co
un
ts
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Co
un
ts
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un
ts
MATCH !!!!MATCH !!!!
0
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2500
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Co
un
ts
The Pfizer Institute for Pharmaceutical Materials ScienceUNIVERSITY OF CAMBRIDGE
Antonio Llinàs Martí
NH
OCl Cl
ONa NH
OCl Cl
O
Na+
NH
OCl Cl
OH
NH
OCl Cl
OHIn Solution
Powder
DiclofenacDiclofenacCharacterisationCharacterisation
0
500
1000
1500
2000
2500
0 10 20 30 40 50
2 Theta
Co
un
ts
Diclofenac AcidC2/c polymorph* Polyhedron (1993), 12, 1361
The Pfizer Institute for Pharmaceutical Materials ScienceUNIVERSITY OF CAMBRIDGE
Antonio Llinàs Martí
0
1000
2000
3000
4000
5000
6000
0 10 20 30 40 50
2 Theta
Co
un
ts
In Solution
Powder
Crystal
NH
OCl Cl
ONaNH
OCl Cl
ONa
Crystallisation
EtOH, RT
X-RaySingle Crystal
X-RayPowder?
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
0 10 20 30 40 50
2 Theta
Co
un
ts
Sodium diclofenac pentahydrateP 2(1)
DiclofenacDiclofenacCharacterisationCharacterisation
* Thanks to John Davies for solving the X-ray structure of this crystal
The Pfizer Institute for Pharmaceutical Materials ScienceUNIVERSITY OF CAMBRIDGE
Antonio Llinàs Martí
In Solution
Powder
Crystal
NH
OCl Cl
ONa NH
OCl Cl
O
Na+
NH
OCl Cl
OH
NH
OCl Cl
OH
NH
OCl Cl
ONa
%50
min
°C40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Wg^-15
min0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Onset 180.48 °C
^exo
SW 8.01eRTASLab: METTLER
%20
Onset 284.30 °C
Wg^-12
min0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 min
°C40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
^exo
SW 8.01eRTASLab: METTLER
Onset 41.08 °C
Onset 263.38 °C
!Diclofenac sodium salt CRYSTALDiclofenac sodium salt CRYSTAL, 13.5900 mg
Wg^-10.5
min
°C40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340
0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300
Step -16.5063 % -2.0550 mg
!Diclofenac Sodium salt CRYSTALDiclofenac Sodium salt CRYSTAL, 12.4500 mg
%20
min0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300
^exo
SW 8.01eRTASLab: METTLER
DiclofenacDiclofenacCharacterisationCharacterisation
DSC- MP = 267.4 ˚C TGA- Anhydrous
DSC- MP = 263.4 ˚C TGA- Pentahydrate
DSC- MP = 180.5 ˚C TGA- Anhydrous
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In Solution
Powder
Crystal Si = 1.53 ± 0.15 % g/ml Si = 1.47 ± 0.12 % g/ml
Si = 1.49 ± 0.09 % g/ml
NH
OCl Cl
ONa NH
OCl Cl
O
Na+
NH
OCl Cl
OH
NH
OCl Cl
OH
NH
OCl Cl
ONa
DiclofenacDiclofenacSolubility (25Solubility (25˚C, I= 0.15 M)˚C, I= 0.15 M)
The Pfizer Institute for Pharmaceutical Materials ScienceUNIVERSITY OF CAMBRIDGE
Antonio Llinàs Martí
In Solution
Powder
Crystal
NH
OCl Cl
ONa NH
OCl Cl
O
Na+
NH
OCl Cl
OH
NH
OCl Cl
OH
NH
OCl Cl
ONa
DiclofenacDiclofenacCompleteComplete
Powder XRD- ?Single Crystal XRD- EA- BADMP (DSC)- 267.4 ˚CTGA- Sodium Salt Anhydrous
Solubility – 1.528 ± 0.15% g/ml
Powder XRD- NEWSingle Crystal XRD- SOLVED Sodium salt PentahydrateP2(1)EA- OKMP (DSC)- 263.4 ˚CTGA- Sodium Salt Pentahydrate
Solubility – 1.472 ± 0.09 g/ml
Powder XRD- SIKLIH01Single Crystal XRD- NOEA- OKMP (DSC)- 180.5 ˚CTGA- Diclofenac Acid Anhydrous
Solubility – 1.488 ± 0.12 % g/ml
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Antonio Llinàs MartíConclusionsConclusions
• Predictive ADMET is in its infancyPredictive ADMET is in its infancy
• Models are not improvingModels are not improving
• Actual databases are no good: bad quality data, Actual databases are no good: bad quality data, no no diverse enoughdiverse enough
• Need of high quality data to build reliable Need of high quality data to build reliable databasesdatabases
• Need of standardization. Same conditions, same Need of standardization. Same conditions, same definition, characterisation, and statistical definition, characterisation, and statistical treatmenttreatment
• Solubility: Intrinsic, 25 ˚C, I = 0.15 M (KCl), purity Solubility: Intrinsic, 25 ˚C, I = 0.15 M (KCl), purity of starting material >99.5 %, Solid of starting material >99.5 %, Solid characterisation.characterisation.
The Pfizer Institute for Pharmaceutical Materials ScienceUNIVERSITY OF CAMBRIDGE
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AcknowledgmentAcknowledgmentss
- University of Cambridge- University of Cambridge
- Pfizer- PfizerDr. Hua GaoDr. Hua Gao
- Unilever Solubility Team- Unilever Solubility TeamProf. Robert Glen (Director)Prof. Robert Glen (Director)Dr. Jonathan Goodman (Group Dr. Jonathan Goodman (Group Leader)Leader)Dr. John Mitchell (Group Leader)Dr. John Mitchell (Group Leader)Dr. Antonio LlinDr. Antonio LlinàsàsDavid PalmerDavid Palmer
To ALL of YOUTo ALL of YOU
- Sirius Analytical - Sirius Analytical Instruments Ltd.Instruments Ltd.
Karl BoxKarl Box