the pfizer institute for pharmaceutical materials science university of cambridge antonio llinàs...

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



Is ADMET important?Is ADMET important?



Why to predict Physico-Chemical Why to predict Physico-Chemical properties? properties?



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)


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



Building a Model Building a Model

Cross Cross ValidationValidation


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


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


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



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



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.




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)




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)





ia. ia. Multi-level Multi-level referencingreferencing





ib. ib. Data errorsData errors



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



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




SolutSolutee

ElectrolyElectrolytete

Non-Non-electrolyteelectrolyte

StronStrongg

WeakWeak




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)



Process of dissolutionProcess of dissolution

Step Step 11

Step Step 22

Step Step 33



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




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




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



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



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



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



NH

OCl Cl

ONa NH

OCl Cl

O

Na+

NH

OCl Cl

OH

NH

OCl Cl

OHIn Solution

Powder


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



NH

OCl Cl

ONa NH

OCl Cl

O

Na+

NH

OCl Cl

OH

NH

OCl Cl

OHIn Solution

Powder


● 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



NH

OCl Cl

ONa NH

OCl Cl

O

Na+

NH

OCl Cl

OH

NH

OCl Cl

OHIn Solution

Powder

DiclofenacDiclofenacCharacterisationCharacterisation

0

1000

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6000

0 10 20 30 40 50

2 Theta

Co

un

ts

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0 5 10 15 20 25 30 35 40 45 50

2 Theta

Co

un

ts

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0 5 10 15 20 25 30 35 40 45 50

2 Theta

Co

un

ts

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2 Theta

Co

un

ts

0

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0 5 10 15 20 25 30 35 40 45 50

2 Theta

Co

un

ts

NO MATCH !!!!NO MATCH !!!!


0

2000

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0 10 20 30 40 50

2 Theta

Co

un

ts


NH

OCl Cl

ONa NH

OCl Cl

O

Na+

NH

OCl Cl

OH

NH

OCl Cl

OHIn Solution

Powder


0

2000

4000

6000

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12000

0 5 10 15 20 25 30 35 40 45 50

2 Theta

Co

un

ts

0

2000

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0 5 10 15 20 25 30 35 40 45 50

2 Theta

Co

un

ts

0

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2 Theta

Co

un

ts

MATCH !!!!MATCH !!!!

0

500

1000

1500

2000

2500

0 10 20 30 40 50

2 Theta

Co

un

ts



NH

OCl Cl

ONa NH

OCl Cl

O

Na+

NH

OCl Cl

OH

NH

OCl Cl

OHIn Solution

Powder


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



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)


* Thanks to John Davies for solving the X-ray structure of this crystal



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

êxo

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

êxo


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

êxo



DSC- MP = 267.4 ˚C TGA- Anhydrous

DSC- MP = 263.4 ˚C TGA- Pentahydrate

DSC- MP = 180.5 ˚C TGA- Anhydrous



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)



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


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.



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

the pfizer institute for pharmaceutical materials science university of cambridge antonio llinàs...

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