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Antonio Llin às Martí

Antonio Llin às Martí. ADMET Prediction Fiction or Reality?. Antonio Llin às Martí The Pfizer Institute for Pharmaceutical Materials Science University of Cambridge. Antonio Llin às Martí. Is ADMET important?. Antonio Llin às Martí. Why to predict Physico-Chemical properties?.

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Antonio Llin às Martí

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  1. Antonio Llinàs Martí ADMET Prediction Fiction or Reality? Antonio Llinàs Martí The Pfizer Institute for Pharmaceutical Materials Science University of Cambridge

  2. Antonio Llinàs Martí Is ADMET important?

  3. Antonio Llinàs Martí Why to predict Physico-Chemical properties?

  4. Antonio Llinàs Martí ADMET predictive models ●Linear models MLR (Multiple Linear Regression) PLS (Partial Least Squares) PCR (Principal Components Regression) ●Non Linear models ANN (Artificial Neural Networks) RF (Random Forest) SVM (Support Vector Machines)

  5. ADMET predictive models Test Set (≈30 %) R2 = 0.98 RMSE = 0.27 BIAS = 0.005 R2 = 0.90 RMSE = 0.68 BIAS = 0.01 Data Set Training Set Cross Validation R2 = 0.78 RMSE = 0.85 BIAS = 0.1 New Data Set Antonio Llinàs Martí Building a Model Good Model R2 ≈ 1 RMSE ≈ 0 BIAS ≈ 0

  6. ADMET predictive models Antonio Llinàs Martí Building Good Data • David Palmer, John Mitchell • Unilever Centre For Molecular Informatics, University of Cambridge

  7. Antonio Llinàs Martí ADMET predictive models 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) • * David Palmer, John Mitchell. Unilever Centre For Molecular Informatics, University of Cambridge

  8. Antonio Llinàs Martí ADMET predictive models Random Forest* RMSE(tr)=0.27 R2(tr)=0.98 Bias(tr)=0.005 RMSE(oob)=0.68 R2(oob)=0.90 Bias(oob)=0.01 RMSE(te)=0.69 R2(te)=0.89 Bias(te)=-0.04 • * David Palmer, John Mitchell. Unilever Centre For Molecular Informatics, University of Cambridge

  9. Antonio Llinàs Martí Problems with the actual literature data bases i. Egregious errors in reporting data and references ii. Poor data quality and/or inadequate documentation procedures Pontolillo, J. and Eganhouse, P., U.S. Department of Interior. U. S. Geological Survey. Water-Resources Investigations Report 01-4201. Reston. Virginia. 2001

  10. Antonio Llinàs Martí Problems with the actual literature data bases i. Egregious 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.

  11. Antonio Llinàs Martí Problems with the actual literature data bases i. Egregious 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)

  12. Antonio Llinàs Martí Problems with the actual literature data bases i. Egregious 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)

  13. ia. Multi-level referencing Antonio Llinàs Martí Problems with the actual literature data bases i. Egregious 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

  14. Antonio Llinàs Martí Problems with the actual literature data bases i. Egregious errors in reporting data and references ib. Data errors Pontolillo, J. and Eganhouse, P., U.S. Department of Interior. U. S. Geological Survey. Water-Resources Investigations Report 01-4201. Reston. Virginia. 2001

  15. Antonio Llinàs Martí ii. Poor data quality and/or inadequate documentation procedures [1] Oliveri-Mandala, E. (1926), Gazzetta Chimica Italiana56, 896-901 [2] Ochsner, A. B., Belloto, R. J., and Sokoloski, T. D. (1985), Journal of Pharmaceutical Sciences74, 132-135

  16. Antonio Llinàs Martí Solubility: definition Huge range of definitions Saq Ksp S0* Kinetic Solubility Thermodynamic Solubility Equilibrium Solubility Apparent Solubility Ionic Solubility Solubility product Intrinsic Solubility Aqueous Solubility Standard Solubility ... Ko* S0 ST K0 Sw

  17. Strong Electrolyte Weak Non-electrolyte Antonio Llinàs Martí Solubility: definition Solute

  18. Antonio Llinàs Martí Solubility: 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)

  19. Step 1 Step 2 Step 3 Antonio Llinàs Martí Process of dissolution

  20. - In general as T Solubility • - In general as salinity Activity coef Solubility • - Common ion effect Solubility • - DOM Solubility • - fv Solubility exponentially Antonio Llinàs Martí Factors Influencing Solubility • Temperature • Salinity • pH • Dissolved • organic matter (DOM) • Co-solvents • Crystallinity • Polymorphism • - If the solute is subject to acid/base reactions then pH is vital in determining water solubility.

  21. Antonio Llinàs Martí Factors Influencing Solubility Crystallinity • Crystallinity decreases the apparent solubility

  22. Antonio Llinàs Martí Factors Influencing Solubility Polymorphism • Crystallising into different crystal forms will result in different melting points and solubilities

  23. ● With DMSO (normal method in industry) Kinetic Solubility ● Equilibria reached? ● Filtering Big errors ● Detection by UV-Vis Chromophores needed Antonio Llinàs Martí Solubility measurements Classical MethodShake Flask Method ● Many published variations of this method

  24. In Solution Powder Diclofenac An Example Antonio Llinàs Martí CheqSol is a new method developed by

  25. In Solution Powder Diclofenac Antonio Llinàs Martí 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 SUPERSATURATED NOT IN EQUILIBRIUM

  26. In Solution Powder Diclofenac Antonio Llinàs Martí 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 SUBSATURATED NOT IN EQUILIBRIUM

  27. Supersaturated Solution Subsaturated Solution In Solution Powder Diclofenac Antonio Llinàs Martí ●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 Si = 1.53 ± 0.15 mg/ml

  28. Diclofenac Characterisation In Solution Powder Antonio Llinàs Martí NO MATCH !!!!

  29. Diclofenac Characterisation In Solution Powder Antonio Llinàs Martí MATCH !!!!

  30. Diclofenac Characterisation In Solution Powder Antonio Llinàs Martí Diclofenac Acid C2/c polymorph * Polyhedron (1993), 12, 1361

  31. Diclofenac Characterisation Crystallisation EtOH, RT X-Ray Single Crystal X-Ray Powder In Solution Powder Crystal Sodium diclofenac pentahydrate P 2(1) Antonio Llinàs Martí ? * Thanks to John Davies for solving the X-ray structure of this crystal

  32. Diclofenac Characterisation In Solution Powder Crystal Antonio Llinàs Martí DSC- MP = 263.4 ˚C TGA- Pentahydrate DSC- MP = 267.4 ˚C TGA- Anhydrous DSC- MP = 180.5 ˚C TGA- Anhydrous

  33. In Solution Powder Crystal Diclofenac Solubility (25˚C, I= 0.15 M) Antonio Llinàs Martí Si = 1.49 ± 0.09 %mg/ml Si = 1.47 ± 0.12 %mg/ml Si = 1.53 ± 0.15 %mg/ml

  34. Diclofenac Complete In Solution Powder Crystal Antonio Llinàs Martí Powder XRD- ? Single Crystal XRD- EA- BAD MP (DSC)- 267.4 ˚C TGA- Sodium Salt Anhydrous Solubility – 1.528 ± 0.15%mg/ml Powder XRD-NEW Single Crystal XRD-SOLVED Sodium salt PentahydrateP2(1) EA- OK MP (DSC)-263.4 ˚C TGA- Sodium Salt Pentahydrate Solubility –1.472 ± 0.09 mg/ml Powder XRD-SIKLIH01 Single Crystal XRD-NO EA- OK MP (DSC)-180.5 ˚C TGA- Diclofenac Acid Anhydrous Solubility –1.488 ± 0.12 % mg/ml

  35. Conclusions Antonio Llinàs Martí • Predictive ADMET is in its infancy • Models are not improving • Actual databases are no good: bad quality data, no • diverse enough • Need of high quality data to build reliable databases • Need of standardization. Same conditions, same definition, characterisation, and statistical treatment • Solubility: Intrinsic, 25 ˚C, I = 0.15 M (KCl), purity of starting material >99.5 %, Solid characterisation.

  36. - Pfizer Dr. Hua Gao Antonio Llinàs Martí Acknowledgments - Sirius Analytical Instruments Ltd. Karl Box - Unilever Solubility Team Prof. Robert Glen (Director)Dr. Jonathan Goodman (Group Leader)Dr. John Mitchell (Group Leader)Dr. Antonio LlinàsDavid Palmer - University of Cambridge To ALL of YOU

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