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Cosmotherm – the Ideal Solvent Toolbox?

Cosmotherm – the Ideal Solvent Toolbox?. Is this our future?. Why is there a need for a “solvent toolbox”?. Reactions depend on solvents Drug substance production and properties are closely related to solvents - choosing solvents for crystallization

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Cosmotherm – the Ideal Solvent Toolbox?

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  1. Cosmotherm – the Ideal Solvent Toolbox?

  2. Is this our future? Presentation Name

  3. Why is there a need for a “solvent toolbox”? • Reactions depend on solvents • Drug substance production and properties are closely related to solvents - choosing solvents for crystallization - determining relative stability in different environments (pseudo polymorphs, co-crystals) • Drug product production and properties can be closely related to compatibility with other excipients • (Polymeric) Dosage forms • Stabilizing amorphous material Presentation Name

  4. Solvents & Reactions • In general all reactants need to be dissolved • Reaction mechanism, rate and byproduct formation may be solvent dependent Presentation Name

  5. Solvent 1 Activation Barrier = kinetics Solvent 2 TS Distribution Coefficient = thermodynamics products reactants Presentation Name

  6. Example: “Simple” SN2 reaction Presentation Name

  7. What happens on a molecular level? Presentation Name

  8. What happens in the COSMO universe? Presentation Name

  9. In charge density profiles Presentation Name

  10. What is the influence of the solvent? Presentation Name

  11. Solvents & Drug Substance • Stability data needed when comparing different compositions (pseudopolymorph or co-crystal) • Solubility data needed for process selection Presentation Name

  12. Polymorphism in COSMO Solvent 1 Polymorph 1 melt Solvent 2 Polymorph 2 Solvent 3 DSC data or solubility fitting COSMO Presentation Name

  13. Pseudo Polymorphism in COSMO Polymorph 1 Solvent 1 melt Solvent 2 mmeelltt melt Solvent 3 Pseudo Polymorph 2 DSC data or solubility fitting COSMO Presentation Name

  14. Presentation Name

  15. Example • Hydrate vs true polymorph • Water as solvent decreases solubility solvate vs true polymorph • Methanol as solvent increases solubility solvate vs true polymorph • Heptane as solvent decreases solubility solvate vs true polymorph The COSMO approach makes its possible to relate stability and solvent composition Presentation Name

  16. Process selection – selecting a solvent • Cooling crystallization – select a high temperature dependence • Antisolvent crystallization – select miscible good solvent / poor solvent pair • Be aware of other restraints – chemical stability, (pseudo)polymorphism Presentation Name

  17. Cooling crystallization – calculate relative solubility at two temperatures Presentation Name

  18. Anti solvent selection – calculate the solubility in a solvent/anti solvent system Example: paracetamol in acetone/heptane Presentation Name

  19. Drug product • Compatibility with polymers (polymer based dosage forms) • Water/oil distribution (important for emulsions and intestinal uptake) Presentation Name

  20. Conclusions Drug Product Phys Chem Prop Process Development Synthesis solubility & stability reactions solvent & method selection solubility & stability Presentation Name

  21. Conclusions • The COSMO approach is a good qualitative toolbox • Calculations are fairly straightforward • A lot of options can be considered • The COSMO approach needs to be improved for use as a quantitative toolbox Presentation Name

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