Presentation on theme: "Rob Geertman 8/23/2014 Cosmotherm – the Ideal Solvent Toolbox?"— Presentation transcript:
Rob Geertman 8/23/2014 Cosmotherm – the Ideal Solvent Toolbox?
28/23/2014Presentation Name Is this our future?
38/23/2014Presentation Name 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
48/23/2014Presentation Name Solvents & Reactions In general all reactants need to be dissolved Reaction mechanism, rate and byproduct formation may be solvent dependent
58/23/2014Presentation Name reactants TS products Activation Barrier = kinetics Distribution Coefficient = thermodynamics Solvent 1 Solvent 2
68/23/2014Presentation Name Example: “Simple” S N 2 reaction
78/23/2014Presentation Name What happens on a molecular level?
88/23/2014Presentation Name What happens in the COSMO universe?
98/23/2014Presentation Name In charge density profiles
108/23/2014Presentation Name What is the influence of the solvent? SolventTemperature (K)Relative rate Pentane3124E-15 Cyclopentane3272E-13 H2OH2O3734E-6 Acetone3675E-4 NMP3756E-3 DMF3869E-3
118/23/2014Presentation Name Solvents & Drug Substance Stability data needed when comparing different compositions (pseudopolymorph or co-crystal) Solubility data needed for process selection
128/23/2014Presentation Name Polymorphism in COSMO Polymorph 1 Polymorph 2 Solvent 1 Solvent 2 Solvent 3 melt DSC data or solubility fittingCOSMO
138/23/2014Presentation Name Pseudo Polymorphism in COSMO Polymorph 1 Pseudo Polymorph 2 Solvent 1 Solvent 2 Solvent 3 melt DSC data or solubility fittingCOSMO mmeelltt melt
158/23/2014Presentation Name 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
168/23/2014Presentation Name 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
178/23/2014Presentation Name Cooling crystallization – calculate relative solubility at two temperatures T=0T=50 compoundlog(x) Delta log(x) pentane propanone methanol propanol ethylacetate furane furfural thf dimethylformamide acetonitrile h2o NMP
188/23/2014Presentation Name Anti solvent selection – calculate the solubility in a solvent/anti solvent system Example: paracetamol in acetone/heptane
198/23/2014Presentation Name Drug product Compatibility with polymers (polymer based dosage forms) Water/oil distribution (important for emulsions and intestinal uptake)
208/23/2014Presentation Name Conclusions Synthesis Phys Chem Prop Process Development Drug Product reactions solubility & stability solvent & method selection solubility & stability
218/23/2014Presentation Name 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