Cosmotherm

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Cosmotherm the Ideal Solvent Toolbox?
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Is this our future?
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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

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Solvents Reactions

• In general all reactants need to be dissolved
• Reaction mechanism, rate and byproduct formation
  may be solvent dependent

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Solvent 1
Activation Barrier kinetics
Solvent 2
TS
Distribution Coefficient thermodynamics
products
reactants
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Example Simple SN2 reaction
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What happens on a molecular level?
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What happens in the COSMO universe?
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In charge density profiles
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What is the influence of the solvent?
Solvent Temperature (K) Relative rate
Pentane 312 4E-15
Cyclopentane 327 2E-13
H2O 373 4E-6
Acetone 367 5E-4
NMP 375 6E-3
DMF 386 9E-3
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Solvents Drug Substance

• Stability data needed when comparing different
  compositions
• (pseudopolymorph or co-crystal)
• Solubility data needed for process selection

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

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Cooling crystallization calculate relative
solubility at two temperatures
T0 T50
compound log(x) log(x) Delta log(x)
pentane -8.73601 -5.81084 -2.92517
propanone -2.12203 -1.39085 -0.73119
methanol -2.01551 -1.23944 -0.77607
2-propanol -2.30919 -1.5227 -0.78649
ethylacetate -3.05291 -2.03874 -1.01417
furane -5.61278 -3.55548 -2.0573
furfural -2.88586 -1.88005 -1.00581
thf -1.10725 -0.90952 -0.19773
dimethylformamide -0.65238 -0.37424 -0.27815
acetonitrile -3.03592 -1.89279 -1.14313
h2o -3.57792 -2.93977 -0.63815
NMP -0.2177 -0.1506 -0.0671
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Anti solvent selection calculate the solubility
in a solvent/anti solvent system
Example paracetamol in acetone/heptane
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Drug product

• Compatibility with polymers (polymer based dosage
  forms)
• Water/oil distribution (important for emulsions
  and intestinal uptake)

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Conclusions
Drug Product
Phys Chem Prop
Process Development
Synthesis
solubility stability
reactions
solvent method selection
solubility stability
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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