Title: Cosmotherm
1Cosmotherm the Ideal Solvent Toolbox?
2Is this our future?
3Why 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
4Solvents Reactions
- In general all reactants need to be dissolved
- Reaction mechanism, rate and byproduct formation
may be solvent dependent
5Solvent 1
Activation Barrier kinetics
Solvent 2
TS
Distribution Coefficient thermodynamics
products
reactants
6Example Simple SN2 reaction
7What happens on a molecular level?
8What happens in the COSMO universe?
9In charge density profiles
10What 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
11Solvents Drug Substance
- Stability data needed when comparing different
compositions - (pseudopolymorph or co-crystal)
- Solubility data needed for process selection
12Polymorphism in COSMO
Solvent 1
Polymorph 1
melt
Solvent 2
Polymorph 2
Solvent 3
DSC data or solubility fitting
COSMO
13Pseudo Polymorphism in COSMO
Polymorph 1
Solvent 1
melt
Solvent 2
mmeelltt
melt
Solvent 3
Pseudo Polymorph 2
DSC data or solubility fitting
COSMO
14(No Transcript)
15Example
- 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
16Process 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
17Cooling 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
18Anti solvent selection calculate the solubility
in a solvent/anti solvent system
Example paracetamol in acetone/heptane
19Drug product
- Compatibility with polymers (polymer based dosage
forms) - Water/oil distribution (important for emulsions
and intestinal uptake)
20Conclusions
Drug Product
Phys Chem Prop
Process Development
Synthesis
solubility stability
reactions
solvent method selection
solubility stability
21Conclusions
- 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