Rob Geertman

04/11/23

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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reactants

TS

products

Activation Barrier = kinetics

Distribution Coefficient =thermodynamics

Solvent 1

Solvent 2

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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

0

5

10

15

20

25

30

35

40

-0.03 -0.02 -0.01 0 0.01 0.02 0.03

start mat

TS(R)

TS(S)

prod (R)

prod (S)

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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

Polymorph 1

Polymorph 2

Solvent 1

Solvent 2

Solvent 3

melt

DSC data or solubility fitting COSMO

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Pseudo Polymorphism in COSMO

Polymorph 1

Pseudo Polymorph 2

Solvent 1

Solvent 2

Solvent 3

melt

DSC data or solubility fitting COSMO

mmeelltt

melt

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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

T=0 T=50

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

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

00.10.20.30.40.50.60.70.80.91

mole fraction acetone

rela

tive

so

lub

ilit

y

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)

Experimental distribution coefficient vs predicted distribution coefficient (pKa from Cosmotherm)

y = 1.0054x + 0.1672

R2 = 0.8229

-4

-3

-2

-1

0

1

2

3

4

-3.0 -2.0 -1.0 0.0 1.0 2.0 3.0 4.0

Log D (experiment)

Lo

g D

(ca

lcu

late

d)

Raniditin

Org4000

Org2324

Org36410

Org2723

Org2322

Org893

Org3340

Org224

Org30268

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Conclusions

Synthesis Phys ChemProp

ProcessDevelopment

DrugProduct

reactions solubility & stability

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