Chiral resolutionand deracemizationthrough co …...3 Personal Expertise! 2.5y, Automation Team Leader UCB Pharma (2007-2009) Process optimization (Crystallization process) Polymorphism

Chiral resolution and deracemization through

co-crystallization

Crystallization workshop

Barcelona, 11th March 2019

Tom Leyssens

2

3

Personal Expertise!

�2.5y, Automation Team Leader UCB Pharma (2007-2009)

�Process optimization (Crystallization process)

�Polymorphism issues, optimization, purity, crystal

form, PSD, …

4

…

??Citric acid

Mandelic acid

Caffeine

Isonicotinamide

??

�UCL Professor in Physical chemistry (2009-…)

Personal Expertise!

60% of all drug compounds contain

at least one chiral center

Enantiomers � ≠ biological

properties

5/1

1

� Regulatory instances push

towards the development of

enantiopure drugs

Chirality and drug compounds

6

Diastereomeric salt formationLess costly process

But only for compounds that can form salts

Chiral chromatography

Used for many compounds

Expensive technique

Resolution by entrainment


Less costly process

Only for conglomerates

7


Entrainment

Enantiospecific

Deracemizat.

Resolution by entrainment/

preferential crystallization

8

9

1. Resolution by entrainment

CaCl2, MgCl2, ZnCl2

� Selectracetam, Brivaracetam, Piracetam, …. CrystEngComm 2014, 5887.

*O. Shemshuk, L. Song, Chem. Comm., 2018.

� Entrainment

Enantiospecific

Deracemizat.

10

� ETI and LEV co-crystals have different stoichiometry!!

� No other forms identified


� Entrainment

Enantiospecific

Deracemizat.

11

� Simulated and experimental XRPD match

Lev.ZnCl2 Eti2.ZnCl2

5 10 15 20 25 30 35 40 45 50

Lev·ZnCl2 calc.

Lev·ZnCl2 exp.

2θ / deg


� Entrainment

Enantiospecific

Deracemizat.

12

LEV + ZnCl2

1:1

2LEV.ZnCl2

2LEV.ZnCl2

+ ZnCl2

ZnCl2ZnCl2


� Entrainment

Enantiospecific

Deracemizat.

13

ETI + ZnCl2

2:1

2 2ETI2.ZnCl2

2LEV(S).ZnCl2

+ 1 eq. ZnCl2

2DEV(S).ZnCl2

+ 1 eq. ETI

Thermodynamically stable

racemic compound

Thermodynamically stable

conglomerate

!!Reversible stoichiometric switch!!


� Entrainment

Enantiospecific

Deracemizat.

14

Understand the solid state thermodynamics (Phase Diagram)

Single Phases

ZnCl2

S-ETIR-ETI

(1:1)-S(1:1)-R

(2:1)

RS-ETI+ S-ETIRS-ETI+ R-ETI RS-ETI

RS

-ET

I + 2:1

1:1 (R) + 1:1 (S)

Mixture of 2 phases

2:1+ RS-ETI

+S-ETI

2:1+ RS-ETI

+R-ETI

2:1+ 1:1 (S) +

S-ETI

2:1+ 1:1 (R) +

R-ETI

2:1+ 1:1 (S) +

1:1 (R)

1:1 (S) + 1:1 (R)

+ ZnCl2

Mixture of 3 phases


� Entrainment

Enantiospecific

Deracemizat.

15

Solvent included

� Importance of this PD: when adding solvent, one can only get one of the

combinations shown above in suspension eg.

� 2:1 + 1:1 (R) + 1:1 (S)

� 2:1 + ZnCl2


� Entrainment

Enantiospecific

Deracemizat.

16

Solvent included

� Importance of this PD: when adding solvent, one can only get one of the

combinations shown above in suspension eg.

� 1:1 (R) + 1:1 (S)


� Entrainment

Enantiospecific

Deracemizat.

� Stoichiometric switch also holds in suspension

17

� Based on reasoning only

Solvent

ETI ZnCl2

ETI +2:1

ETI

2:1

2:1

ZnCl2

1:1 (S)

+2:1

+ 1:1 (R)

1:1 (S)

+ 1:1 (R)

1:1 (S)

+ 1:1 (R)

+ ZnCl2

Stable racemic compound

Stable conglomerate


� Entrainment

Enantiospecific

Deracemizat.

18

� Theory and experiment allign !!!

� In zone V, resolution by entrainment becomes possible!!

Solvent

ETI ZnCl2

ETI +2:1

ETI

2:1

2:1

ZnCl2

1:1 (S)

+2:1

+ 1:1 (R)

1:1 (S)

+ 1:1 (R)

1:1 (S)

+ 1:1 (R)

+ ZnCl2

Stable racemic compound

Stable conglomerate


� Entrainment

Enantiospecific

Deracemizat.

19

Make ternary phase diagrams.

X X X X X X X X X


� Entrainment

Enantiospecific

Deracemizat.

Resolution by

Diasteriomeric/enantiospecific

co-crystal formation

20

21

Diastereomeric salt formationLess costly process

But only for compounds that can form salts

Chiral chromatography

Used for many compounds

Expensive technique

Resolution by entrainment


Less costly process

Only for conglomerates

Entrainment

� Enantiospec.

Deracemizat.

22

Just make some co-crystals, get some structures

and this will get us a publication ….

…

??Citric acid

Mandelic acid

Caffeine

Isonicotinamide

Levetiracetam

2. Enantiospecific/diasteriomeric resolution

Entrainment

� Enantiospec.

Deracemizat.

23

….

TRIAL AND ERROR APPROACH!!!

∆G of a few kcal.mol-1 , while for salts this goes up to 50 kcal.mol-1.

� Only 10% succesrate for cocrystals

� Difficult to become predictive


Entrainment

� Enantiospec.

Deracemizat.

*G. Springuel, T. Leyssens, CrystGrowth Des. 2012-2015.

24

4 co-crystals

40% Succesrate

D-tartaric acid 1:1

citric acid 1:1

citric acid 3:2

Mandelic acid (racemic) 2:1

R-mandelic acid 2:1

p-hydroxy-benzoic acid 1:1

2,3-dihydroxy-benzoic acid 1:1





D-tartaric acid 1:1


S-mandelic acid 1:1


11 co-crystals with 10

different acids

Piracetam

Co-crystals

Levetiracetam

Co-crystals


Entrainment

� Enantiospec.

Deracemizat.

NO

NH2

O

25

D-tartaric acid 1:1

citric acid 1:1

citric acid 3:2


R-mandelic acid 2:1

p-hydroxy-benzoic acid 1:1






D-tartaric acid 1:1


S-mandelic acid 1:1


Piracetam

Co-crystals

Levetiracetam

Co-crystals

NO

NH2

O

(S,S)

(S,R)


Entrainment

� Enantiospec.

Deracemizat.

26 26

Piracetam Co-crystals:

S-tartaric acid R-tartaric acid

S-Mandelic acid R-Mandelic acid


Entrainment

� Enantiospec.

Deracemizat.

27 27

Levetiracetam Co-crystals:

S-tartaric acid R-tartaric acid

S-mandelic R-mandelic

NO

NH2

O


Entrainment

� Enantiospec.

Deracemizat.

28

AND NOW WHAT???


Entrainment

� Enantiospec.

Deracemizat.

29 29

Separate two enantiomers in solution:

� No diastereomeric salts formation

� No column chromatography


Entrainment

� Enantiospec.

Deracemizat.

30 30

Variables:� S enantiomer of API

� R enantiomer of API

� Enantiopure chiral acid (coformer)

� Solvent

� Temperature

5 variables !!!


Entrainment

� Enantiospec.

Deracemizat.

31 31

4 variables !

For a fixed temperature

RS-API

Cocrystal



� Chiral acid (coformer)

� Solvent

� Temperature


Entrainment

� Enantiospec.

Deracemizat.

32 32

RS-API

Cocrystal

Solvent

R-API S-APIRS-API

RS-API

+ liq.

R-API

+ liq.

S-API

+ liq.

R-API +

RS-API +

liq.

S-API +

RS-API +

liq.

At racemic composition

both enantiomers of API

crystallize in the same

crystal lattice

For a fixed temperature


Entrainment

� Enantiospec.

Deracemizat.

RS-API

Cocrystal

33 33

Solvent

S-API S-coformerCocrystal

S-API

+ liq.

S-API

+ CC

+ liq.

CC +

liq.

CC +

S-cof.

+ liq.

S-cof.

+ liq.

Cocrystal formation of S-API

and S-coformer


Entrainment

� Enantiospec.

Deracemizat.

34 34

4 variables !

RS-API

Cocrystal




� Solvent

� Temperature


Entrainment

� Enantiospec.

Deracemizat.

35 35

3 variables

Solvent

S-coformer

S-API

R-

API

S-coformer

S-API

R-

API

Solvent

S-API

R-

API

For a fixed temperature and

a fixed molar% of solvent

S-coformerVariables:� S enantiomer of API



� Solvent

� Temperature


Entrainment

� Enantiospec.

Deracemizat.

36 36

Conditions for an effective chiral resolution:

S-coformer

S-APIR-API

S-coformer

S-coformer +

cocrystal

RS-API

cocrystal

+ RS-API

Liq.

RS-API

Cocrystal

1. Enantiospecific cocrystallization between one enantiomer

of an API and a chiral coformer in solution.


Entrainment

� Enantiospec.

Deracemizat.

37 37

Conditions for an effective chiral resolution:

S-coformer

S-APIR-API

S-coformer

S-coformer +

cocrystal

RS-API

cocrystal

+ RS-API

Liq.

RS-API

Cocrystal

1. Enantiospecific cocrystallization between one enantiomer of an API and a

chiral coformer in solution.

2. Area in which cocrystal solid phase is stable in suspension

need to cross the racemic composition line.


Entrainment

� Enantiospec.

Deracemizat.

38 38

Phase diagram of Etiracetam –

S-mandelic acid in 89%mol of

acetonitril at 9°C

S-2

S-1R-2

I. S-2

II. LSMA co-crystal

II+IV. RS-1 + LSMA

I+II. S-2 + LSMA

Liquid

IV. RS-1

IV+V. RS-1 + R-1

Phase diagram of Etiracetam –

S-mandelic acid in 89%mol of

acetonitril at -10°C

At 9°C At -10°C

Etiracetam – S-mandelic acid in acetonitrile


Entrainment

� Enantiospec.

Deracemizat.

39 39

Seeding

Chiral resolution through enantiospecific co-crystallization in solution

Works on compounds which do not or not easily form salts !!!

High yield (83%) in a single resolution step with 100% of ee

Solvent

Racemic compound

Chiral coformer

Diagram at crystallization

temperature

T� until complete

dissolutionT� to cyst. Temp.

Filtration

and

washing

Mother liquor enriched

in one enantiomer

Cocrystal of one enantiomer

and coformer

100% ee


Entrainment

� Enantiospec.

Deracemizat.

DE-racemization

40

41

AND BEYOND????

MeOH, MeONa

3. Deracemization

Entrainment

Enantiospec.

� Deracemizat.

42

3. Deracemization

Entrainment

Enantiospec.

� Deracemizat.

43

Chirality

Resolution

� Deracem.

3. Deracemization

96% ee, 34% yield

*B. Harmsen, Cryst. Growth Des., 2018, 18, 441-448.

44

Diasteriomeric dynamic deracemizationDuloxetine

FOR SALTS ONLY????

3. Deracemization

Entrainment

Enantiospec.

� Deracemizat.

�Development of a co-crystallization based

one pot deracemization

Addition of racemizing agent

R

R

R

S

S

S

RR

R

SS

SR S

RRSS

SS SS

R S

S RSS

SS SS SS SS SS

R

S

SS SS SS SS

SS SS

R

SS

Addition of

racemic mixture

Addition of

chiral co-former

3. Deracemization

Thank you for your attention!

Documents

Chiral resolutionand deracemizationthrough co …...3 Personal Expertise! 2.5y, Automation Team Leader UCB Pharma (2007-2009) Process optimization (Crystallization process) Polymorphism