Chiral resolution and deracemization through co-crystallization
Crystallization workshop Barcelona, 11 th March 2019
Tom Leyssens 2 Personal Expertise!
‹ 2.5y, Automation Team Leader UCB Pharma (2007-2009)
‹ Process optimization (Crystallization process)
‹ Polymorphism issues, optimization, purity, crystal form, PSD, …
3 Personal Expertise!
‹ UCL Professor in Physical chemistry (2009-…)
?? Citric acid
Mandelic acid
Caffeine … Isonicotinamide
??
4 Chirality and drug compounds
60% of all drug compounds contain at least one chiral center Enantiomers ‰ ≠ biological properties
V Regulatory instances push towards the development of enantiopure drugs
5/1 1 Chirality and drug compounds
Less costly process Resolution by entrainment Only for conglomerates
Less costly process Diastereomeric salt formation But only for compounds that can form salts
Chiral chromatography Used for many compounds Expensive technique
6 Chirality and drug compounds
Entrainment Enantiospecific Deracemizat.
7 Resolution by entrainment/ preferential crystallization
8 1. Resolution by entrainment
V Entrainment Enantiospecific Deracemizat.
CaCl 2, MgCl 2, ZnCl 2
‰ Selectracetam, Brivaracetam, Piracetam, …. CrystEngComm 2014 , 5887 .
9 *O. Shemshuk, L. Song, Chem. Comm., 2018 . 1. Resolution by entrainment
V Entrainment Enantiospecific Deracemizat.
‰ ETI and LEV co-crystals have different stoichiometry!! ‰ No other forms identified 10 1. Resolution by entrainment
Lev.ZnCl 2 Eti 2.ZnCl 2
V Entrainment Enantiospecific Deracemizat.
Lev·ZnCl calc. 2 Lev·ZnCl exp. 2
5 10 15 20 25 30 35 40 45 50
2θ / deg
‰ Simulated and experimental XRPD match
11 1. Resolution by entrainment
LEV + ZnCl 2 1:1 V Entrainment Enantiospecific Deracemizat.
LEV.ZnCl 2
+ ZnCl 2
LEV.ZnCl 2
ZnCl 2
12 1. Resolution by entrainment
ETI + ZnCl 2 2:1
V Entrainment Enantiospecific Deracemizat. Thermodynamically stable ETI 2.ZnCl 2 racemic compound
+ 1 eq. ETI + 1 eq. ZnCl 2
LEV(S).ZnCl 2 Thermodynamically stable conglomerate DEV(S).ZnCl 2
!!Reversible stoichiometric switch!! 13 1. Resolution by entrainment
Understand the solid state thermodynamics (Phase Diagram)
ZnCl 2
Single Phases
V Entrainment 1:1 (S) + 1:1 (R) Mixture of 2 phases + ZnCl Enantiospecific 2 Mixture of 3 phases Deracemizat.
(1:1)-R 1:1 (R) + 1:1 (S) (1:1)-S 2:1+ 1:1 (S) + 1:1 (R)
2:1+ 1:1 (R) + (2:1) 2:1+ 1:1 (S) + R-ETI S-ETI RS-ETI +
2:1+ RS-ETI 2:1+ RS-ETI 2:1 +R-ETI +S-ETI R-ETI RS-ETI+ R-ETI RS -ETI RS-ETI+ S-ETI S-ETI
14 1. Resolution by entrainment Solvent included
V Entrainment Enantiospecific Deracemizat.
‰ 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
15 1. Resolution by entrainment Solvent included
V Entrainment Enantiospecific Deracemizat.
‰ 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)
16 1. Resolution by entrainment
Solvent Stable racemic compound Stable conglomerate V Entrainment
Enantiospecific ETI 2:1 Deracemizat.
1:1 (S) 1:1 (S) + 1:1 (R) +2:1 ZnCl2 ETI +2:1 + 1:1 (R) 1:1 (S) + 1:1 (R) + ZnCl2 ETI 2:1 ZnCl2
‰ Based on reasoning only ‰ Stoichiometric switch also holds in suspension
17 1. Resolution by entrainment
Solvent Stable racemic compound Stable conglomerate V Entrainment
Enantiospecific ETI 2:1 Deracemizat.
1:1 (S) 1:1 (S) + 1:1 (R) +2:1 ZnCl2 ETI +2:1 + 1:1 (R) 1:1 (S) + 1:1 (R) + ZnCl2 ETI 2:1 ZnCl2 ‰ Theory and experiment allign !!! ‰ In zone V, resolution by entrainment becomes possible!!
18 1. Resolution by entrainment
Make ternary phase diagrams.
V Entrainment Enantiospecific Deracemizat.
XXXXXXXXX
19 Resolution by Diasteriomeric/enantiospecific co-crystal formation
20 Chirality and drug compounds
Less costly process Resolution by entrainment Only for conglomerates
Less costly process Entrainment Diastereomeric salt formation But only for compounds that can form salts V Enantiospec. Deracemizat.
Chiral chromatography Used for many compounds Expensive technique
21 2. Enantiospecific/diasteriomeric resolution
Levetiracetam Just make some co-crystals, get some structures and this will get us a publication ….
Entrainment ?? V Enantiospec. Citric acid Deracemizat. Mandelic acid Caffeine … Isonicotinamide
22 2. Enantiospecific/diasteriomeric resolution
Entrainment V Enantiospec. Deracemizat.
…. ∆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 TRIAL AND ERROR APPROACH!!!
23 *G. Springuel, T. Leyssens, CrystGrowth Des. 2012-2015 . 2. Enantiospecific/diasteriomeric resolution
O
NH2
Piracetam N Levetiracetam O Co-crystals Co-crystals
D-tartaric acid 1:1 D-tartaric acid 1:1 citric acid 1:1 Entrainment V Enantiospec. citric acid 3:2 Deracemizat. Mandelic acid (racemic) 2:1 Mandelic acid (racemic) 1:1 R-mandelic acid 2:1 S-mandelic acid 1:1 p-hydroxy-benzoic acid 1:1 2,3-dihydroxy-benzoic acid 1:1 2,4-dihydroxy-benzoic acid 1:1 2,4-dihydroxy-benzoic acid 1:1 2,5-dihydroxy-benzoic acid 1:1 4 co-crystals 3,4-dihydroxy-benzoic acid 1:1 3,5-dihydroxy-benzoic acid 1:1 40% Succesrate 11 co-crystals with 10 24 different acids 2. Enantiospecific/diasteriomeric resolution
Piracetam Levetiracetam Co-crystals Co-crystals
D-tartaric acid 1:1 D-tartaric acid 1:1 citric acid 1:1 Entrainment V Enantiospec. citric acid 3:2 Deracemizat. Mandelic acid (racemic) 2:1 Mandelic acid (racemic) 1:1 R-mandelic acid 2:1 S-mandelic acid 1:1 p-hydroxy-benzoic acid 1:1 2,3-dihydroxy-benzoic acid 1:1 2,4-dihydroxy-benzoic acid 1:1 2,4-dihydroxy-benzoic acid 1:1 2,5-dihydroxy-benzoic acid 1:1 O 3,4-dihydroxy-benzoic acid 1:1 (S,S) NH 3,5-dihydroxy-benzoic acid 1:1 2
N O (S,R) 25 2. Enantiospecific/diasteriomeric resolution
Piracetam Co-crystals: Entrainment V Enantiospec. S-tartaric acid R-tartaric acid Deracemizat.
S-Mandelic acid R-Mandelic acid
26 26 2. Enantiospecific/diasteriomeric resolution O
NH2
N O Levetiracetam Co-crystals: Entrainment V Enantiospec. S-tartaric acid R-tartaric acid Deracemizat.
S-mandelic R-mandelic
27 27 2. Enantiospecific/diasteriomeric resolution
Entrainment V Enantiospec. Deracemizat. AND NOW WHAT???
28 2. Enantiospecific/diasteriomeric resolution
Entrainment V Enantiospec. Deracemizat.
Separate two enantiomers in solution: ° No diastereomeric salts formation ° No column chromatography
29 29 2. Enantiospecific/diasteriomeric resolution
Variables: ‹ S enantiomer of API Entrainment ‹ R enantiomer of API V Enantiospec. ‹ Enantiopure chiral acid (coformer) Deracemizat. ‹ Solvent ‹ Temperature
5 variables !!!
30 30 2. Enantiospecific/diasteriomeric resolution
For a fixed temperature Variables: ‹ S enantiomer of API ‹ R enantiomer of API Entrainment ‹ Chiral acid (coformer) V Enantiospec. ‹ Solvent Deracemizat. ‹ Temperature
4 variables !
Cocrystal
RS-API
31 31 2. Enantiospecific/diasteriomeric resolution
For a fixed temperature
Solvent
Entrainment R-API S-API + liq. + liq. V Enantiospec. RS-API Deracemizat. + liq.
R-API + S-API + RS-API + RS-API + liq. liq.
R-API RS-API S-API
At racemic composition Cocrystal both enantiomers of API crystallize in the same crystal lattice RS-API
32 32 2. Enantiospecific/diasteriomeric resolution
Solvent
Entrainment
S-cof. Enantiospec. S-API V + liq. + liq. CC + Deracemizat. liq.
CC + S-API S-cof. + CC + liq. + liq.
S-API Cocrystal S-coformer
Cocrystal Cocrystal formation of S-API and S-coformer RS-API
33 33 2. Enantiospecific/diasteriomeric resolution
Variables: ‹ S enantiomer of API ‹ R enantiomer of API ‹ Chiral acid (coformer) Entrainment ‹ Solvent V Enantiospec. ‹ Temperature Deracemizat.
4 variables !
Cocrystal
RS-API
34 34 2. Enantiospecific/diasteriomeric resolution
For a fixed temperature and Solvent a fixed molar% of solvent
Variables: Entrainment ‹ S enantiomer of API S-coformer V Enantiospec. ‹ R enantiomer of API Deracemizat. ‹ Chiral acid (coformer) ‹ Solvent ‹ Temperature R- S-coformer API S-API 3 variables
R- API
35 35S-API 2. Enantiospecific/diasteriomeric resolution
Conditions for an effective chiral resolution:
1. Enantiospecific cocrystallization between one enantiomer Entrainment of an API and a chiral coformer in solution. V Enantiospec. Deracemizat. S-coformer
S-coformer
S-coformer + cocrystal
Liq. Cocrystal
RS-API
cocrystal + RS-API
R-API RS-API S-API 36 36 2. Enantiospecific/diasteriomeric resolution
Conditions for an effective chiral resolution:
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 Entrainment need to cross the racemic composition line. V Enantiospec. Deracemizat. S-coformer
S-coformer
S-coformer + cocrystal
Liq. Cocrystal
RS-API cocrystal + RS-API
37 R-API RS-API S-API 37 2. Enantiospecific/diasteriomeric resolution
I. S-2
II. LSMA co-crystal
RS-1 S-2 At 9°C II+IV. + LSMA At -10°C Entrainment I+II. S-2 + LSMA V Enantiospec. Deracemizat. Liquid IV. RS-1
IV+V. RS-1 + R-1
R-2 S-1 Phase diagram of Etiracetam – Phase diagram of Etiracetam – S-mandelic acid in 89%mol of S-mandelic acid in 89%mol of acetonitril at 9°C acetonitril at -10°C
Etiracetam – S-mandelic acid in acetonitrile 38 38 2. Enantiospecific/diasteriomeric resolution
Diagram at crystallization temperature
Seeding
T until complete Solvent dissolution TÚ to cyst. Temp. Entrainment Racemic compound V Enantiospec. Deracemizat.
Chiral coformer Filtration and Cocrystal of onewashing enantiomer Mother liquor enriched and coformer in one enantiomer 100% ee
Chiral resolution through enantiospecific co-crystallization in solution
High yield (83% ) in a single resolution step with 100% of ee
Works on compounds which do not or not easily form salts !!! 39 39 DE-racemization
40 3. Deracemization
AND BEYOND????
Entrainment Enantiospec. V Deracemizat.
MeOH, MeONa
41 3. Deracemization
Entrainment Enantiospec. V Deracemizat.
42 3. Deracemization
Chirality Resolution V Deracem.
96% ee, 34% yield
43 *B. Harmsen, Cryst. Growth Des., 2018 , 18, 441-448. 3. Deracemization
Diasteriomeric dynamic deracemization Duloxetine
Entrainment Enantiospec. V Deracemizat.
44 FOR SALTS ONLY???? 3. Deracemization
‰Development of a co-crystallization based one pot deracemization
R S S S S S R S
R S R R S R S S R S S R S R S S R S R S R R S S SS SS SS SS SS SS SS
Addition of Addition of Addition of racemizing agent racemic mixture chiral co-former Thank you for your attention!