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 + + 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 T 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.