Supramolecular heterosynthons and their role in cocrystal design

Transcription

1 Supramolecular heterosynthons and their role in cocrystal design March 24 th, 2009 ACS National Salt Lake City, Utah Miranda Cheney University of South Florida

2 What is a cocrystal? A stoichiometric multiple component crystal formed between two compounds that, when pure, are solid under ambient conditions: at least one component is molecular and forms a supramolecular synthon with remaining components Also termed molecular complex, molecular adduct, multiple component molecular crystal etc.

3 The first use of co-crystal? The formation and properties of free radicals in a co-crystal crystal complex between 1-1 methylthymine and 9-9 methyladenine have been studied K. Hoogsteen,, 1963 (Acta Crystallogr., 16,, 907) Co-crystal of 1-methylthymine 1 and 9-methyladenine 9 first made by Hoogsteen Schmidt, J.; Snipes, W. Int. J. Radiat.. Biol., 1967, 13,, Popularized by Margaret C. Etter J. Phys. Chem., 1991, 95,

4 Solution: slow evaporation reaction crystallization slurry supercritical fluids Grinding/Milling: solvent-free grinding solvent-drop grinding liquid-assisted grinding kneading Thermal: heating of solids melt crystallization Methodologies

5 Dry grinding Partial conversion to cocrystal after 1h Prepared using kugelchen (little ball) F. Wöhler hler in 1844 (Annalen( Annalen, 51,, 153) MeOH drop grinding Complete conversion to cocrystal within 20 minutes Quinone:Hydroquinone Sakurai T. Acta Crystallogr , B19, 320

6 Pharmaceutical cocrystals Stability (chemical and thermal) Bioavailability (solubility) Cocrystal Controlled Solid-State State Synthesis (C 3 S 3 ) Green chemistry Epitaxial growth Why make cocrystals? SciFinder Scholar, cocrystal, 3/ Non-linear optics Year

7 Pharmaceutical cocrystals A cocrystal in which a pharmaceutically acceptable cocrystal former forms a supramolecular synthon with an API A new form of an API exhibits different physical properties A new form of an API = new intellectual property Cocrystals can be designed A.G. von Heyden FR (1933)

8 70 Recent Case Studies (out of >90 APIs) Fluoxetine HCl (Prozac ) Caffeine:oxalic acid Fluoxetine HCl Concentration (mm) Fluoxetine HCl:Fumaric Acid Fluoxetine HCl:Succinic Acid Fluoxetine HCl Fluoxetine HCl:Benzoic Acid Time (min) Improved solubility S.L. Childs, et al. J. Am. Chem. Soc., 2004 Carbamazepine:saccharin Improved plasma concentration Crystal Growth & Design,, 2003 Eur.. J. Pharm. Biopharm Cocrystals humidity for weeks 8x [1] (M) Jones, W.; Motherwell,, S.D. Trask,, A.V. Cryst.. Growth Des., 5, , 1021, Time (min) Itraconazole Cocrystals as soluble as amorphous form J.F. Remenar,, at al. J. Am. Chem. Soc.,,

9 Fluoxetine HCl (Prozac ) ) dissolution profiles 70 Fluoxetine HCl Concentration (mm) Fluoxetine HCl:Fumaric Acid Fluoxetine HCl:Succinic Acid Fluoxetine HCl Fluoxetine HCl:Benzoic Acid spring-and-parachute-effect Time (min) S.L. Childs, et al. J. Am. Chem. Soc., 126, , 2004

10 Design of cocrystals: Crystal engineering The supramolecular heterosynthon strategy Carboxylic acids: 25% of APIs (only 10% overall); many are pharmaceutically approved for use Alcohols: 33% of APIs acceptor donor G.R. Desiraju Angew.. Chem., 1995, 34, 2311 Analysis of intermolecular contacts can be conducted using Cambridge Structural Database (CSD) lapolc2009

11 CSD Analysis: Alcohol total entries Aliphatic Alcohol-Alcohol Aromatic Alcohol-Alcohol Raw Data: 19092/26314 (73%) aliphatic alcohol 7185/26314 (27%) aromatic alcohol 5405/19092 (28%) aliphatic alcohol homosynthon 983/7185 (14%) aromatic alcohol homosynthon Refined Data: 955/1272 (75%) aliphatic alcohol homosynthon 173/333 (52%) aromatic alcohol homosynthon CSD Conquest 1.10 (August update) Search parameter: organics only, 3D coordinates determined, R 0.075, no ions

12 CSD Analysis: Carboxylic acid 5943 total entries Acid-Acid dimer Raw Data: 1880/5943 (32%) carboxylic acid dimer 156/5943 (3%) carboxylic acid catemer Refined Data: 448/487 (92%) acid dimer 42/487 (9%) acid catemer CSD Conquest 1.10 (August update) Search parameter: organics only, 3D coordinates determined, R 0.075, no ions

13 CSD Analysis: Carboxylic acid vs. Alcohol 1232 total entries Acid-Alcohol heterosynthon (OH...OH) Raw Data: 249/1232 (20%) carboxylic acid homosynthon 329/1232 (27%) alcohol homosynthon 521/1232 (42%) OH OH heterosynthon 552/1232 (45%) C=O OH heterosynthon Refined Data: 89/297 (30%) acid homosynthon 113/297 (38%) alcohol homosynthon 203/297 (68%) OH OH heterosynthon 204/69 (69%) C=O OH heterosynthon CSD Conquest 1.10 (August update) Search parameter: organics only, 3D coordinates determined, R 0.075, no ions

14 CSD Analysis: Alcohol vs. Aromatic Nitrogen 1583 total entries Alcohol-Narom heterosynthon Raw Data: 2304/1583 (19%) alcohol homosynthon 830/1583 (52%) OH N arom heterosynthon Refined Data: 63/247 (26%) alcohol homosynthon 192/247 (78%) OH N arom heterosynthon CSD Conquest 1.10 (August update) Search parameter: organics only, 3D coordinates determined, R 0.075, no ions

15 CSD Analysis: Alcohol vs. Cyano 752 total entries Alcohol-cyano heterosython Raw Data: 115/752 (15%) Alcohol homosynthon 254/752 (34%) OH N C heterosynthon Refined Data: 28/92 (30%) Alcohol homosynthon 68/92 (74%) OH N C heterosynthon CSD Conquest 1.10 (August update) Search parameter: organics only, 3D coordinates determined, R 0.075, no ions

16 CSD Analysis: Carboxylic acid vs. Aromatic Nitrogen 647 total entries Acid-Narom heterosynthon Raw Data: 48/647 (7%) carboxylic acid homosynthon 483/647 (75%) COOH N arom heterosynthon Refined Data: 11/136 (8%) carboxylic acid homosynthon 129/136 (95%) COOH N arom heterosynthon But many molecules contain several functional groups CSD Conquest 1.10 (August update) Search parameter: organics only, 3D coordinates determined, R 0.075, no ions

17 The CSD is more limited when it comes to stats on competition between multiple donors/acceptors e.g. Carboxylic acid, phenol, aromatic nitrogen Nine possible synthons, which ones will form? CSD contains only 12 structures with all 3 moieties only

18 A model for a study of the hierarchy of 3 functional groups Group 1 D2 + A1 D2 D = Donor A = Acceptor A1 A1 OR D2 Group 2 A1 + D2 A1 A1 D2 A1 OR Group 3 A1 D2 + A1 A1 D2 D2 A1 OR D2

19 Model compound study 1 Zaworotko et. al. Cryst. Growth Des. 8, 4533, Cocrystal Mixture Salt New Mixture 13 Cocrystals isolated 2 crystallizations formed salts 8 solvent-drop grinds formed new phases All attempts resulted in mixtures

20 Why was Group 1 so successful? With 2 donors on same molecule paired with molecule with a single acceptor, group 1 can form multiple supramolecular synthons Supramolecular Synthons OH phenol N arom COOH N arom Unfortunately This precludes any conclusions about synthon hierarchy unless cocrystal is 1:1

21 What can we learn about hierarchy from Group 2? Group 3? Group 2 generated many 2 component crystalline forms sustained by the carboxylate-n arom synthon Group 3 = no cocrystals only mixtures, (design of study = cocrystal and COOH-N arom not possible) Therefore: carboxylate-n arom synthon must be > alcohol-n arom synthon COO - HN HN arom

22 Model compound study 2 Phenol, aromatic nitrogen, cyano Three possible synthons CSD contains only 3 structures with all 3 moieties 3 0 0

23 Group 1 Target Molecules Group 2 A1 A2 A1 A2 OR A1 A2 OR Group 3 A2 A2 A1 A2 OR Zaworotko et. al. Mol Pharma. 4, A1 A1

24 Group 1+2 = Cocrystals, Group 3 = Mixtures 3- cyphe 4- cyphe Group 2 (N arom Phenpy Bipy arom,oh+c N) Bipyeta Bipyete = Cocrystal = Mixture Bphe Res Phlgl cynaph m-cyben p-cyben 3-cypy 4-cypy Group 1 (OH, N arom +C N) 3-hypy 4- hyquin Group 3 (C N, OH+N OH+N arom )

25 Why was group 1 and 2 successful? Group 1: Paired a molecule with 1 donor (OH) with a molecule with 2 acceptors (CN, N arom ) (Competition minimal) Group 2 (N arom ) paired molecule with donor + acceptor (6 cocrystals OH N arom ) Group 3 (CN)= cannot form cocrystal and OH N arom OH arom must be > OH N C N arom

26 Competitive studies can be useful in forming pharmaceutical cocrystals... (I) OH N arom Bicalutamide:Bipyethylene P-1 a = 8.274(3)Å b = (3) Å c = (7) Å α = (7)º β = (6) º γ = (7) º V = (9)Å 3 Bicaluatmide is a non-steroidal anti-androgen androgen used in the treatment of prostate cancer Zaworotko et. al. Mol Pharma. 4,

27 But what about stronger synthons? Nicotinic and isonicotinic acid should not be suitable for cocrystal formation since they are sustained by the COOH-N arom synthon Only two cocrystals in CSD (chain present) Can we break the COOH-N arom synthon?

28 Even stronger heterosynthons can be exploited: Head to tail chain motifs broken Vitamin C forms a dominant heterosynthon with carboxylates Lissette Marshall

29 Or cocrystals can be made without disrupting strong interactions Hesperitin : Nicotinic acid cocrystal Citric acid : Isonicotinic acid cocrystal Padmini Karuvu, Dalia Aborayes

30 Conclusions Synthon approach works well for cocrystal formers with 2 complementary functional groups CSD is a valuable tool but does not work so well when >= 3 functional groups present Model compound studies show: Carboxylic acid reliably forms supramolecular synthons with aromatic nitrogen even in presence of an alcohol Alcohol aromatic nitrogen synthon forms reliably in presence of cyano moiety Even strong synthons can be broken

31 Acknowledgements Dr. Michael Zaworotko USF Co-crystal team: Kapil Arora, Tien Ong,, Heather Clarke, Padmini Kuruvu, Dalia Aboryes, Lissette Marshall, David Weyna Metal-Organic team: John Perry IV, Jason Perman $$$ $$$ NSF, Transform Pharmaceuticals