Supramolecular Supramolecular heterosynthonsheterosynthonsand their role in cocrystal designand their role in cocrystal design

Miranda CheneyMiranda CheneyUniversity of South FloridaUniversity of South Florida

March 24March 24thth, 2009, 2009ACS NationalACS National

Salt Lake City, UtahSalt Lake City, Utah

What is a cocrystal?•• A A stoichiometricstoichiometric multiple multiple

component crystal formed component crystal formed between two compounds that, between two compounds that, when pure, are solid under when pure, are solid under ambient conditions: at least one ambient conditions: at least one component is molecular and component is molecular and forms a supramolecular forms a supramolecular synthon with remaining synthon with remaining componentscomponents

•• Also termedAlso termed ““molecular molecular complexcomplex””, , ““molecular adductmolecular adduct””, , ““multiple component molecular multiple component molecular crystalcrystal”” etc.etc.

CoCo--crystal of 1crystal of 1--methylthymine and 9methylthymine and 9--methyladenine first made by methyladenine first made by HoogsteenHoogsteenSchmidt, J.; Snipes, W. Schmidt, J.; Snipes, W. Int. J. Int. J. RadiatRadiat. Biol. Biol., 1967, ., 1967, 1313, 101, 101--109.109.

““The formation and The formation and properties of free properties of free

radicals in a coradicals in a co--crystal crystal complex between 1complex between 1--

methylthymine and 9methylthymine and 9--methyladenine have methyladenine have

been studiedbeen studied””

The first use of The first use of ““coco--crystalcrystal””??

J. Phys. ChemJ. Phys. Chem., 1991, 95, 4601., 1991, 95, 4601--4610.4610.

Popularized by Margaret C. Popularized by Margaret C. EtterEtter19431943--19921992

K. K. HoogsteenHoogsteen, 1963, 1963((ActaActa CrystallogrCrystallogr., ., 1616, 907), 907)

MethodologiesSolution:Solution:•• slow evaporationslow evaporation•• reaction crystallizationreaction crystallization•• slurryslurry•• supercritical fluidssupercritical fluids

Grinding/Milling: Grinding/Milling: •• solventsolvent--free grindingfree grinding•• solventsolvent--drop grinding drop grinding •• liquidliquid--assisted grindingassisted grinding•• kneadingkneading

Thermal:Thermal:•• heating of solidsheating of solids•• melt crystallizationmelt crystallization

Sakurai T. Sakurai T. ActaActa CrystallogrCrystallogr. 1965, B19, 320. 1965, B19, 320

Prepared using Prepared using ““kugelchenkugelchen””(little ball)(little ball)

F. F. WWööhlerhler in 1844 (in 1844 (AnnalenAnnalen, , 5151, 153), 153)

Quinone:HydroquinoneQuinone:Hydroquinone

Partial conversion Partial conversion to cocrystal to cocrystal after 1hafter 1h

Complete conversion Complete conversion to cocrystalto cocrystalwithin 20 minutes within 20 minutes

Dry grindingDry grinding

MeOHMeOH drop grindingdrop grinding

Why make Why make cocrystals?cocrystals?

•• Pharmaceutical Pharmaceutical cocrystalscocrystals––Stability (chemical Stability (chemical

and thermal)and thermal)––Bioavailability Bioavailability

(solubility)(solubility)

•• Cocrystal Controlled Cocrystal Controlled SolidSolid--State Synthesis State Synthesis (C(C33SS33))––Green chemistryGreen chemistry

•• EpitaxialEpitaxial growthgrowth

•• NonNon--linear opticslinear optics0

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SciFinderSciFinder Scholar, cocrystal, 3/2009Scholar, cocrystal, 3/2009

Pharmaceutical cocrystals•• A cocrystal in which a pharmaceutically acceptableA cocrystal in which a pharmaceutically acceptable

cocrystal formercocrystal former forms a supramolecular synthon with forms a supramolecular synthon with anan APIAPI

•• A new form of an API exhibits different physical A new form of an API exhibits different physical propertiesproperties

•• A new form of an API = new intellectual propertyA new form of an API = new intellectual property•• Cocrystals can be designedCocrystals can be designed

A.G. von A.G. von HeydenHeyden FR 769586 (1933)FR 769586 (1933)

Improved solubilityImproved solubilityS.L. Childs,S.L. Childs, et al. J. Am. Chem. Soc., et al. J. Am. Chem. Soc., 2004 2004

Recent Case Studies (out of >90 APIs)

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0 20 40 60 80 100 120Time (min)

Fluo

xetin

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Cl C

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tion

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)

Fluoxetine HCl:Fumaric AcidFluoxetine HCl:Succinic AcidFluoxetine HClFluoxetine HCl:Benzoic Acid

Caffeine:oxalic acid

Cocrystals stable @98% humidity for weeksCocrystals stable @98% humidity for weeksJones, W.; Jones, W.; MotherwellMotherwell, S.D. , S.D. TraskTrask, A.V., A.V.CrystCryst. Growth Des. Growth Des., 5, 1013., 5, 1013--1021, 2005.1021, 2005.

Fluoxetine HCl (Prozac®)

J.F. J.F. RemenarRemenar, at al., at al.J. Am. Chem. Soc.J. Am. Chem. Soc., 2003., 2003.

ItraconazoleCocrystals as soluble as amorphous formCocrystals as soluble as amorphous form

Carbamazepine:saccharinImproved plasma concentrationImproved plasma concentration

Crystal Growth & DesignCrystal Growth & Design, 2003, 2003EurEur. J. . J. PharmPharm. . BiopharmBiopharm. 2007. 2007

8x10-4

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4003002001000Time (min)

S.L. Childs,S.L. Childs, et al. J. Am. Chem. Soc.,et al. J. Am. Chem. Soc.,126, 13335 126, 13335 --13342, 200413342, 2004

FluoxetineFluoxetine HClHCl (Prozac(Prozac®®) dissolution profiles) dissolution profiles

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xetin

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) Fluoxetine HCl:Fumaric AcidFluoxetine HCl:Succinic AcidFluoxetine HClFluoxetine HCl:Benzoic Acid

““springspring--andand--parachuteparachute--effecteffect””

lapolc2009

Design of cocrystals: Crystal engineering““The supramolecular heterosynthon strategyThe supramolecular heterosynthon strategy””

Analysis of intermolecular contacts can be conducted Analysis of intermolecular contacts can be conducted using Cambridge Structural Database (CSD)using Cambridge Structural Database (CSD)

Carboxylic acids: 25% of APIs (only 10% overall); Carboxylic acids: 25% of APIs (only 10% overall); many are many are ““pharmaceutically approvedpharmaceutically approved”” for usefor use

Alcohols: 33% of APIsAlcohols: 33% of APIs

http://http://www.ccdc.cam.ac.ukwww.ccdc.cam.ac.uk//

G.R. G.R. DesirajuDesiraju AngewAngew. Chem., 1995, 34, 2311. Chem., 1995, 34, 2311

acceptoracceptor

donordonor

CSD AnalysisCSD Analysis: : AlcoholAlcohol

AliphaticAlcohol-Alcohol

Raw Data:19092/26314 (73%) aliphatic alcohol7185/26314 (27%) aromatic alcohol5405/19092 (28%) aliphatic alcohol homosynthon983/7185 (14%) aromatic alcohol homosynthon

Refined Data:955/1272 (75%) aliphatic alcohol homosynthon173/333 (52%) aromatic alcohol homosynthon

26314 total entries

CSD Conquest 1.10 (August update) Search parameter: organics only, 3D coordinates determined, R ≥ 0.075, no ions

AromaticAlcohol-Alcohol

CSD AnalysisCSD Analysis: : Carboxylic acidCarboxylic acid

Acid-Acid dimer

5943 total entries

Raw Data:1880/5943 (32%) carboxylic acid dimer156/5943 (3%) carboxylic acid catemer

Refined Data:448/487 (92%) acid dimer42/487 (9%) acid catemer

CSD Conquest 1.10 (August update) Search parameter: organics only, 3D coordinates determined, R ≥ 0.075, no ions

CSD AnalysisCSD Analysis::Carboxylic acid Carboxylic acid

vs. Alcoholvs. Alcohol

Acid-Alcohol heterosynthon (OH...OH)

Raw Data:249/1232 (20%) carboxylic acid homosynthon329/1232 (27%) alcohol homosynthon521/1232 (42%) OH OH heterosynthon552/1232 (45%) C=O OH heterosynthon

Refined Data:89/297 (30%) acid homosynthon113/297 (38%) alcohol homosynthon203/297 (68%) OH OH heterosynthon204/69 (69%) C=O OH heterosynthon

1232 total entries

CSD Conquest 1.10 (August update) Search parameter: organics only, 3D coordinates determined, R ≥ 0.075, no ions

CSD AnalysisCSD Analysis::Alcohol vs. Alcohol vs.

Aromatic NitrogenAromatic Nitrogen

Raw Data:2304/1583 (19%) alcohol homosynthon830/1583 (52%) OH Narom heterosynthon

Refined Data:63/247 (26%) alcohol homosynthon192/247 (78%) OH Narom heterosynthon

Alcohol-Narom heterosynthon

1583 total entries

CSD Conquest 1.10 (August update) Search parameter: organics only, 3D coordinates determined, R ≥ 0.075, no ions

CSD AnalysisCSD Analysis: : Alcohol vs. Alcohol vs. CyanoCyano

Alcohol-cyano heterosython

Raw Data:115/752 (15%) Alcohol homosynthon254/752 (34%) OH N≡C heterosynthon

Refined Data:28/92 (30%) Alcohol homosynthon68/92 (74%) OH N≡C heterosynthon

752 total entries

CSD Conquest 1.10 (August update) Search parameter: organics only, 3D coordinates determined, R ≥ 0.075, no ions

CSD AnalysisCSD Analysis: : Carboxylic acid vs. Carboxylic acid vs. Aromatic NitrogenAromatic Nitrogen

Acid-Narom heterosynthon

Raw Data:48/647 (7%) carboxylic acid homosynthon483/647 (75%) COOH Narom heterosynthon

Refined Data:11/136 (8%) carboxylic acid homosynthon129/136 (95%) COOH Narom heterosynthon

But many molecules contain several functional groups…

647 total entries

CSD Conquest 1.10 (August update) Search parameter: organics only, 3D coordinates determined, R ≥ 0.075, no ions

The CSD is more limited when it comes to stats on The CSD is more limited when it comes to stats on competition between multiple donors/acceptorscompetition between multiple donors/acceptors

•• e.g. Carboxylic acid, phenol, aromatic nitrogene.g. Carboxylic acid, phenol, aromatic nitrogen•• Nine possible synthons, which ones will form?Nine possible synthons, which ones will form?•• CSD contains only 12 structures with all 3 moieties onlyCSD contains only 12 structures with all 3 moieties only

22 9944

88

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D = DonorD = DonorA = AcceptorA = Acceptor

++

A model for a study of the hierarchy of 3 functional groupsA model for a study of the hierarchy of 3 functional groups

++

D1D1 D2D2 A1A1D1D1 D2D2 A1A1

D1D1 D2D2A1A1

D1D1 A1A1 D2D2D2D2

OROR

D1D1 A1A1

D1D1 A1A1 D1D1 A1A1

D2D2A1A1 D1D1

OROR

D2D2A1A1D1D1

D2D2A1A1D2D2A1A1

OROR

Group 1Group 1

Group 2Group 2

Group 3Group 3

Model compound study 1Model compound study 1 Zaworotko et. al. Cryst. Growth Des. 8, 4533, 2008.

13 Cocrystals isolated13 Cocrystals isolated2 crystallizations formed salts 2 crystallizations formed salts

8 solvent8 solvent--drop grinds formed new phasesdrop grinds formed new phasesAll attempts resulted in mixturesAll attempts resulted in mixtures

CocrystalCocrystal

MixtureMixture

SaltSalt

NewNew

MixtureMixture

With 2 donors on same molecule paired with molecule with a single

acceptor, group 1 can form multiple supramolecular synthons

OHOHphenolphenol NNaromarom

COOHCOOH NNaromarom

Unfortunately…This precludes any This precludes any conclusions about conclusions about synthon hierarchy synthon hierarchy

unless cocrystal is 1:1unless cocrystal is 1:1

Why was Group 1 so successful ? Why was Group 1 so successful ? Supramolecular Supramolecular

SynthonsSynthons

COOCOO-- HNHNaromarom

What can we learn about hierarchy from What can we learn about hierarchy from Group 2 ? Group 3 ?Group 2 ? Group 3 ?

Group 2 generated many 2 component crystalline forms Group 2 generated many 2 component crystalline forms sustained by the sustained by the carboxylatecarboxylate--NNaromarom synthonsynthon

Group 3 = no cocrystals only mixtures, Group 3 = no cocrystals only mixtures, (design of study = cocrystal (design of study = cocrystal andand COOHCOOH--NNaromarom not possible) not possible)

Therefore: Therefore: carboxylatecarboxylate--NNaromarom synthon must be > alcoholsynthon must be > alcohol--NNaromarom synthonsynthon

Model compound study 2Model compound study 2

• Phenol, aromatic nitrogen, cyano• Three possible synthons• CSD contains only 3 structures with all 3

moieties

33 00 00

Target MoleculesTarget MoleculesGroup 1

Group 2

Group 3

Zaworotko et. al. Mol Pharma. 4, 401-416.

D1D1 ORORA1A1 A2A2

A1A1 A2A2 D1D1

D1D1 A2A2 D1D1 A2A2

ORORA1A1 A2A2D1D1

D1D1A1A1D1D1A1A1

ORORD1D1A1A1 A2A2

BpheBphe ResRes PhlglPhlgl

33--cypycypy

44--cypycypy

PhenpyPhenpy BipyBipy BipyetaBipyeta BipyeteBipyete

33--cyphecyphe44--cyphecyphe

cynaphcynaph mm--cybencyben pp--cybencyben

33--hypyhypy

44--hyquinhyquin

= Cocrystal = Cocrystal

= Mixture = Mixture

Group 1Group 1(OH, (OH, NNaromarom+C+C≡≡NN))

Group 3Group 3(C(C≡≡N, N, OH+NOH+Naromarom))

Group 2Group 2 ((NNaromarom,OH+C,OH+C≡≡NN))

Group 1+2 = Cocrystals, Group 3 = MixturesGroup 1+2 = Cocrystals, Group 3 = Mixtures

Group 1Group 1: Paired a molecule with 1 donor (OH) with a : Paired a molecule with 1 donor (OH) with a molecule with 2 acceptors (CN, molecule with 2 acceptors (CN, NNaromarom))(Competition minimal)(Competition minimal)

Why was group 1 and 2 successful ?Why was group 1 and 2 successful ?

Group 2 Group 2 ((NNaromarom)) paired molecule with donor + acceptor paired molecule with donor + acceptor (6 cocrystals (6 cocrystals OHOH NNaromarom ))

Group 3Group 3 (CN)=(CN)= cannot form cannot form cocrystal cocrystal andand OHOH NNaromarom

OHOH NNaromarom must bemust be>> OHOH NN≡≡CC

Bicalutamide:BipyethyleneBicalutamide:Bipyethylene

(I) (I) OHOH NNaromarom

Competitive studies can be useful in Competitive studies can be useful in forming pharmaceutical cocrystals...forming pharmaceutical cocrystals...

BicaluatmideBicaluatmide is a nonis a non--steroidal antisteroidal anti--androgen androgen used in the treatment of prostate cancerused in the treatment of prostate cancer

PP--11a = 8.274(3)a = 8.274(3)ÅÅ

b = 10.172(3) b = 10.172(3) ÅÅc = 18.601(7) c = 18.601(7) ÅÅαα = 87.521(7)= 87.521(7)ººββ = 78.256(6) = 78.256(6) ººγγ = 71.067(7) = 71.067(7) ºº

V = 1449.4(9)V = 1449.4(9)ÅÅ33

Zaworotko et. al. Mol Pharma. 4, 401-416.

But what about stronger synthons?But what about stronger synthons?

•• Nicotinic and Nicotinic and isonicotinicisonicotinic acid should not be acid should not be suitable for cocrystal formation since they are suitable for cocrystal formation since they are sustained by the COOHsustained by the COOH--NNaromarom synthonsynthon

•• Only two cocrystals in CSD (chain present)Only two cocrystals in CSD (chain present)•• Can we break the COOHCan we break the COOH--NNaromarom synthon?synthon?

Even stronger Even stronger heterosynthonsheterosynthons can be exploited:can be exploited:

Vitamin C forms a dominant heterosynthon with carboxylates

Head to tail chain motifs broken

LissetteLissette MarshallMarshall

Or cocrystals can be made without disrupting Or cocrystals can be made without disrupting strong interactionsstrong interactions

Hesperitin : Nicotinic acid cocrystal

Citric acid : Isonicotinic acid cocrystal

PadminiPadmini KaruvuKaruvu, , DaliaDalia AborayesAborayes

ConclusionsConclusions•• ““Synthon approachSynthon approach”” works well for cocrystal works well for cocrystal

formers with 2 complementary functional formers with 2 complementary functional groupsgroups

•• CSD is a valuable tool but does not work so well CSD is a valuable tool but does not work so well when >= 3 functional groups presentwhen >= 3 functional groups present

•• Model compound studies show: Model compound studies show: –– Carboxylic acid reliably forms supramolecular synthons Carboxylic acid reliably forms supramolecular synthons

with aromatic nitrogen even in presence of an alcohol with aromatic nitrogen even in presence of an alcohol –– Alcohol Alcohol –– aromatic nitrogen synthon forms reliably in aromatic nitrogen synthon forms reliably in

presence of presence of cyanocyano moietymoiety

•• Even strong synthons can be brokenEven strong synthons can be broken

AcknowledgementsAcknowledgements

••Dr. Michael Dr. Michael ZaworotkoZaworotko

••USFUSF

••CoCo--crystal team: crystal team: KapilKapil AroraArora, , TienTien OngOng, Heather Clarke, , Heather Clarke, PadminiPadmini KuruvuKuruvu, , DaliaDalia AboryesAboryes, , LissetteLissette Marshall, David Marshall, David WeynaWeyna

••MetalMetal--Organic team: John Perry IV, Jason Organic team: John Perry IV, Jason PermanPerman

••$$$ $$$ NSF, Transform Pharmaceuticals NSF, Transform Pharmaceuticals