supramolecular heterosynthons and their role in cocrystal...
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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
e H
Cl C
once
ntra
tion
(mM
)
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
6
4
2
0[1
] (M)
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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0 20 40 60 80 100 120Time (min)
Fluo
xetin
e H
Cl C
once
ntra
tion
(mM
) 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
++
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