crystal engineering strategies: design of new synthons and ... · crystal engineering strategies:...

Crystal Engineering Strategies: Design of new Synthons and

Enhancement of API’s Solubility

Dr. Rafel Prohens

Plataforma de Polimorfisme i Calorimetria

• Physical modification: particle size reduction

• Drug dispersion in carriers: solid dispersions

• Additives/Complexation: cyclodextrins

• Surfactants: microemulsions

• Co-solvents (GRAS approved)

• Solid-state modification: salt formation, solid-state stabilisation of the amorphous state, etc...

Solubility Enhancement of an API

Solid State Methods For ImprovingSolubility And Dissolution Rates

• Habit modification

• Crystal Polymorphism

• Solvates and hydrates

• Salts

• Cocrystals

Crystal Engineering Strategies For ImprovingSolubility And Dissolution Rates

• Habit modification

• Crystal Polymorphism

• Solvates and hydrates

• Salts

• Cocrystals

OVERVIEW

Enhancement of solubility and other properties

Crystal Engineering Strategies

Salts

Hydrates

Cocrystals

Study of Supramolecular Synthons

Squaramides

A Supramolecular Synthon is...

“... a structural unit within supermoleculeswhich can be formed and/or assembled byknown or conceivable synthetic operationsinvolving intermolecular interactions”

G. Desiraju. Angew. Chem Int. Ed 1995, 34, 2311


Component A Component B

ComplementaryFunctional Groups

Using Graph Sets in Hydrogen-bond arrays

To define the morphology of hydrogen bonding patterns in crystal structures

ACCEPTOR H

DONOR

Gad(n) n: number of atoms

H-bonding motif

D: Dimer or finite

C: Chain

S: Intramolecular

R: Ring

Ga: number of acceptors

d: number of donors

Etter, M. C. Acc. Chem. Res. 1990, 23, 120-126

Three case-studies

Solvates/Hydrates Salts

-

--

++

++

-

API

Cocrystals

Solvent Acid/base

Coformer

Three case-studies

Salts

-

--

++

++

-

API

Acid/base

Ziprasidone

HN

OCl

NN

S N

Portell, A; Barbas, R; Font-Bardia, M; Dalmases, P; Prohens, R; Puigjaner, C. CrystEngComm 2009, 11(5), 791

Three case-studies

Solvates/Hydrates

API

Solvent

N

OF

NN

H

OH

O

Norfloxacin

Puigjaner, C; Barbas, R; Portell, A; Font-Bardia, M; Alcobe, X; Prohens, R. Crystal Growth & Design, 2010, 10(7), 2948

Three case-studies

API

Cocrystals

Coformer

APICapsules

Design and study of new synthons

Coformer 2Coformer 1

Synthon 1 Synthon 2

• Low Solubility in water ~ 0.3 µg/mL

• Two ionisable groups in the molecule with pKa values 8.4 and 13.3

Ziprasidone

Salt or Cocrystal?

Cocrystal

Salt

∆pKa = pKa (base) - pKa (acid)

∆pKa < 3

∆pKa > 3

NO

Cl

NN

S N

H

R

OO

H

NO

Cl

NN

S N

H

RO

O

H

Microscale salt screeningAcid pKa Salt Acid pKa Salt

H3PO4

Phosphoric1.96 √

Fumaric3.03 √

Citric

3.13 √

Oxalic

1.27 √

Malic

3.46 √Isethionic

1.66 √

Lactic3.85 X

Glutaric4.34 X

Gluconic

3.86 XGlutamic

4.25 X

Maleic

1.97 X

Armstrong’s

-3.37 X

HO OH

O OO OH

OH

OH

O

OH

HOOH

O OH

O

HOOH

O

OH

OH

OH

OH

OHO

OOH

HOOH

O

O

HOOH

O

O

HO OH

O O

HOS

OH

O O

HO OH

O

NH2

O

S

S

OHO O

HOO O

Aqueous solubilities of Ziprasidone salts

0

200

400

600

800

1000

1200

Free base HCl Mesylate H3PO4 Citrate Fumarate Oxalate Isethionate Malate

µg/mL

0.380

1000

28 3055

236

1121

475

Polymorphic Salt Screening

NO

Cl

NN

S N

H

AcOEt / 60ºC

AcN / 60ºC

AcN / r.t.

Malic acid

Malic acid

Malic acid

Form A

Form B

Form C

Polymorphism of Ziprasidone Malate

Form A

Form B

Form C50 150 250

Form A

Form B

Form C

Temperature (ºC) 300100

^exo

5 15 25 352 Theta

Form A

Form B

Form C

Polymorphism of Ziprasidone Malate

Form A

Form B

Form C50 150 250

Form A

Form B

Form C

Temperature (ºC) 300100

^exo

A - B Enantiotropy

B - C Monotropy

Aqueous solubilities of Ziprasidone malates

Free base HCl Mesylate Malate CMalate A Malate B

1000

800.3

475

989

1084

0

200

400

600

800

1000

1200

Ziprasidone Malate Form C

Otherfunctional

group

N

N

SN

H

NO

Cl

H

O

O

O

OHO

N

N

SN

H

NO

Cl

H

HO

O

O

OHO

H

Ziprasidone Malate Form C

Carboxylichomo synthon

Possible Synthons Observed Synthons

N

N

SN

H

NO

Cl

H

O

O

O

OHO

N

N

SN

H

N OCl

H

H OO

OH O

OHIonic

Interaction

R (9)22

R (8)22

34%

66%

Hierarchy of Synthons: 32 malate structures in the CCDC

1 hit

O O

O O

O

H

OO

OH O

OHH

O

O

O

OHO H

O

O

O

OHO

H

OO

OH O

OH

O

OOH

OOH

O

OO

O OHH

Best acceptor

Best donor Third best donor

Second bestacceptor

NNS N H

N

O

Cl

H

Second bestdonor

Third bestacceptor

O

O

O

OHO H OO

OH O

OH

30 hits 31 hits

3 hits

O

O

O

OHO H OO

OH O

OH

17 hits

2 hits

O

O

O

OHO H

O

O

O

OHO

H

Norfloxacin

3 polymorphic anhydrous forms

Methanolate

Several Hydrates

Salts

Cocrystals

N

OF

NN

O

O

HH

n·H2ON

OF

NN

H

OH

O

“It is a rule that a solvate is always the most stable and therefore theleast soluble form in its own solvent”

Rolf Hilfiker. Polymorphism in the Pharmaceutical Industry. 2006

Neutral Anhydrous forms Zwitterionic hydrates

Solubility HigherLower

Piperazinyl protonated ring in hydrates explains greater solubility

Norfloxacin Bioavailability

A new polymorphic sesquihydrate

22 ºC -69 ºC -35 ºC

Cooling Heating

I II II I


Form I Form II


Form I Form II

Water Channels


Form I Form II

Different Ethyl Conformation

One conformation Two conformations

Hydrates vs Anhydrous

R22 10( )R2

2 8( )

N

OF

N NH

O

OH

N

OF

NNH

O

OH

HH

NH

NHN

OF

N NH2

O

O

H

NO

F N

NH2

OO H

Polymorph Screening

API: non-disclosure agreement

The most stable polymorph ( Form A ) is protected by patent

3 new metastable polymorphs obtainedalways with traces of Form A

APICapsules

Polymorphism Screening

Concomitant Polymorphs

Form A

Form C

G

Metastableforms

Form A

B

C and D

Significantly different synthons


Form C

50ºC

100ºC

120ºC

140ºC

Form D

G

Metastableforms

Form A

B

C and D

Enantiotropy

C D


Form C

Form A

C D

Form A

C D

Form A

Form D

Form A

23 ºC 113 ºC 116 ºC 119 ºC

G

Metastableforms

Form A

B

C and D

Enantiotropy

C D


C and D forms cannot be obtained totally free ofthe patented form A

Cocrystal Screening

Enantiotropy

C D G

Metastableforms

Form A

B

C and D

R (10)33

R (10)33

API-NH3 - Cocrystal Form CAPI-H2O-NHMe2 - Cocrystal

R (10)33

2Θ (º)

Inte

nsity

(a.u

.)

50 ºC

API-NH3 - Cocrystal

70 ºC

90 ºC

100 ºC

110 ºC

120 ºC

Form D

API-NH3 - Cocrystal

Form D

2.9 %

Ammonia Cocrystal

Squaramides in Supramolecular Synthons:

a case study

Double Donor-Acceptor H-bonding Supramolecular Synt hons

O

ON

NR

R

H

H

A

A

anti / anti

O

ON

NH

R

R

H

anti / syn

D

A

R22(n)

D

D

catemer

R N

OR'

H

R N

OR'

HR N

OH

R'

RN

OH

R'

dimer

Form A Form B

C2

C2/c

Head-to-tail H-bonding motif

Only soluble in DMSO

Portell, A; Barbas, R; Braga, D; Polito, M; Puigjaner, C; Prohens, R. CrystEngComm, 2009, 11(1), 52-54

The anti/syn synthon is also geometrically favorable

Very insoluble

NH2

NH2

OO

OO

EtOH

OO

NN HH+

Conformational Equilibrium in Solution (CDCl 3)

Ha Hb Hc

OO

NNHb

NHa N

OO

NNN NHc Hc

2D-NMR Dilution Experiment

OO

NNHb

NHa N

OO

NNN NHc Hc

Ha Hb Hc

240 K

ppm10 9 8

Thermodynamic Equilibrium in Solution

KDcKDabKCDKCM

79086000.562.5

Approximate Values of the Equilbrium Constants

KDcKDabKCDKCM

79086000.562.5

Approximate Values of the Equilbrium Constants

Molecular Electrostatic Potential Surface

Highest ββββ value

Highest αααα value

Hunter, C. A. Angew. Chem. Int. Ed. 2004, 43, 5310-5324

Solution vs Solid State

OO

N NH N

αααα 2.8ββββN 4.0

ββββO 5.1

OO

N NH

H

NN


ββββΟΟΟΟ 5.1

1

N H

Solution vs Solid State

OO

N NH N


ββββO 5.1

OO

N NH

H

NN


ββββΟΟΟΟ 5.1

1

N H

OO

N NH

H

NN

O O

NNH

H

N N

OO

N NH

H

NNO O

NNH

H

N N

OO

N NH NN H

OO

N NH NN H

1a

1b

1c

Solid-solid transition

Two Polymorphs

^exo

Melting and crystallization

Two Polymorphs

^exo

Two Polymorphs

Solid transition

120 ºC 130 ºC 150 ºC

Melting Crystallization from the meltSolid transition

R22(10)

Hirshfeld’s Surfaces

Form I Form II

Two Polymorphs

OO

N OH

N

αααα 2.9

ββββN 4.8

ββββO 4.2

2

βN > βOMEP Surface

Breaking the head-to-tail motif

OO

N OH

N

αααα 2.9

ββββN 4.8

ββββO 4.2

2

βN > βOO

ON

O

HN

O

ON

O

HN

2c

O

ON

O

HN

O

ON

O

HN

2a

OO

N OH

2b

N

OO

N OH

Nor

Breaking the head-to-tail motif

Breaking the head-to-tail synthon

OO

N OH

N

αααα 2.9

ββββN 4.8

ββββO 4.2

2

βN > βO

R22(12)

Stronger competitors cannot inhibit the head-to-tai l synthon

α = 3.4

β = 4.3

β = 4.9

SQ head-to-tail as a scaffold for new cocrystal str uctures

Fumaric acid – squaramide cocrystal

Cocrystal Screening

Synthons not found

Fumaric acid – squaramide cocrystal

Cocrystal Screening

OO

NN

HH

N N

OO

NNHH

N N

OO

OO

H

H

OO

OO

H

HOO

NNHH

N N OO

OO

H

H

Acknowledgements

Dr. Cristina PuigjanerRafa BarbasAnna Portell

Dr. Xavier AlcobéDr. Mercè Font-Bardia

Plataforma de Polimorfisme i Calorimetria

crystal engineering strategies: design of new synthons and ... · crystal engineering strategies:...

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