Cocrystals: The future of improving solubility?

Nar Rodrguez-Hornedo
Department of Pharmaceutical Sciences
University of Michigan
Ann Arbor, Michigan
nrh@umich.edu

Cocrystals have since moved into the realm of crystal engineering

CBZ- saccharin cocrystal

CBZ- nicotinamide cocrystal

nct
cbz

nct
Cocrystals of carbamazepine

(amide homosynthon - strategy I)

Zaworotko, Rodriguez-Hornedo et al. Crystal Growth & Design, 2003, 3:909-919.

An important property of cocrystals

Cocrystal solid-solution equilibria is dictated by solution composition

K sp
1:1

A soln

ABsolid

[ A]

[ B ] [ A][ B ]

[A]

K sp

Bsoln

[B]

- Drug concentration [A] in equilibrium with cocrystal is dependent on

coformer concentration [B]
- Cocrystal Ksp is not concentration dependent (if activity coefficients
are constant)

Cocrystal Ksp and solubility

If at equilibrium

[ A]T

and

[ B]T

K sp

[ B]

A soln

ABsolid

is the analytical concentration

Bsoln

1:1

[A]T

where [X]

[ A]

S AB

[ A]T

K sp
[ B]T

Cocrystal solubility decreases with increasing

coformer concentration

[B]T

Cocrystal solubility determination requires

- solution concentration measurement of both components, A and B, and
- solid phase analysis at equilibrium

Cocrystal solubility dependence on

solubility of its components
S cocrystal
S drug

when

S ligand
S drug

Good and Rodrguez-Hornedo, Crystal Growth & Design, 2009.

10

Consider a series of cocrystals with a range of solubilities

drug

0.1 S

10 S

100 S

The questions is:

What is the desired solubility?
not:
Is there a more soluble form?
BecauseHigh solubility can lead to rapid conversion and hinder performance

What are the consequences of conversion to more stable forms?

Kinetic solubility measurement and in a limited range
It is important to analyze the solid phase at the end
to identify the form(s) at equilibrium

Slow conversion

Rapid conversion

time
Peak concentration may not be an indicator of cocrystal solubility
- Peak is dependent on conversion kinetics
- Extraordinarily high cocrystal solubility may elude detection

How to measure the solubility of a transient

cocrystal phase?
Measure eutectic point

[A]tr

SA

- 2 solid phases coexist in

equilibrium with liquid phase
- [B]tr, [A]tr are fixed at T and pH,
regardless of ratio of two solid
phases

SA:B
[B]tr

Ctr is a key parameter to measure cocrystal solubility and establish stability regions

It only requires a single measurement!

Nehm S. , Rodrguez-Spong, B., and Rodrguez-Hornedo, N. Cryst. Growth & Des., 2006, 6:592-600.

[A]T

Relationship between cocrystal solubility and

eutectic point

[A]tr

Asolid

[B]tr

[B]T

The higher cocrystal solubility the higher the [ligand]tr

Good and Rodrguez-Hornedo, Crystal Growth & Design, 2009.

Aqueous eutectic ligand concentrations

for CBZ cocrystals
[ligand]tr is proportional
to ligand solubility
higher cocrystal solubility
requires higher [ligand]tr

[B]tr
Good and Rodrguez-Hornedo, Crystal Growth & Design, 2009.

Cocrystal solubility is a result of

crystal chemistry
lattice energy
crystal packing
intermolecular interactions

solution chemistry
ionization
complexation
solvent-solute interactions

Gsolution

Glattice

Gsolvation

Customize solubility-pH dependence with cocrystals

Bethune, S.; Huang, N, Jayasankar, A.; Rodrguez-Hornedo, N. Crystal Growth &Design, 2009
pKa,ligand = 4.8, 2.6
pKa,ligand = 3.0

cocrystal

solubility

solubility

cocrystal

drug

drug

pH

pH
1:1 nonionizable API, acidic ligand
carbamazepine-salicylic acid

2:1 nonionizable API, amphoteric ligand

carbamazepine-4-aminobenzoic acid

pKa,API = 3.9, 10.1

pKa,ligand = 3.7

pKa,drug = 3.7
pKa, coformer = 3.0, 4.3

solubility

solubility

drug

cocrystal

2:1 basic API, acidic ligand

Itraconazole-tartaric acid

1:1 zwitterionic API, acidic ligand

gabapentin-3-hydroxybenzoic acid

Observed and predicted Ctr dependence on pH

Solid phases at equilibrium:
CBZ HYD + CBZ-SLC

[A] tr

K sp
[R ] tr

Ka
[H ]

Solid phases at equilibrium:

CBZ HYD + CBZ-4ABA HYD

[ AB]tr

K sp
2
tr

[ R]

K a1, HAB
[H ]

[H ]
K a 2, HAB

[R]tr = [CBZ]tr = 0.0006 M in this pH range

Equations that consider cocrystal dissociation and ligand

ionization predict experimental behavior

IND-SAC cocrystal solubility and dissolution

Phosphate buffer, pH 7.4, 60 and 200 mM

pKa = 4.5
pKa = 1.8

Amount dissolved (mg/ml)

Indomethacin 60 mM
Ind-Sac cocrystal 60 mM
Indomethacin 200 mM
Ind-Sac cocrystal 200 mM

0
0

50

100

150

200
Time (min)

250

300

350

Basavoju, Bostrom and Velaga et al. J Pharm Sci 2008

Alhalawe,Sokolowski, Huang, Rodriguez-Hornedo and Velaga, AAPS 2009

Predicted solubility pH dependence is in agreement with measured dissolution rates

The value of the cocrystal lies in

its ability to tailor solubility and deliver a wide solubility
spectrum

our ability to understand its properties and protect it from

conversion

Cocrystals come with supersaturation

How to quantify the risks?
How to protect it from conversion?
Are we doing the right experiments?
What are the selection criteria?

References

S.J.Nehm, B. Rodrguez-Spong, and N. Rodrguez-Hornedo, Phase Solubility Diagrams of Cocrystals are

Explained by Solubility Product and Solution Complexation, Crystal Growth and Design, 6: 592-600 (2006).

N. Rodrguez-Hornedo, S.J. Nehm, K.F. Seefeldt, Y. Pagn-Torres, and C.J. Falkiewicz, Reaction
Crystallization of Pharmaceutical Molecular Complexes, Molecular Pharmaceutics, 3: 362-367 (2006).

K. Seefeldt, J. Miller, F. Alvarez-Nez and N. Rodrguez-Hornedo, Crystallization Pathways and Kinetics

of Carbamazepine-Nicotinamide Cocrystals From the Amorphous State by In Situ Thermomicroscopy,
Spectroscopy and Calorimetry Studies, Journal of Pharmaceutical Sciences, 96: 1147-1158 (2007).

N. Rodrguez-Hornedo, S. J. Nehm, and A. Jayasankar, Process Analytical Technologies to Analyze and

Control Cocrystallization, American Pharmaceutical Review, March/April 2007.

A. Jayasankar, D. J. Good, and N. Rodrguez-Hornedo, Mechanisms by Which Moisture Generates

Cocrystals, Molecular Pharmaceutics, 4: 360-372 (2007).

S. Childs, N. Rodrguez-Hornedo, L.S. Reddy, A. Jayasankar, C. Maheshwari, L. McCausland, R. Shipplett,

B.C. Stahly, Screening Strategies Based on Solubility and Solution Composition Generate
Pharmaceutically Acceptable Cocrystals of Carbamazepine, CrystEng Comm, 10: 856-864 (2008).

A. Jayasankar, L. S. Reddy, S. Bethune, and N. Rodrguez-Hornedo, Role of Cocrystal and Solution

Chemistry on the Formation and Stability of Cocrystals with Different Stoichiometry, Crystal Growth and
Design, 9: 889-897 (2009).

L. S. Reddy, S. Bethune, A. Jayasankar, and N. Rodrguez-Hornedo, Cocrystals and Salts of Gabapentin:

pH Dependent Cocrystal Stability and Solubility, Crystal Growth and Design, 9: 378-385 (2009).

D. Good and N. Rodrguez-Hornedo, Solubility Advantage of Pharmaceutical Cocrystals, Crystal Growth

and Design, 9: 2252-2264 (2009).

S. Bethune, N. C. Huang, A. Jayasankar, and N. Rodrguez-Hornedo, Understanding and Predicting the

Effect of Cocrystal Components and pH on Cocrystal Solubility, Crystal Growth and Design, 9:3976-3988
(2009).

Evaluation of Ksp from Ctr measurement

(cocrystal + CBZ hydrate in eq with soln)
carbamazepine-salicylic acid

Ka
[H ]

Ksp = 1.1 x 10-6 M2

carbamazepine-4ABA HYD

K a1,HAB
[H ]

[H ]
K a 2,HAB

Ksp = 1.2 x 10-9 M3

How many cocrystals can a drug form?

Piroxicam
50 cocrystals with carboxylic acids
zwitterionic or non-ionic forms of drug

Carbamazepine
35 cocrystals with carboxylic acids, amides, amines
Implications:
need to understand the criteria for cocrystal selection
develop material and resource sparing methods of
characterization

Childs, Stahly et al., Cryst Growth & Design, 2007

Childs, Rodrguez-Hornedo et al., Cryst. Eng. Comm, Web published March 2008

Cocrystals provide a range of aqueous solubility

Some of the cocrystals are

stable in water while
others convert to CBZ(H)
Cocrystal stability appears
to be correlated with ligand
solubility

Childs, Rodrguez-Hornedo et al.,

Cryst. Eng. Comm, Web published March 2008

Cocrystal guest

Stable phase Guest w

in water
(mg/mL

glycolic acid

DH

4040

malonic acid (form A)

DH

1200

malonic acid (form B)

DH

1200

DL-malic acid

DH

1100

glutaric acid

DH

840

L-pyroglutamic acid

DH

630

ketoglutaric acid (form A)

DH

620

L-tartaric acid

DH

400

maleic acid

DH

230

DL-tartaric acid (form B)

DH

190

D-malic acid

DH

190

L-malic acid

DH

170

oxalic acid

DH

92

succinic acid

DH

53.3

adipic acid (form C)

DH

16.4

4-hydroxybenzoic acid (form A)

CC

8.4

4-hydroxybenzoic acid (form B)

CCa

8.4

(+)-camphoric acid (form A)

CC

<10

salicylic acid

CC

benzoic acid

CC

1.2

1-hydroxy-2-naphthoic acid

CC

<5

fumaric acid (form A)

CC

<1

CBZ-NCT cocrystal solubility dependence on ligand concentration

S AB

[ A]T

K sp
[ B]T

K11K sp

Nehm S. , Rodrguez-Spong, B., and Rodrguez-Hornedo, N. Cryst. Growth & Des., 2006, 6:592-600.

Cocrystal solubility dependence on

solution complexation (1:1)
A:Bsolid

Ksp

Asoln + Bsoln

K sp

Asoln + Bsoln

K11

K11

ABsoln

[ A][ B]
[ AB]
[ A][ B]

[ AB]
K sp

Using the mass balances for A and B, the solubility of cocrystal is:

[ A]T
[ A]T

[ A] [ AB]

K sp
[ B]

K sp
[ B ]T

K 11 K sp

If K11Ksp << [B]T, then

K11K sp
K 11 K sp

[ A]T

K sp
[ B]T

K 11 K sp

Cocrystal solubility is increased by a constant value (K11Ksp )

Nehm S. , Rodrguez-Spong, B., and Rodrguez-Hornedo, N. Cryst. Growth & Des., 2006, 6:592-600.

Cocrystal stoichiometries and hydrates

Carbamazepine-4aminobenzoic acid

2:1

Zaworotko et al., 2007

Rodriguez-Hornedo et al. 2009

2:1 monohydrate

1:1

Cocrystal stability in ethanol

Transformation pathways

220

1:1 cocrystal

230

240

250 260 270 280

Raman Shift (1/cm)

290

CBZ(III)

2:1 cocrystal
Jayasankar, Rodriguez-Hornedo et al., Crystal Growth Design, 2009

2:1 cocrystal

CBZ(III)

Cocrystal-solution equilibria for 2:1 and 1:1 CBZ-4ABA

(solvent = ethanol)

CBZ(III) (A)
2:1 cocrystal (A2B)
1:1 cocrystal (AB)
4ABA (B)

Three eutectic points:

c1 - CBZ(III), 2:1 cocrystal
c2 - 2:1 cocrystal, 1:1 cocrystal
c3 - 1:1 cocrystal, 4ABA
c1

Ksp and Kc values were evaluated

from solubility measurements
Curves shown were generated from
fitted equations.

Jayasankar, Rodriguez-Hornedo et al., Crystal Growth Design, 2009

c2

c3

Triangular phase diagram can also be derived from mathematical models and
equilibrium constants Ksp, Kc
Solvent

Stability regions
1-A
2 - 2:1 cocrystal
3 - 1:1 cocrystal
4-B
5 - A + 2:1 cocrystal
6 - 1:1 + 2:1 cocrystal
7 - 2:1 cocrystal + B

4ABA
Jayasankar, Rodriguez-Hornedo et al., Crystal Growth Design, 2009

CBZ

Cocrystal solubility and melt temperature

Good and Rodrguez-Hornedo, Crystal Growth & Design, 2009.

Regression values

Water() EtOH() IPA(X) EtOAc( )

Qualitative inverse relation for cocrystal solubility and Tm

Correlation is worse in water than in organic solvents

Cocrystal solubility dependence on

solubility of its components
S cocrystal
S drug

when

S ligand
S drug

Good and Rodrguez-Hornedo, Crystal Growth & Design, 2009.

10

Can cocrystals impart pH-dependent solubility when

drug is nonionizable?
1:1 cocrystal, RHA

RHA(s)

R = nonionizable drug, HA= acidic ligand

R(aq) + HA(aq)
+

HA

+ A

K sp

[ R ][ HA ]

Ka

[H ][ A ]
[HA ]

Scocrystal = [R]T = [A]T

Scocrystal

K sp

Ka
1
[H ]

Cocrystal solubility increases as [H+] decreases or pH increases.

Nehm, S.; Jayasankar, A.; Rodrguez-Hornedo, N. The AAPS Journal, 2006
Rodrguez-Hornedo, Nehm, and Jayasankar. Cocrystals In The Encyclopedia of Pharmaceutical Technology. 2007.

Cocrystal solubility as a function of ligand and pH

1:1 RHA nonionizable drug (R), acidic ligand (HA), Ligand pKa = 3.0.

Cocrystal solubility and stability

are dependent on

pH
ligand concentration

Ctr is pH dependent

Bethune, S.; Huang, N, Jayasankar, A.; Rodrguez-Hornedo, N. Crystal Growth &Design,2009

Cocrystal solubility and Ctr dependence on pH

1:1 RHA nonionizable drug (R), acidic ligand (HA), Ligand pKa = 3.0.

[A] tr

K sp
[R ] tr

Bethune, S.; Huang, N, Jayasankar, A.; Rodrguez-Hornedo, N. Crystal Growth &Design, 2009

Ka
[H ]

Calculation of cocrystal solubility from Ctr measurements

Measured and predicted Ctr dependence on pH

Predicted solubility dependence on pH

Stoichiometric concentrations

Solid phases at equilibrium:

CBZ HYD + CBZ-4ABA HYD

[ AB]tr

K sp
2
tr

[ R]

K a1, HAB
[H ]

[H ]
K a 2, HAB

[R]tr = [CBZ]tr = 0.0006 M in this pH range

K sp
4

K a1,HAB
[H ]

[H ]
K a 2,HAB

Calculation of phase diagrams from Ctr measurements

Solubility dependence on ligand and pH

[ R]T

K sp
[ AB]T

K a1, HAB
[H ]

[H ]
K a 2, HAB

Cocrystal solubility dependence on pH

Stoichiometric conditions

K sp
4

K a1,HAB
[H ]

[H ]
K a 2,HAB

Acknowledgements

University of Michigan

Sarah Nehm (Bethune)

Adivaraha (Jay) Jayasankar
Neal Huang
David Good
Sreenivas Reddy

Financial Support
NIH Training Grant
AFPE
Boehringer Ingelheim
Purdue-Michigan Consortium on
Supramolecular and Solid State Properties
of Pharmaceuticals