Nair Rodriguez-Hornedo.pdf

Naír Rodríguez-Hornedo

Department of Pharmaceutical Sciences

University of Michigan

Ann Arbor, Michigan

[email protected]

Cocrystals: The future of improving solubility?

cbz

nct

nct

Cocrystals of carbamazepine (amide homosynthon - strategy I)

CBZ- saccharin cocrystal CBZ- nicotinamide cocrystal

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

Cocrystals have since moved into the realm of crystal engineering

An important property of cocrystals

Cocrystal solid-solution equilibria is dictated by solution composition

[B]

[A]

solidAB solnsoln BAspK

1:1

]][[][][ BABAK BAsp

- 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

[B]T

[A] T

If at equilibrium

T

sp

TABB

KAS

][][

][][ AA T and ][][ BB T

Cocrystal solubility decreases with increasing

coformer concentration

Cocrystal solubility determination requires

- solution concentration measurement of both components, A and B, and

- solid phase analysis at equilibrium

1:1where [X] T is the analytical concentration

solidAB solnsoln BAspK

Cocrystal solubility dependence on

solubility of its components

1drugS

cocrystalS

10drugS

ligandS

when

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

S0.1 S

Consider a series of cocrystals with a range of solubilities

10 S 100 S

The questions is:What is the desired solubility?

not:Is there a more soluble form?

drug

Because…High solubility can lead to rapid conversion and hinder performance

time

What are the consequences of conversion to more stable forms?

Kinetic solubility measurement and in a limited range

Slow conversion

Rapid conversion

It is important to analyze the solid phase at the end to identify the form(s) at equilibrium

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?

SA

SA:B

Measure eutectic point

- 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

[B]tr

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

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

It only requires a single measurement!

[A]tr

Relationship between cocrystal solubility and

eutectic point


The higher cocrystal solubility the higher the [ligand]tr

[B]T

[A] T

Asolid

[B]tr

[A]tr

Aqueous eutectic ligand concentrations

for CBZ cocrystals


• [ligand]tr is proportional

to ligand solubility

• higher cocrystal solubility

requires higher [ligand]tr

[B]tr

Cocrystal solubility is a result of

• crystal chemistry– lattice energy

– crystal packing

– intermolecular interactions

• solution chemistry– ionization

– complexation

– solvent-solute interactions

solvationlatticesolution GGG

Customize solubility-pH dependence with cocrystals

2:1 nonionizable API, amphoteric ligand

carbamazepine-4-aminobenzoic acid

cocrystal

drug

pKa,ligand = 4.8, 2.6

so

lub

ilit

y

pH

pKa,drug = 3.7

pKa, coformer = 3.0, 4.3

2:1 basic API, acidic ligand

Itraconazole-tartaric acid

so

lub

ilit

y

1:1 zwitterionic API, acidic ligand

gabapentin-3-hydroxybenzoic acid

cocrystal

drug

pKa,API = 3.9, 10.1

pKa,ligand = 3.7

so

lub

ilit

y

1:1 nonionizable API, acidic ligand

carbamazepine-salicylic acid

drug

pKa,ligand = 3.0

so

lub

ilit

y

pH

cocrystal

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

Observed and predicted Ctr dependence on pH

HABa

HABa

tr

sp

trK

H

H

K

R

KAB

,2

,1

2

][

][1

][][

Solid phases at equilibrium:

CBZ HYD + CBZ-4ABA HYD

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

Equations that consider cocrystal dissociation and ligand

ionization predict experimental behavior

]H[

K1

]R[

K]A[ a

tr

sp

tr


CBZ HYD + CBZ-SLC

0

1

2

3

4

0 50 100 150 200 250 300 350Time (min)

Am

ou

nt

dis

solv

ed

(m

g/m

l) Indomethacin 60 mMInd-Sac cocrystal 60 mM

Indomethacin 200 mMInd-Sac cocrystal 200 mM

IND-SAC cocrystal solubility and dissolution

pKa = 4.5

pKa = 1.8

Phosphate buffer, pH 7.4, 60 and 200 mM

Predicted solubility pH dependence is in agreement with measured dissolution rates

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

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

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. Rodríguez-Spong, and N. Rodríguez-Hornedo, Phase Solubility Diagrams of Cocrystals are Explained by Solubility Product and Solution Complexation, Crystal Growth and Design, 6: 592-600 (2006).

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

• K. Seefeldt, J. Miller, F. Alvarez-Núñez and N. Rodríguez-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. Rodríguez-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. Rodríguez-Hornedo, Mechanisms by Which Moisture Generates Cocrystals, Molecular Pharmaceutics, 4: 360-372 (2007).

• S. Childs, N. Rodríguez-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. Rodríguez-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. Rodríguez-Hornedo, Cocrystals and Salts of Gabapentin: pH Dependent Cocrystal Stability and Solubility, Crystal Growth and Design, 9: 378-385 (2009).

• D. Good and N. Rodríguez-Hornedo, Solubility Advantage of Pharmaceutical Cocrystals, Crystal Growth and Design, 9: 2252-2264 (2009).

• S. Bethune, N. C. Huang, A. Jayasankar, and N. Rodríguez-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)

]H[

K1 a

HAB,2a

HAB,1a

K

]H[

]H[

K1

Ksp = 1.2 x 10-9 M3Ksp = 1.1 x 10-6 M2

carbamazepine-salicylic acid carbamazepine-4ABA HYD

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, Rodríguez-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

Cocrystal guest

Stable phase

in water

Guest water sol.

(mg/mL)b 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 2

benzoic acid CC 1.2

1-hydroxy-2-naphthoic acid CC <5

fumaric acid (form A) CC <1

Childs, Rodríguez-Hornedo et al.,

Cryst. Eng. Comm, Web published March 2008

CBZ-NCT cocrystal solubility dependence on ligand concentration


sp

T

sp

TAB KKB

KAS 11

][][


solution complexation (1:1)

A:Bsolid Asoln + Bsoln

Ksp

Asoln + Bsoln ABsoln

K11

spK

AB

BA

ABK

][

]][[

][11

sp

sp

T KKB

KABAA 11

][][][][

sp

spT

sp

T KKKKB

KA 11

11][][

If K11Ksp << [B]T, thensp

T

sp

T KKB

KA 11

][][

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

]][[ BAK sp

Cocrystal solubility is increased by a constant value (K11Ksp )


1:1

2:1 2:1 monohydrate

Cocrystal stoichiometries and hydrates

Carbamazepine-4aminobenzoic acid

Zaworotko et al., 2007

Rodriguez-Hornedo et al. 2009

220 230 240 250 260 270 280 290

Raman Shift (1/cm)

Cocrystal stability in ethanolTransformation pathways

1:1 cocrystal CBZ(III) 2:1 cocrystal

2:1 cocrystal CBZ(III)

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

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


CBZ(III) (A)

2:1 cocrystal (A2B)

1:1 cocrystal (AB)

4ABA (B)

c2c3

c1

Three eutectic points:

c1 - CBZ(III), 2:1 cocrystal

c2 - 2:1 cocrystal, 1:1 cocrystal

c3 - 1:1 cocrystal, 4ABA

Ksp and Kc values were evaluated

from solubility measurements

Curves shown were generated from

fitted equations.

(solvent = ethanol)

Solvent

4ABA CBZ

23

1

4

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 + B5

6

7

Triangular phase diagram can also be derived from mathematical models and

equilibrium constants Ksp, Kc


Cocrystal solubility and melt temperature

Qualitative inverse relation for cocrystal solubility and Tm

Correlation is worse in water than in organic solvents

Water(○) EtOH(□) IPA(X) EtOAc(△ )

Regression values



solubility of its components

1drugS

cocrystalS

10drugS

ligandS

when


Can cocrystals impart pH-dependent solubility when

drug is nonionizable?

RHA(s) R(aq) + HA(aq)

HA H+ + A-

]HA][R[Ksp

]HA[

]A][H[Ka

Scocrystal = [R]T = [A]T

][1cocrystal

H

KKS a

sp

Nehm, S.; Jayasankar, A.; Rodríguez-Hornedo, N. The AAPS Journal, 2006

Rodríguez-Hornedo, Nehm, and Jayasankar. “Cocrystals” In The Encyclopedia of Pharmaceutical Technology. 2007.

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

1:1 cocrystal, RHA R = nonionizable drug, HA= acidic ligand

Cocrystal solubility as a function of ligand and pH

• Cocrystal solubility and stability

are dependent on – pH

– ligand concentration

• Ctr is pH dependent

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

Bethune, S.; Huang, N, Jayasankar, A.; Rodríguez-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.

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

]H[

K1

]R[

K]A[ a

tr

sp

tr

Calculation of cocrystal solubility from Ctr measurements

Measured and predicted Ctr dependence on pH

HABa

HABa

tr

sp

trK

H

H

K

R

KAB

,2

,1

2

][

][1

][][


CBZ HYD + CBZ-4ABA HYD

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

3

HAB,2a

HAB,1asp

K

]H[

]H[

K1

4

KS

Predicted solubility dependence on pH

Stoichiometric concentrations

Calculation of phase diagrams from Ctr measurements

Cocrystal solubility dependence on pH

Stoichiometric conditions

HABa

HABa

T

sp

TK

H

H

K

AB

KR

,2

,1 ][

][1

][][ 3

HAB,2a

HAB,1asp

K

]H[

]H[

K1

4

KS

Solubility dependence on ligand and pH

University of Michigan

• Sarah Nehm (Bethune)

• Adivaraha (Jay) Jayasankar

• Neal Huang

• David Good

• Sreenivas Reddy

Acknowledgements

Financial Support

•NIH Training Grant

•AFPE

•Boehringer Ingelheim

•Purdue-Michigan Consortium on Supramolecular and Solid State Properties of Pharmaceuticals

Documents

Nair Rodriguez-Hornedo.pdf