Naír Rodríguez-Hornedo
Department of Pharmaceutical Sciences
University of Michigan
Ann Arbor, Michigan
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
Good and Rodríguez-Hornedo, Crystal Growth & Design, 2009.
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
Good and Rodríguez-Hornedo, Crystal Growth & Design, 2009.
• [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
Solid phases at equilibrium:
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
Nehm S. , Rodríguez-Spong, B., and Rodríguez-Hornedo, N. Cryst. Growth & Des., 2006, 6:592-600.
sp
T
sp
TAB KKB
KAS 11
][][
Cocrystal solubility dependence on
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 )
Nehm S. , Rodríguez-Spong, B., and Rodríguez-Hornedo, N. Cryst. Growth & Des., 2006, 6:592-600.
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
Jayasankar, Rodriguez-Hornedo et al., Crystal Growth Design, 2009
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
Jayasankar, Rodriguez-Hornedo et al., Crystal Growth Design, 2009
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
Good and Rodríguez-Hornedo, Crystal Growth & Design, 2009.
Cocrystal solubility dependence on
solubility of its components
1drugS
cocrystalS
10drugS
ligandS
when
Good and Rodríguez-Hornedo, Crystal Growth & Design, 2009.
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
][][
Solid phases at equilibrium:
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