This one hour presentation provides an overview of meaningful characterization methods to guide cocrystal and additive selection and key indicators of cocrystal solubility and thermodynamic stability.

1. Naír Rodríguez-Hornedo
Department of Pharmaceutical Sciences
University of Michigan
Ann Arbor, Michigan
nrh@umich.edu
Engineering Cocrystal Solubility and
Streamlining Cocrystal Early Development
Sponsored by Crystal Pharmatech

2. This talk will present approaches to
– effectively synthesize cocrystals
– identify meaningful cocrystal stability indicators
– rationally select additives to fine-tune solubility and
stability
without the time and material consuming requirements of
traditional methods.
Success of pharmaceutical cocrystals lies in our
ability to evaluate and understand its properties

3. Cocrystals
• are crystals that contain two or more different
molecular components
• components are solids at room temperature
• often rely on hydrogen-bonded assemblies between
neutral molecules of the active pharmaceutical
ingredient (API) and other components
• are a homogenous (single) crystalline phase with
well-defined stoichiometries AB, AB2, etc

4. • Technological innovation
– Molecular level design of crystals with multiple
components
– Develop large number of cocrystals for a given drug
• Motivation for cocrystal discovery
– Enhanced product performance, controlled delivery
– IP protection, lifecycle management, etc
• Customize material properties
– Solubility
– Dissolution
– Bioavailability
Cocrystals

5. Strategies to enhance aqueous
solubilities
Solid phase structure/
chemistry
– crystallinity
– lattice energy
– crystal packing
– intermolecular interactions
Solution phase chemistry
– ionization
– micellar solubilization
– complexation
– solvent-solute interactions
solvation
lattice
solution G
G
G Δ
+
Δ
=
Δ
Main barrier in aqueous media
due to hydrophobic nature of drug molecule

6. How high can dissolution rates be?
ITZ-succinic acid
Sporanox, marketed amorphous
Crystalline ITZ
ITZ-L-tartaric acid
ITZ-L-malic acid
Itraconazole-succinic acid cocrystal
Cocrystal dissolution rates can be as high as for amorphous form of ITZ.
Remenar, Morissette, Peterson, Moulton, MacPhee, Guzman, and Almarsson. “Crystal engineering of novel cocrystals of a triazole
drug with 1,4-dicarboxylic acids.” Journal of the American Chemical Society. 125: 8345-8457 (2003).

7. Increase Dissolution Rates and Bioavailability
McNamara D,, Childs, S, et al., Pharm. Res., 2006
API: 2-[4-(4-chloro-2-fluorophenoxy)phenyl] pyrimidine-4-carboxamide
cocrystal
API
API
cocrystal

8. 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.

9. Cocrystals of carbamazepine
carboxylic acid-amide heterosynthon – strategy II
CBZ-Succinic acid CBZ-Benzoic acid
Childs, Rodríguez-Hornedo et al. Cryst. Eng. Comm, 2008

10. An important property of cocrystals
Cocrystal solid-solution equilibria is dictated by solution composition
[B]
[A]
solid
AB
soln
soln B
A +
1:1
]
][
[
]
[
]
[ B
A
B
A
K B
A
sp ≈
= γ
γ
Drug concentration [A] in equilibrium with cocrystal is dependent on coformer concentration [B]
sp
K

11. Generate supersaturation to nucleate cocrystal by
increasing [A] or/and [B]
⎟
⎟
⎠
⎞
⎜
⎜
⎝
⎛ −
= 2
3
b
2
3
o
)
(ln
)
T
k
(
3
16
exp
v
N
J
σ
υ
πγ
2
/
1
sp
K
]
B
][
A
[
σ
⎟
⎟
⎠
⎞
⎜
⎜
⎝
⎛
=
For a cocrystal AB:
[B]T
[A]
T
SA
SAB
where, σ = supersaturation
Nucleation rate:
SB
J as σ
σmax

12. Reaction Crystallization Method (RCM)
Nehm S. , Rodríguez-Spong, B., and Rodríguez-Hornedo, N. Cryst. Growth & Des., 2006, 6:592-600
Rodríguez-Hornedo et al., Molecular Pharmaceutics 2006, 3: 362-367
[B]tr
B(solution) + A(solution) → AB(solid)

13. ! "
#
Solution composition has a fundamental role in generating
cocrystalline phase
1:1
Evaporation of 1:1 solution
Reaction Crystallization
Saturation of reactants
generates supersaturation
of cocrystal

14. High throughput cocrystal screening by RCM
Raman shift indicates cocrystal formation
240 260 280 300 320 340
Raman Shift (1/cm)
370 380 390 400 410 420
Raman Shift (1/cm)
760 765 770 775 780 785 790 795 800 805 810
Raman Shift (1/cm)
CBZ
Cocrystals
Raman microscope

15. Cocrystals provide a range of aqueous solubility
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, CrystEng Comm, 10: 856-864 (2008).
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
Carbamazepine cocrystals
coformers Solid phase in water

16. Stability indicating thermodynamic
parameters for solid forms
• Polymorphs: Transition temperature
• Hydrates/anhydrous: Critical water activity or critical RH
• Salts: pHmax
• Amorphous: Tg, glass transition temperature
• Cocrystals: ?
• Cocrystal hydrates: ?

17. [A]
T,
drug
concentration
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

18. How to measure the solubility of a transient
cocrystal phase?
SA
SA:B
• Eutectic or transition point
- Scocrystal = Sdrug
(cocrystal solubility in terms of
drug moles)
- 2 solid phases in equilibrium
with solution
[B]tr
Nehm S. , Rodríguez-Spong, B., and Rodríguez-Hornedo, N. Cryst. Growth & Des., 2006, 6:592-600.
Key parameter to measure cocrystal solubility and establish stability regions
It can be estimated from a single experiment!
[A]tr
- solution composition [B]tr, [A]tr
is fixed at T and pH, regardless
of ratio of two solid phases

19. [B]T
[A]
T
Eutectic point is an experimentally measurable equilibrium
SA
SAB
Two solid phases (AB and A)
at equilibrium with
solution (A +B+ AB+…)
[B]tr
Good, D. and Rodríguez-Hornedo, N. Cryst. Growth & Des., 2009
[A]tr

20. Cocrystal eutectic constant (Keu) as indicator of
phase behavior and solubility
- Cocrystal (1:1) is thermodynamically stable at Keu ≤ 1
- Single eutectic measurement allows for estimation of cocrystal to
drug solubility ratio
ABsolid ! Asoln + Bsoln
Keu =
[coformer]eu
[drug]eu
=
Ksp
Sdrug
2
!
"
#
$
%
&
substitute Scocrystal
2
= Ksp
Keu = '2
where ' =
Scocrystal
Sdrug
!
"
#
$
%
&
Good, D. and Rodríguez-Hornedo, N. Crystal Growth & Design (2010)

21. Relationship between Keu and cocrystal
solubility
Keu and α are solvent and pH dependent
α = Scocrystal /Sdrug
K
eu
Keu = α2
- Keu is an important indicator of
solubility for unstable or
metastable cocrystals
- Direct information about stability
and solubility relative to drug
carbamazepine-saccharin
carbamazepine-salicylic acid
Good, D. and Rodríguez-Hornedo, N. Crystal Growth & Design (2010)

22. Eutectic constant was established to provide key information
for enantioseparation processes

23. Cocrystal solubility dependence on
solubility of its components
Good and Rodríguez-Hornedo, Crystal Growth & Design, 2009.
Scc =150 x Sdrug
Scc =2 x Sdrug
water
oganic solvent

24. S
0.1 S
Range of solubilities from solid forms
10 S 100 S
drug
High solubility can lead to rapid conversion and hinder performance
Select solid form that meets dose requirements
polymorphs, solvates
amorphous, cocrystals, salts

25. Why is solution phase equilibria essential
to control cocrystal solubility/stability?
RHA – 1:1 cocrystal of R and HA
R – nonionizable drug
HA – weakly acidic coformer

26. 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
⎟
⎟
⎠
⎞
⎜
⎜
⎝
⎛
+
= +
]
[
1
cocrystal
H
K
K
S 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

27. Cocrystal solubility is sensitive to
coformer concentration and pH
• Cocrystal has a pH max
– pH where Scc = Sdrug
at [R]T = [A]T
• At pH > pHmax, Scc > Sdrug
• Eutectic points are pH dependent
– [R]eu and [A]eu where Scc =Sdrug
1:1 RHA, nonionizable drug (R), acidic coformer (HA), coformer pKa = 3.0.
Bethune, S.; Huang, N, Jayasankar, A.; Rodríguez-Hornedo, N. Crystal Growth &Design,2009
Drug solubility
Cocrystal solubility
pH max
Cocrystal solubility and stability can depend strongly on pH

28. Cocrystal solubility and
stability dependence on pH
1:1 RHA nonionizable drug (R), acidic coformer (HA), coformer pKa = 3.0.
Bethune, S.; Huang, N, Jayasankar, A.; Rodríguez-Hornedo, N. Crystal Growth &Design, 2009
⎟
⎠
⎞
⎜
⎝
⎛
+
= +
]
[
1
]
[
]
[
H
K
R
K
A a
eu
sp
eu
Drug solubility
Cocrystal solubility
1.0
0.5
1.5
2.0
2.5
3.0
pH max
Eutectic
concentration
(mM)
pH

29. Solubility and [coformer]tr as a function of pH
⎟
⎟
⎠
⎞
⎜
⎜
⎝
⎛
+
+
=
+
+
HAB
a
HAB
a
tr
sp
tr
K
H
H
K
R
K
AB
,
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 coformer
ionization predict experimental behavior
Carbamazepine-4 amino-benzoic acid hydrate cocrystal (2:1)
Bethune, S.; Huang, N, Jayasankar, A.; Rodríguez-Hornedo, N. Crystal Growth &Design, 2009

30. Customize solubility-pH dependence with cocrystals
2:1 nonionizable API, amphoteric ligand
carbamazepine-4-aminobenzoic acid
cocrystal
drug
pKa,ligand = 4.8, 2.6
solubility!
pH
pKa,drug = 3.7
pKa, coformer = 3.0, 4.3
2:1 basic API, acidic ligand
Itraconazole-tartaric acid
solubility
1:1 zwitterionic API, acidic ligand
gabapentin-3-hydroxybenzoic acid
cocrystal
drug
pKa,API = 3.9, 10.1
pKa,ligand = 3.7
solubility!
1:1 nonionizable API, acidic ligand
carbamazepine-salicylic acid
drug
pKa,ligand = 3.0
solubility!
pH
cocrystal
Bethune, S.; Huang, N, Jayasankar, A.; Rodríguez-Hornedo, N. Crystal Growth &Design, 2009

31. Surfactants
Are commonly used
– in pharmaceutical development
– in dissolution media
– as formulation aids
to enhance wetting and solubility of hydrophobic drugs
Whereas the micellar solubilization of single component crystals
has been thoroughly studied, that of cocrystals is less well known.
Key question:
How do surfactants that solubilize drug, influence cocrystal
solubility?
Scocrystal,total
Scocrystal,aq
=
Sdrug,total
Sdrug,aq
?

32. Surfactant effect on cocrystal conversion in aqueous media
CBZ-SLC CBZ dihydrate
CBZ-SLC CBZ-SLC
Huang, N. and Rodríguez-Hornedo, N. Crystal Growth & Design (2010)
Carbamazepine-salicylic acid (1:1)
Surfactant stabilizes cocrystal
Is this a kinetic or a thermodynamic effect?
What are the underlying mechanisms?

33. Surfactant effect on eutectic concentrations
Carbamazepine-salicylic acid (1:1)
Keu = 4.8
• Keu decreases with SLS
Keu >1 in water
Keu <1 in 1%SLS
• There is a reversal in
thermodynamic stability
• Cocrystal becomes less
soluble and more stable
than drug
Ignoring this behavior will lead to incorrect cocrystal solubility assessment
SLS 0.24% (CMC)
Scc 2.3 Sdrug
Keu = 0.6
0.8 Sdrug
Huang, N. and Rodríguez-Hornedo, N. Crystal Growth & Design (2010)

34. (RHA, cocrystal)
(aqueous pseudophase)
(micellar pseudophase)
Ksp
Ks
R
Micellar solubilization of cocrystal components and
cocrystal solubility
Huang, N. and Rodríguez-Hornedo, N. Crystal Growth & Design (2010)
hydrophobic drug R
hydrophilic coformer HA

35. Micellar solubilization and cocrystals
Equilibrium reactions
Cocrystal solubility can be expressed by considering the above equilibria
For the case where only drug is solubilized by micelle (Ks
HA = 0) and [HA]aq = [HA]T)
Huang, N. and Rodríguez-Hornedo, N. Crystal Growth & Design (2010)

36. Micellar solubilization of a hydrophobic drug
in aqueous solution
and [M]m = [M]T - CMC
SR,aq
[M]T, total surfactant concentration
where
Huang, N. and Rodríguez-Hornedo, N. Crystal Growth & Design (2010)

37. Micellar solubilization can impart thermodynamic
stability to cocrystal phase
Saturation curves intersect at a
critical stabilization concentration (CSC)
Scocrystal = Sdrug
at [M]T>CSC
cocrystal is stable
[M]T, total surfactant concentration
Huang, N. and Rodríguez-Hornedo, N. Crystal Growth & Design (2010)

38. Cocrystal solubility dependence on Ks and
surfactant concentration
Due to differential solubilization,
Scocrystal is dependent on the relative
magnitude of Ks
R compared to Ks
HA
The critical stabilization concentration
(CSC) jncreases with coformer
solubilization
Huang, N. and Rodríguez-Hornedo, N. Crystal Growth & Design (2010)

39. Cocrystal solubility and CSC
Predicted and experimental behavior
Huang, Rodríguez-Hornedo, Submitted to J Pharm Sci, 2011.
Cocrystal and drug solubilities converge as they approach CSC

40. CSC can be evaluated by several methods
1. solid phase stability as a function of [surfactant]
2. cocrystal solubility in water with equations that
describe micellar solubilization
3. cocrystal solubility as a function of [surfactant]

41. CSC: cocrystal stability as a function of surfactant
concentration by solid phase analysis (1)
CBZ-SAC (1:1), pH 2.2
unstable
stable
Huang, Rodríguez-Hornedo, J Pharm Sci, 2011

42. CSC: Predicted from measured cocrystal aqueous
solubility and mathematical equations (2)
Huang, Rodríguez-Hornedo, J Pharm Sci, 2011
( )
= + R
R,T R,aq s
S S 1 K [M]
( ) +
⎛ ⎞
= + + +
⎜ ⎟
⎝ ⎠
a
R HA
RHA,T sp s s
K
S K 1 K [M] 1 K [M]
[H ]
Cocrystal Drug

43. CSC: Measure cocrystal and drug solubilities as a
function of surfactant concentration (3)
Huang, Rodríguez-Hornedo, J Pharm Sci, 2011.

44. Cocrystal solubility and CSC
Predicted and experimental behavior
Huang, Rodríguez-Hornedo, J Pharm Sci, 2011.

45. CSC values of CBZ cocrystals
Cocrystal pH
Scocrystal/Sdrug
in terms of
CBZ mM
CSC range
measured from
solid phase
stability in SLS
solutions (1)
mM SLS
CSC calculated from
measured cocrystal
solubility in water (2)
mM SLS
CSC range
measured from
cocrystal solubility
in SLS solutions (3)
mM SLS
CBZ-SLC (1:1) 3.0 2.5 15 < CSC ≤ 20
23 (CMC = 9 mM)
20 (CMC = 6 mM)
18 < CSC < 27
CBZ-SAC (1:1) 2.2 4.5 50 < CSC ≤ 55 44 35 < CSC < 50
CBZ-4ABA-HYD (2:1) 4.0 3.5 69 < CSC ≤ 104 92 70 < CSC < 140
CBZ-SUC (2:1) 3.1 4.5 120 < CSC ≤ 140 187 140 < CSC
Within the same cocrystal stoichiometry, higher cocrystal solubility → higher CSC
Between stoichiometries, higher drug content → higher CSC
Results from the three methods are in very good agreement
Huang, Rodríguez-Hornedo, J Pharm Sci, 2011.

46. A useful estimate of the surfactant influence on cocrystal
solubilization from knowledge of drug solubilization
This expression is obtained by combining equations that describe micellar
solubilization of drug and cocrystal
Drug (SR, total) =
Cocrystal (SRHA, total) =
Scocrystal,total = Scocrystal,aq
Sdrug,total
Sdrug,aq

47. A useful estimate of the surfactant influence on cocrystal
solubilization from knowledge of drug solubilization
Scocrystal,total
Scocrystal,aq
=
Sdrug,total
Sdrug,aq
⎛
⎝
⎜
⎞
⎠
⎟
n
n+m
For a cocrystal RnXm

48. Preferential solubilization modulates thermodynamic
stability of cocrystals
Huang, Rodríguez-Hornedo, CrystEngComm 2011.
- In the absence of surfactant
Scc, total > Sdrug, total
cocrystal to drug conversion is favorable
- In surfactant solution above CSC,
Scc, total < Sdrug, total
cocrystal to drug conversion is unfavorable
Cocrystal becomes thermodynamically stable!
Under stoichiometric solution composition

49. Huang, Rodríguez-Hornedo, CrystEngComm 2011.
• synthesize cocrystals under
stoichiometric solution conditions
• protect cocrystal from conversion during
development, dissolution and storage
Implications for cocrystal synthesis and
development

50. Cocrystal CSC is highly sensitive to pH
Huang, Rodríguez-Hornedo, submitted to JPharmSci (2011) Ksp = 1 mM2, Ks
R = 1 mM-1, pKa = 4, SR,aq = 0.2 mM
cocrystal
drug
CSC

51. Stability indicating thermodynamic
parameters for solid forms
• Polymorphs: Transition temperature
• * Hydrates/anhydrous: Critical water activity or critical RH
• * Salts: pHmax
• Amorphous: Tg, glass transition temperature
• * Cocrystals: Keu, or [coformer]eu and [drug]eu, pHmax, CSC
• * Cocrystal hydrates: …..+ critical water activity
* Equilibria represent eutectic points
where 2 solid phases coexist in eq with solution phase.

52. 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?

53. Summary
• Cocrystal eutectic or transition concentrations
– are key indicators of thermodynamic stability and solubility
– guide cocrystal and additive selection with reduced material and time
requirements
• Cocrystal solubility and stability can be engineered via solution
phase chemistry
– ionization and complexation of cocrystal components
– micellar solubilization of cocrystal components
– polymer or other additive interactions with cocrystal components
• Preferential solubilization of cocrystal components explains the
reversal in thermodynamic stability of cocrystal and drug crystal
(CSC)
– provides a rational basis for surfactant or additive selection
– has important implications on process and formulation design of
cocrystals

54. University of Michigan
• Neal Huang, PhD
• David Good, PhD
• Sarah Nehm (Bethune), PhD
• Jay Jayasankar, PhD
• Sreenivas Reddy, PhD
Acknowledgements
Financial Support
• NIH Training Grant
• AFPE Predoctoral Fellowship
• Warner Lambert, F. Lyons, G. and P. Amidon
Fellowships from College of Pharmacy,
University of Michigan
Thanks to you for participating
and
to Crystal Pharmatech for sponsoring this webinar

55. 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).
• 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).
• D. Good and N. Rodríguez-Hornedo, Cocrystal Eutectic Constants and Prediction of Solubility Behavior, Crystal Growth and
Design, 10: 1028-1032 (2010).
• N. Huang and N. Rodríguez-Hornedo, Effect of Micellar Solubilization on Cocrystal Solubility and Stability, Crystal Growth and
Design, DOI: 10.1021/cg1002176, Web published April 2010.
• A. Jayasankar, L. Roy, and N. Rodríguez-Hornedo, Transformation Pathways of Cocrystal Hydrates when Coformer Modulates
Water Activity, Journal of Pharmaceutical Sciences, (2010).
• D. Good, C. Miranda and N. Rodríguez-Hornedo, Dependence of Cocrystal Formation and Thermodynamic Stability on Moisture
Sorption by Amorphous Polymer, CrystEngComm, (2010).