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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
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
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
• 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
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
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
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
Polymorphism Screening
Form C
50ºC
100ºC
120ºC
140ºC
Form D
G
Metastableforms
Form A
B
C and D
Enantiotropy
C D
Polymorphism Screening
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
Polymorphism Screening
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
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
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
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
αααα 2.1ββββN 4.2
ββββΟΟΟΟ 5.1
1
N H
Solution vs Solid State
OO
N NH N
αααα 2.8ββββN 4.0
ββββO 5.1
OO
N NH
H
NN
αααα 2.1ββββN 4.2
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
Two Polymorphs
Solid transition
120 ºC 130 ºC 150 ºC
Melting Crystallization from the meltSolid transition
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
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