Contents

Chapter 1 Pharmaceutical Salts and Co-crystals: Retrospect and

Prospects 1
Gautam R. Desiraju
Acknowledgement 6
References 6
Chapter 2 Fundamental Aspects of Salts and Co-crystals 9
Andrew D. Bond
2.1 Introduction 9
2.2 Denitions: Salts and Co-crystals 10
2.3 Supramolecular Chemistry, Intermolecular
Interactions and Crystal Packing 12
2.3.1 Supramolecular Synthons 13
2.3.2 The Cambridge Structural Database 14
2.3.3 Supramolecular Yield 17
2.4 Design Strategies for Salts and Co-crystals 18
2.4.1 Synthon Hierarchy and Synthon Interference 18
2.4.2 Ternary and Quaternary Co-crystals 22
2.4.3 Salts or Co-crystals? 24
2.5 Concluding Remarks 26
References 27
Chapter 3 Role of Fluorine in Weak Interactions in Co-crystals 29
Seetha Lekshmi Sunil, Susanta K. Nayak, Venkatesha
R. Hathwar, Deepak Chopra and Tayur N. Guru Row
3.1 Introduction 29
3.1.1 Co-crystals and Salts 31
RSC Drug Discovery Series No. 16
Pharmaceutical Salts and Co-crystals
Edited by Johan Wouters and Luc Que re
r Royal Society of Chemistry 2012
Published by the Royal Society of Chemistry, www.rsc.org
vii
D
o
w
n
l
o
a
d
e
d

o
n

1
6
/
0
6
/
2
0
1
3

0
1
:
2
1
:
0
1
.

P
u
b
l
i
s
h
e
d

o
n

0
4

N
o
v
e
m
b
e
r

2
0
1
1

o
n

h
t
t
p
:
/
/
p
u
b
s
.
r
s
c
.
o
r
g

|

d
o
i
:
1
0
.
1
0
3
9
/
9
7
8
1
8
4
9
7
3
3
5
0
2
-
F
P
0
0
7
3.2 Role of Intra- and Intermolecular Interactions 32
3.2.1 HalogenHalogen Interactions 32
3.3 Debate on Organic Fluorine 34
3.3.1 Topological Analysis of the Electron Density
of Compounds Containing Organic Fluorine:
Insights from Experimental and Theoretical
Electron Density Analysis 35
3.4 Conclusions 38
Acknowledgement 39
References 39
Chapter 4 Polymorph Prediction of Small Organic Molecules,
Co-crystals and Salts 44
Frank J. J. Leusen and John Kendrick
4.1 Introduction 44
4.1.1 Relevance of Crystal Structure Prediction 44
4.1.2 Historic Overview 45
4.2 Theory of Crystal Structure Prediction 47
4.2.1 Lattice Energy Calculations 47
4.2.2 Searching for Potential Structures 55
4.3 Application Examples 61
4.3.1 Blind Tests of Crystal Structure Prediction 61
4.3.2 Co-crystals 67
4.3.3 Solvates 73
4.3.4 Salts 76
4.4 Outlook 82
References 83
Chapter 5 Shape and Polarity in Co-crystal Formation:
Database Analysis and Experimental Validation 89
L. Fabian and T. Friscic
5.1 Introduction 89
5.2 Database Analysis of Molecular Properties
in Co-crystals 92
5.2.1 Compilation of the Co-crystal Database 92
5.2.2 Statistical Analysis 93
5.2.3 Results and their Interpretation 93
5.3 Experimental Testing of Shape and Polarity Preferences 97
5.3.1 Co-crystal Screening Methods 98
5.3.2 Prioritising Screening Experiment by
Molecular Descriptors 99
5.3.3 Combined Eect of Synthons and Shape 102
5.3.4 Identication of New Intermolecular
Interactions 104
viii Contents
D
o
w
n
l
o
a
d
e
d

o
n

1
6
/
0
6
/
2
0
1
3

0
1
:
2
1
:
0
1
.

P
u
b
l
i
s
h
e
d

o
n

0
4

N
o
v
e
m
b
e
r

2
0
1
1

o
n

h
t
t
p
:
/
/
p
u
b
s
.
r
s
c
.
o
r
g

|

d
o
i
:
1
0
.
1
0
3
9
/
9
7
8
1
8
4
9
7
3
3
5
0
2
-
F
P
0
0
7
View Online
5.4 Conclusions 108
Acknowledgements 108
References 108
Chapter 6 Role of Co-crystals in the Pharmaceutical Development
Continuum 110
Nate Schultheiss and Jan-Olav Henck
6.1 Introduction 110
6.2 Common Solid-state Strategies for API
Property Modication 111
6.3 Co-crystals and their Characterization 112
6.4 Co-crystals and their Role in the Pharmaceutical
Development Process 113
6.5 Using Co-crystals to Alter Physicochemical Properties
of APIs 115
6.5.1 Stability 115
6.5.2 Solubility 116
6.5.3 Bioavailability 119
6.6 Additional Development Factors for Co-crystals 121
6.6.1 Taste Masking 121
6.6.2 Scale-up 123
6.6.3 Polymorphism 123
6.7 Conclusions 124
Acknowledgement 125
References 125
Chapter 7 Solid Forms and Pharmacokinetics 128
N. Biswas
7.1 Introduction 128
7.1.1 Impact of Solid Form on the Pharmacokinetics 131
7.1.2 Important PK Parameters 133
7.2 Dissolution and Solubility 135
7.2.1 Eect of dissolution on absorption 136
7.2.2 Impact of Dissolution Rate on Bioavailability 137
7.2.3 Case Studies Demonstrating the Relationship
Between Dissolution Rate and Bioavailability 138
7.2.4 Adverse Eects 141
7.3 Signicance of Altered Dissolution Properties 142
7.3.1 Case Studies 142
7.4 Selection of Solid Form Based on the Therapeutic
Condition: Case Study of Indinavir 144
7.5 Manipulation of the Pharmacological Action of a
Drug by Co-Crystallization: Case Study of Insulin 146
ix Contents
D
o
w
n
l
o
a
d
e
d

o
n

1
6
/
0
6
/
2
0
1
3

0
1
:
2
1
:
0
1
.

P
u
b
l
i
s
h
e
d

o
n

0
4

N
o
v
e
m
b
e
r

2
0
1
1

o
n

h
t
t
p
:
/
/
p
u
b
s
.
r
s
c
.
o
r
g

|

d
o
i
:
1
0
.
1
0
3
9
/
9
7
8
1
8
4
9
7
3
3
5
0
2
-
F
P
0
0
7
View Online
7.6 Toxicity Caused by Co-crystal Formation 149
7.7 Conclusion 150
References 151
Chapter 8 Application of Mechanochemistry in the Synthesis and
Discovery of New Pharmaceutical Forms: Co-crystals, Salts
and Coordination Compounds 154
Tomislav Friscic and William Jones
8.1 Introduction 155
8.2 Historical Overview 155
8.3 Overview of Mechanochemical Methodologies 157
8.3.1 Comparison with Solvent-based
Co-crystallisation Techniques 157
8.3.2 Screening for Co-crystals Using Neat and
Liquid-assisted Grinding 159
8.3.3 Control of Polymorphism Using
Mechanochemistry 161
8.3.4 Control of Co-crystal Stoichiometry Using
Mechanochemistry 162
8.4 Examples of Pharmaceutical Co-crystal Synthesis and
Screening Using Mechanochemistry 165
8.5 Mechanistic Aspects of Co-crystal
Mechanosynthesis 168
8.5.1 Mass Transfer Mediated by a Vapour Phase 168
8.5.2 Mechanochemical Co-crystallisation Mediated
by a Eutectic 170
8.5.3 Mechanochemical Co-crystallisation Mediated
by an Amorphous Phase 172
8.5.4 Kinetic Eects in the Mechanosynthesis of
Co-crystals 173
8.6 Three-component Pharmaceutical Solids 175
8.6.1 Chiral and Racemic Co-crystals and
Co-crystal-Co-crystal Reactions 175
8.6.2 Co-crystal Hydrates 176
8.6.3 Hostguest systems 178
8.7 Mechanochemical Synthesis of
Pharmaceutical Salts 179
8.8 Mechanochemical Synthesis of MetalOrganic
Pharmaceutical Derivatives 180
8.9 Conclusions 182
Acknowledgements 182
References 183
x Contents
D
o
w
n
l
o
a
d
e
d

o
n

1
6
/
0
6
/
2
0
1
3

0
1
:
2
1
:
0
1
.

P
u
b
l
i
s
h
e
d

o
n

0
4

N
o
v
e
m
b
e
r

2
0
1
1

o
n

h
t
t
p
:
/
/
p
u
b
s
.
r
s
c
.
o
r
g

|

d
o
i
:
1
0
.
1
0
3
9
/
9
7
8
1
8
4
9
7
3
3
5
0
2
-
F
P
0
0
7
View Online
Chapter 9 Co-crystallization in Solution and Scale-up Issues 188
E. Gagnie`re, D. Mangin, S. Veesler and F. Puel
9.1 Introduction 188
9.2 Concepts and Phenomenon Involved in a
Co-crystallization Process in Solution 189
9.2.1 Supersaturation 189
9.2.2 Nucleation 190
9.2.3 Crystal Growth 190
9.2.4 Dissolution 191
9.2.5 Metastable Phases and their Transition:
Solution-mediated Phase Transition (SMPT) 192
9.3 Thermodynamic and Kinetic Aspects of a
Co-crystallization Process 193
9.3.1 Phase Diagram 194
9.3.2 Relative Stability of the Solid Phases in
Solution 195
9.3.3 Kinetic Pathways in a Phase Diagram 197
9.4 Development of a Co-crystallization Process 204
9.4.1 Prerequisite 204
9.4.2 Co-crystal Screening 205
9.4.3 Determination of Operating Conditions in
Batch Mode 206
9.4.3.1 Choice of Safe Operating Regions
(Initial Conditions andPhase Diagram) 207
9.4.3.2 Seeding Strategy 207
9.4.3.3 Manipulation of Co-crystal
Components 208
9.5 Conclusions 208
Acknowledgements 209
References 209
Chapter 10 Analytical Techniques and Strategies for Salt/Co-crystal
Characterization 212
Susan M. Reutzel-Edens
10.1 Introduction 212
10.2 Analytical Techniques 213
10.2.1 X-ray Diraction 214
10.2.2 Thermal Analysis 216
10.2.3 Microscopy 219
10.2.4 Vibrational (Raman, IR) Spectroscopy 222
10.2.5 Solid State NMR Spectroscopy 223
10.2.6 Moisture Sorption Analysis 226
xi Contents
D
o
w
n
l
o
a
d
e
d

o
n

1
6
/
0
6
/
2
0
1
3

0
1
:
2
1
:
0
1
.

P
u
b
l
i
s
h
e
d

o
n

0
4

N
o
v
e
m
b
e
r

2
0
1
1

o
n

h
t
t
p
:
/
/
p
u
b
s
.
r
s
c
.
o
r
g

|

d
o
i
:
1
0
.
1
0
3
9
/
9
7
8
1
8
4
9
7
3
3
5
0
2
-
F
P
0
0
7
View Online
10.3 Integrated Approaches to the Solid State
Characterization of Salts and Co-crystals 227
10.3.1 Form Identication/Phase Purity 228
10.3.2 Proton Transfer in the Solid State 231
10.3.3 Thermodynamic Stability 237
10.3.4 Storage and Process-induced Phase
Transformations 242
10.4 Conclusions 243
References 243
Chapter 11 Co-crystal Solubility and Thermodynamic Stability 247
L. Roy, M.P. Lipert and N. Rodrguez-Hornedo
11.1 Introduction 247
11.2 Co-crystal Solubility 248
11.2.1 Key Concepts 248
11.2.2 Factors that Inuence Solubility 250
11.3 Tailoring Co-crystal Solubility via Solution
Phase Chemistry 253
11.3.1 Ionization 254
11.3.2 Micellar Solubilization 259
11.4 Co-crystal Thermodynamic Stability and Solubility
Evaluation 268
11.4.1 Co-crystal Thermodynamic Stability 268
11.5 Eutectic Point Measurement 272
11.6 Co-crystal Solubility Measurement 273
11.6.1 Thermodynamic Equilibrium Methods 273
11.6.2 Kinetic Methods 275
11.7 Conclusions 276
References 276
Chapter 12 Application of Phase Diagrams in Co-crystal Search and
Preparation 280
Timo Rager and Rolf Hilker
12.1 Introduction 280
12.2 Binary Phase Diagrams 281
12.3 Thermodynamic Selection Criteria
for Co-crystal Formers 284
12.4 Ternary Phase Diagrams 285
12.5 Thermodynamic Selection Criteria for Suitable
Preparation Conditions 289
12.6 Possible Failures in Co-crystal Search 291
xii Contents
D
o
w
n
l
o
a
d
e
d

o
n

1
6
/
0
6
/
2
0
1
3

0
1
:
2
1
:
0
1
.

P
u
b
l
i
s
h
e
d

o
n

0
4

N
o
v
e
m
b
e
r

2
0
1
1

o
n

h
t
t
p
:
/
/
p
u
b
s
.
r
s
c
.
o
r
g

|

d
o
i
:
1
0
.
1
0
3
9
/
9
7
8
1
8
4
9
7
3
3
5
0
2
-
F
P
0
0
7
View Online
12.7 Phase Diagrams for Most Ecient Co-crystal Search 293
12.8 Phase Diagrams for Optimized
Co-crystal Preparation 295
12.9 Conclusion 297
Further Reading 297
Chapter 13 Limits of the Co-crystal Concept and Beyond 300
Gerard Coquerel
13.1 Most Frequent Heterogeneous Equilibria Related to
Co-crystals 300
13.2 Compounds that could be Dened as Hybrid
SaltCo-crystals 303
13.2.1 Example 1: Resolution of Fenuramine 305
13.2.2 Example 2: Trimebutine Maleate 305
13.2.3 Example 3: a Hybrid SaltCo-crystal 305
13.3 Co-crystals of Alike Molecules (including
Enantiomers, Isomers, Diastereomers . . .) 306
13.4 Hostguest Compounds: Co-crystals at least
Partially Driven by Inclusion Phenomena
at the Molecular Level 311
13.5 Conclusions 314
Acknowledgements 315
References 315
Chapter 14 Co-crystals: Commercial Opportunities and Patent
Considerations 318
Marcel Homan and Jerey A. Lindeman
14.1 Introduction 319
14.2 Co-crystals Engineering Pharmaceutical
Properties/Creating Commercial Value 319
14.3 Denition of a Co-crystal 321
14.4 Patentability of Co-crystals 323
14.5 Information for Eective Co-crystal Patents 325
14.6 Conclusions 327
References 328
Chapter 15 Concluding Remarks using Piracetam as a Learning
Model 330
Johan Wouters, Anaelle Tilborg and Luc Quere
References 336
xiii Contents
D
o
w
n
l
o
a
d
e
d

o
n

1
6
/
0
6
/
2
0
1
3

0
1
:
2
1
:
0
1
.

P
u
b
l
i
s
h
e
d

o
n

0
4

N
o
v
e
m
b
e
r

2
0
1
1

o
n

h
t
t
p
:
/
/
p
u
b
s
.
r
s
c
.
o
r
g

|

d
o
i
:
1
0
.
1
0
3
9
/
9
7
8
1
8
4
9
7
3
3
5
0
2
-
F
P
0
0
7
View Online
Chapter 16 Monographs of most Frequent Co-Crystal Formers 338
Johan Wouters, Sandrine Rome and Luc Quere
16.1 Introduction 338
16.2 Monographs on Co-crystal Formers 340
Acknowledgements 340
References 377
Subject Index 383
xiv Contents
D
o
w
n
l
o
a
d
e
d

o
n

1
6
/
0
6
/
2
0
1
3

0
1
:
2
1
:
0
1
.

P
u
b
l
i
s
h
e
d

o
n

0
4

N
o
v
e
m
b
e
r

2
0
1
1

o
n

h
t
t
p
:
/
/
p
u
b
s
.
r
s
c
.
o
r
g

|

d
o
i
:
1
0
.
1
0
3
9
/
9
7
8
1
8
4
9
7
3
3
5
0
2
-
F
P
0
0
7
View Online