Crystal Engineering of Organic Cocrystals by The Solid-State Grinding Approach

Top Curr Chem (2005) 254: 41– 70
DOI 10.1007/b100995
© Springer-Verlag Berlin Heidelberg 2005
Crystal Engineering of Organic Cocrystals

by the Solid-State Grinding Approach
Andrew V. Trask · William Jones ( )
University of Cambridge, Department of Chemistry, Lensfield Road, Cambridge CB2 1EW, UK
wj10@cam.ac.uk
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
2 A Historical Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
3 Cocrystals Produced Exclusively by the Grinding Approach . . . . . . . . . . . . 53
4 A Recent Enhancement to the Grinding Approach . . . . . . . . . . . . . . . . . 59
5 Structure Determination from Powder XRD Data . . . . . . . . . . . . . . . . . 64
6 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Abstract Crystal engineering of organic cocrystals is gaining interest across a variety of

disciplines. The solid-state grinding approach to preparing cocrystals is an alternative to the
traditional method of solution crystallisation, and possesses several distinct advantages. This
review first demonstrates that the approach of solid-state cocrystal preparation is well
established in the literature by providing a brief historical account of its applications. Several
cases are then examined in which certain cocrystal materials can be prepared only by solid-
state grinding methodologies. These examples underscore the importance of this approach
in the search for new cocrystal materials. This is particularly advantageous when searching
for new cocrystal stoichiometries. The focus then turns to a recent modification of the solid-
state grinding process, in which small quantities of solvent are introduced either to increase
solid-state cocrystallisation kinetics or to provide polymorph control – the latter having par-
ticular significance in the pharmaceutical field. Finally, a significant analytical advancement
with direct implications for the field of solid-state cocrystal preparation is considered by
examining recent examples of crystal structure determination from powder X-ray diffraction
data.
Keywords Solid-state grinding · Cocrystal formation · Crystal engineering ·

Pharmaceutical materials · Polymorphism
Abbreviations
XRD X-ray diffraction
42 A. V. Trask · W. Jones
1
Introduction
One flourishing area in the field of crystal engineering is based upon the for-
mation of crystalline molecular complexes, or cocrystals. Cocrystals may be de-
fined as materials which contain two or more discrete molecular entities in the
crystal lattice. Crystal engineering, when applied to cocrystal systems, gener-
ally involves the design and study of new materials in order to widen the
knowledge base of successful engineering strategies, and the application of
that knowledge to provide cocrystals with specific properties for a multitude
of applications. Crystal engineering is actively applied within a variety of
scientific disciplines as diverse as materials science, nanotechnology and the
pharmaceutical industry [1].
In designing a cocrystal, it is necessary to evaluate the potential intermole-
cular interactions that a given molecule may exhibit. Due to their robust and
directional nature, hydrogen bonds are a valuable tool in cocrystal synthesis.
Hydrogen bonds of varying strengths may be employed, including the tradi-
… … …
tional OH O and OH N strong hydrogen bonds and the weaker CH p or
…
CH Cl variety. Other intermolecular associations which may be employed in
…
cocrystal design include halogen–halogen, nitro–nitro and p p interactions,
among others [2–4].
Cocrystals are often prepared by a traditional solution crystallisation ap-
proach such as solvent evaporation, cooling, or anti-solvent addition. There
are a number of reasons for the popularity of the solution-based approach.
Solution crystallisation can yield large, well-formed single crystals, from which
one may easily evaluate crystal habit and surface features. Analysis of the dif-
fraction pattern of a single crystal is typically the best means of obtaining an
absolute crystal structure determination. Further, solution crystallisation is an
established and effective purification step.
There are, however, several accompanying drawbacks to the solution-based
approach to cocrystal formation. The solubility of the starting components is
one obstacle, as a suitable solvent for all ingoing materials must be identified
before cocrystallisation may occur. Unexpected solvate formation may also
pose a problem. The solvent employed in the cocrystallisation may possess the
ability to interfere with the desired cocrystal intermolecular interactions,
and thus may become incorporated into the crystal lattice. In this way, solvate
formation hampers rational cocrystal design. In the case of polymorphic
cocrystal systems, it could be the case that solution crystallisation leads to an
undesired kinetically controlled metastable polymorph. An additional draw-
back to cocrystallisation from solution is the typically large volume of solvent
necessary to prepare the cocrystals. As cocrystals emerge as products in
industrial applications, avoidable waste streams will be increasingly scrutinised
as environmentally and fiscally imprudent.
An alternative to the solution-based approach exists in the approach of
solid-state grinding. The act of solid-state grinding to induce chemical change,

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Top Curr Chem (2005) 254: 41– 70

Crystal Engineering of Organic Cocrystals

3 Cocrystals Produced Exclusively by the Grinding Approach . . . . . . . . . . . . 53

4 A Recent Enhancement to the Grinding Approach . . . . . . . . . . . . . . . . . 59

5 Structure Determination from Powder XRD Data . . . . . . . . . . . . . . . . . 64

Abstract Crystal engineering of organic cocrystals is gaining interest across a variety of

Keywords Solid-state grinding · Cocrystal formation · Crystal engineering ·

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