Professional Documents
Culture Documents
Review Pharmaceutical Co-Crystals
Review Pharmaceutical Co-Crystals
Pharmaceutical Co-Crystals
PEDDY VISHWESHWAR, JENNIFER A. McMAHON, JOANNA A. BIS, MICHAEL J. ZAWOROTKO
Department of Chemistry, University of South Florida, CHE205, 4202 East Fowler Avenue, Tampa, Florida 33620
Keywords: crystal engineering; hydrogen bond; pharmaceutical co-crystal; polymorphism; supramolecular synthesis
INTRODUCTION
Crystalline forms of active pharmaceutical ingredients, APIs, have traditionally been limited
to salts, polymorphs, and solvates (including
hydrates).1 Given the high intrinsic value of APIs
and the importance of structure and composition
in the context of both intellectual property
and bioavailability, it is perhaps surprising
that systematic approaches to the development
of a new broad class of API, pharmaceutical cocrystals, have only been attempted in recent
years.216 Co-crystals represent a long known
class of compounds, a prototypal example of
which is quinhydrone, which was reported at
least as early as 1844 and 1893.17,18 However,
how narrowly or broadly one defines the term cocrystal remains a matter of topical debate. For
Correspondence to: Michael J. Zaworotko (Telephone: 813974-4129; Fax: 813-974-3203; E-mail: xtal@usf.edu)
Journal of Pharmaceutical Sciences, Vol. 95, 499516 (2006)
2006 Wiley-Liss, Inc. and the American Pharmacists Association
499
500
VISHWESHWAR ET AL.
PHARMACEUTICAL CO-CRYSTALS
501
502
VISHWESHWAR ET AL.
pharmaceutical co-crystals. The polymorphic tendency of APIs varies greatly, but the consensus
seems to be that most APIs are at some time or
another going to display polymorphic behavior.
However, the extent of polymorphism of APIs is
almost certainly going to be limited to a handful of
crystal forms. Solvates (including hydrates) can
be more numerous, and in certain cases very large
numbers of solvates can be observed. Indeed,
sulfathiazole is inordinately promiscuous in
terms of solvate formation, with over one hundred
solvates found.85 Salt forms can also be numerous, with over 90 acids and 30 bases considered
suitable for pharmaceutical salt selection.86
Examples of compounds possessing a dozen or
more crystalline salt forms have been published.87,88 However, it is important to remember
that salt formation is generally directed at one
acidic or basic functional group. In contrast, cocrystals can simultaneously address multiple
functional groups in an API, including those that
are not acidic or basic enough to form a salt. In
addition, the space is not limited to binary
combinations since tertiary68 and quaternary89
co-crystals are realistic possibilities. Co-crystal
formers that are suitable for pharmaceutical use
remain to be enumerated fully, but there are over
a hundred solid materials with generally
regarded as safe (GRAS) status (including food
additives and other well-accepted substances) and
sub-therapeutic amounts of eminently safe drug
substances, such as aspirin and acetaminophen,
are also legitimate co-crystal formers. The space
of pharmaceutical co-crystals would therefore
appear to be large with thousands of possibilities
for any given drug, especially when at least two
hydrogen bonding moieties are present in an API.
Furthermore, it is unlikely that applications of cocrystals in the context of the pharmaceutical
industry will be limited to form and formulation.
For example, a co-crystal might be used to isolate
or purify an API during its processing and the cocrystal former could be discarded prior to formulation. In addition, co-crystallization with
homochiral co-crystal formers might be used to
separate enantiomers.
PHARMACEUTICAL CO-CRYSTALS
503
No. of Entries
130448
9621
94900
1600a
1487b
21a
100c
7.3c
72.7c
1.7d
1.1c
1.5d
The CSD searches were conducted with only organic crystal structures. A CSD search with only
organics as a parameter also retrieves structures containing metals like Na, K, Ca etc. Such entries
were excluded from the statistics quoted above (CSD Conquest 1.7, Aug05 update, 355,071 entries).
a
Only one refcode was counted for each polymorphic compound.
b
Co-crystals sustained by strong hydrogen bonds.
c
Percentages with respect to organic crystal structures only.
d
Percentages with respect to 94,900and 1,487 sub-totals, respectively.
McCrone defined polymorphism as a solid crystalline phase of a given compound resulting from
the possibility of at least two different arrangements of the molecules of that compound in the
solid state.90 McCrones definition is particularly
appropriate in the context of APIs since they
manifest themselves via multiple modes of selforganization or self-assembly. Similar issues face
agrochemicals, explosives, dyes, pigments, flavors, and confectionery products.
As revealed by Table 1,91 polymorphism92 95
has been observed in ca. Single component
crystals (1.7%) versus ca. 1.5% of co-crystals.
These numbers are likely to be significantly
underreported. However, there are so few examples of polymorphic co-crystals that it would be
appropriate to address such structures individually in order to determine the origin of the
polymorphism. There are 21 hydrogen bonded
co-crystals in the CSD that exhibit polymorphism
but there are only 11 for which atomic coordinates
are available for all the forms: (CSD refcodes)
AJAJEA, 01; EXUQUJ, 01; HADKUT, 01; JICTUK01, 10; MACCID, 01, 02; MUROXA, 01;
PDTOMS10, 11; PTZTCQ, 01; QUIDON, 02;
TECCAF01, 02; and ZIGPAG, 01. A detailed
analysis96 of the crystal packing in these 11
compounds indicates that their polymorphism is
not linked to the supramolecular synthons that
sustain the co-crystal. Rather, it appears to be the
result of subtle conformational or packing
changes. Indeed, to our knowledge there have
not yet been any examples of supramolecular
isomerism45 in co-crystals. If these observations
hold true over a broader range of compounds it
would suggest that co-crystals represent a desirDOI 10.1002/jps
504
VISHWESHWAR ET AL.
DOI 10.1002/jps
PHARMACEUTICAL CO-CRYSTALS
505
506
VISHWESHWAR ET AL.
PHARMACEUTICAL CO-CRYSTALS
507
508
VISHWESHWAR ET AL.
PHARMACEUTICAL CO-CRYSTALS
509
Figure 7. Views of the intermolecular hydrogen bonding in 2a (a) and 2b (b). Note the
carboxylic acid-amide supramolecular heterosynthon, IV in both the co-crystals and
tetrameric motif in 2b.
510
VISHWESHWAR ET AL.
Figure 8. Examples of fake pharmaceutical cocrystals found in the literature: (a) HEKRUK, Trimethoprim sulfametrole, a salt. (b) JATMEW, 3-[2(N0 , N0 -dimethylhydrazino)-4-thiazolylmethylthio]-N2sulfamoylpropionamidine maleic acid. Structural parameters suggest formation of a salt. (c) SAGQEWa
propionic acid solvate of mebendazole.
PHARMACEUTICAL CO-CRYSTALS
CONCLUSIONS
Whereas there is a clear need for greater understanding and control of crystalline forms in the
context of pharmaceutical development, the concepts of supramolecular synthesis, and crystal
engineering remain largely underexploited. This
contribution highlights the need to think supramolecularly for structural analysis of APIs. In
particular, applying the concepts of supramolecular synthesis and crystal engineering to the
development of pharmaceutical co-crystals represents a paradigm that offers many opportunities
related to drug development and delivery. It
seems inevitable that pharmaceutical co-crystals
will gain a broader foothold in drug formulation.
7.
8.
9.
ACKNOWLEDGMENTS
We are grateful for financial support from Transform Pharmaceuticals, 29 Hartwell Avenue, Lexington, MA 02421.
10.
REFERENCES
11.
DOI 10.1002/jps
12.
13.
14.
15.
16.
511
512
VISHWESHWAR ET AL.
DOI 10.1002/jps
PHARMACEUTICAL CO-CRYSTALS
DOI 10.1002/jps
513
514
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
VISHWESHWAR ET AL.
DOI 10.1002/jps
PHARMACEUTICAL CO-CRYSTALS
108.
109.
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.
121.
DOI 10.1002/jps
122.
123.
124.
125.
126.
127.
128.
129.
130.
131.
132.
133.
134.
515
516
VISHWESHWAR ET AL.
142.
143.
144.
145.
146.
147.
DOI 10.1002/jps