Transferability of cocrystallization propensities between aromatic and heteroaromatic amides
Struct Chem
Transferability of cocrystallization propensities between aromatic and heteroaromatic amides
Piotr Cysewski 0 1
0 Chair and Department of Physical Chemistry, Pharmacy Faculty, Collegium Medicum of Bydgoszcz, Nicolaus Copernicus University in Torun ́ , Kurpin ́skiego 5, 85-950 Bydgoszcz , Poland
1 & Piotr Cysewski
New virtual cocrystal screening was proposed taking advantage of the similarities between cocrystallization landscapes of different compounds. Assuming that cocrystallization propensities can be modeled by miscibility affinities of liquid components under supercooled conditions, the quantitative rules of likeness were formulated and validated for 45 aromatic and heteroaromatic amides interacting with a variety of coformers. The most important finding comes from the observed linear trends between the values of mixing enthalpies of amides with respect to a reference molecule. Particularly isonicotinamide was found as a very convenient comparative system since it constitutes 97 binary cocrystals. Many experimentally observed cocrystals were used for supporting the analogy hypothesis, which states that a properly selected reference molecule, for which cocrystals were experimentally documented, can provide practical information about cocrystallization propensities of another compound provided that two criterions are met, namely sufficiently high similarities and high enough affinities. Hence, it is not necessary to perform experimental cocrystallization of every pair of coformers since miscibility in the solid state of one compound can be transferred
Cocrystal screening; Mixing enthalpy; COSMO-RS; Active pharmaceutical ingredients; Amides; Solubility
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to another one at least in the case of aromatic or
heteroaromatic amides.
Introduction
Cocrystals are important products of materials science, and
many branches of industry take advantage [
1
] of the
possibility of tuning properties of solids [
2
]. This covers,
among other domains, the pharmaceutical [
3, 4
],
agrochemical [
5, 6
] or high-energy industries [
6–8
]. Not all
multicomponent solids are classified as cocrystals [
9
] since
at least two criterions must be met [
9–13
]. First of all, after
cocrystallization, the molded homogeneous phase should
comprise stoichiometric proportions of the components.
Besides, all coformers should be solids under ambient
conditions. The possibility of alteration of the
physicochemical properties after successful cocrystallization is
especially welcomed in the case of active pharmaceutical
ingredients (API). There are many examples of significant
improvements of API behaviors both in vivo and in vitro
[
14, 15
] due to enhancement of pharmacokinetic properties
as solubility [
4, 16, 17
] and bioavailability [
18–20
]. Also
many other physicochemical properties can be modulated
by cocrystallization including stability [
21–24
],
hygroscopicity [
25
] and prolonged shelf life [
26
]. Among many
drugs, aromatic amides acting either as APIs or as
excipients attract nowadays substantial attention [
27–35
]. These
compounds are known for their important roles in medical
applications. For example, vitamin B3 or PP are synonyms
for nicotinamide, which is an important compound
functioning as a component of the coenzyme NAD [
36
].
Pyrazinamide with its bacteriostatic and bacteriocidal
activities, acting as an efficient antitubercular agent [
37
],
was also recognized as an important medication. Also
salicylamide and ethenzamide are known as analgesic and
antipyretic drugs [
38
]. They are used as non-prescription
painkillers belonging to nonsteroidal anti-inflammatory
agents with medicinal uses similar to those of aspirin.
Temozolomide, known under different brand names as
Temodar, Temodal or Temcad, is an orally administered
alkylating agent used in chemotherapy for treatment of
some types of brain cancer and a first-line treatment for
glioblastoma multiforme [
39, 40
].
Majority of aromatic or heteroaromatic amides are
poorly soluble in water, and cocrystallization with more
soluble formers might be one of the remedies for this
limitation [
4
]. Although many pharmaceutical cocrystals
containing amides have been studied [
27–35
], the data
deposited in the Cambridge Structural Database (CSD) [
41
]
are rather variable in the sense that many coformers were
used for synthesis of diverse cocrystals. For example
cocrystals of fumaric acid with benzamide, isonicotinamide
or nicotinamide are known under refcodes YOPBUB,
LUNNOX and EDAPOQ, respectively, but there is no
information about solids of these coformers with
temozolomide. There are information about 4-hydroxybenzoic
acid and 4-nitrobenzoic acid cocrystallization with
isonicotinamide, but cocrystal of nicotinamide is known only
with the former compound. There are many such ‘‘gaps,’’
which can be highlighted by retrieving of corresponding
data from the latest edition of the CSD. Of course, lack of
the structu (...truncated)