Propensity of salicylamide and ethenzamide cocrystallization with aromatic carboxylic acids

Propensity of salicylamide and ethenzamide cocrystallization with
aromatic carboxylic acids
Maciej Przybyłek a
, Dorota Ziółkowska b
, Karina Mroczyńska c
, Piotr Cysewski a,
⁎
a
Department of Physical Chemistry, Pharmacy Faculty, Collegium Medicum of Bydgoszcz, Nicolaus Copernicus University in Toruń, Kurpińskiego 5, 85-950 Bydgoszcz, Poland
b
University of Technology and Life Sciences in Bydgoszcz, Faculty of Chemical Technology and Engineering, Seminaryjna 3, 85-326 Bydgoszcz, Poland
c
Research Laboratory, Faculty of Chemical Technology and Engineering, Seminaryjna 3, 85-326 Bydgoszcz, Poland
a b s t r a c ta r t i c l e i n f o
Article history:
Received 7 January 2016
Received in revised form 13 February 2016
Accepted 15 February 2016
Available online 17 February 2016
Chemical compounds studied in this article:
Salicylamide (PubChem CID: 5147)
Ethenzamide (PubChem CID: 3282)
Benzoic acid (PubChem CID: 243)
Salicylic acid (PubChem CID: 338)
Acetylsalicylic acid (PubChem CID: 2244)
4-Acetamidobenzoic acid (PubChem CID:
19266)
2,6-Dihydroxybenzoic acid (PubChem CID:
9338)
3,4-Dihydroxybenzoic acid (PubChem CID: 72)
2,4-Dihydroxybenzoic acid (PubChem CID:
1491)
4-Hydroxybenzoic acid (PubChem CID: 135)
The cocrystallization of salicylamide (2-hydroxybenzamide, SMD) and ethenzamide (2-ethoxybenzamide, EMD)
with aromatic carboxylic acids was examined both experimentally and theoretically. The supramolecular synthe-
sis taking advantage of the droplet evaporative crystallization (DEC) technique was combined with powder dif-
fraction and vibrational spectroscopy as the analytical tools. This led to identification of eleven new cocrystals
including pharmaceutically relevant coformers such as mono- and dihydroxybenzoic acids. The cocrystallization
abilities of SMD and EMD with aromatic carboxylic acids were found to be unexpectedly divers despite high for-
mal similarities of these two benzamides and ability of the R2,2(8) heterosynthon formation. The source of diver-
sities of the cocrystallization landscapes is the difference in the stabilization of possible conformers by adopting
alternative intramolecular hydrogen boding patterns. The stronger intramolecular hydrogen bonding the weaker
affinity toward intermolecular complexation potential. The substituent effects on R2,2(8) heterosynthon proper-
ties are also discussed.
© 2016 Elsevier B.V. All rights reserved.
Keywords:
Salicylamide
Ethenzamide
Pharmaceutical cocrystals
Miscibility
Aromatic carboxylic acids
1. Introduction
Many pharmaceutical applications of multicomponent solids
such as cocrystals, salts, solvates and clathrates have been explored
recently (Fernandes et al., 2003; Grifasi et al., 2015; Jug and
Bećirević-Laćan, 2004; Salameh and Taylor, 2006; Shan and Zaworotko,
2008; Steed, 2013; Vishweshwar et al., 2006; Xu et al., 2014). Particularly,
the cocrystallization is a useful approach of solubility enhancement
(Childs et al., 2013; Good and Rodríguez-Hornedo, 2009; Grifasi et al.,
2015; McNamara et al., 2006) and other property improvements
(Hiendrawan et al., 2015a; Karki et al., 2009; Sanphui et al., 2015; Sun
and Hou, 2008). However, not all multicomponent solids are classified
as cocrystals (Thakuria et al., 2013) and according to the most often ac-
cepted definition (Aakeröy and Salmon, 2005; Aitipamula et al., 2012a;
Bhogala and Nangia, 2008; Jones et al., 2011; Thakuria et al., 2013) two
conditions must be met. First of all, coformers should be solid under
ambient settings. Besides, after cocrystallization the formed homoge-
neous phase should comprise stoichiometric proportions of the compo-
nents. Especial attention has been paid to pharmaceutical cocrystals
comprising active pharmaceutical ingredient (API) cocrystalized with
molecular complex of some excipients. These pharmaceutically accepted
coformers are to be non-toxic and naturally occurring substances
(Aitipamula et al., 2012a; Musumeci et al., 2011; Thakuria et al., 2013;
Zhang et al., 2014). Substantial effort has been made in the exploration
of supramolecular systems leading to rapid development of cocrystals
screening both experimentally and theoretically. There are many
methods of multicomponent crystals preparation classified into two
European Journal of Pharmaceutical Sciences 85 (2016) 132–140
⁎ Corresponding author.
E-mail address: piotr.cysewski@cm.umk.pl (P. Cysewski).
http://dx.doi.org/10.1016/j.ejps.2016.02.010
0928-0987/© 2016 Elsevier B.V. All rights reserved.
Contents lists available at ScienceDirect
European Journal of Pharmaceutical Sciences
journal homepage: www.elsevier.com/locate/ejps

broad categories depending on the cocrystal growth rate (Manin et al.,
2014a), namely fast kinetic methods and slow thermodynamic ap-
proaches. Both can be implemented on variety manners including sol-
vent evaporation (Hattori et al., 2015; Hiendrawan et al., 2015a; Lin
et al., 2013; Przybyłek et al., 2016; Rahman et al., 2011), spray drying
(Alhalaweh and Velaga, 2010; Alhalaweh et al., 2013; Patil et al.,
2014), neat and liquid assistant grinding (Hiendrawan et al., 2015a;
Karki et al., 2007; Sanphui et al., 2015; Sun and Hou, 2008), slurry
cocrystallization (Bučar et al., 2010; Kojima et al., 2010; Takata et al.,
2008), melting methods (Rahman et al., 2011; Repka et al., 2013; Yan
et al., 2015) and supercritical fluids techniques (Cuadra et al., 2016;
Hiendrawan et al., 2015b; Padrela et al., 2010, 2009). It is worth men-
tioning that many pharmaceutical cocrystals containing amides acting
either as API or excipients have been studied recently (Aitipamula
et al., 2015, 2012b, 2009; Cuadra et al., 2016; Furuta et al., 2015; Gryl
et al., 2008; Manin et al., 2014a, 2014b; Wang et al., 2013). The
compounds containing amino-carbonyl group including aromatic
amides, play many important roles in the medical applications. For
examples nicotinamide (vitamin B3), pyrazinamide (antitubercular
agent), vindesine (phytogenic and antineoplastic agent, tubulin modu-
lator), L-glutamine (nutritional supplement), cerulenin (antifungal
antibiotic), carbamazepine (anticonvulsant), nepafenac and the title
compounds (non-steroidal anti-inflammatory drugs) can be found
within DrugBank and WHO Collaborating Centre for Drug Statistics
Methodology (WHOCC) databases. On the other hand many drugs
acting as cyclooxygenase-2 (COX-2) inhibitors belong to the class of
carboxylic acids. For example salicylic acid, aspirin and ibuprofen
exhibit such activity. However, it was observed (Kalgutkar et al., 2000;
Qandil, 2012) that amide and ester derivatives of anti-inflammatory
agents have less gastric side effects. Another application of carboxylic
acids is pharmaceutical excipients (Rowe, 2009). Noteworthy, benzoic
acid and its derivatives have been often used as pharmaceutical
cocrystal formers (Berry et al., 2008; Caira et al., 1995; Lin et al., 2015;
Manin et al., 2014a, 2014b; Schultheiss and Newman, 2009;
Varughese et al., 2010). From pharmaceutical viewpoint particularly
important is the class of phenolic acids obtained after hydroxyl substit-
uents attachment to aromatic ring of benzoic acid. According to many
reports, these compounds reveal antioxidant activity (Piazzon et al.,
2012; Rice-Evans et al., 1996; Sroka and Cisowski, 2003) and possess
antimicrobial properties (Baskaran et al., 2013). Furthermore, the
phenolic acids are added to food, cosmetics and pharmaceutical
formulations to improve their stability (Ash and Ash, 2004; Jones
et al., 2006; Vangala et al., 2011).
The aim of this study is to examine the cocrystallization landscape of
two active pharmaceutical ingredients (API) namely salicylamide and
ethenzamide with aromatic carboxylic acids, including pharmaceutical-
ly relevant compounds such as acetylsalicylic acid, 4-acetamidobenzoic
acid (acedoben) as well as mono- and dihydroxybenzoic acids. For this
purpose a droplet evaporative crystallization (DEC) technique has been
applied. This fast and efficient method has been previously developed
(Cysewski et al., 2014; Przybyłek et al., 2015) and successfully applied
for cocrystal screening (Przybyłek et al., 2016). The experimental data
characterizing salicylamide and ethenzamide cocrystallization propen-
sities are also enriched by theoretical screening and detailed analysis
of R2
2
(8) heterosynthon properties.
2. Materials and methods
2.1. Materials
All chemicals were applied without purification, as received from
commercial suppliers. APIs considered in this study namely, salicylamide
(2-hydroxybenzamide, SMD) and ethenzamide (2-ethoxybenzamide,
EMD) were obtained from Avantor Performance Materials Poland S.A.
(Gliwice, Poland). Also the following compounds were taken from this
provider, namely methanol, benzoic acid (BA), 2-fluorobenzoic acid
(2FBA), 2-chlorobenzoic acid (2CBA), salicylic acid (SA), acetylsalicylic
acid (aspirin, ASA), 4-acetamidobenzoic acid (acedoben, 4ABA) 3-
hydroxybenzoic acid (3HBA), 2,6-dihydroxybenzoic acid (2,6DHBA),
2,5-dihydroxybenzoic acid (2,5DHBA) and 3,4-dihydroxybenzoic
acid (3,4DHBA). From Sigma-Aldrich (USA) there were purchased
the following chemicals 2,4-dihydroxybenzoic acid (2,4DHBA), 3,5-
dihydroxybenzoic acid (3,5DHBA), 4-hydroxybenzoic acid (4HBA), 2-
bromobenzoic acid (2BBA) and 2-iodobenzoic acid (2IBA).
2.2. Samples preparation procedure and measurements
The cocrystals screening was performed taking advantage of the
droplet evaporative crystallization (DEC) technique (Cysewski et al.,
2014; Przybyłek et al., 2016, 2015). This very simple, time and chemical
preserving approach, yet very efficient, was already validated and suc-
cessfully applied for new cocrystals preparation (Przybyłek et al.,
2016). In this technique the crystallite deposited on the glass surface
is analyzed based on the powder X-ray diffraction (PXRD) and Fourier
transform infrared-total attenuated reflectance techniques. The DEC
procedure consists of mixing methanolic solutions of SMD (0.7 M),
EMD (0.1 M) and potential cocrystal formers in 1:1 proportions and
allowing the fast drying of the 20 μL-droplets of these mixtures after
dropping on the glass surface. The cocrystal occurrence was confirmed
by comparison of PXRD and FTIR-ATR spectra of bi-component crystal-
lites with ones recorded for pure components under the same condi-
tions. In the case of low solubility of API the crystallite layers were
obtained after repeating of evaporation up to 5 times for obtaining the
PXRD diffraction patterns of sufficient quality.
The FTIR-ATR spectra reported in this study were recorded using
Bruker Alpha-PFT-IR spectrometer with diamond attenuated total
reflection (ATR) equipment. The PXRD patterns were performed using
PW3050/60 goniometer with Empyrean XRD tube Cu LFF DK303072
(5°–40° 2θ range, 0.02° step with). All diffraction patterns were
preprocessed in Reflex module of Accelrys Material Studio 8.0 (Accelrys,
San Diego, 2015) including Kα2 stripping, background subtraction,
curve smoothing and normalization.
2.3. Calculation details
2.3.1. Mixing enthalpy estimation
The excess thermodynamic functions characterizing components af-
finities in liquid state under super cooled conditions are often used as a
measure of cocrystallization propensities (Eckert and Klamt, 2014;
Loschen and Klamt, 2015). This post-quantum mechanical thermody-
namic analysis takes advantage of the Conductor like Screening Model
for Real Solvents model (COSMO-RS) (Klamt and Schüürmann, 1993;
Klamt, 2011) for sigma profiles generation at semiempirical AM1
(Dewar et al., 1985) level. Based on the statistical analysis offered by
COSMOtherm software (Eckert and Klamt, 2014) (parametrization
BP_SVP_AM1_C30_1501.ctd) it is possible to obtain the mixing enthal-
py. The negative enough values of mixing enthalpy are supposed to
indicate that the mixture is thermodynamically favored over the pure
component liquids. The miscibility under super cooled liquid is often
associated with miscibility in the solid state, hence documenting the
ability of cocrystallization (Loschen and Klamt, 2015). The geometries
of all amides and coformers were optimized using MOPAC2012 (Maia
et al., 2012; Stewart, 2016) both in the gas phase and in the condensed
phase modeled with and aid of the COSMO-RS approach.
2.3.2. Computations of the substituent effects on the heterosynthon
properties
The full gradient optimization was performed for 180 pairs
of para-substituted benzoic acid analogues with salicylamide or
enthenzamide using ΩB97XD density functional with 311++G**
basis set as implemented in GAUSSIAN package (Frisch et al., 2009).
The contributions to the pair stabilization energy were performed
133M. Przybyłek et al. / European Journal of Pharmaceutical Sciences 85 (2016) 132–140

based on the absolutely-localized orbitals method (ALMO) implement-
ed in QChem package (Shao et al., 2014). In this approach it is possible
to decompose the total intermolecular binding energy into several
contributions including the charge-transfer (CT) portion of the binding
energy (Krylov and Gill, 2013). Besides, the amount of bidirectional
charge transfer from and to monomers interacting via hydrogen bond-
ing can be quantified utilizing complementary occupied-virtual orbitals
formalism (Khaliullin et al., 2008). In order to obtain more accurate
results the basis set superposition error (BSSE) was included during in-
termolecular interactions energies calculations taking advantage of
counterpoise procedure (Boys and Bernardi, 1970; Simon et al., 1996).
3. Results and discussion
Focusing attention on cocrystal landscape of salicylamide (SMD) and
ethenzamide (EMD) is justified by their analgesic and antipyretic prop-
erties. Both SMD and EMD are non-prescription drugs belonging to non-
steroidal anti-inflammatory agents with medicinal uses similar to those
of aspirin. Typically they are administered in combination with other
components as acetaminophen, aspirin or caffeine in the over-the-
counter pain remedies. These drugs are poorly soluble in water and
cocrystallization with more soluble formers might be one of the remedy
to this limitation. The selected coformers belonging to the group of well
soluble aromatic carboxylic acids seem to be a rational choice especially
that many of them such as BA, SA, 3HBA, 4HBA, 2,4DHBA and 3,4DHBA
are known to be non-toxic and approved food additives. Hence, they
can be found on GRAS (Generally Recognized as Safe) or EAFUS (Every-
thing Added to Food in the United States) lists. In this paper the
cocrystallization landscapes of both SMD and EMD are studied experi-
mentally for limited number of coformers and further extended via
computational analysis. Finally, the R2
2
(8) heterosynthon responsible
for the major energetic contributions to the solid stabilization is charac-
terized in details based on quantum chemistry computations.
3.1. Experimental evidences of cocrystals formation
The solid state mixtures comprising salicylamide or ethenzamide
and one of 15 aromatic carboxylic acids were prepared and analyzed ac-
cording to previously described procedure (Przybyłek et al., 2016). The
complete documentation of experimental results for all analyzed sys-
tems is provided in the supporting materials in Fig. S1–S22. Here, in
the main text only exemplary cases are discussed. The identification of
the cocrystals formation can be confirmed by direct inspection of the
corresponding PXRD patterns. The fortunate circumstance of reducing
majority of signals obtained from oriented samples compared to bulk
crystallization allows for almost immediate identification of the new
peaks characterizing molecular complexes in the solid state. Additional
confirmation comes from FTIR spectra offering further proof by
documenting occurrence of band shifts related to alteration of intermo-
lecular interactions mainly due to changes in the hydrogen bonding pat-
terns. For example cocrystallization of both studied benzamides with
2,4-dihydroxybenzoic acid can be inferred from Fig. 1. In this case the
SMD-2,4HBA binary system is detectable by new small diffraction sig-
nals at 2θ = 6.8° and 26.8°, which cannot be assigned to pure compo-
nents and these signals most probably correspond to new cocrystal
phase. In the case of EMD-2,4HBA mixture a new intense PXRD peak
at 2θ = 18.9° appears as a consequence of cocrystal formation. Since it
is often observed overlapping of the reflexes coming from cocrystals
with peaks that might come from pure components additional confir-
mation is desirable and for this purpose the FTIR-ATR method is often
used. As it can be inferred from Fig. 1b and d there are significant chang-
es in the absorption bands shifts when comparing to vibrational spectra
recorded for mixtures with pure components. As it can be directly in-
ferred from Fig. 1b, formation of the SMD-2,4DHBA cocrystal leads to
the relatively small blue shift (from 3394 to 3412 cm−1
) of N–H
stretching mode absorption band, (NH) and significant red shift (from
3370 to 3303 cm−1
) of O–H stretching absorption band, v(OH). Changes
in the O–H stretching vibration mode regions of carboxylic acids
induced by new hydrogen bonds formation can be observed on spectra
recorded for other mixtures as well. However, in the majority of cases
the observed (NH) shifts are much more noticeable. Noteworthy, partic-
ularly significant blue shifts appeared in the case of EMD cocrystals
(Fig. 1d,supplementary Figs. S12, S13, S16, S20–S22). As we reported
in the previous work (Przybyłek et al., 2016), similar (NH) analogical
shifts were also observed for cocrystals of urea and carboxylic aromatic
acids. This regularity can be explained by the formation of a new NH⋯O
hydrogen bonding involving amide and carboxylic acid.
Similar analysis scrutinized using data provided in the supporting
materials allows for documenting the cocrystallization landscapes of
both studied here drugs. The conclusions drawn from performed
experiments were summarized in Table 1 proving identification of elev-
en new cocrystals that have not been previously reported. The content
of Table 1 was enriched by cocrystals identified by other authors includ-
ing records deposited in the Cambridge Structural Database. There are
positive and negative observations of drugs miscibility in the solid
state. Although in the former case the conclusion is definitive in the
case of lack of identification of cocrystal the inference is not the abso-
lute. The full confirmation of solids immiscibility can be obtained only
from full phase diagram and classification as simple eutectic system
(Berry et al., 2008; Cherukuvada and Guru Row, 2014; Prasad et al.,
2014; Yamashita et al., 2014, 2013) since successful cocrystallization
can depend on conditions of synthesis (Friščić et al., 2009; Gagnière
et al., 2009; Leyssens et al., 2012; Manin et al., 2014a, 2014b;
Schartman, 2009). However, DEC technique applied in this study was
found to be quite reliable tool for urea/aromatic carboxylic acids misci-
bility screening (Przybyłek et al., 2016). Noteworthy, formation of the
SMD-BA and the EMD-4HBA molecular complexes in the solid state
was confirmed also in the earlier studies (Aitipamula et al., 2012b;
Manin et al., 2014a). According to our observations, the SMD-BA
cocrystal formation can be evidenced by the appearance of an intense
peak at 2θ = 14.7° on the diffraction pattern and additionally by a char-
acteristic v(NH) blue shift from 3395 to 3406 cm−1
on the FTIR-ATR
spectra (supplementary Fig. S1). In the case of the EMD-4HBA system,
multicomponent crystal phase can be confirmed by overlapping of the
majority of PXRD peaks with diffraction pattern of EMD-4HBA mono-
crystal reported by Aitipamula et al. (2012b) (Fig. S20). The above ex-
amples demonstrate once again the reliability of DEC cocryslallization
procedure.
3.2. Extending of SMD and EMD cocrystallization landscapes
The data provided in Table 1 led to the conclusion that
cocrystallization is quite common for both studied benzamides. These
abilities of ethenzamide seem to be slightly broader compared to
salicylamide. Although the list of carboxylic acid used as coformers is
quite extended it would be interesting to analyze the cocrystallization
potential of SMD and EMD from much broader perspective. For this
purpose the CSD was searched against all carboxylic acids that were
used as coformers involved in any binary cocrystals. This led to the set
of great variety of aromatic carboxylic acids distinguishable by the
type, number and positions of the substituents attached to the aromatic
ring. The resulting set of 161 acids was then used as probe for
cocrystallization landscape of SMD and EMD. For this purpose the values
of mixing enthalpies (Hmix) were estimated using approach offered by
COMSOtherm program (Eckert and Klamt, 2014). It is worth mention-
ing that the post-quantum mechanical thermodynamic analysis based
on the Conductor like Screening Model for Real Solvents (COSMO-RS)
has been widely applied for pharmaceutics miscibility with different ad-
ditives and solubility evaluations (Abramov et al., 2012; Connelly et al.,
2015; Klamt, 2012, 2011; Klamt et al., 2002; Loschen and Klamt, 2015;
Pozarska et al., 2013). The dissemination of Hmix charactering all of con-
sidered here pairs is presented in Fig. 2 in the form of smoothed
134 M. Przybyłek et al. / European Journal of Pharmaceutical Sciences 85 (2016) 132–140

Fig. 1. PXRD and FTIR-ATR characteristics of salicylamide-2,4-dihydroxybenzoic acid (SMD-2,4HBA) (a, b) and ethenzamide-2,4-dihydroxybenzoic acid (EMD-2,4HBA) (c, d) crystallites
deposited on the glass surface. Our experimental PXRD data (black lines) were enriched with simulated diffraction patterns of coformers (gray lines). The polymorph I and II of 2,4-
dihydroxybenzoic acid are denoted by refcodes ZZZEEU08 and ZZZEEU04, respectively.
Table 1
Salicylamide (SMD) and 2-ethoxybenzamide (EMD) cocrystals screening results enriched with the examples taken from the literature and CSD. The experimental evidences of new mo-
lecular complexes reported in this study are given in supplementary materials as indicated by ﬁgure numbers.
Cocrystal former
Cocrystal identiﬁcation
SMD Source EMD Source
Benzoic acid (BA) Yes Manin et al. (2014a), Fig. S1a
Yes Fig. S12a
2-Fluorobenzoic acid (2FBA) Yes Fig. S2a
Yes Fig. S13a
2-Chlorobenzoic acid (2CBA) No Fig. S3a
No Fig. S14a
2-Bromobenzoic acid (2BBA) No Fig. S4a
No Fig. S15a
2-Iodobenzoic acid (2IBA) No Fig. S5 Yes Fig. S16a
4-Acetamidobenzoic acid (4ABA) Yes Manin et al. (2014a, 2014b) No Fig. S17a
Acetylsalicylic acid (ASA) No Manin et al. (2014a) No Fig. S18a
Salicylic acid (SA) Yes Manin et al. (2014a) Yes REHSAAb
3-Hydroxybenzoic acid (3HBA) No Fig. S6a
No Fig. S19a
4-Hydroxybenzoic acid (4HBA) Yes Fig. S7a
Yes Aitipamula et al. (2012b), Fig. S20a
2,4-Dihydroxybenzoic acid (2,4DHBA) Yes Fig. 1 Yes Fig. 1
2,5-Dihydroxybenzoic acid (2,5DHBA) Yes Fig. S8a
Yes QULLUFb
2,6-Dihydroxybenzoic acid (2,6DHBA) Yes Fig. S9a
Yes GEQXEHb
3,4-Dihydroxybenzoic acid (3,4DHBA) No Fig. S10a
Yes Fig. S21a
3,5-Dihydroxybenzoic acid (3,5DHBA) No Fig. S11a
Yes Fig. S22a
a
This study experiment documented in supporting materials.
b
CSD refcode.

histograms. These curves confirm mentioned discrepancy in the
cocrystallization abilities between both of analyzed drugs. Indeed, the
majority of aromatic carboxylic acids seem to be freely miscible with
ethenzamide. The red line in Fig. 2 defines the critical value of Hmix
showing high probability of miscibility. In the case of EMD almost 99%
of mixtures with acids fall into this region. On the contrary the histo-
gram of salicylamide interactions with carboxylic acids is more shifted
toward higher values of Hmix, what results in reduction of miscible
pars down to about 76% cases. It is well known that urea is very good
cocrystal former (Przybyłek et al., 2016) being able to cocrystalize
with variety of compounds (Alhalaweh et al., 2013, 2010; Chang and
Lin, 2011; Deutsch and Bernstein, 2008; Martí-Rujas et al., 2011; Powell
et al., 2015; Tothadi, 2014; Videnova-Adrabińska, 1996). This is also
confirmed by corresponding plot in Fig. 2 documenting that about 99%
of aromatic carboxylic acids exhibit miscibility under super cooled
conditions what is regarded (Klamt, 2012) as sufficient condition for
cocrystallization. Thus, ethenzamide is more similar to urea than
benzamide, which is able to form the homogeneous mixtures with
94% of acids.
3.3. The R2
2
(8) heterosynthon properties
It is typical for cocrystals formed by benzamides with carboxylic
acids to adopt the hydrogen bonding motive classified by graph descrip-
tor as R2
2
(8) heterosynthon (Etter et al., 1990; Grell et al., 2000) in which
the carboxylic and amide groups are able to form 8-center ring stabi-
lized by two very strong hydrogen bonds. Both interacting components
are able to play the role of donor and acceptor, what forms two alterna-
tive channels allowing for electron density flow in both directions.
There is another interesting aspect related to conformations of studied
here benzamides, namely both molecules can benefit its stability from
intra-molecular hydrogen bonds formed between amide group and ox-
ygen atom of hydroxy- or ethoxy-substituent. As it is documented in
Scheme 1 there are two alternative types of such intramolecular stabili-
zation in the case and SMD only one for EMD. The intramolecular inter-
actions of salicylamide in the form A are much stronger if compared to B
conformer. As a consequence the estimated Boltzmann probability of A
isomer is five orders higher suggesting that this structure is predomi-
nant. In the case of EMD there is only one possibility of intramolecular
hydrogen bonding by adoption of form B and this configuration is sup-
posed to dominate over other isomers. Interestingly, formation of the
R2
2
(8) heterosynthon does not significantly alter these observations. Al-
though, small substituent effect can be observed as it is documented in
Fig. 3, for both benzamides the energy difference between conformers A
and B is promoted by the presence of electron withdrawing groups and
slightly reduced by the effect of electron donating groups. Thus, the
relative stability of conformers is not affected by intermolecular interac-
tions and formation of R2
2
(8) heterosynthon with aromatic carboxylic
acids.
Although, there are high structural similarities of both analyzed
drugs the attached substituent to the second position can alter donating
and accepting capabilities of the amide group. The precise quantification
of this phenomenon can be obtained by studying substituent effects on
the heterosynthon properties. For this purpose 180 para-substituted an-
alogues of benzoic acids were built by attachment of variety of substit-
uents in the para-position and used for pair preparation with either
SMD or EMD. The selected groups cover wide range of Hammett con-
stant values, σp, (Hansch et al., 1991) offering precise and complete in-
terpretation of the studied heterosynthon sensitivity to acids strength.
The first interesting property of such pairs is the energy of intermolecu-
lar interactions. For all optimized pairs the binding energy was
Fig. 2. The distributions of Hmix characterizing pairs of amides with either of 161 aromatic
carboxylic acids involved in binary systems deposited in CSD. Apart from data of SMD and
EMD also ones for benzamide (BMD) and urea (U) were provided. The percentages in the
legend denote population of pairs with high affinities of components defined by
Hmix ≤ −0.57 kcal/mol (Eckert and Klamt, 2014; Loschen and Klamt, 2015) and this
threshold was marked with the red line.
Scheme 1. The schematic representation of structures of ethenzamide (2-
ethoxybenzamide, EMD) and salicylamide (2-hydroxybenzamide, BMD).
Fig. 3. The substituent effect on relative stabilities of pairs formed by two alternative
conformations of SMD and EMD.

estimated including the corrections for basis superposition error and
accounting also for the dispersion contributions. In Fig. 4 the presented
plots characterize the interactions of SMD and EMD with each of studied
para substituted carboxylic acids. Additionally, for comparison purposes
plots documenting similar effects on benzamide and urea were also pro-
vided. It is clearly noticeable that the stabilization energies of pairs
formed by each of these four amides with benzoic acids analogues are
fairly linear function of Hammett constant values. The attachment of
electron donating substituent weakens the interactions with considered
amides. On the contrary the more electron withdrawing nature of the
substituent the more stable pairs of such aromatic carboxylic acids
with all four amides. The distributions presented on both panels of
Fig. 4 clarify previously mentioned discrepancies in the cocrystallization
propensities between salicylamide and ethenzamide. The stabilization
contribution coming from the heterosynthon formation of the former
amide is significantly lower if compared to EMD. This trend is not affect-
ed by acid strength and that is why distributions of mixing enthalpies
are so divers for SMD and EMD. This observation is additionally con-
firmed by histograms provided in Fig. 4b. It is worth mentioning that
the origin of the observed discrepancies in intermolecular interactions
between studied benzamide is different orientation of substituent
adopted by both amides. This leads to the alternate patterns of intra-
molecular hydrogen bonds. In the case of salicylamide it is observed
the intramolecular bonding of O–H…O type, while for ethenzamide
the O…H–N type of hydrogen bond is formed. This has consequences
on the ability of intermolecular interactions and increase of intramolec-
ular stabilization of the R2
2
(8) heterosynthon. There are also other inter-
esting consequences of intra-stabilization effect. It is quite expected that
the presence of the electron withdrawing groups makes the synthon
more polar what can be quantified by amount of charge transfer from
benzamide to carboxylic acid (B → A) and vice versa (A → B). This prop-
erty expressed in terms of portion of electron charge dislocation is
presented in Fig. 5.
It is interesting to note that the stronger electron withdrawing char-
acter of the substituent the higher the charge transfer toward aromatic
acid from either of amides. However, SMD is less prone to this effect
compared to EMD, what in the light of mentioned intra-stability is
quite understandable. The channel formed by carbonyl oxygen center
is more affected by intramolecular hydrogen bonding in this case. The
lack of such intramolecular interaction in the case of benzamide and
urea results in much higher readiness to electron density outflow.
Thus, EMD is more similar in this aspect to benzamide than to
salicylamide. The stronger resistance of SMD to substituent effect on
B → A electron transfer can also be inferred from the slops of linear
trends presented in Fig. 5a. This value is about 30% lower for SMD com-
pared to EMD. The transfer of electron charge from amide toward acid is
also associated with opposite effect, what can be inferred from Fig. 5b.
This alternative channel of R2
2
(8) heterosynthon involves carbonyl
group on the acid side. However, the observed charge transfer is pro-
nounced in much lesser extend suggesting much stronger electron
withdrawing character of carboxylic group than amide fragment. The
observed absolute values of partial electron transfer are 3–5 times
smaller in the A → B way compared to opposite direction. Furthermore,
the absolute values of slopes are also 2–3 times smaller suggesting
much smaller substituent effect on this kind of synthon polarization.
Thus, taking into account both channels it is possible to conclude that
formation of the R2
2
(8) heterosynthon results in enrichment of the elec-
tron density on the acidic site irrespectively of the nature of the substit-
uent. This conclusion holds also for benzamide and urea. It is also
interesting to mention that apart from energetic and electronic effects
of substituent nature there are also numerous geometric consequences
on the R2
2
(8) heterosynthon structure. For example it is observed defor-
mation of the synthon geometry with the increase of electron with-
drawing character of the substituent leading to increase of skewness
of the system. This parameter defined as the mean value of so-called
Donohue angles (Donohue, 1968) can be used for description of the ge-
ometries of hydrogen bonds involved on synthon formation (Katrusiak,
1995, 1993). This is associated with systematic increase of O–H…O′ and
decrease of O…H′–O′ hydrogen bonds lengths with the rise of the elec-
tron withdrawing strength of the substituent. Here, the prime sign is
used for denoting centers located on carboxylic groups. This is consis-
tent for both studied here drugs.
4. Conclusions
The cocrystallization abilities of salicylamide and ethenzamide with
aromatic carboxylic acids are unexpectedly divers. Despite high formal
similarities of these two benzamides the propensities of cocrystal for-
mation explored both experimentally and theoretically revealed origin
of this fundamental difference. The formal analogy between SMD and
EMD comes from ability of the formation of the same intermolecular
pattern denoted by graph descriptor as R2
2
(8) heterosynthon. However,
difference in stabilization of possible conformers by adopting alterna-
tive intramolecular hydrogen boding patterns is the main source of
the observed difference in the cocrystallization landscape. Since
salicylamide (SMD) and ethenzamide (EMD) are efficient analgesic
and antipyretic drugs administered as non-prescription non-steroidal
anti-inflammatory agents in combination with other components
Fig. 4. The intermolecular interactions of pairs comprising salicylamide, ethenzamide, benzamide or urea with para-substituted benzoic acid analogues. On left panel (a) the absolute
values of binding energy are provided, while on the right side (b) the corresponding smoothed histograms of ΔEBSSE were collected.

their miscibility in the solid state is important aspect of pharmaceutical
relevance. Both APIs are poorly soluble in water and cocrystallization
with more soluble coformers seems to be one of the simplest way of
modulating their bio-availability. Particularly concentration on non-
toxic and much better soluble aromatic carboxylic acids as potential
coformers is rational also from the perspective of structural pattern rec-
ognition via R2
2
(8) heterosynthon.
The experiment observation of solid state miscibility of considered
herein APIs with a set of substituted benzoic acid derivatives was
assessed by means of supramolecular synthesis, taking advantage of
the efficient DEC technique combined with powder diffraction and vi-
brational spectroscopy as the analytical tools. As it was documented
above the phenolic acids turned out to be a good class of ethenzamide
cocrystals formers and since they can prevent drugs from degradation,
addition of these compounds to pharmaceutical formulations can po-
tentially improve also their shelf life. It is worth mentioning that
cocrystallization is an approach which gives the best dispersion of phar-
maceutical ingredients and hence the most effective interaction with
APIs. Finally the identification of eleven new cocrystals by means of
DEC experimental approach confirms its usefulness and extends it
applicability range.
Acknowledgments
This work utilized the COSMOtherm software kindly provided
by COSMOlogic. This research was supported in part by PL-Grid In-
frastructure (plgpiotrc2015b). The allocation of computational fa-
cilities of Academic Computer Centre “Cyfronet” AGH/Krakow/
POLAND is also acknowledged.
Appendix A. Supplementary data
Supplementary data to this article can be found online at http://dx.
doi.org/10.1016/j.ejps.2016.02.010.
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Supplementary materials
Propensity of salicylamide and ethenzamide cocrystallization with aromatic carboxylic
acids
Maciej Przybyłek1
, Dorota Ziółkowska2
, Karina Mroczyńska3
, Piotr Cysewski1*
1
Chair and Department of Physical Chemistry, Pharmacy Faculty, Collegium Medicum of Bydgoszcz,
Nicolaus Copernicus University in Toruń, Kurpińskiego 5, 85-950 Bydgoszcz, Poland,
piotr.cysewski@cm.umk.pl
2
University of Technology and Life Sciences in Bydgoszcz, Faculty of Chemical Technology and
Engineering, Seminaryjna 3, 85-326 Bydgoszcz, Poland;
3
Research Laboratory, Faculty of Chemical Technology and Engineering, Seminaryjna 3, 85-326
Bydgoszcz
List of figures
1. PXRD and FTIR-ATR characteristics of salicylamide-carboxylic acid mixtures
Fig. S1. PXRD and FTIR-ATR characteristics of salicylamide-benzoic acid (SMD-BA) crystallite layers
deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched with simulated
diffraction patterns of coformers (grey lines).
Fig. S2. PXRD and FTIR-ATR characteristics of salicylamide-2-fluorobenzoic acid (SMD-2FBA) crystallite
layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched with
simulated diffraction patterns of coformers (grey lines).
Fig. S3. PXRD and FTIR-ATR characteristics of salicylamide-2-chloroobenzoic acid (SMD-2CBA)
crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines) were enriched
with simulated diffraction patterns of coformers (grey lines).
Fig. S4. PXRD and FTIR-ATR characteristics of salicylamide-2-bromobenzoic acid (SMD-2BBA)
Fig. S5. PXRD and FTIR-ATR characteristics of salicylamide-2-iodobenzoic acid (SMD-2IBA) crystallite
Fig. S6. PXRD and FTIR-ATR characteristics of salicylamide-3-hydroxybenzoic acid (SMD-3HBA)
with simulated diffraction patterns of coformers (grey lines). The monoclinic and orthorhombic
polymorphs of 3-hydroxybenzoic acid are denoted by refcodes BIDLOP and BIDLOP02, respectively.
Fig. S8. PXRD and FTIR-ATR characteristics of salicylamide-2,5-dihydroxybenzoic acid (SMD-2,5DHBA)
with simulated diffraction patterns of coformers (grey lines). The orthorhombic and monoclinic
polymorphs of 2,6-dihydroxybenzoic acid and hydrate (dotted line) are denoted by refcodes LEZJAB,
LEZJAB01 and LEZJEF, respectively.
Fig. S10. PXRD and FTIR-ATR characteristics of salicylamide-3,4-dihydroxybenzoic acid (SMD-
3,4DHBA) crystallite layers deposited on glass surfaces. Our experimental PXRD data (black lines)
were enriched with simulated diffraction patterns of coformers (grey lines).

were enriched with simulated diffraction patterns of coformers (grey lines). The polymorph I and II of
3,5-dihydroxybenzoic acid are denoted by refcodes WUYPOW and WUYPOW01, respectively.
2. PXRD and FTIR-ATR characteristics of ethenzamide-carboxylic acid mixtures
Fig. S12. PXRD and FTIR-ATR characteristics of ethenzamide-benzoic acid (EMD-BA) crystallite layers
Fig. S13. PXRD and FTIR-ATR characteristics of ethenzamide-2-fluorobenzoic acid (EMD-2FBA)
Fig. S14. PXRD and FTIR-ATR characteristics of ethenzamide-2-chlorobenzoic acid (EMD-2CBA)
Fig. S15. PXRD and FTIR-ATR characteristics of ethenzamide-2-bromobenzoic acid (EMD-2BBA)
Fig. S16. PXRD and FTIR-ATR characteristics of ethenzamide-2-iodobenzoic acid (EMD-2IBA) crystallite
Fig. S17. PXRD and FTIR-ATR characteristics of ethenzamide-4-acetamidobenzoic acid (EMD-4ABA)
Fig. S18. PXRD and FTIR-ATR characteristics of ethenzamide-acetylsalicylic acid (EMD-ASA) crystallite
Fig. S19. PXRD and FTIR-ATR characteristics of ethenzamide-3-hydroxybenzoic acid (EMD-3HBA)
with simulated diffraction patterns of coformers and cocrystal (grey lines). Cocrystal formation was
confirmed by Aitipamula et al. (2012b).
Fig. S21. PXRD and FTIR-ATR characteristics of ethenzamide-3,4-dihydroxybenzoic acid (EMD-

1. PXRD and FTIR-ATR characteristics of salicylamide-carboxylic acid mixtures
Fig. S1. PXRD and FTIR-ATR characteristics of salicylamide-benzoic acid (SMD-BA) crystallite layers
5 10 15 20 25 30 35 40
relativeintensity
2[]
SMD
BA
BA (BENZAC02)
SMD-BA
SMD (SALMID01)
0.0
0.2
0.4
0.6
0.8
1.0
2000 2500 3000 3500
normalizedtransmitance
wave number [cm-1]
SMD-BA
BA
SMD

Fig. S2. PXRD and FTIR-ATR characteristics of salicylamide-2-fluorobenzoic acid (SMD-2FBA) crystallite
5 15 25 35
relativeintensity
2[]
SMD
2FBA
2FBA (FBENZA)
SMD-2FBA
SMD (SALMID01)
0.0
0.2
0.4
0.6
0.8
1.0
2000 2500 3000 3500
wave number [cm-1]
SMD-2FBA
2FBA
SMD

Fig. S3. PXRD and FTIR-ATR characteristics of salicylamide-2-chloroobenzoic acid (SMD-2CBA)
5 15 25 35
relativeintensity
2[]
SMD
2CBA
2CBA (CLBZAC)
SMD-2CBA
SMD (SALMID01)
0.0
0.2
0.4
0.6
0.8
1.0
2000 2500 3000 3500
wave number [cm-1]
SMD-2CBA
2CBA
SMD

Fig. S4. PXRD and FTIR-ATR characteristics of salicylamide-2-bromobenzoic acid (SMD-2BBA)
5 10 15 20 25 30 35 40
relativeintensity
2[]
SMD
2BBA
2BBA (BRBZAC)
SMD-2BBA
SMD (SALMID01)
0.0
0.2
0.4
0.6
0.8
1.0
2000 2500 3000 3500
wave number [cm-1]
SMD-2BBA
2BBA
SMD

Fig. S5. PXRD and FTIR-ATR characteristics of salicylamide-2-iodobenzoic acid (SMD-2IBA) crystallite
5 10 15 20 25 30 35 40
relativeintensity
2[]
SMD
2IBA
2IBA (OIBZAC)
SMD-2IBA
SMD (SALMID01)
0.0
0.2
0.4
0.6
0.8
1.0
1800 2300 2800 3300
wave number [cm-1]
SMD-2IBA
2IBA
SMD

5 10 15 20 25 30 35 40
relativeintensity
2[]
SMD
3HBA
3HBA (BIDLOP02)
3HBA (BIDLOP)
SMD-3HBA
SMD (SALMID01)
0.0
0.2
0.4
0.6
0.8
1.0
2300 2800 3300
wave number [cm-1]
SMD-3HBA
3HBA
SMD

5 10 15 20 25 30 35 40
relativeintensity
2[]
SMD
4HBA
4HBA (JOZZIH)
SMD-4HBA
SMD (SALMID01)
0.0
0.2
0.4
0.6
0.8
1.0
2000 2500 3000 3500
wave number [cm-1]
SMD-4HBA
4HBA
SMD

5 10 15 20 25 30 35 40
relativeintensity
2[]
SMD
2,5DHBA
2,5DHBA
(BESKAL01)
SMD-2,5DHBA
SMD (SALMID01)
0.0
0.2
0.4
0.6
0.8
1.0
2300 2800 3300
wave number [cm-1]
SMD-2,5DHBA
2,5DHBA
SMD

with simulated diffraction patterns of coformers (grey lines). The orthorhombic and monoclinic
polymorphs of 2,6-dihydroxybenzoic acid and hydrate (dotted line) are denoted by refcodes LEZJAB,
LEZJAB01 and LEZJEF, respectively.
5 15 25 35
relativeintensity
2[]
SMD
2,6DHBA
SMD-2,6DHBA
SMD (SALMID01)
2,6DHBA
(LEZJAB)
2,6DHBA hydrate
(LEZJEF)
2,6DHBA
(LEZJAB01)
0.0
0.2
0.4
0.6
0.8
1.0
2300 2800 3300
wave number [cm-1]
SMD-2,6DHBA
2,6DHBA
SMD

5 10 15 20 25 30 35 40
relativeintensity
2[]
SMD
3,4DHBA
SMD (SALMID01)
SMD-3,4DHBA
3,4DHBA (WUYNUA)
0.0
0.2
0.4
0.6
0.8
1.0
2000 2500 3000 3500
wave number [cm-1]
SMD-3,4DHBA
3,4DHBA
SMD

5 10 15 20 25 30 35 40
relativeintensity
2[]
SMD
3,5DHBA
SMD (SALMID01)
SMD-3,5DHBA
3,5DHBA
(WUYPOW01)
3,5DHBA
(WUYPOW)
0.0
0.2
0.4
0.6
0.8
1.0
2300 2800 3300
wave number [cm-1]
SMD-3,5DHBA
3,5DHBA
SMD

2. PXRD and FTIR-ATR characteristics of ethenzamide-carboxylic acid mixtures.
Fig. S12. PXRD and FTIR-ATR characteristics of ethenzamide-benzoic acid (EMD-BA) crystallite layers
5 10 15 20 25 30 35 40
relativeintensity
2[]
EMD
BA
BA (BENZAC02)
EMD-BA
EMD (DUKXAJ)
0.0
0.2
0.4
0.6
0.8
1.0
2000 2500 3000 3500
wave number [cm-1]
EMD-BA
BA
EMD

Fig. S13. PXRD and FTIR-ATR characteristics of ethenzamide-2-fluorobenzoic acid (EMD-2FBA)
5 10 15 20 25 30 35 40
relativeintensity
2[]
EMD
2FBA
2FBA (FBENZA)
EMD-2FBA
EMD (DUKXAJ)
0.0
0.2
0.4
0.6
0.8
1.0
2000 2500 3000 3500
wave number [cm-1]
EMD-2FBA
2FBA
EMD

Fig. S14. PXRD and FTIR-ATR characteristics of ethenzamide-2-chlorobenzoic acid (EMD-2CBA)
5 15 25 35
relativeintensity
2[]
EMD
2CBA
2CBA (CLBZAC)
EMD-2CBA
EMD (DUKXAJ)
0.0
0.2
0.4
0.6
0.8
1.0
2000 2500 3000 3500
wave number [cm-1]
EMD-2CBA
2CBA
EMD

Fig. S15. PXRD and FTIR-ATR characteristics of ethenzamide-2-bromobenzoic acid (EMD-2BBA)
5 15 25 35
relativeintensity
2[]
EMD
2BBA
2BBA (BRBZAC)
EMD-2BBA
EMD (DUKXAJ)
0.0
0.2
0.4
0.6
0.8
1.0
2000 2500 3000 3500
wave number [cm-1]
EMD-2BBA
2BBA
EMD

Fig. S16. PXRD and FTIR-ATR characteristics of ethenzamide-2-iodobenzoic acid (EMD-2IBA)
5 15 25 35
relativeintensity
2[]
EMD
2IBA
2IBA (OIBZAC)
EMD-2IBA
2EMD (DUKXAJ)
0.0
0.2
0.4
0.6
0.8
1.0
2000 2500 3000 3500
wave number [cm-1]
EMD-2IBA
2IBA
EMD

Fig. S17. PXRD and FTIR-ATR characteristics of ethenzamide-4-acetamidobenzoic acid (EMD-4ABA)
5 10 15 20 25 30 35 40
relativeintensity
2[]
EMD
4ABA
4ABA (DIXFAR)
EMD-4ABA
EMD (DUKXAJ)
0.0
0.2
0.4
0.6
0.8
1.0
2000 2500 3000 3500
wave number [cm-1]
EMD-4ABA
4ABA
EMD

Fig. S18. PXRD and FTIR-ATR characteristics of ethenzamide-acetylsalicylic acid (EMD-ASA) crystallite
5 10 15 20 25 30 35 40
relativeintensity
2[]
EMD
ASA
ASA (ACSALA01)
EMD-ASA
EMD (DUKXAJ)
0.0
0.2
0.4
0.6
0.8
1.0
2000 2500 3000 3500
wave number [cm-1]
EMD-ASA
ASA
EMD

5 15 25 35
relativeintensity
2[]
EMD
3HBA
3HBA (BIDLOP02)
3HBA (BIDLOP)
EMD-3HBA
EMD (DUKXAJ)
0.0
0.2
0.4
0.6
0.8
1.0
2300 2800 3300
wave number [cm-1]
EMD-3HBA
3HBA
EMD

with simulated diffraction patterns of coformers and cocrystal (grey lines). Cocrystal formation was
confirmed by Aitipamula et al. (2012b).
5 10 15 20 25 30 35 40
relativeintensity
2[]
EMD
4HBA
4HBA (JOZZIH)
EMD-4HBA
EMD (DUKXAJ)
EMD-4HBA
(Aitipamula et al. 2012b)
0.0
0.2
0.4
0.6
0.8
1.0
2000 2500 3000 3500
wave number [cm-1]
EMD-4HBA
4HBA
EMD

5 15 25 35
relativeintensity
2[]
EMD
3,4DHBA
EMD (DUKXAJ)
EMD-3,4DHBA
3,4DHBA (WUYNUA)
0.0
0.2
0.4
0.6
0.8
1.0
2000 2500 3000 3500
wave number [cm-1]
EMD-3,4DHBA
3,4DHBA
EMD

5 10 15 20 25 30 35 40
relativeintensity
2[]
EMD
3,5DHBA
EMD (DUKXAJ)
EMD-3,5DHBA
3,5DHBA
(WUYPOW01)
3,5DHBA
(WUYPOW)
0.0
0.2
0.4
0.6
0.8
1.0
2300 2800 3300
wave number [cm-1]
EMD-3,5DHBA
3,5DHBA
EMD

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