Utilization of oriented crystal growth for screening of aromatic carboxylic acids cocrystallization with urea

Utilization of oriented crystal growth for screening of aromatic
carboxylic acids cocrystallization with urea
Maciej Przybyłek a
, Dorota Ziółkowska b
, Mirosław Kobierski c
, Karina Mroczyńska d
,
Piotr Cysewski a,n
a
Department of Physical Chemistry, 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
University of Technology And Life Sciences in Bydgoszcz, Faculty of Agriculture and Biotechnology, Department of Soil Science and Soil Protection,
Bernardyńska 6, 85-029 Bydgoszcz, Poland
d
Research Laboratory, Faculty of Chemical Technology and Engineering, Seminaryjna 3, 85-326 Bydgoszcz, Poland
a r t i c l e i n f o
Article history:
Received 25 June 2015
Received in revised form
1 October 2015
Accepted 19 October 2015
Available online 27 October 2015
Keywords:
A1 Crystallites
A1 Surfaces
A1 X-ray diffraction
B1 Acids
B1 Aromatic compounds
a b s t r a c t
The possibility of molecular complex formation in the solid state of urea with benzoic acid analogues was
measured directly on the crystallite films deposited on the glass surface using powder X-ray dif-
fractometry (PXRD). Obtained solid mixtures were also analyzed using Fourier transform infrared
spectroscopy (FTIR). The simple droplet evaporation method was found to be efficient, robust, fast and
cost-preserving approach for first stage cocrystal screening. Additionally, the application of orientation
effect to cocrystal screening simplifies the analysis due to damping of majority of diffraction signals
coming from coformers. During validation phase the proposed approach successfully reproduced both
positive cases of cocrystallization (urea:salicylic acid and urea:4-hydroxy benzoic acid) as well as pairs of
co-formers immiscible in the solid state (urea:benzoic acid and urea:acetylsalicylic acids). Based on
validated approach new cocrystals of urea were identified in complexes with 3-hydroxybenzoic acid, 2,4-
dihydroxybenzoic acid, 2,5-dihydroxybenzoic acid, 2,6-dihydroxybenzoic acid and 3,5-dihydroxybenzoic
acid. In all cases formation of multicomponent crystal phase was confirmed by the appearance of new
reflexes on the diffraction patterns and FTIR absorption band shifts of O–H and N–H groups.
& 2015 Elsevier B.V. All rights reserved.
1. Introduction
According to widely accepted definition [1] a cocrystal is a
homogeneous crystalline solid that contains stoichiometric
amounts of discrete neutral molecular species, which are solids
under ambient conditions. These kind of solution differ from other
dispersions as eutectic or monotectic systems by congruent
melting and a molecular complex formation of a definite propor-
tions of interaction components [2–4]. The practical application of
organic solid alloys encompassing variety industries as pharma-
ceutical, textile, paper, chemical processing, photographic, pro-
pellants or electronics [5] stimulated growth of accumulated
knowledge and diversity of obtained materials. This explosion of
interests resulted in 7688 structures of binary cocrystals solved so
far [6] not counting hydrates, solvates, clathrates nor organome-
tallic species. The change of physicochemical properties of
cocrystals with respect of the coformers is especially useful and
important in the case of active pharmaceutical ingredients (API).
There are many examples of significant improving of API behaviors
both in vivo and in vitro [7–12]. The advantages of cocrystalliza-
tion for pharmaceutical industry are not only related to bioavail-
ability enhancement but also to the increase of stability [13],
hygroscopicity decrease [14], mechanical properties improvement
[15] and also due to intellectual property issues [16].
Urea is a quite common former of cocrystals and in the Cam-
bridge Structural Database (CSD) [6]. One can find more than 100
records documenting its involvement in multicomponent com-
pounds. One of the reason of so common occurrence of urea is the
diversity of possible interactions offered by two amino groups.
Although, the pure urea crystal is deposited 18-times in the CSD
corresponding to measurements at different temperatures but only
one polymorphic form is reported, which adopts tetragonal system
of P421m symmetry. Urea molecule can form strong intermolecular
hydrogen bonds and can act both as acceptor and donor. Indeed, the
carbonyl group is very strong acceptor center interacting with three
neighboring urea molecules via four hydrogen bonds. The bi-center
interactions with amino groups lead to formation of 1D columns
each surrounded by four identical chains. The stabilization of
Contents lists available at ScienceDirect
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Journal of Crystal Growth
http://dx.doi.org/10.1016/j.jcrysgro.2015.10.015
0022-0248/& 2015 Elsevier B.V. All rights reserved.
n
Corresponding author.
E-mail address: piotr.cysewski@cm.umk.pl (P. Cysewski).
Journal of Crystal Growth 433 (2016) 128–138

resulting perpendicular 2D sheets is gained via hydrogen bonds
formed with amino groups [17–24]. This ability of divers hydrogen
bonding is the source of observed variety of cocrystals structures of
urea since it can cocrystalize with polar coformers as for example
with salicylic acid (SLCADC) but also with non-polar species as for
instance with 1,10-phenanthroline (AMILUD). The other interesting
feature of the cocrystals formed by urea is significant diversity of
stoichiometry of complexes found in the solid phase. Although the
1:1 ratio predominates in cocrystals but one can find as high as 10:1
proportion in the case of urea-2,12-tridecanedione (MISNOR). Also
many drugs can cocrystalize with urea as for example barbital
(BARBUR) – a hypnotic and sedative agent also used in veterinary
practice for central nervous system depression, febuxostat (HIQ-
QUV) – inhibiting xanthine oxidase, nitrofurantoin (ORUXUV) – an
antibiotic usually used for treatment of urinary tract infections or
betonicin (REGKUK) – a psychoactive agent. On the other hand there
are many drugs that have not been cocrystalized with urea as for
example aspirin (acetylsalicylic acid) – a common prototypical
analgesic having anti-inflammatory and antipyretic properties.
However, structurally very similar salicylic acid used as analgesics
was successfully cocrystalized with urea (SLCADC). Besides, urea in
some case can form eutectic or monotectic mixtures with organic
compounds for example with 4-chloronitrobenzene [25]. There is
remarkably small data about cocrystallization of urea with other
aromatic carboxylic acids. Apart from salicylic acid also 3,5-dini-
trosalicylic acid (NUHYAQ), 1,1-binaphthyl-2,20
-dicarboxylic acid
(ROGKOO), trimesic acid (benzene-1,3,5-tricarboxylic acid) (CEKSIU)
and 4-hydroxycarboxylic acid (JOZZIH) cocrystalize with urea in the
monoclinic system. The orthorhombic crystal system is typical for 4-
aminobenzoic acid:urea cocrystal (NUHYEU). Finally the triclinic
system is observed in the case of o-phthalic acid (NUHYIY,
NUHYIY01) and 5-nitrosalicylic acid (NUHXUJ) cocrystals with urea.
It is slightly surprising that no more structures of urea cocrystals
with other aromatic carboxylic acid were determined, despite the
fact that stabilization of such potential systems might be gained
from quite common R-COOH Á Á Á H2NCO-R heterosynthon of
C2
2(8) type. These observations suggest that predicting of the ability
of cocrystal formation of urea with other coformers is not straight-
forward and non-trivial task. This is the starting point of our
investigations. There are many ways of cocrystal preparation and
among them the mechanochemical approach [26] is commonly
used. In fact, this method was applied for obtaining the very first
cocrystal of quinone and hydroquinone [27]. Besides, many alter-
native methods were adopted for cocrystallization purposes [28] as
for example sonication [29], melting [30] including direct phase
transition observations under thermal microscopy [31] and many
other techniques. Generally speaking, two basic categories of
cocrystals screening methods can be distinguished: thermodynamic
(slow crystal growth) and kinetic (fast crystallization) [32–34]. Par-
ticularly noteworthy are the latter methods relying on the fast
solution evaporation like spray drying [35], spin coating [36],
microwave-accelerated evaporative crystallization [37–39] and dro-
plet evaporation [40–46]. Hence, they are routinely utilized for
cocrystals synthesis [47–49]. One of the form of such crystallization
are preparation of oriented samples. As we reported previously
[45,46] the crystallization on the polar surfaces leads to interesting
effect of reducing number of peaks on PXRD spectra if measure-
ments are performed directly on thin layer deposits. The origin of
this phenomena is the orientation effect of exposed faces toward
solution which exhibits both the highest adhesive and cohesive
properties [45,46]. It is worth noting that, PXRD measurements of
so-called oriented samples is commonly used in geology and soil
science [50–53]. Noteworthy, preparation of oriented phenzaine–
chloranilic acid cocrystal thin films using sublimation method was
reported by Thompson et al. [54]. The main advantage of oriented
samples measurements is enhancing the intensity of certain
diffraction signals and diminishing majority of the rest. Therefore, it
is interesting to see if oriented samples measurements can be useful
in identification of cocrystal formation what stands for the purpose
of this paper. Below, the verification of proposed methodology of
identification of known cocrystals of urea with aromatic carboxylic
acids is followed by screening of urea cocrystallization landscape for
finding new homogeneous bi-component solids that were not-
reported in the literature so far.
2. Materials and methods
2.1. Chemicals
All analytical grade chemicals were purchased from commercial
suppliers and used without further purification. Urea (U, CAS:
57-13-6), benzoic acid (BA, CAS: 65-85-0), salicylic acid (SA, CAS:
69-72-7), acetylsalicylic acid (ASA, CAS: 50-78-2), 3-hydroxybenzoic
acid (3HBA, CAS: 99-06-9), 2,5-dihydroxybenzoic acid (2,5DHBA,
gentisic acid, CAS: 490-79-9), 2,6-dihydroxybenzoic acid (2,6DHBA,
γ-resorcylic acid, CAS: 303-07-1) and methanol (CAS: 67-56-1)
were obtained from POCH (Poland). Other compounds namely,
4-hydroxybenzoic acid (4HBA, CAS: 99-96-7), 2,4-dihydroxybenzoic
acid (2,4DHBA, β-resorcylic acid, CAS: 89-86-1), 3,5-dihydrox-
ybenzoic acid (3,5DHBA, CAS: 99-10-5) were purchased from Sigma-
Aldrich (USA). Structures of used dicarboxylic acids were presented
on Scheme 1.
2.2. Crystallization and samples preparation procedures
First, 0.724 M methanolic solutions of coformers were prepared
and mixed together to obtain urea/carboxylic acid solutions at
unimolar composition. Then, such mixtures and the pure compo-
nents solutions were used for preparing of crystallite layers
according to previously described procedure [45,46]. This method
involves placing of 20 ml of the solution on glass microscope slide
and letting for fast evaporation at 43 °C under atmospheric
pressure.
Additional cocrystallization experiments were performed for
all new cocrystals (2,4DHBA, 2,5DHBA, 2,6DHBA, 3,5DHBA and
3HBA) for alternative verifications. The PXRD patterns recorded for
oriented crystallites were compared with diffractograms of pow-
der samples obtained using mechanochemical method and bulk
evaporation approach. In the case of the mechanochemical
method, coformers crystals were mixed in the 1:1 M proportion
and ground in the mortar for an hour. The bulk evaporation
cocrystallization 30 ml of methanolic solutions were evaporated in
a glass beaker at 43 °C under atmospheric pressure.
2.3. Measurements
The Fourier transform infrared (FTIR) spectra were recorded on
a Bruker Alpha-PFT-IR spectrometer (Bruker, Germany) with a
diamond attenuated total reflection (ATR) crystal. Powder X-ray
diffraction (PXRD) patterns were recorded with the use of Goni-
ometer PW3050/60 armed with Empyrean XRD tube Cu LFF
DK303072. Diffraction data were collected in the range of 2θ
between 5° and 40° with 0.001° step width. The patterns were
processed in Reflex module of Accelrys Material Studio 8.0 [55] by
Kα2 stripping, background computation and subtraction followed
by curve smoothing and normalization.
3. Results and discussion
In this study, the possibilities of binary homogeneous mixture
formation of urea in solid state with nine aromatic carboxylic acids
M. Przybyłek et al. / Journal of Crystal Growth 433 (2016) 128–138 129

were examined. In the first part the interest was focused on such
pairs, where structures are known. This step ensures the reliability
of cocrystallization on the glass surface and allows for demon-
stration of usefulness of sample orientation for cocrystal screening.
After validation of proposed procedure by positive examples
additional verification was performed for such coformers that are
known to be able to form simple eutectic systems instead of
molecular complex in the solid state. In the third part the results of
actual seeking of new cocrystals are documented.
3.1. Validation of cocrystal screening method
The efficacy of cocrystal identification after deposition on the
glass film is demonstrated in Fig. 1, where the experimental PXRD
spectra of coformers and U–SA cocrystal are presented. Addition-
ally, plots were augmented with simulated spectra obtained using
CIF-content deposited in CSD. First of all the strong orientation
effect is visible both for urea and salicylic acid. In the former case
the most dominant signal characterizing crystallites deposited on
glass is positioned at 2θ¼22.2° what corresponds to (110) Miller
plane. This is not surprising since on the single crystals XRD
spectra of urea this signal is also the most intense. The orientation
effect is especially pronounced in the case of salicylic acid, what
has already been documented [46]. The formation of U–SA
cocrystal on the surface is indisputable since direct comparison
with SLCAD01 signals confirms overlapping of all the most sig-
nificant peaks. The orientation effect is not so spectacular as for
monomers, but still identification of cocrystal is straightforward.
Besides, the analysis of FTIR spectra shows evidences of new
hydrogen bonding pattern. The consequence of molecular complex
formation in the case of amides and carboxylic acids is shifting of
N–H and O–H stretching vibrations in comparison to pure cofor-
mers [56–59]. It is worth mentioning that U–SA cocrystal has
already been studied by means of vibrational spectroscopy [60].
Our measurements agree with reported spectra of U–SA and sev-
eral absorption bands characteristic for intermolecular interac-
tions between urea and salicylic acid can be identified. First of all,
there is a broad and intense band located at 1898 cmÀ1
. This signal
corresponds to a stretching vibration of carboxylic group forming
intermolecular C(O)OH∙∙∙O¼C(NH2)2 hydrogen bond. For com-
parison in the case of pure salicylic acid crystallites O–H stretching
bands are located in the range from 3236 cmÀ1
to 2539 cmÀ1
. Our
observation agrees with reported IR spectra [61] and confirms
existence of two distinct types of N–H vibrational modes, namely
out-of-phase stretching (asymmetric, νas(NH)) and in-phase
stretching (symmetric, νs(NH)) vibrations. As it is shown in
Fig. 1, the νas(NH) vibration is located at 3431 cmÀ1
and
3471 cmÀ1
for pure urea and urea–salicylic acid molecular com-
plex, respectively. This indicates that formation of NH∙∙∙O inter-
action results in blue-shift of out-of-phase NH stretching absorp-
tion band. On the other hand in the case of N–H in-phase
stretching mode, a significant red-shift from 3260 down to
3215 cmÀ1
can be observed.
The second example of positive cocrystallization of urea with
aromatic carboxylic acids is the case of 4HBA. Although the U–
4HBA cocrystal has already been solved and discussed [62] but
FIGURES
Scheme 1. The schematic representation of hydroxycarboxylic acids structures used for cocrystals synthesis.
M. Przybyłek et al. / Journal of Crystal Growth 433 (2016) 128–138130

neither structure nor XRD spectra were deposited in CDS. It is
reported however, that the 2:1 complex of urea and 4HBA crys-
tallizes as triclinic system in the P1 space group. As one can infer
from Fig. 2 the crystallization on glass surfaces also leads to
molecular complex. Formation of a new multicomponent crystal
can be evidenced by a new signal located at 2θ¼13.5°. Further-
more, cocrystal formation can be confirmed by means of FTIR
spectroscopy. However, in this case the shift of absorption bands is
less pronounced than in the case of U–SA cocrystal. As a con-
sequence of U–4HBA molecular complex formation the three
bands located in the O–H stretching region are shifted from
2548 cmÀ1
, 2664 cmÀ1
and 2825 cmÀ1
to 2559 cmÀ1
, 2690 cmÀ1
and 2817 cmÀ1
, respectively.
Presented analysis of successful identification of cocrystalliza-
tion on the glass surfaces is a promising circumstance, suggesting
usefulness of adopted screening method for further applications.
However, before seeking of new cocrystals, also negative cases
should be considered. For this purpose there were considered two
structurally very similar compounds such as benzoic acid and
acetylsalicylic acid. The lack of structures of these cocrystals in CSD
[6] is not accidental. As it was revealed by thermomicroscopic
measurements the U–BA [63] and U–ASA [64] binary systems
exhibit simple eutectic behavior. The thaw melt method [65] as
very useful in detailed analysis of miscibility of solid and liquid
mixtures proved the lack of molecular complex formation in the
entire range of concentrations. In both cases the single invariant
point the for either of systems was identified. The characteristic
melting temperature of eutectic mixture was measured. Further-
more, the direct inspection of binary phase diagrams shows neg-
ligible formation of solid solutions or molecular compounds. The
lack of clustering of coformers and consequently solidification of
two distinct phases is also confirmed by excess thermodynamic
functions. Interestingly, our experiments on crystallization of
these two pairs on glass surface also failed to identify cocrystal
formation. Indeed, as it is presented in supporting materials (see
Fig. S1 and S2) the lack of cocrystal is directly provable since
complete overlapping of single component PXRD patterns with
signals measured for 1:1 mixtures of urea with benzoic or acet-
ylsalicylic acids was observed. Inspection of FTIR spectra, showed
that absorption bands corresponding to N–H and O–H in U–BA and
U–ASA mixtures are not shifted when compared to signals of pure
co-formers. However in the case of FTIR spectra of U–ASA mixture
two new absorption bands located at 2850 cmÀ1
and 2919 cmÀ1
might be noticed. Appearance of these characteristic sharp signals
corresponding to CH stretching vibrational modes is typical for
adsorbed or occluded methanol [66–70]. This is understandable,
since methanol was used as a solvent in the evaporative crystal-
lization procedure.
3.2. New cocrystals of urea with aromatic carboxylic acids
The usefulness of glass surfaces for cocrystal screening relying
on the orientation effect is documented in the case of such
hydroxycarboxylic aromatic acids as 2,4DHBA, 2,5DHBA, 2,6DHBA,
3,5DHBA and 3HBA. These compounds were selected since to our
best knowledge there are no reports on their cocrystallization with
urea. The possibility of molecular complexes formation was eval-
uated by inspection of both PXRD and FTIR spectra recorded for
crystallite layers. The FTIR analysis omitted dactyloscopic region
and absorption bands in the regions corresponding to O–H and N–
H stretching vibrational modes were taken into account.
5 10 15 20 25 30 35 40
relativeintensity
2θ[ ]
U (glass)
SA (glass)
SA (SALIAC)
U-SA (glass)
U−SA (SLCADC01)
U(UREAXX23)
0.2
0.4
0.6
0.8
1.0
1700 2200 2700 3200 3700 4200
normalizedtransmitance
wave number [cm-1
]
U-SA
SA
U
°
Fig. 1. The measured PXRD and FTIR patterns of urea (U), salicylic acid (SA) and cocrystal (U–SA) deposited on the glass surface. The diffraction plots were augmented with
the simulated spectra of single component crystals and U–SA cocrystal. Codes represent deposits found in CSD [6].

3.2.1. Cocrystallization of 2,4-dihydroxybenzoic acid with urea
The 2,4-dihydroxybenzoic acid can crystallize in three distinct
polymorphic forms (I: ZZZEEU08, II: from ZZZEEU01 to ZZZEEU07,
III: ZZZEEU) [71–74]. Unfortunately the latter was not solved and
neither space group nor structure factors are available. On the
other hand computational studied suggest that only two poly-
morph are to be considered as the most stable at room tempera-
ture [71]. Our measurements of PXRD spectra of single compo-
nents crystal deposited on glass surface demonstrated very strong
orientation effect of 2,4DHBA since only one diffraction peak can
be observed at 2θ¼13.7°. This signal is associated with (021)
Miller plane, what suggests existence on the glass surface exclu-
sively polymorph II. This is quite expected since it is thermo-
dynamically the most stable polymorphic form at room tempera-
ture [71]. Interestingly, β-resorcylic acid, as many other hydro-
xybenzoic acids, can readily form solvates [71,75–80]. The struc-
ture of 2,4-dihydroxybenzoic acid hemihydrate has been solved
[76] (QIVTUK) and corresponding diffractogram was also supplied
in Fig. 3. It is practically impossible to distinguish hydrate from dry
crystal due to strong overlapping of registered signals. Thus, traces
of water in air or methanol might also have influence the solid
formation on glass surfaces. The ability of formation of a multi-
component crystal with urea can be confirmed by the appearance
of two intense diffraction peaks at 2θ¼8.4° and 2θ¼9.7°. Fur-
thermore, in the case of U–2,4DHBA cocrystal, there is a significant
shift of N–H stretching bands from 3260 cmÀ1
to 3312 cmÀ1
and
from 3431 cmÀ1
to 3461 cmÀ1
(Fig. 3). Also shift of the O–H
stretching vibrations from 2559 cmÀ1
to 2594 cmÀ1
can be
observed as a consequence of complex formation in the solid state.
The gentisic acid acting as analgesic, antirheumatic and anti-
arthritic agent can adopt two polymorphic forms, namely I: BES-
KAL01 and II: BESKAL, from BESKAL02 to BESKAL14 [73,81–82].
According to literature, 2,5-dihydroxybenzoic acid does not form
hydrate and also no hydrate structure was found in the CSD [6,83].
The most stable from the thermodynamic point of view [73] is the
polymorph crystallizing in monoclinic system (Pa space group). As
it is documented in Fig. 4 the same polymorph is also present on
the glass surface. The most intense reflexes observed on the PXRD
spectra of 2,5DHBA are located at 2θ¼15.8°, 2θ¼17.5° and
2θ¼30.9°. They correspond to (200), (210) and (311) Miller planes,
respectively. The formation of U–2,5DHBA cocrystal can be infer-
red from the most intense signal placed at 2θ¼12.9°, which is
typical for cocrystal rather than for coformers. The PXRD signals of
U–2,5DHBA cocrystal possess additional two signals located at
2θ¼15.6° and 2θ¼18.8°. However, only latter can be used for
additional confirmation of cocrystal occurrence since the former
corresponds to the (200) crystal face of 2,5DHBA. In the case of U–
2,5DHBA complex the characteristic broad absorption band with a
maximum at 1864 cmÀ1
appears on the FTIR spectra. It is worth
mentioning that similar band was observed also in the case of SA–
U complex (Fig. 1). Moreover, the presence of C(O)OH∙∙∙O¼C
(NH2)2 hydrogen bond can be confirmed by observed red-shift of
O–H stretching band from 3260 cmÀ1
to 3115 cmÀ1
along with
shifts in the N–H stretching region.
The γ-resorcylic acid has been found to form two distinct
polymorphs [79,84]. The first one crystallizes in the orthorhombic
5 10 15 20 25 30 35 40
relativeintensity
2θ[ ]
U (glass)
4HBA (glass)
4HBA (JOZZIH)
U-4HBA (glass)
U (UREAXX23)
0.0
0.2
0.4
0.6
0.8
1.0
1740 2240 2740 3240 3740
wave number [cm-1]
U-4HBA
4-HBA
U
°
Fig. 2. The measured PXRD and FTIR patterns of urea (U), 4-hydroxybenzoic acid (4HBA) and cocrystal (U–U–4HBA) deposited on glass surfaces. The diffraction plots were
augmented with the simulated spectra of single component crystals. Codes represent deposits found in CSD [6].

system (LEZJAB) and the other one as monoclinic crystal (LEZ-
JAB01). Besides, 2,6DHBA can form monohydrate, which structure
was deposited in CSD under code LEZJEF. After inspection of PXRD
spectra provided in Fig. 5 one can directly conclude that γ-
resorcylic acid crystallizes on glass surface as mixture of dry and
monohydrate solids. This is probable caused by the moisture
sorption. Both crystals show strong orientation effect and on the
glass surface only one polymorph of 2,6DHBA is to be expected.
From the perspective of this project the most interesting is the
documentation of U–2,6DHBA occurrence. As shown on Fig. 5 the
crystallization of binary mixture on glass surface leads to forma-
tion of single component urea crystals, what is suggested by
strongest signal located at 2θ¼22.3°. However, this is not the only
solid appearing on the surface. The diffraction peak placed at
2θ¼12.9° suggests presence of new crystal phase. The inspection
of FTIR spectra confirms this suggestion. There is clearly visible
broad absorption band located at 1805 cmÀ1
, which is character-
istic for hydrogen bonding between urea and carboxylic acid.
Furthermore, formation of cocrystal can be also evidenced by
several shifts of absorption bands at the O–H and N–H stretching
regions making spectra of U–2,6DHBA distinct from pure compo-
nents patterns.
The next studied case focuses on 3,5-dihydroxybenzoic acid.
This compound is known to exist in solid state as one of two
polymorphs (I: WUYPOW and II: WUYPOW01) both sharing the
same space group in triclinic system [75]. Also it is known the
hemihydrate of the α-resorcylic acid [85], which structure is
available in CSD under code OKEMAT. As it is presented in Fig. 6
these three solids have quite distinct diffraction characteristics. It
appears that on glass surface the hemihydrate predominates and
its grow has strong oriented. There is observed single and intense
peak located at 2θ¼26.9° what enables straightforward identifi-
cation of the form present in thin films. Interestingly, the α-
resorcylic acid can form molecular complex with urea what can be
directly documented after inspection of the PXRD spectra. The
most significant signal is located at 2θ¼10.8°, which seems to
unique for U-3,5DHBA cocrystal. There are also other peaks on
PXRD plots, but they overlap with hydrate or dry 3,5-dihydrox-
ybenzoic acid solids. Additional confirmation of existence of U-
35DHBA system can be inferred from FTIR spectra. As it is visible in
Fig. 6 significant shifts of small N–H absorption band from
3260 cmÀ1
to 3394 cmÀ1
can be observed.
3.2.5. Cocrystallization of 3-hydroxybenzoic acid with urea
The last considered here carboxylic acid was 3-hydroxybenzoic
acid, which is known to be produced in the gut microflora as one
of the three main metabolites formed from the catechin diet. The
3-HBA solids can adopt two distinct polymorphic form crystalizing
either in monoclinic (BIDLOP) or orthorhombic (BIDLOP01,
BIDLOP02) crystallographic systems [86,87]. No hydrate structure
is available in CSD. The PXRD spectra of 3-HBA presented in Fig. 7
suggests that both of orthorhombic forms might be present on the
glass crystallites. The signals cannot be univocally separated and in
this case the orientation effect is not useful in the identification of
polymorphic forms. As it is presented in Fig. 7 formation of the
cocrystal phase can be evidenced by the new reflex on the dif-
fraction pattern located at 2θ¼5.5°. However, the most intense
diffraction peak comes from pure urea suggesting a non uni-molar
5 10 15 20 25 30 35 40
relativeintensity
2θ[ ]
U (glass)
2,4DHBA (glass)
2,4DHBA
(ZZZEEU08)
U-2,4DHBA (glass)
U (UREAXX23)
2,4DHBA
(ZZZEEU04)
2,4DHBA hydrate
(QIVTUK)
U-2,4DHBA (grinding)
U-2,4DHBA (bulk)
0.2
0.4
0.6
0.8
1.0
2000 2500 3000 3500 4000
wave number [cm-1 ]
U-2,4DHBA
2,4DHBA
U
°
Fig. 3. The measured PXRD and FTIR patterns of urea (U), 2,4-hydroxybenzoic acid (2,4HBA) and cocrystal (U–2,4HBA) crystallite deposited on glass surfaces. Additionally,
diffraction plots were augmented with the simulated spectra based on data deposited in CSD [6] and cocrystallization via two alternative methods.

5 10 15 20 25 30 35 40
relativeintensity
2θ[ ]
U (glass)
2,5DHBA (glass)
2,5DHBA
(BESKAL01)
U-2,5DHBA (glass)
U (UREAXX23)
2,5DHBA
(BESKAL08)
U-2,5DHBA (bulk)
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1700 2200 2700 3200 3700
wave number [cm-1
]
U-2,5DBA
2,5DHBA
U
°
5 10 15 20 25 30 35 40
relativeintensity
2θ[ ]
U (glass)
2,6DHBA (glass)
U-2,6DHBA (glass)
U (UREAXX23)
2,6DHBA
(LEZJAB)
2,6DHBA hydrate
(LEZJEF)
2,6DHBA
(LEZJAB01)
U-2,6DHBA bulk)
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1700 2200 2700 3200 3700
wave number [cm-1]
U-2,6DHBA
2,6DHBA
U
°

5 10 15 20 25 30 35 40
relativeintensity
2θ[ ]
U (glass)
3,5DHBA (glass)
U (UREAXX23)
U-3,5DHBA (glass)
3,5DHBA (WUYPOW)
3,5DHBA (WUYPOW01)
3,5DHBA hydrate
(OKEMAT)
U-3,5DHBA (bulk)
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1750 2250 2750 3250 3750
wave number [cm-1]
U-3,5DHBA
3,5DHBA
U
°
Fig. 6. The measured PXRD and FTIR patterns of urea (U), 3,5-hydroxybenzoic acid (3,5HBA) and cocrystal (U-3,5HBA) crystallite deposited on glass surfaces. Additionally,
5 10 15 20 25 30 35 40
relativeintensity
2θ[ ]
U (glass)
3HBA (glass)
3HBA (BIDLOP01)
3HBA (BIDLOP)
U-3HBA (glass)
U (UREAXX23)
U-3HBA (grinding)
U-3HBA (bulk)
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
2000 2500 3000 3500 4000
relativetransmitance
wave number [cm-1]
U-3HBA
3HBA
U
°
Fig. 7. The measured PXRD and FTIR patterns of urea (U), 3-hydroxybenzoic acid (3HBA) and cocrystal (U-3HBA) crystallite deposited on glass surfaces. Additionally,

complexation. Furthermore, the FTIR spectra shown in Fig. 7
confirms occurrence of the hydrogen bond between U and 3HBA.
The intermolecular interactions in U-3HBA molecular complex
differ from coformers what can be evidenced by the blue-shifts of
OH stretching bands from 2842 cmÀ1
to 2971 cmÀ1
and from
3083 cmÀ1
to 3151 cmÀ1
.
4. Conclusions
As it was reported in our previous studies [45,46], anisotropic
crystal growth during droplet evaporation on the polar surfaces
depends on the adhesive and cohesive properties of crystal faces.
The role of intermolecular interactions on the orientation effect
was also described in case of thin layers obtained using sublima-
tion method [88]. Moreover, according to Schweicher et al.,
orientation of terthiophene crystal thin films obtained during
directional thermal gradient crystallization can be explained
within the framework of equilibrium crystal morphology calcula-
tion, which is based on the crystal faces energetics analysis [89].
Since the lattice energy calculations showed that multicomponent
crystals are generally more energetically stable than pure com-
ponents crystals [90–92], it is understandable that cocrystals faces
growth on the surface under oriented crystallization conditions is
favorable and hence the appearance of diffraction peaks corre-
sponding to cocrystal is highly probable. Therefore, despite of the
fact that orientation effect leads to significant reduction of PXRD
peaks, new cocrystal phase can be identified. In this study, the
ability of molecular complex formation in the solid state was
documented for series of aromatic carboxylic acids with urea. For
this purpose the cocrystallization was performed on glass surfaces
using simple drop evaporate method. The direct measurements of
obtained deposits were done using both PXRD and FTIR techni-
ques. The comparison of signals characterizing single component
with those observed for binary mixtures of urea with several
aromatic carboxylic acids allows for identification of several new
cocrystals. Although, this method is unsuitable for crystal structure
solution due to significant reduction of peaks number in diffrac-
tion spectra but is useful as the first stage tool in the cocrystal
screening. The strong orientation effect on surfaces dampens many
signals in PXRD spectra and distinguishing of cocrystal from
coformers is much simpler. Before application the procedure to
new cocrystal finding the validation stage successfully identified
cases of both cocrystallization and pairs of coformers not being
able to cocrystalize. Indeed, two positive cases known in the lit-
erature were confirmed, namely U–SA and U–4HBA. Additionally,
two binary mixtures of eutectic character also pointed out efficacy
of utilized technique for identification of such negative examples.
The pairs comprising urea and either benzoic acid or aspirin is
known as simple eutectic mixture. In both cases, the measured
signals of crystallites deposited on surfaces obtained from 1:1
stoichiometric solutions were substantially indistinguishable from
single components signals. The proposed method seems to be
suited as preliminary tool for cocrystal screening and offers several
advantages worth emphasizing. First of all this is very simple, time
saving technique enabling for robust screening without sophisti-
cated equipment. Due to small volume of the solution the eva-
poration process takes seconds and several samples on the glass
plates can be prepared at the same time. Furthermore, the PXRD
measurements can be fasten due to the fact that the most sig-
nificant analytical signals belong to low 2θ region and rarely
reaching 30°. The method is very cheap since microliters of solu-
tion are used for measurements. That is why proposed approach
seems to be especially valuable in cocrystal screening of active
pharmaceutical ingredients. What is also worth mentioning, the
protocol can be applied for cases of low solubility by scanning the
film several times and accumulating even small intensity signals.
Of course there is practical limit due to possible noise, which is
especially disturbing in the cases of high contribution from
amorphous phase. However, in reported cases this was not a ser-
ious issue. If additive measuring is not sufficient one can repeat
several times the procedure of dropping and evaporating. This
results in thicker crystallite. However this reduces the orientation
effect and spectra are more similar to the bulk crystallization. After
identification of positive cocrystallization pairs one can apply
traditional methods for cocrystal formation as for example
mechanochemical approach restricting synthesis only to such
cases, which were pre-screened on glass surfaces. In studied bin-
ary mixtures the 1:1 M ratio of coformers was used, but in general
one can study other proportions for identification of stoichiometry
of molecular complex formation in the cocrystal, what will be the
subject of further investigations.
Appendix A. Supplementary material
Supplementary data associated with this article can be found in
the online version at http://dx.doi.org/10.1016/j.bios.2014.05.063.
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