Vibrational spectroscopic studies of cocrystals and salts. 3. cocrystal products formed by benzenecarboxylic acids and their sodium salts

Article abstract of DOI:10.1021/cg100099w

X-ray powder diffraction, differential scanning calorimetry, infrared absorption spectroscopy, and Raman spectroscopy have been used to study the phenomenon of salt formation in four benzenecarboxylic acids (benzoic acid, phenylacetic acid, hydrocinnamic acid, and 4-phenylbutanoic acid), and in the 1:1 stoichiometric products formed by the cocrystallization of a free acid and a sodium salt. Assignments were derived for the observed peaks in both infrared absorption and Raman spectra of the reactants and their products. In all instances, it was observed that the energy of the antisymmetric stretching mode of the carbonyl group of the free benzenecarboxylic acid invariably shifted to higher energies when that acid formed a cocrystal with a sodium salt of another benzenecarboxylic acid. In addition, the symmetric stretching mode of the benzenecarboxylic acid carbonyl group disappeared in the Raman spectrum of its sodium salt and was also absent in the Raman spectrum of the cocrystal product. It was also found that the antisymmetric carboxylate anion stretching mode, the symmetric carboxylate anion stretching mode, the out-of-plane carboxylate deformation mode, and the vibrational modes associated with the phenyl ring and alkane side chains were not useful spectroscopic tools to differentiate cocrystal and sodium salt, as the observed differences of these vibrational modes did not exhibit significantly consistent differences between the various forms.

Full text of DOI:10.1021/cg100099w

DOI: 10.1021/cg100099w
Vibrational Spectroscopic Studies of Cocrystals and Salts. 3. Cocrystal
Products Formed by Benzenecarboxylic Acids and Their Sodium Salts
2
010, Vol. 10
1990–2003
Harry G. Brittain*
Center for Pharmaceutical Physics, 10 Charles Road Milford, New Jersey 08848
Received January 22, 2010; Revised Manuscript Received February 17, 2010
ABSTRACT: X-ray powder diffraction, differential scanning calorimetry, infrared absorption spectroscopy, and Raman
spectroscopy have been used to study the phenomenon of salt formation in four benzenecarboxylic acids (benzoic acid,
phenylacetic acid, hydrocinnamic acid, and 4-phenylbutanoic acid), and in the 1:1 stoichiometric products formed by the
cocrystallization of a free acid and a sodium salt. Assignments were derived for the observed peaks in both infrared absorption
and Raman spectra of the reactants and their products. In all instances, it was observed that the energy of the antisymmetric
stretching mode of the carbonyl group of the free benzenecarboxylic acid invariably shifted to higher energies when that
acid formed a cocrystal with a sodium salt of another benzenecarboxylic acid. In addition, the symmetric stretching
mode of the benzenecarboxylic acid carbonyl group disappeared in the Raman spectrum of its sodium salt and was also absent
in the Raman spectrum of the cocrystal product. It was also found that the antisymmetric carboxylate anion stretching mode,
the symmetric carboxylate anion stretching mode, the out-of-plane carboxylate deformation mode, and the vibrational modes
associated with the phenyl ring and alkane side chains were not useful spectroscopic tools to differentiate cocrystal and sodium
salt, as the observed differences of these vibrational modes did not exhibit significantly consistent differences between the
various forms.
Introduction
In the preceding works in this series, in-depth studies have
been conducted regarding the use of vibrational spectroscopy
as a means to study the intermolecular interactions existing in
In a previous study, the existence of an interesting 1:1 salt-
cocrystal formed by the interaction of benzoic acid with
benzylammonium benzoate was demonstrated using X-ray
powder diffraction (XRPD) and differential scanning calori-
1,9
the solid-state forms of salts and cocrystals. Other workers
have used infrared absorption spectroscopy as a means to
correlate intermolecular interactions in solution with the
1
metry (DSC). Full assignments for the infrared absorption
10
structural synthons that assemble into crystals. In some
and Raman spectra of the cocrystal were made, and by tracing
the perturbations in group energies relative to the starting free
acid and salt, a series of conclusions were reached regarding
the intermolecular interactions existing in the cocrystal. For
example, a significant alteration of the antisymmetric carbo-
nyl stretching mode of benzoic acid was found to take place,
resulting in a large shift in energy and splitting of the band. In
addition, study of the energies of the phenyl ring modes
enabledthededuction thatformationof the cocrystalinvolved
interactions between the phenyl rings of the benzoic acid and
the benzylammonium benzoate salt that did not accompany
formation of the salt from benzoic acid and benzylamine.
The principle that salts of organic molecules can form
cocrystals with carboxylic acids is well established in the
literature. For example, the existence of a 1:1 salt-cocrystal
of fluoxetine hydrochloride and benzoic acid has been demon-
strated, as have 2:1 salt-cocrystals of the drug substance with
cases, the existence of similarities between the growth synthon
and the structural synthon was detected, but in others it was
deduced that the solution-phase assembliesneeded to undergo
significant molecular rearrangement in order to form crystal
nuclei. In another study, infrared absorption spectroscopy
and single-crystal diffractionstudieswere used tostudy a large
number of solid-state products consisting of theophylline and
interactive molecules characterized by comparable ionization
11
constant differences. These workers obtained 13 cocrystals,
5 salts, and 2 complexes having mixed ionization states, and
ultimately proposed that screening studies be more based on
identification of solid-state forms and not on pK differences.
A
In the present work, the phenomena of salt and cocrystal
formation have been studied for the series of benzenecar-
boxylic acids whose structures are provided in Figure 1,
primarily from the viewpoint of perturbations in molecular
vibrations that are associated with the various species. The
compounds studied in this work are characterized by an
increasing degree of separation between the phenyl and
carboxylate groups, enabling an investigation to be made
regarding the roles of synthon formation and phenyl ring
interaction.
2
succinic and fumaric acids. The intermolecular interactions
existing in these systems represent examples of the types of
anion coordination anion-templated assembly that have been
3
recently described. In another work, the salt-cocrystal
formed by tiotropium fumarate with fumaric acid has been
shown to be more stable than were the simpler salt and salt-
4
solvate fumarate solid forms. It is clear that such salt-
cocrystal systems greatly extend the scope of crystalline forms
Materials and Methods
Benzoic acid(BZA), phenylacetic acid(PAA), hydrocinnamicacid
HCA), and 4-phenylbutanoic acid (4PBA) were purchased from
5-8
ofdrug substances, thus providing anevenwiderlandscape
for investigators seeking to improve upon the physical proper-
ties of a given drug substance.
(
Sigma-Aldrich, and each free acid was wetted with methanol and
ground to dryness in a mortar before use. The sodium salts of these
r
pubs.acs.org/crystal
Published on Web 02/25/2010
2010 American Chemical Society

Article
Crystal Growth & Design, Vol. 10, No. 4, 2010 1991
Figure 1. Structures of the benzenecarboxylic acids used in the
present study.
carboxylic acids were prepared by dissolving 500 mg quantities of
each acid in a 1:1 stoichiometric amount of 0.2 N sodium hydroxide
solution, and then evaporating the solution to dryness. The recovered
solids were transferred to a mortar, wetted with methanol, and then
ground to dryness. Cocrystal products were prepared following the
same general procedure, where accurately weighed amounts of free
acid and sodium salt (1:1 stoichiometry based on nonsolvated
masses) were placed in a mortar, wetted with methanol, and then
ground to dryness.
Figure 2. X-ray powder diffraction patterns of benzoic acid (blue
trace), sodium benzoate (green trace), and the 1:1 benzoic acid/
sodium benzoate cocrystal (red trace).
XRPD patterns were obtained using a Rigaku MiniFlex powder
diffraction system, equipped with a horizontal goniometer operating
in the θ/2θ mode. The X-ray source was nickel-filtered KR emission
˚
of copper (1.54184 A). Samples were packed into the sample holder
using a backfill procedure and were scanned over the range of 3.5-
4
rate of 1 point per second, these scanning parameters equate to a step
0 deg 2θ at a scan rate of 0.5 deg 2θ/min. Using a data acquisition
size of 0.0084 deg 2θ.
Measurements of DSC were obtained on a TA Instruments
2
910 thermal analysis system. Samples of approximately 1-2 mg
were accurately weighed into an aluminum DSC pan, and then
covered with an aluminum lid that was crimped in place. The samples
were then heated at a heating rate of 10 °C/min from ambient
temperature to termination temperatures in the range of 150-
2
25 °C, depending on the system under study.
Fourier-transform infrared (FTIR) absorption spectra were ob-
-1
tained at a resolution of 4 cm using a Shimadzu model 8400S
infrared spectrometer, with each spectrum being obtained as the
average of 25 individual spectra. The data were acquired using the
attenuated total reflectance sampling mode, where the samples were
clamped against the ZnSe crystal of a Pike MIRacle single reflection
horizontalATR samplingaccessory. Raman spectra wereobtainedin
the fingerprint region using a Raman Systems model R-3000HR
-
1
spectrometer, operated at a resolution of 5 cm and using a laser
wavelength of 785 nm. The data were acquired using front-face
scattering from a thick powder bed contained in an aluminum sample
holder.
Figure 3. Infrared absorption spectra in the fingerprint region of
benzoic acid (blue trace), sodium benzoate (green trace), and the 1:1
benzoic acid/sodium benzoate cocrystal (red trace).
Results
A. Benzoic Acid, Sodium Benzoate, and their Homo-
Cocrystal Product. XRPD patterns obtained for benzoic
acid, sodium benzoate, and the BZA-Na-BZA cocrystal
product are shown in Figure 2, where one may note that
the differences in powder patterns demonstrate the existence
of three different crystal structures. DSC thermograms of
these substances confirmed the existence of distinctly differ-
ent crystalline species. The DSC thermogram of benzoic acid
consisted of a single melting endothermic transition, char-
acterized by a temperature maximum at of 123 °C and an
enthalpy of fusion equal to 133 J/g. The DSC thermogram of
the sodium benzoate salt consisted solely of a desolvation
endotherm, which exhibited a temperature maximum of
69 °C and an enthalpy of desolvation equal to 74 J/g. These
thermal characteristics may be contrasted with those of the
BZA-Na-BZA cocrystal product, for which the DSC thermo-
gram consisted of a single melting endothermic transition,
having a temperature maximum at of 144 °C and an enthalpy
of fusion equal to 52 J/g.

1
992 Crystal Growth & Design, Vol. 10, No. 4, 2010
Brittain
Table 1. Assignments of the Major Bands in the Fingerprint Region of the Infrared Absorption Spectra of Benzoic Acid, Sodium Benzoate, and their 1:1
Cocrystal Product
benzoic
acid
benzoic acid/sodium
benzoate cocrystal
sodium
benzoate
assignment
assignment
ring torsion mode
C-H out-of-plane bending mode
ring torsion mode
C-H deformation mode
C-H rocking mode
665
683
704
806
652
679
706
798, 787
677
704
C-H deformation mode
8
8
20
45
820
845
out-of-plane C-H mode
out-of-plane C-H deformation mode
out-of-plane ring bending mode
933
-
9
01
920
COO out-of-plane deformation
C-C stretching mode
1001
1026
1072
1128
1186
1257
1323
in-plane ring C-H mode
in-plane ring C-H mode
in-plane ring C-H mode
C-H twisting mode
1026
1070
1119
1176
1250
1327
1028
1068
in-plane ring C-H mode
in-plane ring C-H mode
carbonyl in-plane deformation
C-C ring stretching mode
1308
1402
C-C ring stretching mode
symmetric COO stretching mode
-
1
408
OH out-of-plane deformation of COOH
C-C ring stretching mode
1421
1452
1450
551
-
1
1547
1595
antisymmetric COO stretching mode
C-C ring stretching mode
C-C ring stretching mode
COOH stretching mode
1583
1601
1678
1597
1697
C-C ring stretching mode
are effectively the same. It is not unexpected that the most
interesting changes associated with either the salt or cocrys-
tal formation are associated with the motions of the benzoic
carboxylate group. For example, the loss of the -COOH
-
1
asymmetric stretching mode of benzoic acid (1678 cm ) and
-
1
appearance of the antisymmetric (1547 cm ) and symmetric
-
1
1402 cm ) stretching modes of the benzoate COO ion
-
(
represents the normal spectral perturbation that takes place
upon formation of the carboxylate salt. All of these
same vibrational modes are present in the spectrum of the
BZA-Na-BZA cocrystal, with the most interesting difference
being the increase in frequency of the COOH stretching
-
1
.
mode from 1678 to 1697 cm
The Raman spectra of benzoic acid, sodium benzoate, and
the BZA-Na-BZA cocrystal product in the fingerprint region
are shown in Figure 4. The origins of the vibrational modes
associated with the various Raman scattering peaks were
2
2-25
assigned through the use of published compilations,
2
6,27
works dealing specifically with benzoic acids,
1
and works
The results of this
9,21
covering the spectra of benzoate salts.
analysis are provided in Table 2.
As had been noted for the infrared absorption spectra, the
modes associated with the carbon skeleton were not appre-
ciably different in the Raman spectra of the three substances.
Once again, the most interesting differences between the
forms were found to be associated with the carboxylate
group. Formation of the sodium benzoate salt was demon-
strated in the Raman spectra as a loss of the weak symmetric
Figure 4. Raman spectra in the fingerprint region of benzoic acid
blue trace), sodium benzoate (green trace), and the 1:1 benzoic
acid/sodium benzoate cocrystal (red trace).
(
-
1
As shown in Figure 3, benzoic acid, sodium benzoate, and
the BZA-Na-BZA cocrystal product exhibited a number of
significant differences in the fingerprint region of their
infrared absorption spectra. The molecular vibrational
modes of the major absorbance peaks were assigned through
carbonyl stretching mode (1631 cm ) of the acid and in
the appearance of a carboxylate anion stretching mode in
-
1
the spectrum of the salt at 1267 cm . Formation of the
BZA-Na-BZA cocrystal product was found to result in a
loss of the carboxylic acid in-plane deformation mode
1
2-14
-1
the use of published compilations,
works conducted
or works covering the
The results of this analysis
(1287 cm ) and a shift of the carboxylate anion stretching
-1
1
5-18
-1
specifically on benzoic acids
1
mode from 1267 cm to 1251 cm . In addition, the
frequency of the symmetric carboxylic acid stretching mode
9-21
spectra of benzoate salts.
are provided in Table 1.
-
1
-1
(1631 cm ) was found to increase to 1696 cm in the
spectrum of the cocrystal.
1
,9
As has been noted in the previous papers, the degree of
perturbation in the frequencies of the carbon-carbon and
carbon-hydrogen modes is relatively minor across the three
substances, which indicates that the basic skeletal motions
B. Phenylacetic Acid, Sodium Phenylacetate, and their
Homo-Cocrystal Product. The XRPD patterns obtained
for phenylacetic acid, sodium phenylacetate, and the 1:1

Article
Crystal Growth & Design, Vol. 10, No. 4, 2010 1993
Table 2. Assignments of the Major Bands in the Fingerprint Region of the Raman Spectra of Benzoic Acid, Sodium Benzoate, and Their 1:1 Cocrystal
Product
benzoic
acid
benzoic acid/sodium
benzoate cocrystal
sodium
benzoate
assignment
assignment
C-C þ ring deformation modes
416
611
398
611
396
609
673
C-C þ ring deformation modes
ring torsion mode
ring torsion mode
symmetric COO deformation mode
-
6
73
783
37
C-H out-of-plane bending mode
790
997
8
839
1002
C-C þ ring deformation modes
in-plane C-C deformation mode
of phenyl ring
in-plane C-C deformation mode of phenyl ring
1001
1025
1138
in-plane C-H deformation mode
C-H rocking mode
in-plane C-H deformation mode
1023
1070
1129
1026
in-plane C-H deformation mode
1139
1155
1179
in-plane C-H deformation mode
C-H twisting mode
C-H in-plane bending mode
1157
1181
C-H in-plane bending mode
COOH in-plane deformation mode
1176
1287
-
1
251
1267
symmetric COO stretching mode
C-C ring stretching mode
C-H twisting mode
1361
1441
1372
1431
1433
1567
1601
C-H twisting mode
C-H ring in-plane bending mode
C-C ring stretching mode
C-C ring stretching mode
symmetric carbonyl stretching mode
1601
1631
1600
1696
Figure 5. X-ray powder diffraction patterns of phenylacetic acid
blue trace), sodium phenylacetate (green trace), and the 1:1 phe-
nylacetic acid/sodium phenylacetate cocrystal (red trace).
Figure 6. Infrared absorption spectra in the fingerprint region of
phenylacetic acid (blue trace), sodium phenylacetate (green trace),
and the 1:1 phenylacetic acid/sodium phenylacetate cocrystal (red
trace).
(
PAA-Na-PAA cocrystal product are shown in Figure 5, and
the nonequivalence of the three powder patterns demon-
strates that the structure of the cocrystal product is different
than either the initial free acid or sodium salt.
temperature maximum of 43 °C (estimated enthalpy of
fusion equal to 48 J/g).
While the DSC thermogram of phenylacetic acid con-
sisted of a single melting endothermic transition (tempera-
ture maximum at of 78 °C and enthalpy of fusion equal
to 113 J/g), the DSC thermogram of the sodium phenyl-
acetate salt was quite complicated. Three overlapping
desolvation endothermic transitions were noted, having
temperature maxima of 59, 68, and 84 °C. The summed
desolvation enthalpy of these transitions exceeded 250 J/g,
and the desolvated substance was eventually found to
melt with decomposition at 195 °C. The DSC thermo-
gram of the PAA-Na-PAA cocrystal product exhibited a
single melting endothermic transition, characterized by a
As shown in Figure 6, phenylacetic acid, sodium phenyl-
acetate, and the PAA-Na-PAA cocrystal product exhibited
significant differences in the fingerprint region of their
infrared absorption spectra that provides information re-
garding the nature of the interactions in the cocrystals. Other
than an ab initio study of the vibrational modes of the
phenylacetate ion, little guidance is available in the litera-
ture to facilitate a complete assignment of the infrared
absorption bands of phenylacetic acid and its derivatives.
However, since this species differs from benzoic acid only
by the presence of a single methylene group bridging
the carboxylic acid and phenyl groups, the important
2
8

1
994 Crystal Growth & Design, Vol. 10, No. 4, 2010
Brittain
Table 3. Assignments of the Major Bands in the Fingerprint Region of the Infrared Absorption Spectra of Phenylacetic Acid, Sodium Phenylacetate, and
Their 1:1 Cocrystal Product
phenyl-acetic
acid
phenylacetic acid/sodium
phenylacetate cocrystal
sodium
phenyl-acetate
assignment
assignment
C-H out-of-plane bending mode
ring torsion mode
677
698
677
694
7
748
843
25
729
C-H deformation mode
COOH out-of-plane bending mode
out-of-plane C-H deformation mode
out-of-plane ring bending mode
in-plane ring C-H mode
752
839
924
1030
1074
1186
1227
1337
841
932
1030
1074
1186
out-of-plane C-H deformation mode
out-of-plane ring bending mode
in-plane ring C-H mode
in-plane ring C-H mode
2
CH twisting mode
935
1030
1074
1180
1225
1342
in-plane ring C-H mode
CH
2
twisting mode
carbonyl in-plane deformation
C-C ring stretching mode
1329
1385
C-C ring stretching mode
symmetric COO stretching mode
-
1
390
OH out-of-plane deformation of COOH
C-C ring stretching mode
1406
1452
1499
1450
1497
1537
1713, 1726
1450
1497
1558
C-C ring stretching mode
C-C ring stretching mode
antisymmetric COO stretching mode
C-C ring stretching mode
-
COOH stretching mode
1691
spectra bands were assigned by guidance from authoritative
2-14
1
sources
The results of this analysis are provided in Table 3.
and analogy to the benzoic acid assignments.
Relative little perturbation in the frequencies of the car-
bon-carbon and carbon-hydrogen modes was noted in the
FTIR spectra, indicating that the interactions among the
phenyl groups is effectively the same for the three substances.
The most dramatic changes in the spectra were observed in
the antisymmetric -COOH stretching mode of the carboxy-
late group, where deprotonation of the carboxylic acid group
to form leads to a large shift in frequency of this vibrational
-
1
-1
mode (i.e., 1691 cm to 1558 cm ). In the PAA-Na-PAA
-
cocrystal, the frequency of the antisymmetric COO stretch-
ing mode of the salt was found to undergo a decrease in
-
1
energy down to 1537 cm , a behavior that stands in contrast
to the lack of such shifting for the BZA-Na-BZA cocrystal.
The antisymmetric COOH stretching mode of the acid
was found to increase in energy in the cocrystal, and this
band was observed to split into two components (1713 and
-1
1
726 cm ).
The Raman spectra obtained in the fingerprint region
for phenylacetic acid, sodium phenylacetate, and the PAA-
Na-PAA cocrystal product are shown in Figure 7. The
vibrational modes associated with these Raman scattering
peaks were assigned through the use of the published
Figure 7. Raman spectra in the fingerprint region of phenylacetic
acid (blue trace), sodium phenylacetate (green trace), and the 1:1
phenylacetic acid/sodium phenylacetate cocrystal (red trace).
2
2-25
compilation,
of phenylacetic acid and phenylacetate salts.
of this analysis are provided in Table 4.
works dealing specifically with the spectra
2
8,29
The results
The most significant trends observed in the Raman spectra
of the three substances were associated with vibrational
modes of the carboxylate group. Formation of the sodium
phenylacetate salt was demonstrated in the Raman spectra as
a loss of the symmetric carbonyl stretching mode (1653
and the HCA-Na-HCA cocrystal product are shown in
Figure 8, and, once again, the nonequivalence of the three
powder patterns demonstrates that the structure of the
cocrystal product is different than either the initial free acid
or sodium salt. The DSC thermogram of hydrocinnamic
acid consisted of a single melting endothermic transition
(temperature maximum at of 50 °C and enthalpy of fusion
equal to 96 J/g), while the thermogram of the sodium
hydrocinnamate salt consisted of a broad and split desolva-
tion endotherm (temperature maxima of 84 and 100 °C, with
an overall desolvation enthalpy of approximately 66 J/g).
The DSC thermogram of the HCA-Na-HCA cocrystal
product consisted of a single melting endothermic transition,
characterized by a temperature maximum of 123 °C and an
enthalpy of fusion equal to 53 J/g.
-1
cm ) of the acid, and that the energy of the -COOH
-
1
deformation mode of the acid (1341 cm ) shifted down to
-
1
294 cm in the salt. This energy of the symmetric COO
-
1
stretching mode (1294 cm ) was found to undergo only a
-
1
-1
minor shift to 1287 cm in the spectrum of the PAA-
Na-PAA cocrystal product. However, the frequency of the
symmetric carboxylic acid stretching mode was found to
undergo a significant shift toward higher energy (1653 to
-1
1
721 cm ) in the cocrystal product.
C. Hydrocinnamic Acid, Sodium Hydrocinnamate, and
their Homo-Cocrystal Product. The XRPD patterns ob-
tained for hydrocinnamic acid, sodium hydrocinnamate,
As shown in Figure 9, hydrocinnamic acid, sodium hydro-
cinnamate, and the HCA-Na-HCA cocrystal product exhibited

Article
Crystal Growth & Design, Vol. 10, No. 4, 2010 1995
Table 4. Assignments of the Major Bands in the Fingerprint Region of the Raman Spectra of Phenylacetic Acid, Sodium Phenylacetate, and Their 1:1
Cocrystal Product
phenyl-acetic
acid
phenylacetic acid/sodium
phenylacetate cocrystal
sodium
phenyl-acetate
assignment
assignment
C-C þ ring deformation modes
ring torsion mode
in-plane ring deformation mode
ring torsion þ C-H deformation
modes
361
475
616
746
378
469
615
744
387
471
614
759
C-C þ ring deformation modes
ring torsion mode
in-plane ring deformation mode
ring torsion þ C-H deformation
modes
C-H out-of-plane bending mode
C-H out-of-plane bending mode
in-plane C-C deformation mode
of phenyl ring
790
836
1000
783
834
1000
838
1000
C-H out-of-plane bending mode
in-plane C-C deformation mode of
phenyl ring
in-plane C-H deformation mode
C-H in-plane bending mode
COOH in-plane deformation mode
1026
1188
1341
1027
1185
1026
1194
in-plane C-H deformation mode
C-H in-plane bending mode
-
1
287
1294
1409
1600
symmetric COO stretching mode
C-C ring stretching mode
C-C ring stretching þ C-H
in-plane bending modes
1406
1602
1401
1600
C-C ring stretching mode
C-C ring stretching þ C-H
in-plane bending modes
symmetric carbonyl stretching mode
1653
1721
Figure 8. X-ray powder diffraction patterns of hydrocinnamic
acid (blue trace), sodium hydrocinnamate (green trace), and
the 1:1 hydrocinnamic acid/sodium hydrocinnamate cocrystal
Figure 9. Infrared absorption spectra in the fingerprint region of
hydrocinnamic acid (blue trace), sodium hydrocinnamate (green
trace), and the 1:1 hydrocinnamic acid/sodium hydrocinnamate
cocrystal (red trace).
(
red trace).
significant differences in the fingerprint region of their infrared
absorption spectra. Using the ab initio study of the vibrational
modes of the hydrocinnamate (i.e., the 3-phenylpropionate)
-
1
stretching mode increased in energy to 1699 cm , and the
-
-1
COO stretching mode decreased in energy to 1549 cm
.
30
12-14
ion in conjunction with the authoritative sources
and
The Raman spectra obtained in the fingerprint region
for hydrocinnamic acid, sodium hydrocinnamate, and the
HCA-Na-HCA cocrystal product are shown in Figure 10.
As before, the vibrational modes associated with these Raman
scattering peaks were assigned using the published compi-
analogy to the phenylacetate studies, assignments for the ob-
served absorption bands of three species were deduced. These
are provided in Table 5.
The infrared absorption bands of the free acid and sodium
salt bore a significant degree of similarity to each other,
with the only major difference being noted in the antisym-
metric carbonyl band region. Here, the energy of the free
2
2-25
lation
and the ab initio study of the vibrational modes of
3
0
the hydrocinnamate ion. The results of this analysis are pro-
vided in Table 6. Formation of the sodium hydrocinnamate
salt was evidenced in the Raman spectra by the disappearance
of the weak free acid symmetric carbonyl stretching mode at
-
1
acid stretching mode (1693 cm ) underwent a significant
-
1
decrease in energy down to 1554 cm upon formation of the
sodium salt and the consequent deprotonation of the car-
boxylic acid group. Interestingly, in the HCA-Na-HCA
cocrystal the energies of these modes were only slightly
shifted relative to those of their components. The COOH
-1
1642 cm . Formation of the HCA-Na-HCA cocrystal pro-
-
duct caused an increase in energy of the symmetric COO
-
1
stretching mode from 1270 to 1294 cm , and in a decrease in
energy of the COO out-of-plane bending mode from
-

1
996 Crystal Growth & Design, Vol. 10, No. 4, 2010
Brittain
Table 5. Assignments of the Major Bands in the Fingerprint Region of the Infrared Absorption Spectra of Hydrocinnamic Acid, Sodium Hydrocinnamate,
and their 1:1 Cocrystal Product
hydro-cinnamic hydrocinnamic acid/sodium sodium
acid hydrocinnamate cocrystal hydro-cinnamate
assignment
assignment
C-H out-of-plane bending mode
ring torsion mode
683
700
723
756
785
694
696
691
698
722
C-H out-of-plane bending mode
ring torsion mode
C-H deformation mode
C-H deformation mode
COOH out-of-plane bending mode
CH rocking mode
744
789
2
787
901
933
1003
1028
1082
1163
2
CH rocking mode
-
9
05
C-COO stretching mode
out-of-plane ring bending mode
out-of-plane ring bending mode
932
937
005
-
1
COO out-of-plane deformation
in-plane C-H mode
in-plane ring C-H mode
in-plane ring C-H mode
1047
1084
1157
1219
1030
1078
1151
1217
in-plane ring C-H mode
CH
2
twisting mode
COOH in-plane deformation
CH
2
twisting mode
-
1
240
1233
1309
1350
COO in-plane deformation
C-C ring stretching mode
C-C ring stretching mode
1302
1358
1408
1427
1452
1497
1308
1362
1408
1420
1454
1495
CH twisting mode
OH out-of-plane deformation of COOH
CH scissor mode
2
CH
2
twisting mode
2
1418
1441
1496
1554
CH
2
scissor mode
C-C ring stretching mode
C-C ring stretching mode
C-C ring stretching mode
C-C ring stretching mode
antisymmetric COO stretching mode
-
1549
1699
COOH antisymmetric stretching mode
1693
of the sodium 4-phenylbutanoate salt consisted of a weak
desolvation endotherm (temperature maximum of 96 °C, with
a desolvation enthalpy of 11 J/g). The DSC thermogram of the
4PBA-Na-4PBA cocrystal product formed by these reactants
consisted of a single melting endothermic transition, having a
temperature maximum of 67 °C and an enthalpy of fusion
of 28 J/g.
As shown in Figure 12, 4-phenylbutanoic acid, sodium
-phenylbutanoate, and the 4PBA-Na-4PBA cocrystal
4
product exhibit a number of important differences in the
fingerprint region of their infrared absorption spectra. In the
absence of any specific studies dealing with the vibrational
assignments form 4-phenylbutanoate, the assignments for
the observed bands shown in Table 7 were deduced using
1
2-14
authoritative references
and analogy to the hydro-
cinnamate studies. The most interesting findings were asso-
ciated with the antisymmetric carbonyl region, where the
-
1
energy of the free acid stretching mode at 1686 cm was
found to undergo a peak splitting and decrease in energy to
-
1
556 and 1573 cm upon formation of the sodium salt.
1
In the 4PBA-Na-4PBA cocrystal, the splitting in the COO
-
-
1
salt vibrational modes increased to 1553 and 1582 cm
.
The energy of the COOH stretching mode increased from
-
1
686 cm to 1705 cm upon formation of the cocrystal
-1
1
structure. In addition, the COO in-plane deformation
-
Figure 10. Raman spectra in the fingerprint region of hydrocin-
namic acid (blue trace), sodium hydrocinnamate (green trace), and
the 1:1 hydrocinnamic acid/sodium hydrocinnamate cocrystal (red
trace).
-
1
mode was found to shift from 1225 cm in the salt to
-
1
1259 cm in the 4PBA-Na-4PBA cocrystal.
The Raman spectra obtained in the fingerprint region for
-phenylbutanoic acid, sodium 4-phenylbutanoate, and the
4
-
1
65 cm in the salt to 557 cm in the cocrystal. Otherwise,
-1
5
4PBA-Na-4PBA cocrystal product are shown in Figure 13.
As with the infrared spectra, the vibrational modes the
Raman scattering peaks were assigned using published
the scattering bands in the various Raman spectra were
remarkably consistent.
D. 4-Phenylbutanoic Acid, Sodium 4-Phenylbutanoate, and
their Homo-Cocrystal Product. The XRPD patterns obtained
for 4-phenylbutanoic acid, sodium 4-phenylbutanoate, and the
2
2-25
compilations
and by analogy to the hydrocinnamate
peak assignments. The results of this analysis are provided in
Table 8. Formation of the sodium 4-phenylbutanoate salt
resulted in the disappearance of the weak free acid symmetric
4PBA-Na-4PBA cocrystal product are shown in Figure 11,
-
1
demonstrating by their nonequivalence that the structure
of the cocrystal product is unique relative to those of the
initial free acid or initial sodium salt. The DSC thermogram
obtained for 4-phenylbutanoic acid consisted of a single melt-
ing endothermic transition (temperature maximum at of 52 °C
and enthalpy of fusion equal to 113 J/g), while the thermogram
carbonyl stretching mode at 1647 cm . Formation of the
4PBA-Na-4PBA cocrystal product caused a slight decrease
-
in energy of the symmetric COO stretching mode from
-
1
1286 cm to 1282 cm , and in a decrease in energy of the
-1
-
-1
COO out-of-plane bending mode from 584 cm in the salt
-1
to 561 cm in the cocrystal.

Article
Crystal Growth & Design, Vol. 10, No. 4, 2010 1997
Table 6. Assignments of the Major Bands in the Fingerprint Region of the Raman Spectra of Hydrocinnamic Acid, Sodium Hydrocinnamate, and Their 1:1
Cocrystal Product
hydrocinnamic acid/
sodium hydrocinnamate
cocrystal
hydro-cinnamic
acid
sodium
hydro-cinnamate
assignment
assignment
C-C þ ring deformation modes
336
447
336
449
565
613
721
C-C þ ring deformation modes
ring torsion mode
445
57
613
738
ring torsion mode
COO out-of-plane bending mode
-
5
in-plane ring deformation mode
ring torsion þ C-H deformation
modes
616
749
in-plane ring deformation mode
ring torsion þ C-H deformation
modes
C-H out-of-plane bending mode
C-COOH stretching mode
C-H out-of-plane bending mode
in-plane C-C deformation mode
of phenyl ring
812
898
920
996
820
897
928
995
813
C-H out-of-plane bending mode
926
994
C-H out-of-plane bending mode
in-plane C-C deformation mode
of phenyl ring
in-plane C-H deformation mode
C-H twisting mode
1028
1154
1200
1024
1149
1199
1294
1411
1021
1157
1186
1270
1411
in-plane C-H deformation mode
C-H twisting mode
CH
2
wagging mode
2
CH wagging mode
-
symmetric COO stretching mode
C-C ring stretching mode
C-C ring stretching mode
CH scissor mode
1409
1448
1583, 1602
2
1428
1583, 1603
2
CH scissor mode
C-C ring stretching þ C-H
1583, 1603
C-C ring stretching þ C-H
in-plane bending modes
symmetric carbonyl stretching mode
n-plane bending modes
1642
Figure 11. X-ray powder diffraction patterns of 4-phenylbutanoic
acid (blue trace), sodium 4-phenylbutanoate (green trace), and the
Figure 12. Infrared absorption spectra in the fingerprint region of
-phenylbutanoic acid (blue trace), sodium 4-phenylbutanoate
green trace), and the 1:1 cocrystal of 4-phenylbutanoic acid with
4
(
1:1 cocrystal of 4-phenylbutanoic acid with sodium hydrocinna-
mate (red trace).
sodium hydrocinnamate (red trace).
E. Hetero-Cocrystal Products formed by the Interaction of
Benzenecarboxylic Acids with the Sodium Salt of a Different
Benzenecarboxylic Acid. Additional studies into the effect of
cocrystal formation on the energies of the vibrational modes
of the components were conducted on the mixed products
formed by the cocrystallization of benzenecarboxylic acids
with the sodium salt of a different benzenecarboxylic acid. A
given heterococrystal product was formed by the interaction
of carboxylic acid (A) with the sodium salt of carboxylic acid
heterococrystal products were all found to differ from the
XRPD patterns of their reactants, establishing the existence
of authentic cocrystals.
The XRPD evaluation of these product pairs showed
that in every system, the pairs of heterococrystal products
exhibited exactly the same crystal structure regardless
of which entity was initially present as the sodium salt
and which was initially present as the free carboxylic
acid. For example, an identical BZA-Na-PAA cocrystal
product was obtained by the solvent-drop grinding of
benzoic acid with sodium phenylacetate, or by the
solvent-drop grinding of phenylacetic acid with sodium
benzoate. In general, all of the heterococrystal products
(B), and then another product was generated by the interac-
tion of carboxylic acid (B) with the sodium salt of carboxylic
acid (A). For cocrystal products that could be obtained in a
solid form, the XRPD patterns shown in Figure 14 for the

1
998 Crystal Growth & Design, Vol. 10, No. 4, 2010
Brittain
Table 7. Assignments of the Major Bands in the Fingerprint Region of the Infrared Absorption Spectra of 4-Phenylbutanoic Acid, Sodium
4
-Phenylbutanoate, and Their 1:1 Cocrystal Product
4-phenylbutanoic acid/
-phenyl-butanoic sodium 4-phenylbutanoate
4
sodium
4-phenyl-butanoate
assignment
acid
cocrystal
assignment
C-H out-of-plane bending mode
ring torsion mode
C-H deformation mode
676
699
729
782
855
696
724
785
854
696
732
787
851
ring torsion mode
C-H deformation mode
CH rocking mode
CH rocking mode
out-of-plane C-H deformation mode
2
2
out-of-plane C-H deformation
mode
-
903
935
1028
1082
1186
1221
906
934
1031
1080
1189
COO out-of-plane deformation
out-of-plane ring bending mode
in-plane C-H mode
out-of-plane ring bending mode
in-plane ring C-H mode
in-plane ring C-H mode
931
1033
1084
1199
1212
in-plane ring C-H mode
CH
2
twisting mode
CH
2
twisting mode
COOH in-plane deformation
-
1
259
1225
1314
1354
COO in-plane deformation
C-C ring stretching mode
C-C ring stretching mode
1300
1343
1410
1436
1461
1498
1310
1352
1404
CH twisting mode
OH out-of-plane deformation of COOH
CH scissor mode
2
CH
2
twisting mode
2
1431
1452
1496
CH
2
scissor mode
C-C ring stretching mode
C-C ring stretching mode
1452
1495
553, 1582
C-C ring stretching mode
C-C ring stretching mode
antisymmetric COO
-
1
1556, 1573
stretching mode
COOH antisymmetric stretching mode
1686
1705
DSC analysis of the heterococrystal products revealed
them to be relatively low-melting, nonsolvated solids.
The BZA-Na-PAA cocrystal exhibited a melting endotherm
having a temperature maximum of 72 °C (enthalpy of fusion
equal to 49 J/g), which was fairly comparable to the thermal
profile of the BZA-Na-HCA cocrystal (temperature maxi-
mum of 93 °C and an enthalpy of fusion of 43 J/g). The BZA-
Na-4PBA cocrystal was obtained as a waxy solid for which
no really definable melting endotherm could be identified in
its DSC thermogram. The PAA-Na-HCA cocrystal was
characterized by a melting endotherm having a temperature
maximum of 63 °C (enthalpy of fusion equal to 33 J/g), while
the HCA-Na-4PBA cocrystal was also obtained as a waxy
solid, for which the temperature maximum of the melting
endotherm was 52 °C and the enthalpy of fusion was 21 J/g.
As mentioned above, the fact that the PAA-Na-4PBA
product could not be obtained in solid form precluded its
analysis by DSC.
Infrared absorption spectra obtained in the finger-
print region are shown in Figure 15 for the six hetero-
cocrystal systems. The spectra of the various cocrystal
products exhibited a significant degree of similarity
to each other, which enabled the spectral band assign-
ments deduced for the homococrystal products to be of
use in assigning the origins of the bands in the hetero-
cocrystal spectra. These assignments are collected in
Table 9.
Figure 13. Raman spectra in the fingerprint region of 4-phenylbu-
tanoic acid (blue trace), sodium 4-phenylbutanoate (green trace),
and the 1:1 cocrystal of 4-phenylbutanoic acid with sodium hydro-
cinnamate (red trace).
The same overall trends noted in the infrared spectra of
the homococrystals were observed in the spectra of the
heterococrystals. Most importantly, the energies of the
carbonyl antisymmetric stretching modes were observed
to undergo increases in the cocrystals relative to the
energies in the respective benzenecarboxylic acids. While
the frequency of this absorption band was observed over
were found to be less crystalline than were the homo-
cocrystal products discussed in the preceding sec-
tions.
Interestingly, the PAA-Na-4PBA product was only ob-
tained as an oil that could not be solidified under any set of
circumstances, and the BZA-Na-4PBA product could only
be obtained in an amorphous form. Normally, these char-
acteristics would preclude the PAA-Na-4PBA and BZA-Na-
-
1
an approximate frequency range of 1700-1730 cm in the
homococrystal systems, a smaller degree of shifting
-
1
(approximate frequency range of 1690-1700 cm ) was
noted for the heterococrystal systems. Given that the
reduced masses of the bonds involved is comparable in
the systems, one concludes that the force constant of the
4
PBA products from being classified as cocrystals, but their
respective vibrational spectra will provide a rationale for a
type of cocrystal definition.

Article
Crystal Growth & Design, Vol. 10, No. 4, 2010 1999
Table 8. Assignments of the Major Bands in the Fingerprint Region of the Raman Spectra of 4-Phenylbutanoic Acid, Sodium 4-Phenylbutanoate, and Their
:1 Cocrystal Product
1
4
-phenylbutanoic acid/
4
-phenyl-butanoic
acid
sodium 4-phenylbutanoate
cocrystal
sodium
4-phenyl-butanoate
assignment
ring torsion mode
C-C þ ring deformation modes
assignment
ring torsion mode
468
508
471
494
476
511
584
615
750
C-C þ ring deformation modes
-
5
61
COO out-of-plane bending mode
in-plane ring deformation mode
ring torsion þ C-H deformation
modes
616
747
613
746
in-plane ring deformation mode
ring torsion þ C-H deformation
modes
C-H out-of-plane bending mode
C-COOH stretching mode
C-H out-of-plane bending mode
in-plane C-C deformation mode
of phenyl ring
810
888
912
997
807
896
928
995
814
C-H out-of-plane bending mode
930
997
C-H out-of-plane bending mode
in-plane C-C deformation mode
of phenyl ring
in-plane C-H deformation mode
C-H rocking mode
1028
1059
1155
1182
1206
1023
1060
1151
1183
1200
1027
1057
1152
1176
1202
1286
in-plane C-H deformation mode
C-H rocking mode
C-H twisting mode
C-H twisting mode
C-H in-plane bending mode
C-H in-plane bending mode
CH
2
wagging mode
2
CH wagging mode
-
1
282
symmetric COO stretching mode
CH twisting mode
C-C ring stretching mode
CH scissor mode
C-C ring stretching þ C-H
in-plane bending modes
symmetric carbonyl stretching
mode
2
1343
1407
1439
1332
1412
1442
1417
1437
1581, 1601
C-C ring stretching mode
2
2
CH scissor mode
1582, 1602
1582, 1603
C-C ring stretching þ C-H
in-plane bending modes
1647
Figure 14. X-ray powder diffraction patterns of the five heteroco-
crystal products formed by the interaction of a benzenecarboxylic
acid with the sodium salt of a different benzenecarboxylic acid and
which could be obtained in solid form. The spectra are labeled to
indicate the identity of each cocrystal product.
Figure 15. Infrared absorption spectra in the fingerprint region of
the six heterococrystal products formed by the interaction of a
benzenecarboxylic acid with the sodium salt of a different benzene-
carboxylic acid. The spectra are labeled to indicate the identity of
each cocrystal product.
carbonyl antisymmetric stretching modes is less perturbed
in the heterococrystal systems relative to the homococrys-
tal systems. This conclusion would imply that the ener-
getics of heterococrystal interaction are less than those
of homococrystal interaction, which would in turn be
consistent with the lower degrees of crystallinity observed
for the homococrystal products.
The energies of most of the other vibrational modes
were found to be fairly similar in the homococrystal and
heterococrystal products. For example, the degree of

2
000 Crystal Growth & Design, Vol. 10, No. 4, 2010
Brittain

Article
Crystal Growth & Design, Vol. 10, No. 4, 2010 2001
shifting in the carboxylic acid anion modes in the com-
ponent salts upon formation of the cocrystals was found
to be comparable in both categories.
It is significant to note that even though the PAA-Na-
PBA and BZA-Na-4PBA products were not obtained in
4
a crystalline solid-state form, their infrared absorption
spectra exhibited peaks that were shifted from those of
their reactants in a manner entirely consistent with the
authentic cocrystal products. This finding would indicate
that a similar type of supramolecular synthon existing
in the crystalline cocrystal products must also exist in
the PAA-Na-4PBA and BZA-Na-4PBA products, even
though these materials were not obtained in a crystalline
form.
Raman spectra obtained in the fingerprint region are
shown in Figure 16 for the six heterococrystal systems.
As has been noted for their infrared absorption, the
spectra of the various cocrystal products exhibited a
significant degree of similarity to each other, which also
facilitated the deduction of spectral band assignments for
the heterococrystal spectra through comparison to the
assignments reached for the spectra of the homococrystal
products. Assignments deduced in this manner are col-
lected in Table 10, and most of the trends contained in the
table have been discussed above. The main effect of
cocrystal formation in these systems was a slight decrease
-
in energy of the symmetric COO stretching mode, and a
-
decrease in energy of the COO out-of-plane bending
mode.
Figure 16. Raman spectra in the fingerprint region of the six
heterococrystal products formed by the interaction of a benzene-
carboxylic acid with the sodium salt of a different benzenecar-
boxylic acid. The spectra are labeled to indicate the identity of
each cocrystal product.
Discussion
A number of interesting trends emerged from study
of the vibrational spectra of benzenecarboxylic acids,
their sodium salts, and the 1:1 products formed by
the cocrystallization of the acid and its salt. Many
other infrared spectroscopic studies have established
that the antisymmetric stretching mode of the carboxylic
acid carbonyl group undergoes a drastic shift to lower
energies upon formation of its salt form. In the present
work, the general trend has emerged that this same
vibrational mode shifts to higher energies when the
benzenecarboxylic acid forms a cocrystal with its sodium
salt.
compounds, the free acid absorption band was observed to
-
1
.
increase in energy to 1694 cm
In most systems, the energy of the antisymmetric
carboxylate anion stretching mode decreased when the
cocrystal was formed using its sodium salt. However, this
trend was not shown to exist in the benzoic acid/sodium
benzoate cocrystal, and the energy of this band increased
slightly on passing from the salt form to the cocrystal. In
1
the previous work, the energy of this vibrational mode
was found to decrease in the benzoic acid/benzylammo-
nium benzoate cocrystal relative to that in the benzylam-
monium benzoate salt form.
One may deduce from the present analysis that for
salt and cocrystal systems involving carboxylic acid
groups that the energy of the antisymmetric stretching
mode of the carbonyl group can be used to deduce the
nature of the species formed. When the free acid absorp-
tion band (approximate frequency range of 1680-
The vibrational frequencies of the symmetric carboxy-
late anion stretching mode were not found to be use-
ful spectroscopic tools to differentiate cocrystal and
sodium salt, as the observed differences between the
two forms were effectively random and as many increases
were detected as decreases. The energy of the out-of-
plane deformation mode proved to be equally ineffective
in this regard as the vibrational frequency was equiva-
lent in both the salt form and in the cocrystal. Neither
of these vibrational modes was particularly useful for
differentiation purposes in the corresponding Raman
spectra.
Finally, while significant differences in energy among
the multitude of vibrational modes associated with the
phenyl ring and alkane side chain were observed to exist in
the spectra of the free acid, its sodium salt, and their
cocrystal product, no general trends emerged from the
spectral assignments that could serve as form differentia-
tion selection rules.
-
1
1
690 cm ) disappears entirely and becomes replaced by
the corresponding anion band (approximate frequency
-
1
range of 1550-1600 cm ), one has observed the forma-
tion of a salt species. On the other hand, when the free
acid absorption band undergoes a small shift toward
higher energy (approximate frequency range of 1700-
-
1
1
730 cm ), one has observed the formation of a cocrystal
species.
The same set of observations were made in a previous work
involving benzoic acid, the benzylammonium benzoate salt,
1
and their 1:1 cocrystal. In that work, formation of the salt
was evidenced by the loss of the free acid absorption band at
-
1
678 cm and the observation of the corresponding anion
1
band at 1514 cm . In the 1:1 cocrystal formed by these two
-
1

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002 Crystal Growth & Design, Vol. 10, No. 4, 2010
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Crystal Growth & Design, Vol. 10, No. 4, 2010 2003
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