Vibrational spectroscopic studies of cocrystals and salts. 4. cocrystal products formed by benzylamine, α-methylbenzylamine, and their chloride salts

Article abstract of DOI:10.1021/cg2002628

The chloride salts formed by benzylamine and α-methylbenzylamine have been characterized using X-ray powder diffraction, differential scanning calorimetry, and infrared absorption spectroscopy. In addition, X-ray powder diffraction and differential scanning calorimetry have been used to establish formation or lack of formation of the 1:1 stoichiometric salt-cocrystal products containing the chloride salts and their respective free bases. For α-methylbenzylamine (which contains a single dissymmetric center), the chiral identities of the free bases and chloride salts were found to play a determining role as to whether a salt-cocrystal product could or could not be formed. It was found that a salt-cocrystal product could only be formed if the salt and free base were of opposite absolute configurations. For those systems where the existence of cocrystals was demonstrated, assignments were derived for the observed peaks in the infrared absorption spectra of the reactants and their products.

Full text of DOI:10.1021/cg2002628

ARTICLE
pubs.acs.org/crystal
Vibrational Spectroscopic Studies of Cocrystals and Salts.
4. Cocrystal Products formed by Benzylamine, r-Methylbenzylamine,
and their Chloride Salts
Harry G. Brittain*
Center for Pharmaceutical Physics, 10 Charles Road Milford, New Jersey 08848, United States
ABSTRACT: The chloride salts formed by benzylamine and R-
methylbenzylamine have been characterized using X-ray powder
diffraction, differential scanning calorimetry, and infrared absorption
spectroscopy. In addition, X-ray powder diffraction and differential
scanning calorimetry have been used to establish formation or lack of
formation of the 1:1 stoichiometric salt-cocrystal products containing
the chloride salts and their respective free bases. For R-methylbenzy-
lamine (which contains a single dissymmetric center), the chiral
identities of the free bases and chloride salts were found to play a
determining role as to whether a salt-cocrystal product could or could
not be formed. It was found that a salt-cocrystal product could only be
formed if the salt and free base were of opposite absolute configura-
tions. For those systems where the existence of cocrystals was demon-
strated, assignments were derived for the observed peaks in the infrared absorption spectra of the reactants and their products.
’ INTRODUCTION
and their salts, the present study is concerned with the formation
of salt-cocrystal products resulting from the interaction of basic
substances with their corresponding acid addition salts. Thus, the
present study relates to the scope of intermolecular interactions
existing in these systems containing different modes of anion
coordination and anion-templated assemblies.11
The present work investigates the salt-cocrystal systems formed
by benzylamine and R-methylbenzylamine with their correspond-
ing chloride salts. The formation of a particular salt-cocrystal
product (or the absence of its formation) was demonstrated by
means of X-ray powder diffraction and differential scanning
calorimetry. Subsequently, trends in the energies of molecular
vibrations were used to deduce selection rules that could be more
generally used as additional tools for the identification and
characterization of salt-cocrystal species.
It has been demonstrated for the first time that stereoselectiv-
ity can exist in the formation of salt-cocrystal products when the
interacting species contain centers of dissymmetry. In particular,
it has been found that a salt-cocrystal product could be formed if
the salt and free base were of opposite absolute configurations,
but that no cocrystallization would take place if the salt and free
base were of the same absolute configuration.
As the science of crystal engineering continues to yield new
supramolecular synthons capable of being assembled into an
ever-widening sphere of crystalline solids, the scope of suitable
intermolecular interactions continues to grow. Schultheiss and
Newman1 have summarized six definitions of a cocrystal that go
beyond the definition of Aaker€oy, who had proposed that a
cocrystal is a homogeneous crystalline solid that contains stoi-
chiometric amounts of discrete neutral molecular species that are
solids under ambient conditions.2 Part of the expansion in scope
reflects developments in cocrystals having pharmaceutical inter-
est, and where the drug substance is present in an ionic form.3ꢀ5
The question of whether a given species is a cocrystal or a salt has
been addressed, considering the effect of the overall crystal
structure on the ionization state and degree of proton transfer
in such species.6,7
One area of cocrystal research that has not received a great
deal of attention concerns the systems where salts of organic
molecules form cocrystals with the neutral organic molecule
from which the salt was made. For example, the existence of a
salt-cocrystal product formed by the cocrystallization of tiotro-
pium fumarate with fumaric acid has been demonstrated and
shown to be more stable than either the salt or salt-solvate solid
forms.8 In this laboratory, vibrational spectroscopy has been used
to study intermolecular interactions in the 1:1 salt-cocrystal
formed by the interaction of benzoic acid with benzylammonium
benzoate,9 as well as the salt-cocrystal products formed by a series
of benzenecarboxylic acids and their sodium salts.10
’ MATERIALS AND METHODS
Benzylamine, (R)- and (S)-R-methylbenzylamine were obtained
from Aldrich and were used as received. The chloride salts of these
Received: March 1, 2011
Whereas the aforementioned studies investigated the phe-
nomenon of salt-cocrystal formation among acidic substances
Revised:
Published: April 19, 2011
April 15, 2011
r
2011 American Chemical Society
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Figure 2. Infrared absorption spectra in the fingerprint region of
benzylamine (black trace), benzylammonium chloride (red trace), and
the 1:1 benzylamine/benzylammonium chloride salt-cocrystal (blue
trace).
Figure 1. X-ray powder diffraction patterns of benzylammonium
chloride (red trace) and the 1:1 benzylamine/benzylammonium chlor-
ide salt-cocrystal (blue trace).
phenylalkylamines were prepared by dissolving approximately 250 mg
quantities in 10 mL of methanol, to which was added a 1:1 stoichiometric
amount of 2.0 N hydrochloric acid (obtained from Spectrum Chemicals).
The solutions were allowed to evaporate to dryness, whereupon the
recovered solids were transferred to a mortar, wetted with methanol, and
ground until solid. Salt-cocrystal products were prepared using the wet-
grinding method, where accurately weighed equimolar amounts of free
amine and chloride salt were placed in a mortar, ground to create
homogeneity in the mix, wetted with two drops of methanol, and then
the mixture was ground until dry. As will be discussed below, the process
was usually completed fairly rapidly, but in a few instances the mixtures
required a long period of time to become fully dry.
X-ray powder diffraction (XRPD) patterns were obtained using a
Rigaku MiniFlex powder diffraction system (X-ray source being nickel-
filtered KR emission of copper), equipped with a horizontal goniometer
operating in the θ/2θ mode. Samples were packed into the sample
holder using a backfill procedure and were scanned over the range of
3.5ꢀ40 deg 2θ at a scan rate of 0.5 degrees 2θ/min. Using a data
acquisition rate of 1 point per second, these scanning parameters equate
to a step size of 0.0084 degrees 2θ.
Measurements of differential scanning calorimetry (DSC) were ob-
tained on a TA Instruments 2910 thermal analysis system. Samples of
approximately 1ꢀ2 mg were accurately weighed into an aluminum DSC
pan and then covered with an aluminum lid that was crimped in place.
Samples were heated at a rate of 10 °C/min from ambient temperature to
termination temperatures in the range of 150 to 225 °C, depending on
the system under study. Thermally induced weight loss measurements
were performed using an Ohaus MB-45 moisture balance.
Fourier-transform infrared (FTIR) absorption spectra were obtained
at a resolution of 2 cmꢀ1 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 MIRaclesingle reflection horizontal ATR sampling
accessory.
’ RESULTS AND DISCUSSION
A. Benzylamine, Benzylammonium Chloride, and their
Salt-Cocrystal Product. The interaction of benzylamine (BZA):
with benzylammonium chloride was the first system to be
investigated. During the solvent-drop grinding process used,
no odor of benzylamine could be detected, and the ground
solids were found to dry down to a powdered solid in less than
30 min. This observation was taken as an initial indication of the
formation of a salt-cocrystal product.
Since benzylamine is a liquid at room temperature, its XRPD
pattern could not be obtained. The benzylammonium chloride
(BZA-Cl) salt and the benzylamineꢀbenzyl-ammonium chlor-
ide (BZA-Cl-BZA) salt-cocrystal were both obtained in solid
form, so their respective XRPD patterns are shown in Figure 1.
Although the two diffraction patterns are somewhat similar in
appearance, the formation of a BZA-Cl-BZA salt-cocrystal prod-
uct was confirmed by the presence of additional diffraction peaks
in its powder pattern.
The DSC thermograms obtained for the solid products
confirmed that a salt-cocrystal product was produced by the
interaction between benzylamine and benzylammonium chlor-
ide. The DSC thermogram of the BZA-Cl salt demonstrated this
product to be nonsolvated, as the thermogram contained only a
single thermally induced endothermic transition. Owing to its
high temperature (maximum at 200 °C; enthalpy of fusion equal
to 34 J/g), this event was assigned to melting of the salt. The
BZA-Cl-BZA salt-cocrystal was also found to be nonsolvated,
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Table 1. Assignments of the Major Bands in the Fingerprint Region of the Infrared Absorption Spectra of Benzylamine,
Benzylammonium chloride, and Their 1:1 Salt-Cocrystal Product
BZA-Cl-BZA
salt-cocrystal
benzyl-ammonium
chloride
free base vibrational mode assignment
benzylamine
chloride salt vibrational mode assignment
in-plane ring deformation mode
629
692
743
791
814
619
692
744
791
in-plane ring deformation mode
CꢀH out-of-plane deformation mode
CꢀH out-of-plane phase deformation mode
out-of-plane ring deformation mode
696
733
777
CꢀH out-of-plane deformation mode
CꢀH out-of-plane phase deformation mode
out-of-plane ring deformation mode
NH2 out-of-plane bending mode
851
879
920
879
920
NH3þ out-of-plane bending mode
CH2 rocking mode
932
CꢀC stretching mode
974
1024
1059
970
968
1032
1059
1113
CꢀC stretching mode
999
in-plane CꢀH deformation mode
in-plane CꢀH deformation mode
1030
1040
1059
1074
1113
1144
1188
1215
in-plane CꢀH deformation mode
in-plane CꢀH deformation mode
in-plane CꢀH deformation mode
NH2 rocking mode
1155
1178
1202
1267
in-plane CꢀH deformation mode
in-plane CꢀH deformation mode
NH2 rocking mode
1190
1215
in-plane CꢀH deformation mode
in-plane CꢀH deformation mode
1283
1302
1331
1346
1383
1454
1468
1475
1497
1562
1585
1597
1628
1315
1346
1383
1454
1466
1477
1497
NH3þ rocking mode
CꢀN stretching mode
1350
1385
1452
CꢀN stretching mode
CꢀC ring stretching mode
CꢀC ring stretching mode
CH2 deformation mode
CH2 deformation mode
CꢀC ring stretching mode
CꢀC ring stretching mode
CꢀC ring stretching mode
CꢀC ring stretching mode
1495
CꢀC ring stretching mode
CꢀC ring stretching mode
1589
1605
CꢀC ring stretching mode
CꢀC ring stretching mode
NH3þ symmetric bending mode
1597
exhibiting a melting endothermic transition at a temperature of
132 °C with an enthalpy of fusion equal to 48 J/g.
of the free amine and its chloride salt were associated with the
amine group and its protonation. The most important change
associated with salt formation was the loss of the broad absorp-
tion band associated with the free amine ꢀNH2 out-of-plane
bending mode at 851 cmꢀ1 and the appearance of the relatively
As shown in Figure 2, benzylamine, benzylammonium chlor-
ide, and the BZA-Cl-BZA salt-cocrystal exhibited several signifi-
cant differences in the fingerprint region of their FTIR spectra
that are consistent with formation of the salt-cocrystal product.
In order fully interpret the spectra, the molecular vibrational
modes of the major absorbance bands of benzylamine and
benzylammonium chloride were assigned through the use of
published compilations12ꢀ15 and works conducted specifically
on phenylalkylamines and their derivatives.16ꢀ25 Assignments
for the absorption bands of the salt-cocrystal were made when-
ever possible by extrapolation. The results of this analysis are
provided in Table 1.
þ
sharp ꢀNH3 out-of-plane bending mode at 879 cmꢀ1. In
addition, the pair of free amine ꢀNH2 rocking modes at 1155
and 1267 cmꢀ1 were lost upon formation of the chloride salt, and
the ꢀNH3þ rocking mode was observed at 1315 cmꢀ1
.
The formation of the BZA-Cl-BZA salt-cocrystal led to addi-
tional perturbations in the fingerprint region of its FTIR spec-
þ
trum. Although the ꢀNH3 out-of-plane bending mode was
observed at 879 cmꢀ1 (the same as for the chloride salt),
perturbed ꢀNH2 rocking modes were evident at 1144 and
1283 cmꢀ1. In addition, the ꢀNH3 rocking mode of the salt
þ
In general, the energies of the carbonꢀcarbon ring modes and
the carbonꢀhydrogen deformation modes were comparable for
the three substances, indicating that the motions associated with
the basic organic skeleton were effectively equivalent. Not
surprisingly, the most important differences between the spectra
underwent a shift to 1331 cmꢀ1. It was interesting to note the
appearance of new absorption bands at 932, 999, 1074, 1302, and
1562 cmꢀ1 whose origin could not be deduced from knowledge
of the assignments of either the free base or chloride salt. Perhaps
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þ
most significant is the appearance of the ꢀNH3 symmetric
bending mode (1628 cmꢀ1) in the spectrum of the BZA-Cl-BZA
salt-cocrystal which was not observed in the spectrum of the
hydrochloride salt.
Formation of the benzylammonium chloride salt from benzyl-
amine was most evident by the disappearance of the antisym-
metric and symmetric stretching bands associated with the ꢀNH2
group (3285 and 3371 cmꢀ1, respectively). Upon formation of
the salt, thþe antisymmetric and symmetric stretching bands of
the ꢀNH3 group shift to lower energy, and one observed a
rather broad absorption around 2965 cmꢀ1 that represents an
overlapping system with the aromatic ꢀCH stretching modes.
One of the aliphatic ꢀCH2ꢀ stretching modes shifted tþo
2880 cmꢀ1 upon salt formation, and overtones of ꢀNH3
deformation modes not observed in the spectrum of the free
amine become evident as absorption bands at 2573, 2691, and
However, as shown in Figure 3, the phenomena of salt
formation was most evident in the high-frequency region of
the FTIR spectrum (a full summary of the peak assignments is
found in Table 2). For the free amine, the aliphatic ꢀCH2ꢀ
symmetric and antisymmetric stretching modes are observed at
2856 and 2916 cmꢀ1, respectively, while the aromatic ꢀCH
stretching modes are found at 3026, 3061, and 3084 cmꢀ1
.
2754 cmꢀ1
.
As evident in Figure 3, the high-frequency FTIR spectrum of
the BZA-Cl-BZA salt-cocrystal resembled that of the benzylam-
monium chloride salt. The broad band formed by the overlap of
the ꢀNH3þ antisymmetric and symmetric stretching bands with
the aromatic ꢀCH stretching modes was now observed as a
broad band around 2970 cmꢀ1, the aliphatic ꢀCH2ꢀ stretching
modes shifted to 2885 cmꢀ1, and the ꢀNH3þ overtone modes
were observed at 2573, 2691, and 2754 cmꢀ1. Most significant,
however, is the appearance of a new absorption band at
3290 cmꢀ1 in the spectrum of the BZA-Cl-BZA salt-cocrystal,
which has been assigned as one of the ꢀNH3þ stretching modes.
B. r-Methylbenzylamine, r-Methylbenzylammonium
Chloride, and their Salt-Cocrystal Products. The R-methyl-
benzylamine (mBZA) system:
adds an interesting complication in that the compound contains
one center of dissymmetry and is therefore capable of existing as
a racemic mixture or as separated enantiomers. This stereochem-
istry therefore presents an opportunity to examine any possible
stereoselectivity in the salt-cocrystal formation, since the choice
of enantiomeric identities of the amine and salt precursors, and
Figure 3. Infrared absorption spectra in the high-frequency region of
benzylamine (black trace), benzylammonium chloride (red trace), and
the 1:1 benzylamine/benzylammonium chloride salt-cocrystal (blue
trace).
Table 2. Assignments of the Major Bands in the High-Frequency Region of the Infrared Absorption Spectra of Benzylamine,
Benzylammonium chloride, and their 1:1 Salt-Cocrystal Product
BZA-Cl-BZA
salt-cocrystal
benzyl-ammonium
chloride
free base vibrational mode assignment
benzylamine
chloride salt vibrational mode assignment
2573
2691
2754
2573
2691
2754
overtone band
overtone band
overtone band
symmetric CH2 stretching mode
2856
2916
2885
2880
2965
3053
aliphatic CH2 stretching mode
composite band
antisymmetric CH2 stretching mode
2970
3030
3055
aromatic CH stretching mode
aromatic CH stretching mode
aromatic CH stretching mode
3026
3061
3084
aromatic CH stretching mode
3290 (NH3þ
stretching mode)
NH2 symmetric stretching mode
3285
3371
NH2 antisymmetric stretching mode
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(R)mBZA-Cl-(R)mBZA salt-cocrystal product were effectively
the same. This finding strongly suggests that a salt-cocrystal
product could not be formed during the solvent-drop grinding
process, and the olfactory observation of phenylalkylamine odor
indicates that the free amine simply volatilized during the
grinding process. In the absence of a mechanism to incorporate
the phenylalkylamine into a suitable solid-state structure, the final
product of the attempted interaction would simply be the
residual chloride salt precursor.
These results confirm the existence of stereoselectivity in
formation of R-methylbenzyl-amine salt-cocrystal products, since
only the interaction of (R)mBZA-Cl and (S)mBZA formed the
anticipated salt-cocrystal product, and the attempted interaction of
(R)mBZA-Cl and (R)mBZA yielded only the (R)mBZA-Cl salt.
The trends noted in the XRPD patterns of the R-methylben-
zylamine products were confirmed in their thermal analysis
profiles. None of the salts or salt-cocrystal products exhibited
an endothermic transition at low temperatures and were there-
fore determined to be nonsolvated in nature. In its thermogram,
the (R)mBZA-Cl-(S)mBZA salt-cocrystal product exhibited a
melting endothermic transition characterized by a lower tem-
perature (maximum at 159 °C) and a significantly higher
enthalpy of fusion (equal to 124 J/g) when compared to the
analogous features observed for relative to (R)mBZA-Cl salt
(i.e., temperature maximum of 171 °C and enthalpy of fusion
equal to 75 J/g).
Figure 4. X-ray powder diffraction patterns of (R)-R-methylbenzylam-
monium chloride (red trace), and the (R)mBZA-Cl-(R)mBZA (blue
trace) and (R)mBZA-Cl-(S)mBZA (green trace) salt-cocrystal products.
On the other hand, the melting endotherm obtained for the
product obtained by the attempted interaction of (R)mBZA-Cl
and (R)mBZA was found to be equivalent to that of the
(R)mBZA-Cl salt within experimental error (i.e., temperature
maximum at 172 °C and enthalpy of fusion equal to 79 J/g). The
DSC results therefore confirm the formation of a (R)mBZA-
Cl-(S)mBZA salt-cocrystal product and the nonexistence of
a(R)mBZA-Cl-(R)mBZA salt-cocrystal product.
the consequent presence of two centers of dissymmetry in a salt-
cocrystal product, could result in homodiastereomer and hetero-
diastereomer products.
The existence of stereoselectivity became apparent during
the solvent-drop grinding process used to promote the interac-
tion between enantiomeric resolved R-methylbenzylamine and
R-methylbenzylammonium chloride precursors. No amine odor
was detected during the grinding of (R)-R-methylbenzylamine
with (S)-R-methylbenzylammonium chloride, or during the
grinding of (S)-R-methylbenzylamine with (R)-R-methylbenzy-
lammonium chloride indicating incorporation of the phenylalky-
lamine into a salt-cocrystal product. These ground solids were
found to yield a dry powdered solid in less than 30 min. On the
other hand, a strong phenylalkylamine odor was noted during the
grinding of (R)-R-methylbenzylamine with (R)-R-methylbenzy-
lammonium chloride, and during the grinding of (R)-R-methyl-
benzylamine with (R)-R-methylbenzylammonium chloride.
That the products of these interactions required overnight
periods to fully dry down to a powdered solid is strongly
suggestive that a salt-cocrystal product was not formed during
these solvent-drop grinding processes.
Since the (R) and (S) forms of R-methylbenzylamine are all
liquids at room temperature, their XRPD patterns could not
be obtained, and the (R) and (S) enantiomerically pure forms of
R-methylbenzylammonium chloride exhibited identical XRPD
patterns. The XRPD patterns obtained for the (R)mBZA-Cl salt
are found in Figure 4, along with the patterns of the (R)mBZA-
Cl-(R)mBZA and (R)mBZA-Cl-(S)mBZA salt-cocrystal prod-
ucts. The XRPD pattern of the (R)mBZA-Cl-(S)mBZA salt-
cocrystal product was found to contain a sufficient number of
distinctions relative to the chloride salt so as to confirm the
formation of a salt-cocrystal product.
The trends associated with the peaks in the fingerprint region
within the FTIR spectra of (R)mBZA, the (R)mBZA-Cl salt, and
the (R)mBZA-Cl-(S)mBZA salt-cocrystal product may be ob-
served in the spectra shown in Figure 4. The existence of stereo-
selectivity in the formation of salt-cocrystal products was again
demonstrated, since the spectrum of the (R)mBZA-Cl-(R)mBZA
product was effectively the same as that of the (R)mBZA-Cl salt.
The FTIR spectrum of the (R)mBZA-Cl-(S)mBZA product was
unique, confirming the existence of the salt-cocrystal product.
The vibrational origins of the major absorbance bands ob-
served in the various FTIR spectra were derived as before,
namely, using published compilations12ꢀ15 and works conducted
specifically on phenylalkylamines and their derivatives16ꢀ25 to
obtain the assignments collected in Table 3. As noted with the
benzylamine series, the most important effects evident in the
spectra were associated with the protonation of the free amine to
yield the chloride salt. The free amine ꢀNH2 out-of-plane
bending mode at 841 cmꢀ1 and the two free amine ꢀNH2
rocking modes at 1155 and 1279 cmꢀ1 were lost upon formation
of the chloride salt, being rþeplaced by a sharp peak at 879 cmꢀ1
derived from the ꢀNH3 out-of-plane bending mode and
the ꢀNH3þ rocking mode at 1317 cmꢀ1, respectively. Finally,
þ
the ꢀNH3 symmetric bending mode was observed at
1620 cmꢀ1 in the spectrum of the chloride salt.
The formation of the (R)mBZA-Cl-(S)mBZA salt-cocrystal
caused the appearance of additional perturbationþs in the finger-
print region of its FTIR spectrum. The ꢀNH3 ouþt-of-plane
bending mode shifted to 895 cmꢀ1, and the ꢀNH3 rocking
On the other hand, aside from some small differences in
relative intensity, the XRPD patterns of (R)mBZA-Cl and the
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Table 3. Assignments of the Major Bands in the Fingerprint Region of the Infrared Absorption Spectra of (R)-r-Methylbenzy-
lamine, (R)-r-Methylbenzylammonium chloride, and the two Diastereomeric 1:1 Salt-Cocrystal Products
free base vibrational mode (R)-R-methyl-
(R)mBZA-Cl-(S)mBZA (R)mBZA-Cl-(R)mBZA
(R)-R-methyl-benzyl-
chloride salt vibrational mode
assignment
assignment
benzyl-amine
salt-cocrystal
salt-cocrystal
ammonium chloride
CꢀH out-of-plane
deformation mode
CꢀH out-of-plane phase
deformation mode
out-of-plane ring
698
696
696
696
748
762
CꢀH out-of-plane
deformation mode
CꢀH out-of-plane phase
deformation mode
out-of-plane ring deformation
mode
752
766
812
748
762
762
841
deformation mode
NH2 out-of-plane bending
mode
895
881
879
NH3þ out-of-plane bending
mode
905
916
CH2 rocking mode
912
997
912
991
914
991
CH2 rocking mode
CꢀC stretching mode
CꢀC stretching mode
in-plane CꢀH deformation
mode
CꢀC stretching mode
996
1001
1026
1003
1018
1003
1019
in-plane CꢀH deformation
mode
1022
in-plane CꢀH deformation
1032
1067
1134
1032
1067
1132
in-plane CꢀH deformation
mode
mode
in-plane CꢀH deformation
mode
1055
1105
1053
1111
1151
1186
1232
in-plane CꢀH deformation
mode
in-plane CꢀH deformation
mode
in-plane CꢀH deformation
mode
NH2 rocking mode
in-plane CꢀH deformation
mode
1155
1184
1176
1229
1176
1229
in-plane CꢀH deformation
mode
in-plane CꢀH deformation
mode
1236
in-plane CꢀH deformation
mode
NH2 rocking mode
CH3 deformation mode
1279
1292
1290
1315
1333
1371
1292
1317
1333
1383
1292
1317
1337
1383
CH3 deformation mode
NH3þ rocking mode
CꢀN stretching mode
CH3 symmetric deformation
mode
CꢀN stretching mode
CH3 symmetric
1329
1367
deformation mode
1387
1452
1495
1514
1549
1585
1599
1610
1393
1452
1497
1393
1454
1497
CꢀC ring stretching mode
CꢀC ring stretching mode
CꢀC ring stretching mode
CꢀC ring stretching mode
CꢀC ring stretching mode
1450
1491
CꢀC ring stretching mode
CꢀC ring stretching mode
1585
1603
CꢀC ring stretching mode
CꢀC ring stretching mode
NH3þ symmetric bending
mode
1601
1622
1601
1620
mode of the salt underwent a slight shift to 1315 cmꢀ1. Unlike
the BZA-Cl-BZA salt-cocrystal where perturbed ꢀNH2 rocking
mode bands could be observed in the spectrum, no such bands
were evident in the spectrum of the (R)mBZA-Cl-(S)mBZA salt-
cocrystal. Only four new absorption bands (at 812, 905, 1514,
and 1549 cmꢀ1) were observed which could not be assigned on
the basis of assignments pertaining to either the free base or the
chloride salt. For the (R)mBZA-Cl-(S)mBZA salt-cocrystal,
the ꢀNH3þ symmetric bending mode was found to undergo a
modest shift down to 1628 cmꢀ1
.
As shown in Figure 3 and summarized in Table 4, the
phenomena of salt formation was again highly visible in the
high-frequency region of the FTIR spectrum. Formation of
the R-methylbenzylammonium chloride salt was demonstrated
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Table 4. Assignments of the Major Bands in the High-Frequency Region of the Infrared Absorption Spectra of (R)-r-
Methylbenzylamine, (R)-r-Methylbenzylammonium chloride, and the two Diastereomeric 1:1 Salt-Cocrystal Products
free base vibrational mode (R)-(methyl-
(R)mBZA-Cl-(S)mBZA (R)mBZA-Cl-(R)mBZA
(R)-(methyl-benzyl-
chloride salt vibrational mode
assignment
assignment
benzyl-amine
salt-cocrystal
salt-cocrystal
ammonium chloride
2505
2573
2617
2691
2735
2494
2588
2635
2685
2737
2494
2584
2635
2685
2739
overtone band
overtone band
overtone band
overtone band
overtone band
symmetric CH2 stretch
2866
2924
2887
2920
2887
2956
2885
2955
aliphatic CH2 stretch
composite band
antisymmetric CH2 stretch
aliphatic CH3 stretch
aromatic CH
2961
3024
3061
3082
2965
2972
aromatic CH
3034
3063
aromatic CH
þ
3248 (antisymmetric NH3
stretch)
antisymmetric NH2 stretch
symmetric NH2 stretch
3288
3366
þ
3292 (symmetric NH3
stretch)
to merge into absorption bands associated with the aromaticꢀCH
stretching modes, resulting in a broad absorption band around
2955 cmꢀ1. A large number of overtone bands not observed in
the spectrum of the free amine were observed at energies of 2494,
2584, 2635, 2685, and 2739 cmꢀ1
.
Once again, the pattern of high-frequency absorption bands
associated with the (R)mBZA-Cl-(R)mBZA product and the
(R)mBZA-Cl salt could not be distinguished, which is consistent
with the lack of formation of a salt-cocrystal product. However,
formation of the (R)mBZA-Cl-(S)mBZA salt-cocrystal product
was amply demonstrated by the presence of absorption bands
associated with the perturbed symmetric (3292 cmꢀ1) and
antisymmetric (3248 cmꢀ1) ꢀNH3þ stretching modes.
C. Formation of Mixed Salt-Cocrystal Products. The de-
monstrated stereoselectivity associated with the R-methylbenzy-
lamine system indicated that a study of possible mixed salt-
cocrystal products would be of interest. In a previous study, it was
found that mixed salt-cocrystal products could be formed by the
solvent-drop grinding of a benzenecarboxylic acid with the
sodium salt of a different benzenecarboxylic acid.10 To learn
whether a similar interaction could take place between the
benzylamines of the present investigation, a study of the inter-
action of (R)-R-methylbenzylamine with benzylammonium
chloride and a study of the interaction of (R)-R-methylbenzy-
lammonium chloride with benzylamine was undertaken.
The XRPD patterns obtained for the BZA-Cl and (R)mBZA-
Cl salts are found in Figure 7 together with the pattern of the
(R)mBZA-Cl-BZA salt-cocrystal product that had been pre-
pared by the interaction of (R)-R-methylbenzylamine with
benzylammonium chloride. It was found that while the diffrac-
tion pattern of the salt-cocrystal product contained a number of
scattering peaks in common with the XRPD of BZA-Cl, a
sufficient number of differences were observed that indicated
Figure 5. Infrared absorption spectra in the fingerprint region of (R)-R-
methylbenzylamine (black trace), (R)-R-methylbenzylammonium
chloride (red trace), and the (R)mBZA-Cl-(R)mBZA (blue trace) and
(R)mBZA-Cl-(S)mBZA (green trace) salt-cocrystal products.
by the disappearance of the antisymmetric and symmetric
stretching bands associated with the ꢀNH2 group (3288 and
3366 cmꢀ1, respectively). Upon formation of the salt, the
absorption bands of the ꢀNH3þ stretching modes were found
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Figure 8. Infrared absorption spectra in the fingerprint region of
benzylammonium chloride (green trace), (R)-R-methylbenzylammo-
nium chloride (blue trace) and their 1:1 cocrystal product (red trace).
Figure 6. Infrared absorption spectra in the high-frequency region of
(R)-R-methyl-benzylamine (black trace), (R)-R-methylbenzylammo-
nium chloride (red trace), and the (R)mBZA-Cl-(R)mBZA (blue trace)
and (R)mBZA-Cl-(S)mBZA (green trace) salt-cocrystal products.
Figure 9. Infrared absorption spectra in the high-frequency region of
benzylammonium chloride (green trace), (R)-R-methylbenzylammo-
nium chloride (blue trace), and their 1:1 cocrystal product (red trace).
Figure 7. X-ray powder diffraction patterns of benzylammonium
chloride (green trace), (R)-R-methylbenzylammonium chloride (blue
trace), and their 1:1 cocrystal product (red trace).
interaction of (R)-R-methylbenzylamine with benzylammo-
nium chloride.
The DSC thermogram of the mixed (R)mBZA-Cl-BZA salt-
cocrystal product was found to be more complicated than any of the
other salt-cocrystal products. Whereas the other salt-cocrystal
products were obtained as nonsolvates, the mixed salt-cocrystal
the formation of a new crystalline species. Although not shown
in the figure, the XRPD pattern of the salt-cocrystal product
formed by the interaction of benzylamine with (R)-R-methyl-
benzylammonium chloride was equivalent to the XRPD of
the salt-cocrystal product that had been prepared by the
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Table 5. Assignmentsof Key Absorption Bands in theInfrared
Absorption Spectra of the BenzylamineꢀBenzylammonium
Chloride, the (R)-r-Methylbenzylamineꢀ(S)-r-Methylbenzy-
lammonium Chloride, and the (R)-r-Methylbenzylamineꢀ
Benzylammonium Chloride Salt-Cocrystal Products
with salts, namely, benzoic acid with benzylammonium benzoate,9
or benzenecarboxylic acids and their sodium salts.10 In the present
work, the scope of potential salt-cocrystal products has been
extended, with phenylalkylamine precursors being shown to form
(in most instances) salt-cocrystal products with phenylalkylam-
monium chloride salts.
Of great significance is the demonstration that stereoselectiv-
ity can exist in the formation of salt-cocrystal products when the
interacting species contain centers of dissymmetry. Specifically, it
has been found that a salt-cocrystal product forms as long as the
salt and free base are of opposite absolute configurations, and no
cocrystallization takes place when the salt and free base are of the
same absolute configuration.
(R)mBZA-
vibrational mode BZA-Cl-BZA (R)mBZA-Cl-BZA
Cl-(S)mBZA
assignment
salt-cocrystal
salt-cocrystal
salt-cocrystal
NH3þ out-of-plane
bending mode
879
879
895
NH2 rocking mode
NH2 rocking mode
1144
1283
1155
1273
1151
obscured by CH3
deformation
mode
The basic approach in these studies has been to use X-ray
powder diffraction and differential scanning calorimetry investi-
gations to initially prove (or disprove) the existence of a
particular salt-cocrystal species, and then to use vibrational
spectroscopy as a means to deduce additional details of the
intermolecular interactions. While the previous studies indicated
that the fingerprint region (600ꢀ1800 cmꢀ1) of the infrared
absorption spectrum contained the most valuable information
for characterization of benzenecarboxylic acid salt-cocrystals,9,10
the present study indicated that the high-frequency region
(2400ꢀ3700 cmꢀ1) was most useful in differentiating between
salts and salt-cocrystals when amine functionalities were in-
NH3þ rocking
mode
NH3þ symmetric
1331
1628
1317
1616
1315
1610
3292
bending mode
þ
symmetric NH3
3290
3309
stretch
product was obtained in the form of a methanol solvate. The DSC
thermogram of the mixed salt-cocrystal product contained a large
desolvation transition having a temperature maximum of 64 °C
(enthalpy of desolvation equal to 96 J/g). The desolvated product
exhibited two additional endothermic transitions, one at a tempera-
ture of 138 °C (enthalpy equal to 22 J/g) and the other at 193 °C
(enthalpy equal to 15 J/g). No changes in baseline character were
noted for either transition, ruling out the possibility that either
transition was associated with an endothermic decomposition.
Using an isothermal heating process, the total volatile content
of the solvated benzylamineꢀ(R)-R-methylbenzylammonium
chloride salt-cocrystal product was determined to be 11%. The
theoretical methanol content for a 1:1 stoichiometric solvate of
the mixed salt-cocrystal product was calculated to be 10.8%,
establishing that this product was obtained in the form of a
monomethanol solvate.
The infrared absorption spectrum of the benzylamineꢀ(R)-
R-methylbenzylammonium chloride salt-cocrystal product was
found to be the same as the spectrum of the (R)-R-methyl-
benzylamineꢀbenzylammonium chloride salt-cocrystal product,
confirming the existence of a single (R)mBZA-Cl-BZA salt-
cocrystal product. Figures 8 and 9 contrast the infrared absorp-
tion spectra in the fingerprint and the high-frequency regions,
respectively, of the mixed (R)mBZA-Cl-BZA salt-cocrystal prod-
uct with the corresponding spectra of the BZA-Cl-BZA and
(R)mBZA-Cl-(S)mBZA cocrystal products. A summary of the
energies of the key salt-cocrystal vibrational bands is found in
Table 5, where it may be noted that the energy of the symmetric
NH3þ stretching mode around 3300 cmꢀ1 is most diagnostic of
salt-cocrystal formation. All of the key absorption bands can be
attributed to perturbed amine or ammonium group frequencies,
which would be anticipated by the sharing of the chloride ion
between the two phenylalkylamine groups.
þ
volved. The energies of the symmetric NH3 stretching mode
around 3000 cmꢀ1 were found to be of particularþimportance in
this regard, although the energies of the NH3 out-of-plane
bending mode (around 880 cmꢀ1) and the NH3þ rocking mode
(around 1320 cmꢀ1) also have good utility.
The appearance of additional vibrational modes not directly
attributable to either constituent situation was evident in the
present study of phenylalkylamine salt-cocrystals, and this re-
presents a different situation than that of the previously reported
system of benzenecarboxylic acids and their sodium salts. In the
latter system, assignments for all vibrational modes in the salt-
cocrystal products could be made on the basis of the assignments
for the individual components.9,10 This would imply the vibra-
tional modes of the components in the benzenecarboxylic acid/
sodium salt systems largely retain their individual patterns of
molecular motion. On the other hand, a number of vibrational
modes in phenylalkylamine salt-cocrystals had no precursor in
the spectra of either the free amine or the amine salt, and the
existence of the modes would signify the existence of more
delocalization in the vibrational patterns of this latter system.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: hbrittain@centerpharmphysics.com.
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In previous works, it was shown that salt-cocrystal products
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