Vibrational Spectroscopic Studies of Cocrystals and Salts. 2. The Benzylamine-Benzoic Acid System Harry G. Brittain Center for Pharmaceutical Physics, 10 Charles Road, Milford, New Jersey 08848
CRYSTAL GROWTH & DESIGN 2009 VOL. 9, NO. 8 3497–3503
ReceiVed February 16, 2009; ReVised Manuscript ReceiVed May 4, 2009
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 the 1:1 stoichiometric product formed by benzylamine and benzoic acid. Full understanding of the effects of salt formation on the energies of the vibrational modes of motion was obtained by the complete assignment of the spectra of the starting materials and of the benzylammonium benzoate product. In addition, benzoic acid was found to form a 1:1 cocrystal with the benzylammonium benzoate salt, and this product was also characterized using the full range of techniques. Both infrared absorption and Raman spectroscopies were found to be useful vibrational spectroscopic techniques for characterization of the products, with the phenomenon of salt formation leading to the strongest perturbations in the vibrational modes associated with the carboxylic acid group of benzoic acid and the amine group of benzylamine. Little change in the energies of the vibrational modes associated with the carbon-carbon and carbon-hydrogen portions of the compounds was observed, demonstrating that the structural changes associated with the salt formation only affected the energies of the vibrational modes directly involved in the proton transfer and ion association. However, perturbations in the carbon-carbon and carbon-hydrogen vibrational modes were observed in the benzoic acid cocrystal with benzylammonium benzoate, demonstrating the importance of the phenyl rings in the cocrystal formation. Introduction In his review on pharmaceutical cocrystals, Zaworotko noted that while formation of salt species was generally directed between acidic and basic groups of interacting synthons, cocrystals could involve the interactions between multiple functional groups of the associated molecules.1 Since the use of salt forms of medicinal agents as means to enhance solubility, dissolution, and bioavailability is well established in the pharmaceutical field,2-5 it is appropriate to develop analytical tools capable of distinguishing between salts and cocrystals. Salts and cocrystals have been defined as multicomponent crystals that can be distinguished from each other by the degree of proton transfer between an acid and a base, with salts being characterized by more or less complete proton transfer and cocrystals with little or no transfer.6,7 The degree of proton transfer, and the ability of a salt species to resist disproportionation, can be estimated through knowledge of the ionization constants of the involved synthons.8 In a survey study of over 80 salts and cocrystals prepared by the interaction of carboxylic acids and N-heterocyclic compounds, it was reported that structure prediction and targeted synthesis appeared to be more difficult for salts than for cocrystals.9 The concept of a continuum having salts and cocrystals located at the extreme ends of the scale suggests that techniques sensitive to the degree of proton transfer would be of complementary value to crystallographic studies. Since it is to be expected that such intermolecular interactions would necessarily perturb the frequencies of any vibrational modes associated with the association process, it is clear that detailed studies of the energies of molecular vibrations in salt and cocrystal systems would be of additional value. In one such work, infrared absorption spectroscopy was found to be extremely useful in understanding details of the cocrystal interactions between benzamide and benzoic acid in stoichiometric and non- stoichiometric mixtures.10 In another work, the analytical potential of near-infrared spectroscopy was shown to be useful for cocrystal screening when conducted in tandem with Raman spectroscopy.11
In the present work, the results of salt formation between benzoic acid (I) and benzylamine (II):
have been studied primarily from a vibrational spectroscopic point of view but also with supporting X-ray powder diffraction
Figure 1. X-ray powder diffraction patterns of benzoic acid (red trace) and the 1:1 stoichiometric benzylammonium benzoate salt (black trace).
10.1021/cg9001972 CCC: $40.75 2009 American Chemical Society Published on Web 05/22/2009
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and benzoic acid. Indeed, salts formed by benzylamines and benzoic acids have been studied from both a crystallographic12,13 and a solubility14,15 perspective. During the conduct of studies on nonstoichiometric mixtures of benzylamine and benzoic acid, the formation of a cocrystal between benzoic acid and the benzylammonium benzoate salt was detected. Characterization of this product was also performed, and its vibrational spectroscopy was also critically compared with the spectroscopy of its component materials. Materials and Methods
Figure 2. Infrared absorption spectra obtained for benzoic acid (blue trace), benzylamine (red trace), and the 1:1 stoichiometric benzylammonium benzoate salt (black trace).
and thermal analysis. Given the difference in pKa values for these compounds, and their known chemistry, it is fully anticipated that a salt would be formed between benzylamine
Benzylamine and benzoic acid were purchased from Sigma-Aldrich, with the benzoic acid being recrystallized from methanol before use. The 1:1 stoichiometric benzylammonium benzoate salt was prepared on the 500 mg scale by dissolving an accurately weighed amount of benzoic acid in methanol, and then adding the stoichiometric amount of benzylamine to this solution. The resulting solution was thoroughly mixed and then allowed to evaporate to dryness under ambient conditions. The 1:1 cocrystal of benzylammonium benzoate with benzoic acid was prepared by weighing an equal amount of the reactants in a 50-mL beaker, dissolving in methanol, and then allowing the solution to evaporate to dryness. This product was then transferred to an agate mortar, wetted with 50 µL of methanol, and then ground until the product was completely dry. X-ray Powder Diffraction. X-ray powder diffraction (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 Å). Samples were packed into the sample holder using a backfill procedure, and were scanned over the range of 3.5 to 40 degrees 2θ at a scan rate of 0.5 degrees 2θ/min. Using a data acquisition rate of 1 point per second, the scanning parameters equate to a step size of 0.0084 degrees 2θ. Calibration of the diffractometer system pattern
Table 1. Assignments of the Major Bands in the Fingerprint Region of the Infrared Absorption Spectra of Benzoic Acid, Benzylamine, and the 1:1 Benzylammonium Benzoate Salt assignment COOH out-of-plane deformation
benzoic acid
benzylammonium benzoate salt
933
922 978 1001 1034 1068 1136 1171 1221 1300 1317 1348 1373 1412 1443 + 1456 1514 (carboxylate anion mode) 1589 1599
C-C stretching mode in-plane C-H mode in-plane C-H mode in-plane C-H mode
1001 1026 1072 1128
in-plane C-H mode carbonyl in-plane deformation C-C ring stretching mode
1186 1257 1323
OH out-of-plane deformation of COOH C-C ring stretching mode
1421 1452
C-C ring stretching mode C-C ring stretching mode carbonyl stretching mode of COOH dimer
1583 1601 1678
benzylamine 980
assignment C-C stretching mode
1026 1059 1155 1178 1202
in-plane C-H mode in-plane C-H mode in-plane C-H mode NH2 rocking mode in-plane C-H mode
1352 1385
C-N stretching mode C-C ring stretching mode
1452
C-C ring stretching mode
1587 1603
C-C ring stretching mode C-C ring stretching mode
Table 2. Assignments of the Major Bands in the High-Frequency Region of the Infrared Absorption Spectra of Benzoic Acid, Benzylamine, and the 1:1 Benzylammonium Benzoate Salt assignment
benzoic acid benzylammonium benzoate salt benzylamine
carbonyl in-plane and C-C ring modes C-H stretching + C-C ring modes C-H stretching + C-C ring modes
2557 2606 2671
carbonyl in-plane and C-C ring modes carbonyl in-plane and C-C ring modes
2831 2874
OH and CH stretching modes CH stretching mode CH stretching mode
2975 3072
2517 2598 2648 2739 (amine stretching modes) 2781 (amine stretching modes) 2827 2878 2957 3036
assignment C-H stretching + C-C ring modes CH stretching + C-C ring modes
2860 2916
C-C ring modes C-C ring modes
3026 3061 3084 3292 3366
CH stretching mode CH stretching mode CH stretching mode hydrogen-bonded NH2 asymmetric stretching mode hydrogen-bonded NH2 asymmetric stretching mode
Benzylamine-Benzoic Acid System
Figure 3. Expanded infrared absorption spectra in the carbonyl section of the fingerprint region of benzoic acid (blue trace), benzylamine (red trace), and the 1:1 stoichiometric benzylammonium benzoate salt (black trace). was effected by scanning an aluminum plate, and using the aluminum scattering peaks having d-spacings of 2.338 Å and 2.024 Å to verify both the angle and scan rate. Differential Scanning Calorimetry. Measurements of differential scanning calorimetry (DSC) were obtained on a TA Instruments 2910 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 over the range of 20-175 °C, at a heating rate of 10 °C/min. Infrared Spectroscopy. Infrared absorption spectra were obtained at a resolution of 4 cm-1 using a Shimadzu model 8400S Fouriertransform 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 horizontal ATR sampling accessory. Raman Spectroscopy. Raman spectra were obtained in the fingerprint region using a Raman Systems model R-3000HR spectrometer, operated at a resolution of 5 cm-1 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.
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Figure 4. Expanded infrared absorption spectra in the carbonyl section of the high-frequency region of benzoic acid (blue trace), benzylamine (red trace), and the 1:1 stoichiometric benzylammonium benzoate salt (black trace).
Results and Discussion A. Benzoic Acid, Benzylamine, and the 1:1 Benzylammonium Benzoate Salt. XRPD patterns obtained for benzoic acid and the stoichiometric 1:1 benzylammonium benzoate salt are shown in Figure 1 (since benzylamine is a liquid at room temperature, no diffraction data could be obtained). The diffraction patterns of the two materials were found to be very different, with the salt exhibiting characteristic scattering peaks at 15.1, 19.1, 20.6, and 22.5 degrees 2θ, and benzoic acid exhibiting characteristic scattering peaks at 16.2 and 17.2 degrees 2θ. The DSC thermogram of benzoic acid consisted of a single endothermic event attributed to melting of the compound, which exhibited a maximum at 123.7 °C and an enthalpy of fusion equal to 139.1 J/g. Formation of the 1:1 benzylammonium benzoate salt led to a melting endotherm which, after a few weak endothermic transitions, was observed at the higher temperature of 130.4 °C and associated with an enthalpy of fusion equal to 112.7 J/g.
Figure 5. Raman spectra in the fingerprint region obtained for benzoic acid (blue trace), benzylamine (red trace), and the 1:1 stoichiometric benzylammonium benzoate salt (black trace).
As shown in Figure 2, benzylamine, benzoic acid, and benzylammonium benzoate exhibited a number of significant differences in the fingerprint region of their infrared absorption spectra. In order to track the changes in the energies of the vibrational modes more effectively, the origins of the major absorbance peaks were assigned through the use of published compilations,16 works conducted specifically on benzoic acids17-20 or benzylamines.21 The results of this analysis are provided in Tables 1 and 2.
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Table 3. Assignments of the Major Bands in the Fingerprint Region of the Raman Spectra of Benzoic Acid, Benzylamine, and the 1:1 Benzylammonium Benzoate Salt assignment
benzoic acid
benzylamine
assignment
in-plane C-C deformation mode of phenyl ring in-plane C-H deformation mode in-plane C-H deformation mode in-plane C-H deformation mode
996
benzylammonium benzoate salt 996
996
1023 1070 1127
1018
1023
in-plane C-C deformation mode of phenyl ring in-plane C-H deformation mode
in-plane C-H deformation mode
1175
1131 1155 1177 1217
1153 1171 1201
-NH2 rocking mode in-plane C-H deformation mode C-N stretching mode
COOH in-plane deformation mode C-C ring stretching mode
1287 1319
1336
C-C ring stretching mode
C-C ring stretching mode
1440
1456
C-C ring stretching mode
C-C ring stretching mode CdO stretching mode
1599 1629
1602
C-C ring stretching mode
1317 1393 (symmetric CdO stretching mode) 1452 1518 (antisymmetric CdO stretching mode) 1598
In the fingerprint region of the infrared spectra, very little perturbation of the frequencies of the carbon-carbon and carbon-hydrogen modes was observed, indicating that the basic skeletal motions were effectively the same in benzylammonium benzoate as in the starting materials. The most drastic changes that took place upon formation of the salt were the shifts in frequencies associated with the motions of the benzoic carboxylic acid group. A large decrease in the frequency of the carbonyl stretching band was observed, while a slight increase in the frequency of the deformation mode was noted. These spectral shifts and changes in relative intensity are illustrated in Figure 3, which shows the expanded spectrum in the upper portion of the fingerprint region of the reactants and of benzylammonium benzoate. Formation of a salt of benzoic acid can therefore be deduced on the basis of disappearance of the carbonyl stretching mode of the free acid and the appearance of a carboxylate anion band resulting from the deprotonation. The high-frequency region of the infrared spectrum of benzoic acid is dominated by the absorption bands associated with
carbon-hydrogen and carbon-oxygen vibrational modes, while the spectrum of benzylamine is dominated by the symmetric and antisymmetric stretching modes of the hydrogen-bonded NH2 group. Formation of the benzylammonium benzoate salt caused complete disappearance of the amine stretching bands, but the new absorption features attributable to the ammonium group were noted to be strongly overlapped with the mostly unperturbed carbon-hydrogen absorption bands. These spectral changes are illustrated in Figure 4, where formation of the salt form is demonstrated by the disappearance of the absorption bands associated with the free amine group. While the modes associated with the carbon skeleton were found to be substantially the same in the Raman spectra of benzylamine and benzoic acid, substantial differences associated with their respective functional groups were noted in the spectra. As illustrated in Figure 5, the carbon skeleton modes of benzylammonium benzoate were largely unchanged, while the Raman bands associated with the functional groups did undergo substantial change upon salt formation. The origins of the major
Figure 6. X-ray powder diffraction patterns obtained for benzoic acid (red trace), the stoichiometric 1:1 benzylammonium benzoate salt (blue trace), and the 1:1 cocrystal formed between benzoic acid and benzylammonium benzoate (black trace).
Figure 7. Infrared absorption spectra obtained for benzoic acid (red trace), the stoichiometric 1:1 benzylammonium benzoate salt (blue trace), and the 1:1 cocrystal formed between benzoic acid and benzylammonium benzoate (black trace).
Benzylamine-Benzoic Acid System
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Figure 8. Expanded infrared absorption spectra in the carboxylate region obtained for benzoic acid (red trace), the stoichiometric 1:1 benzylammonium benzoate salt (blue trace), and the 1:1 cocrystal formed between benzoic acid and benzylammonium benzoate (black trace).
scattering peaks were assigned through the use of published compilations22 and literature studies,23,24 and the results of this analysis are collected in Table 3. The effect of salt formation is demonstrated in the Raman spectra as a loss of the benzoic acid carbonyl stretching mode at 1629 cm-1, and in the appearance of strong symmetric and weak antisymmetric carboxylate anion stretching modes in the spectrum of the salt at 1393 and 1518 cm-1, respectively. In addition, the carboxylic acid in-plane deformation mode of the benzoic acid synthon is not present in the Raman spectrum of benzylammonium benzoate. B. Benzoic Acid, Benzylammonium Benzoate, and their 1:1 Cocrystal. Additional insight into the benzylamine-benzoic acid system was obtained through studies of the crystallographic, thermal, and spectroscopic properties of nonstoichiometric mixtures
of benzylamine and benzoic acid. Owing to the reactivity of benzylamine to carbon dioxide in the atmosphere, this work was only performed for mixtures where the mole fraction of benzoic acid exceeded that of benzylamine. The XRPD and spectroscopic results indicated the existence of a new species in mixtures having mole fractions of benzoic acid around 0.75, which would correspond to a cocrystal composition formed of equal amounts of benzoic acid and benzylammonium benzoate. The DSC thermogram of the benzoic acid/benzylammonium benzoate cocrystal was found to consist of a single melting endotherm having a maximum at 104.5 °C, and an enthalpy of fusion equal to 55.9 J/g. These values are considerably reduced relative the analogous values obtained for benzoic acid (maximum at 123.7 °C, and enthalpy of fusion equal to 139.1 J/g) and the 1:1 benzylammonium benzoate salt (maximum at 130.4 °C, and enthalpy of fusion equal to 112.7 J/g). The DSC thermograms obtained for nonstoichiometric mixtures of benzoic acid and benzylamine for which the benzoic acid mole fraction was 0.75 ( 0.1 all exhibited a melting endotherm around 105 °C that was attributable to the benzoic acid/benzylammonium benzoate cocrystal. The existence of a benzoic acid/benzylammonium benzoate cocrystal was further supported by XRPD studies, and the diffraction patterns of the cocrystal product are contrasted with those of benzoic acid and benzylammonium benzoate in Figure 6. It was observed that the XRPD of the cocrystal contained numerous scattering peaks not observed in the patterns of either benzoic acid or the benzylammonium benzoate salt. Characteristic scattering peaks of the cocrystal, not found in the XRPD of either benzoic acid or benzylammonium benzoate, were observed at angles of 9.8, 10.3, 12.4, 15.4, 19.4, 21.5, 23.2, 27.1, 29.2, and 32.8 degrees 2θ. As shown in Figure 7, the infrared absorption spectra of benzoic acid, benzylammonium benzoate, and their 1:1 cocrystal product were not very different in the high-frequency region of the spectrum, but significant differences were observed in the fingerprint region (see Figure 8). Since the absorption spectra of benzoic acid and the benzylammonium benzoate salt had been previously interpreted, this facilitated assignment of the origins of the absorption bands in the fingerprint region of their 1:1 cocrystal, and these assignments are found in Table 4. As would be expected, formation of the cocrystal led to significant perturbations in the frequencies of the functional groups; the largest change was observed in the antisymmetric carbonyl
Table 4. Assignments of the Major Bands in the Fingerprint Region of the Infrared Absorption Spectra of Benzoic Acid, Benzylammonium Benzoate, and the 1:1 Cocrystal Product assignment COOH out-of-plane deformation
benzoic acid 933
C-C stretching mode in-plane C-H mode in-plane C-H mode in-plane C-H mode
1001 1026 1072 1128
in-plane C-H mode carbonyl in-plane deformation C-C ring stretching mode
1186 1257 1323
OH out-of-plane deformation of COOH C-C ring stretching mode
1421 1452
C-C ring stretching mode C-C ring stretching mode carbonyl stretching mode
1583 1601 1678
benzoic acid/benzylammonium benzoate cocrystal 901 935 + 924 974 1001 1026 1068 1119 1151 1175 1225 1258 + 1292 1315 1387 1414 1454 1512 (carboxylateanion mode) 1583 1616 1651 + 1691
benzyl-ammonium benzoate salt 922 978 1001 1034 1068 1136 1171 1221 1300 1317 1348 1373 1412 1443 + 1456 1514 (carboxylateanion mode) 1589 1599
assignment
C-C stretching mode C-C stretching mode in-plane C-H mode in-plane C-H mode in-plane C-H mode NH2 rocking mode in-plane C-H mode C-N stretching mode C-C ring stretching mode C-C ring stretching mode C-C ring stretching mode C-C ring stretching mode
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Figure 9. Expanded Raman spectra obtained for benzoic acid (red trace), the stoichiometric 1:1 benzylammonium benzoate salt (blue trace), and the 1:1 cocrystal formed between benzoic acid and benzylammonium benzoate (black trace).
stretching mode of benzoic acid, which underwent both a large shift in energy as well as a band splitting. The carbonyl in-plane and out-of-plane deformation modes effectively maintained their identities even in the cocrystal, while the C-N stretching mode of the salt could not be observed in the spectrum of the cocrystal. Interesting trends were noted in the energies of the phenyl ring modes of the benzoic acid benzylammonium benzoate cocrystal. While the energies of most of these modes were essentially the same in the cocrystal as in the benzylammonium benzoate salt, the energy of one of the in-plane C-H modes (i.e., 1026 cm-1) reverted to the energy it exhibited in the benzoic acid reactant. The same behavior was also observed for one of the C-C stretching modes (i.e., 1583 cm-1), while the energy of another C-C stretching modes (i.e., 1616 cm-1) actually increased in energy relative to the energies of the analogous modes in either benzoic acid or in the benzylammonium benzoate salt. These observations provide evidence that
formation of the cocrystal involves additional interactions between the phenyl rings of the benzoic acid and the benzylammonium benzoate salt that did not take place when the salt was formed from benzoic acid and benzylamine. As shown in Figure 9, the Raman spectra obtained in the fingerprint region for benzoic acid, benzylammonium benzoate salt, and their 1:1 cocrystal contained additional information regarding the intermolecular interactions associated with the cocrystal formation. Assignments for the observed Raman bands are collected in Table 5. The most significant trend noted was the appearance of a carbonyl stretching band observed at a considerably higher frequency relative to the analogous mode in benzoic acid. In addition, the antisymmetric carbonyl stretching mode of the benzylammonium benzoate salt was found to undergo a substantial decrease in energy. These trends demonstrate the main positions of interaction in the cocrystal. Changes in the phenyl ring modes were also observed in the Raman spectrum of the benzoic acid/benzylammonium benzoate cocrystal, where it was observed that the energies of most of the Raman-intense modes were somewhat shifted relative to either benzoic acid or the benzylammonium benzoate salt. Paralleling the infrared absorption band trends, the energy of one of the benzylammonium benzoate in-plane C-H modes (i.e., 1023 cm-1) reverted to the energy of the benzoic acid reactant. The same behavior was also observed for one of the C-C stretching modes (i.e., 1320 cm-1), while the energy of another C-C stretching modes (i.e., 1444 cm-1) took on an intermediate value relative to the energies of the analogous modes in either benzoic acid or in the benzylammonium benzoate salt. The observations deduced from the Raman spectra provide additional evidence that formation of the cocrystal involves additional interactions between the phenyl rings of the benzoic acid and the benzylammonium benzoate salt that did not take place when the salt was formed from benzoic acid and benzylamine. C. Comparison of the Vibrational Spectroscopic Properties of the Benzamide-Benzoic Acid System and those of the Benzylamine-Benzoic Acid System. The criteria that differentiate a salt from a cocrystal have been discussed at length, with the structural difference essentially being that a proton is shared between an acid and a base in a cocrystal and transferred in the case of a salt.6 The concept of a salt-cocrystal continuum can also be probed in suitable systems through the use of other techniques as well. Consequently, a comparison of the conclusions reached in the present study of the benzylam-
Table 5. Assignments of the Major Bands in the Fingerprint Region of the Raman Spectra of Benzoic Acid, Benzylamine, and the 1:1 Benzylammonium Benzoate Salt assignment
benzoic acid
benzoic acid/benzylammonium benzoate cocrystal
benzyl-ammonium benzoate salt
in-plane C-C deformation mode of phenyl ring in-plane C-H deformation mode in-plane C-H deformation mode in-plane C-H deformation mode
996
999
996
1023 1070 1127
1023
1018
in-plane C-C deformation mode of phenyl ring in-plane C-H deformation mode
in-plane C-H deformation mode
1175
1131 1155 1177 1217
-NH2 rocking mode in-plane C-H deformation mode C-N stretching mode
COOH in-plane deformation mode C-C ring stretching mode
1287 1319
1132 1154 1182 1221 1285 1320 1389
C-C ring stretching mode
1440
1444 1493
C-C ring stretching mode CdO stretching mode
1599 1629
1599 1694
1317 1393 (symmetric CdO stretching mode) 1452 1518 (antisymmetric CdO stretching mode) 1598
assignment
C-C ring stretching mode C-C ring stretching mode C-C ring stretching mode
Benzylamine-Benzoic Acid System
monium benzoate salt system with those of the previously reported benzamide-benzoic acid cocrystal system10 is useful. The most important difference between the systems studied in these two works was that well-defined regions of cocrystal product were shown to exist in mixed benzamide-benzoic acid solids, while the existence of both a salt and a cocrystal was found that was dependent on the molar ratio of the constituents for the mixed benzylamine-benzoic acid solids. These findings support those reached by Aakero¨y et al.,9 who concluded that, “the formation of salts tends to wreak havoc when attempting to combine two or more solids into the same crystalline lattice in a reliable and predictable manner.” These workers went on to state, “There is undoubtedly a dramatic difference in structural behavior between the two classes of compounds at least when comparing cocrystals of carboxylic acids and carboxylate salts.” While these trends are necessarily evident in X-ray diffraction patterns and thermal analysis thermograms, they are most evident in the vibrational spectra of the systems. For example, in the benzamide-benzoic acid cocrystal system, the fundamental nature of the pattern of molecular vibrations was perturbed, but not greatly altered.10 The amide -NH2 stretching band derived from the benzamide reactant was observed to split in the spectrum of the cocrystal, and this splitting persisted as long as an identifiable cocrystal phase existed in the solid. However, the band system only shifted slightly in energy, and could therefore still be readily identified. The cocrystal behavior may be contrasted with the salt behavior, where the free amine bands of benzylamine became completely replaced in benzylammonium benzoate with the absorption bands associated with the ammonium group, and could only be identified on the basis of frequency correlation tables. The formation of a new vibrational band corresponding to the antisymmetric stretching mode of the carboxylate anion is diagnostic for formation of the salt, which interestingly did not significantly change when a cocrystal was formed between the salt and additional benzoic acid. Another vibrational spectral region of significance is the upper end of the fingerprint region, where formation of the cocrystal caused simple broadening in the carbonyl band region around 1650 cm-1, but very little shifting in energy.10 This broadening arises from formation of an overlapped combination of the outof-plane deformation modes associated with each reactant, but does not result in the generation of any dramatic spectral shifts. On the other hand, the carbonyl bands associated with the free benzoic acid became drastically shifted in energy in the benzylammonium benzoate salt system, which could be taken as proof of the existence of a salt as opposed to a cocrystal. Finally, it was concluded that Raman spectroscopy was not a useful technique in the characterization of the benzamidebenzoic acid cocrystal system, as the spectrum of the cocrystal was only barely distinguishable from the superimposed spectra of the two synthons.10 However, Raman spectroscopy proved to be quite useful in the study of both the benzylammonium benzoate salt and the cocrystal formed by this salt with benzoic acid. Alterations in the energies of bands associated with the carbonyl vibrations of the carboxylate group were shown to be sensitive to fine details of the solids.
References (1) Vishweshwar, P.; McMahon, J. A.; Bis, J. A.; Zaworotko, M. J. Pharmaceutical Cocrystals. J. Pharm. Sci. 2006, 95, 499–516.
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