Vibrational Spectroscopic Studies of Cocrystals and Salts. 1. The

Vibrational Spectroscopic Studies of Cocrystals and Salts. 1. The Benzamide-Benzoic Acid System Harry G. Brittain Center for Pharmaceutical Physics, 10 Charles Road, Milford, New Jersey 08848

CRYSTAL GROWTH & DESIGN 2009 VOL. 9, NO. 5 2492–2499

ReceiVed December 23, 2008; ReVised Manuscript ReceiVed March 6, 2009

ABSTRACT: X-ray powder diffraction, differential scanning calorimetry, infrared absorption spectroscopy, and Raman spectroscopy have been used to study the phenomenon of cocrystal formation in stoichiometric and nonstoichiometric mixtures of benzamide and benzoic acid. Although Raman spectroscopy was not useful in characterization of the products, trends in the infrared absorption bands of the various products were used to demonstrate a number of important aspects regarding the nature of the interactions in the cocrystal. Little change in the vibrational modes associated with the phenyl groups of the respective reactants took place upon cocrystal formation, but changes in intensities of the various vibrational modes associated with the amide group of benzamide and the carboxylic acid group of benzoic acid were observed upon formation of the cocrystal. A phase diagram of the system was deduced from thermal analyses of the nonstoichiometric mixtures, and the infrared absorption spectra of these materials were used to obtain additional insight into the nature of these solids. Introduction Modification of the physical properties of drug substances has been a subject of great interest to the pharmaceutical industry for some time, and the generation of new design elements that facilitate the generation of crystalline products having superior qualities represents an active area of research.1 This line of work has led pharmaceutical scientists into realms of crystal engineering and supramolecular synthesis, causing them to become interested in the mixed crystal systems that have become known as cocrystals.2 Use of the term “cocrystal” is not without controversy,3,4 but is likely to be continued4,5 as long as all of the components in the mixed crystal themselves exist as solids under ambient conditions.6 Hydrogen bonding is one of the most important fundamental interactions that causes association of organic molecules,7-11 forming the building block units known as supramolecular synthons.12 One example of a supramolecular synthon is the molecular dimer that exists in crystals of carboxylic acids,13 and which may be typified by the specific instance of benzoic acid:14

Another supramolecular synthon of interest would be the molecular dimer that exists in crystals of organic amides,15 and which may be typified by the specific instance of benzamide:16

Aakeroÿ has summarized guidelines for cocrystal formation from supramolecular synthons as being constructed from discrete neutral molecular species that are solids at ambient temperatures, and where the cocrystal is a structurally homogeneous crystalline material that contains the building blocks in definite stoichiometric amounts.17 One of the binary motifs described by

Aakeroÿ that would be caused by heteromeric hydrogen-bond interactions is the interaction between a phenyl-carboxylic acid and a phenyl-amide, with the molecules being linked into a dimeric species through O · · · H-N and O-H · · · O hydrogen bonds.18 and which would be exemplified by the supramolecular synthon that would result from the dimerization of benzoic acid and benzamide:

This mode of interaction has been empirically observed in the crystal structures of the cocrystals formed by benzamide and pentafluorobenzoic acid.19,20 In cocrystal systems, it is to be anticipated that any protons taking part in the hydrogen bonding that forms a supramolecular synthon would be more likely to be shared as opposed to being transferred. Since any degree of proton transfer would be expected to influence the energies of vibrational modes associated with the functional groups, one way to study the interactions would be through evaluation of the effects exerted on patterns of molecular vibrations by formation of the supramolecular synthon. The utility of infrared absorption spectroscopy as a means to supplement crystallographic methods in the differentiation between cocrystals and salts has been demonstrated for a large number of systems.21 In the present work, detailed vibrational spectroscopic studies have been carried out on the cocrystal system formed by benzoic acid and benzamide. The goals of this work were 2-fold: (1) to determine which vibrational modes were most affected by formation and assembly of the supramolecular synthons, and (2) to determine the magnitude of perturbation in vibrational frequencies of the involved modes. These goals necessitated assignment of most of the observed spectral features in the vibrational bands of the benzoic acid and benzamide reactants, and tracking the energies of these bands in stoichiometric and nonstoichiometric mixtures of the two. The spectroscopic results

10.1021/cg801397t CCC: $40.75  2009 American Chemical Society Published on Web 03/20/2009

Vibrational Spectroscopic Studies of Cocrystals and Salts

Crystal Growth & Design, Vol. 9, No. 5, 2009 2493

were supported by X-ray powder diffraction and differential scanning calorimetry studies of the same materials. Materials and Methods Benzamide and benzoic acid were purchased from Sigma-Aldrich, and were recrystallized from methanol before use. The products studied in this work were initially prepared using solvent-drop mediated solidstate grinding,22,23 where the composition of the product (i.e., stoichiometric or nonstoichiometric) was determined by the amounts of reactants initially taken. In this approach, exact amounts of benzamide and benzoic acid were weighed directly in an agate mortar to yield approximately 500 mg of total product, wetted with 50 µL of methanol, and then ground until the product was completely dry. Alternatively, exactly weighed amounts of benzamide and benzoic acid were directly weighed in a 50 mL beaker, whereupon the solids were completely dissolved in methanol, and the resulting solutions allowed to evaporate under ambient conditions. However, it was observed that the method of preparation did not alter the measured physical properties of the products as materials obtained by either procedure were found to be identical. 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 was effected by scanning an aluminum plate, and using the aluminum scattering peaks having d-spacings of 2.338 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.

Figure 1. X-ray powder diffraction patterns of benzoic acid (blue trace), benzamide (red trace), and the stoichiometric 1:1 cocrystal of these (black trace).

Results and Discussion Benzamide, Benzoic Acid, and the Stoichiometric 1:1 Cocrystal Product. XRPD patterns obtained for benzamide, benzoic acid, and the 1:1 cocrystal product of these are shown in Figure 1. Even though the benzamide and benzoic acid reactants are characteristic by comparable unit cell parameters,14,16 the two compounds still exhibit differences in their powder patterns. While both solids exhibited a strong scattering peak at around 16.2 degrees 2θ, benzoic acid exhibited a characteristic scattering peak at 17.2 degrees 2θ and benzamide exhibited a characteristic scattering peak at 22.6 degrees 2θ. The 1:1 stoichiometric cocrystal product did exhibit a strong scattering peak at 16.25 degrees 2θ, but it also exhibited strong scattering peaks at 23.4 and 25.95 degrees 2θ that had no correspondence in the diffraction patterns of the starting materials. DSC thermograms of benzamide, benzoic acid, and their 1:1 cocrystal product are shown in Figure 2. The thermogram of benzoic acid (melting endotherm maximum at 123.7 °C;

Figure 2. Differential scanning calorimetry thermograms of benzoic acid (blue trace), benzamide (red trace), and the stoichiometric 1:1 cocrystal of these (black trace).

enthalpy of fusion equal to 139.1 J/g) was found to be similar to that of benzamide (melting endotherm maximum at 128.9 °C; enthalpy of fusion equal to 158.1 J/g). The DSC thermogram of the 1:1 stoichiometric product proved formation of the benzamide-benzoic acid cocrystal, as this substance exhibited a melting endotherm maximum at 82.2 °C that was characterized by an enthalpy of fusion equal to 117.5 J/g. The infrared absorption spectra of benzamide, benzoic acid, and their 1:1 cocrystal product were found to exhibit a number of differences in both the fingerprint region and in the highfrequency region. In order to evaluate the trends in the spectra more effectively, the origins of the major absorbance peaks were

2494

Crystal Growth & Design, Vol. 9, No. 5, 2009

Brittain

Table 1. Assignments of the Major Bands in the Fingerprint Region of the Infrared Absorption Spectra of Benzoic Acid, Benzamide, and their 1:1 Cocrystal Product assignment

benzoic (cm-1)

cocrystal (cm-1)

benzamide (cm-1) 918

COOH out-of-plane deformation C-C stretching mode in-plane C-H mode in-plane C-H mode in-plane C-H mode

933 1001 1026 1072 1128

in-plane C-H mode carbonyl in-plane deformation C-C ring stretching mode

1186 1288 1323

OH out-of-plane deformation of COOH C-C ring stretching mode C-H in-plane + C-C stretching modes C-C ring stretching mode C-C ring stretching mode

1421 1452 1497 1583 1601

carbonyl stretching mode of COOH dimer

928 1001 1026 1072 1122 1148 1186 1288 1319 1402 1450 1495 1578 1603 1622 1651

assignment carbonyl out-of-plane deformation

1001 1026 1072 1121 1142 1180 1298 1319 1398

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 carbonyl in-plane deformation C-C ring stretch amide-III band (C-N stretch and N-H bend)

1448 1495 1576

C-C ring stretch C-H in-plane + C-C stretch C-C ring stretch

1622 1651

amide-II band (NH2 scissor) hydrogen bonded amide-I band (C-N and CdO stretching mode combination)

1678

Table 2. Assignments of the Major Bands in the High-Frequency Region of the Infrared Absorption Spectra of Benzoic Acid, Benzamide, and their 1:1 Cocrystal Product assignment

benzoic (cm-1)

cocrystal (cm-1)

combination: carbonyl in-plane and C-C ring modes combination: CH + C-C modes combination: CH and C-C modes combination: carbonyl in-plane and C-C ring modes combination: carbonyl in-plane and C-C ring modes combination: OH and CH stretching modes CH stretching mode

2557 2606 2671 2831 2874 2975 3072

2534 2602 2654 2814 2887

first assigned through the use of published compilations,24 studies specifically conducted on benzoic acids,25-28 amides in general,29 and on benzamide in particular.30 The results of this analysis are provided in Tables 1 and 2. It was found that very little perturbation of the frequencies of the carbon-carbon and carbon-hydrogen modes was observed in the fingerprint region of the infrared spectra, indicating that the basic skeletal motions were effectively the same in the cocrystal as they were in the initial reactants. However, the vibrational bands associated with the amide group of benzamide and the bands associated with the carboxyl group of benzoic acid were found to undergo significant changes. As shown in Figure 3, the absorption bands observed in the carbonyl region for the cocrystal product (around 1650 cm-1) are seen to consist of a broadened and overlapped envelope that contains the out-of-plane deformation modes derived from the respective initial reactants. However, careful examination of the contour of the band system of the cocrystal in this region enables one to note the contributions of the barely shifted bands due to each reactant. The lack of shifting in the vibrational frequencies indicates that the patterns of molecular motion of the supramolecular synthon are not significantly different relative to those of the initial reactants. This finding would indicate that the force constants of the homosupramolecular synthons (i.e., benzamide and benzoic acid) are not strongly changed upon formation of the heterosupramolecular synthon of the cocrystal. The high-frequency region of the benzoic acid infrared absorption spectrum is dominated by bands associated with carbon-hydrogen and oxygen-hydrogen vibrational modes, while the spectrum of benzamide is dominated by the two stretching modes of the hydrogen-bonded NH2 group and one

3069 3169 3310 3371 3420

benzamide (cm-1)

assignment

3065 3165

CH stretching mode H-bonded NH2 stretching modes

3362

H-bonded NH2 stretching modes

strong C-H stretching mode. As illustrated in Figure 4, a strong perturbation of the combination bands associated with the carboxylate group of the benzoic acid synthon was observed in the cocrystal, as well as a splitting of one of the benzamide

Figure 3. Expanded infrared absorption spectra in the carbonyl section of the fingerprint region of benzoic acid (blue trace), benzamide (red trace), and the stoichiometric 1:1 cocrystal of these (black trace).


Figure 4. Expanded infrared absorption spectra in the carbonyl section of the high-frequency region of benzoic acid (blue trace), benzamide (red trace), and the stoichiometric 1:1 cocrystal of these (black trace).

Figure 5. Raman spectra in the fingerprint region obtained for benzoic acid (blue trace), benzamide (red trace), and the stoichiometric 1:1 cocrystal of these (black trace).

NH2 group stretching modes. This latter phenomenon is also evident in Figure 4, where the formation of the cocrystal species is particularly demonstrated by the presence of new bands observed at 3310 and 3420 cm-1. In contrast, the Raman spectra of benzamide and benzoic acid (shown in Figure 5) were found to be substantially the same. The origins of the major scattering peaks were assigned through the use of published compilations31 and literature studies,32,33 and the results of this analysis are collected in Table 3. The


Raman spectrum of the 1:1 cocrystal product was found to effectively be a superimposition of the spectra of the starting materials, and the only effect of cocrystal formation evident in the Raman spectra of Figure 5 is the disappearance of the weak amide-I band of benzamide in the cocrystal product. Non-Stoichiometric Mixtures of Benzamide, Benzoic Acid, and Cocrystal Product. Additional insight into the cocrystal phenomena of the benzamide-benzoic acid system was obtained through studies of the crystallographic, thermal, and spectroscopic properties of nonstoichiometric mixtures of benzamide and benzoic acid. Expanded views of the XRPD patterns of benzamide, its 1:1 cocrystal product with benzoic acid, and three nonstoichiometric cocrystal products having benzamide mole fractions equal to 0.816, 0.751, and 0.669 are shown in Figure 6. It was observed that while most of the characteristic scattering peaks of the benzamide reactant became broadened and reduced in intensity in the 0.816 benzamide mole fraction mixture, strong new diffraction peaks appeared at scattering angles of 18.05 and 19.35 degrees 2θ. The XRPD pattern of the 0.751 benzamide mole fraction mixture was essentially the same as that obtained for the 0.816 mixture, although an increase in intensity of the 26.5 degree 2θ peak was observed. In the benzamide mole fraction 0.666 mixture the scattering peaks at 18.05 and 26.5 degrees 2θ were seen to decrease considerably in intensity, while scattering peaks at angles of 17.5 and 26.0 degrees 2θ were seen to gain intensity. In the XRPD pattern of the stoichiometric cocrystal, the scattering peaks at 18.05 and 26.5 degrees 2θ were effectively of negligible intensity, and were replaced by the characteristic cocrystal scattering peaks at angles of 17.4, 23.4, and 25.95 degrees 2θ. The trends in XRPD patterns of the benzamide-rich mixtures appear to indicate a progression in physical phases as the composition is systematically varied. Small amounts of benzoic acid completely disrupt the benzamide crystal structure, forming an intermediate structure that is stable as long as the mole fraction of benzamide in the solids exceeds 0.75. Once the mole fraction of benzamide is decreased to 0.67, the solid appears to consist of two phases, one being the intermediate phase and the other being the cocrystal phase. It is presumed that these different structures would consist of varying amounts of benzamide-benzoic acid supramolecular synthon zones interspersed in a perturbed benzamide structure. Continued increase in benzoic acid content results information of the 1:1 cocrystal phase and its characteristic XRPD pattern. The XRPD patterns of benzoic acid, its 1:1 cocrystal product with benzamide, and three nonstoichiometric cocrystal products having benzoic acid mole fractions equal to 0.819, 0.749, and 0.666 are shown in Figure 7. In this series, the XRPD pattern of the mixture having a benzoic acid mole fraction of 0.819 is barely distinguishable from the pattern of benzoic acid itself. The pattern of the 0.749 benzoic acid mole fraction mixture is also nearly the same as that of benzoic acid, although one peak having a scattering angle of 21.6 degrees 2θ did double in relative intensity. In the mixture having a benzoic acid mole fraction of 0.666, one finds a large decrease in intensity of the 16.25 degree 2θ peak, a shift of the most intense peak to 17.35 degrees 2θ, and growth of a new peak at 21.85 degrees 2θ. The XRPD pattern of the cocrystal was found to represent a drastic change from the XRPD of even the 0.666 benzoic acid mole fraction peak, with the major scattering peak shifting slightly to 17.40 degrees 2θ and strong new peaks being observed at scattering angles of 23.4 and 25.95 degrees 2θ.

2496


Brittain

Table 3. Assignments of the Major Bands in the Fingerprint Region of the Raman Spectra of Benzoic Acid, Benzamide, and their 1:1 Cocrystal Product assignment in-plane in-plane in-plane in-plane

C-C deformation mode of phenyl ring C-H deformation mode C-H deformation mode C-H deformation mode

benzoic (cm-1) cocrystal (cm-1) benzamide (cm-1) 996 1023 1070 1127

in-plane C-H deformation mode COOH in-plane deformation mode C-C ring stretching mode

1175 1287 1319

C-C ring stretching mode

1440

C-C ring stretching mode CdO stretching mode

1599 1629

996 1021 1072 1119 1144 1174 1285 1318 1410 1449 1495 1568 1602 1628

assignment

996 1020 1069 1119 1142 1173

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 NH2 rocking mode in-plane C-H deformation mode

1411 1448 1494 1569 1602

C-N stretching mode C-C ring stretching mode C-H in-plane + C-C stretching mode amide-II band C-C ring stretching mode

1683

amide-I band

The XRPD patterns of the benzoic acid-rich mixtures represent less of a progression in physical phases than did the benzamide-rich series. Small amounts of benzamide appear to be unable to significantly disrupt the benzoic acid crystal structure, and the only evidence for an intermediate structure is the slightly perturbed XRPD pattern of the 0.666 mol fraction mixture. This observation would indicate that the strength of the benzamide-benzoic acid supramolecular synthon is less than the strength of the benzoic acid-benzoic acid supramolecular synthon. Extensive formation of the stoichiometric cocrystal phase would appear only to be possible when the mole fraction of benzamide approaches that of benzoic acid, as indicated by the discontinuity in crystal structure observed when the amount of benzamide equaled the amount of benzoic acid. Trends in the DSC thermograms provided additional insight into the nature of the nonstoichiometric products. Every one of the thermograms of nonstoichiometric mixtures contained a sharp, well-defined, endothermic transition at approximately 82 °C that was attributable to melting of the benzamide-benzoic

acid cocrystal component. The thermograms also contained broader endothermic features located at temperatures higher than the melting of the cocrystal, which were attributed to the melting of residual reactant in the nonstoichiometric mixtures. The transition temperatures, as measured by the maxima in melting endothermic events, were used to generate the phase diagram of the benzamide-benzoic acid system that is shown in Figure 8. The phase diagram of the benzamide-benzoic acid system is seen to consist of a single eutectic, where the eutectic composition is that of the 1:1 stoichiometric cocrystal. For this type of phase diagram, all solids maintained at temperatures below the eutectic temperature must necessarily consist of mixtures of a solid having the eutectic composition and a solid consisting of the excess reactant. For the benzamide-benzoic acid system, this means that the nonstoichiometric products will necessarily consist of mixtures of the 1:1 stoichiometric cocrystal and excess benzamide or benzoic acid. This system cannot be a simple conglomerate, even though the phase diagram has the

Figure 6. X-ray powder diffraction patterns obtained for benzamide (blue trace), and the stoichiometric cocrystal with benzoic acid (black trace). Also shown are the patterns for nonstoichiometric cocrystal products, where the mole fraction of benzamide was 0.816 (green trace), 0.751 (magenta trace), and 0.669 (red trace).

Figure 7. X-ray powder diffraction patterns obtained for benzoic acid (blue trace), and the stoichiometric cocrystal with benzamide (black trace). Also shown are the patterns for nonstoichiometric cocrystal products, where the mole fraction of benzoic acid was 0.819 (green trace), 0.749 (magenta trace), and 0.666 (red trace).


Figure 8. Temperature maxima of the melting endothermic transitions observed in the differential scanning calorimetry thermograms of the initial reactants, their stoichiometric and nonstoichiometric mixtures, plotted as a function of the benzoic acid mole fraction. The data points for the cocrystal are shown as solid circles, while the data points for residual reactant are shown as open circles.

Figure 9

appropriate form. A conglomerate system would require the existence of separate crystals of cocrystal and excess reactant, for which the XRPD pattern of any nonstoichiometric mixture would be a simple summation of the XRPD of the cocrystal and the XRPD of the excess reactant. However, since the XRPD patterns of the nonstoichiometric mixtures were not mere superimpositions, it is concluded that the nonstoichiometric solids must consist of solid solutions. Depending on the relative ratios of the initial reactants, these solution solutions could consist either of cocrystal zones in a matrix of excess reactant,


Figure 10. Expanded infrared absorption spectra in the high-frequency region obtained for benzoic acid (blue trace), and the stoichiometric cocrystal with benzamide (black trace). Also shown are the patterns for nonstoichiometric cocrystal products, where the mole fraction of benzoic acid was 0.819 (green trace), 0.749 (magenta trace), and 0.666 (red trace).

Figure 11. Expanded infrared absorption spectra in the high-frequency region obtained for benzamide (blue trace), and the stoichiometric cocrystal with benzoic acid (black trace). Also shown are the patterns for nonstoichiometric cocrystal products, where the mole fraction of benzamide was 0.816 (green trace), 0.751 (magenta trace), and 0.669 (red trace).

or excess reactant zones in matrix of cocrystal. In these mixed solids, the presence of one solid type perturbs the structure of the other. These conclusions are supported by trends in the vibrational spectra of these same materials, with the spectral features of the infrared absorption spectra being the most

2498


Figure 12. Expanded infrared absorption spectra in the carbonyl region obtained for benzoic acid (blue trace), and the stoichiometric cocrystal with benzamide (black trace). Also shown are the patterns for nonstoichiometric cocrystal products, where the mole fraction of benzoic acid was 0.819 (green trace), 0.749 (magenta trace), and 0.666 (red trace).

Brittain

Figure 14. Expanded infrared absorption spectra in the carboxyl deformation region of benzoic acid (blue trace), and the stoichiometric cocrystal with benzamide (black trace). Also shown are the patterns for nonstoichiometric cocrystal products, where the mole fraction of benzoic acid was 0.819 (green trace), 0.749 (magenta trace), and 0.666 (red trace).

with the thermal analysis results that indicated the better ability of excess benzoic to inhibit the cocrystal formation in mixed products. The infrared spectra of the nonstoichiometric products also provide an understanding of the broadened band carbonyl band around 1650 cm-1 that is also diagnostic for the existence of the benzamide-benzoic acid cocrystal. As discussed above, this feature consists of an overlapped combination of the out-ofplane deformation modes associated with each reactant substance. As the spectra in the expanded infrared absorption spectra of Figures 11 and 12 show, the broad feature is derived from separate carbonyl contributions from benzoic acid and from benzamide. In fact, the expanded spectra show the existence of a near-isosbestic point at approximately 1665 cm-1.

Figure 13. Expanded infrared absorption spectra in the carbonyl region obtained for benzamide (blue trace), and the stoichiometric cocrystal with benzoic acid (black trace). Also shown are the patterns for nonstoichiometric cocrystal products, where the mole fraction of benzamide was 0.816 (green trace), 0.751 (magenta trace), and 0.669 (red trace).

useful in this regard. The expanded infrared spectra shown in Figures 9 and 10 for mixtures deficient in benzamide and benzoic acid, respectively, all contain an additional amide -NH2 stretching band that is diagnostic for the benzamidebenzoic acid cocrystal. The intensity of this split band is higher for a given mole fraction of benzamide relative to the equivalent mole fraction of benzoic acid, in agreement

If the carbonyl band of benzoic acid is not strongly affected by the cocrystal formation, then it follows that the main interaction point must be with the -OH group. This is evident in the spectra shown in Figure 13, where the region associated with the carboxyl deformation band in benzoic acid is plotted along with the spectra of the stoichiometric and nonstoichiometric cocrystal products. The spectra indicate a loss of intensity for the carboxyl deformation absorption, and an increase in intensity of the amide-III band contributed by benzamide. Besides contribution from the C-N stretching mode that is not expected to be affected by cocrystal formation, the amide-III band also contains a contribution from the N-H bending mode which would be perturbed by cocrystal formation. In fact, the energy of this band does not change on passing from the stoichiometric cocrystal through the benzamide-rich products, indicating that the band probably becomes entirely C-N stretching in character. In the spectra of these latter products,


the carboxyl deformation band contributed by benzoic acid cannot be observed. Conclusions The existence of a benzamide-benzoic acid cocrystal has been demonstrated in both stoichiometric and nonstoichiometric mixtures through the use of X-ray powder diffraction and thermal analysis. While Raman spectroscopy did not prove to be a useful technique in the characterization of the products, infrared absorption spectroscopy could be used to demonstrate a number of important aspects regarding the nature of the interactions in the cocrystal. The amide -NH2 stretching band derived from benzamide was found to become split in the spectrum of the cocrystal, and this splitting was retained as long as an identifiable cocrystal phase existed in the various mixed solids. Formation of the cocrystal causes broadening in the carbonyl band region around 1650 cm-1 that is also diagnostic for the existence of the benzamide-benzoic acid cocrystal. This feature consists of an overlapped combination of the out-ofplane deformation modes associated with each synthon. This mode of interaction appears to perturb the force constants of the carbonyl groups involved in the interaction nearly as much as the perturbation experienced by the -NH2 group of the amide group. The other main interaction point is with the -OH group, as evidenced by the loss of the benzoic acid carboxyl deformation band in the cocrystal.

References (1) Rodrı´guez-Hornedo, N. Cocrystals: molecular design of pharmaceutical materials. Mol. Pharmaceutics 2007, 4, 299–300. (2) Vishweshwar, P.; McMahon, J. A.; Bis, J. A.; Zaworotko, M. J. Pharmaceutical cocrystals. J. Pharm. Sci. 2006, 95, 499–516. (3) Desiraju, G. R. Crystal and co-crystal. CrystEngComm 2003, 5, 466– 467. (4) Dunitz, J. D. Crystal and co-crystal: a second opinion. CrystEngComm 2003, 5, 506. (5) Bond, A. D. What is a co-crystal. CrystEngComm 2007, 9, 833–834. (6) Zaworotko, M. J. Molecules to crystals, crystals to molecules. . and back again. Cryst. Growth Des. 2007, 7, 4–9. (7) Etter, M. C. Encoding and decoding hydrogen-bond patterns of organic compounds. Acc. Chem. Res. 1990, 23, 120–126. (8) Etter, M. C.; MacDonald, J. C. Graph-set analysis of hydrogen-bond patterns in organic crystals. Acta Crystallogr., Sect. B 1990, 46, 256– 262. (9) Etter, M. C. Hydrogen bonds as design elements in organic chemistry. J. Phys. Chem. 1991, 95, 4601–4610. (10) Aakeroÿ, C. B.; Seddon, K. R. The hydrogen bond and crystal engineering. Chem. Soc. ReV. 1993, 22, 397–407. (11) Aakeroÿ, C. B. Crystal engineering: strategies and architectures. Acta Crystallogr., Sect B 1997, 53, 569–586. (12) Desiraju, G. R. Supramolecular synthons in crystal engineering: a new organic synthesis. Angew. Chem., Int. Ed. 1995, 34, 2311–2327. (13) Leiserowitz, L. Molecular packing modes: carboxylic acids. Acta Crystallogr., Sect. B 1976, 32, 775–802.

Crystal Growth & Design, Vol. 9, No. 5, 2009 2499 (14) Sim, G. A.; Robertson, J. M.; Goodwin, T. H. The crystal and molecular structure of benzoic acid. Acta Crystallogr. 1955, 8, 157– 164. (15) Leiserowitz, L.; Schmidt, G. M. J. Molecular packing modes. Part III. Primary amides. J. Chem. Soc. (A) 1969, 237, 2–2382. (16) Blake, C. C. F.; Small, R. W. H. The crystal structure of benzamide. Acta Crystallogr., Sect. B 1972, 28, 2201–2206. (17) Aakeroÿ, C. B.; Salmon, D. J. Building co-crystals with molecular sense and supramolecular sensibility. CrystEngComm 2005, 7, 439– 448. (18) Leiserowitz, L.; Nader, F. The molecular packing modes and the hydrogen-bonding properties of amide:dicarboxylic acid complexes. Acta Crystallogr., Sect. B 1977, 33, 2719–2733. (19) Reddy, L. S.; Nangia, A.; Lynch, V. M. Phenyl-perfluorophenyl synthon mediated cocrystallization of carboxylic acids and amides. Cryst. Growth Des. 2004, 4, 89–94. (20) Janowski, W.; Gdaniec, M.; Połon´ski, T. The 2:1 cocrystal of benzamide and pentafluorobenzoic acid. Acta Crystallogr., Sect. C 2006, 62, o492-o494. (21) Childs, S. L.; Stahly, G. P.; Park, A. The salt-cocrystals continuum: the influence of crystal structure on ionization state. Mol. Pharmaceutics 2007, 4, 323–338. (22) Pedireddi, V. R.; Jones, W.; Chorlton, A. P.; Docherty, R. Creation of crystalline supramolecular arrays: A comparison of cocrystal formation from solution and by solid-state grinding. Chem. Commun. 1996, 987–988. (23) Shan, N.; Toda, F.; Jones, W. Mechanochemistry and co-crystal formation: effect of solvent on reaction kinetics. Chem. Commun. 2002, 2372–2373. (24) Bellamy, L. J. AdVances in Infrared Group Frequencies; Methuen & Co.: London, 1968. (25) Hadzˇi, D.; Sheppard, N. The infrared absorption bands associated with the COOH and COOD groups in dimeric carboxylic acids. I. The region from 1500 to 500 cm-1. Proc. Royal Soc. London 1953, A216, 247–266. (26) Bratozˇ, S.; Hadzˇi, D.; Sheppard, N. The infrared absorption bands associated with the COOH and COOD groups in dimeric carboxylic acids. II. The region from 3700 to 1500 cm-1. Spectrochim. Acta 1956, 8, 249–261. (27) Gonza´lez-Sańchez, F. Infrared spectra of the benzene carboxylic acids. Spectrochim. Acta 1958, 12, 17–33. (28) Hadzˇi, D.; Pintar, M. The OH in-plane deformation and the C-O stretching frequencies in monomeric carboxylic acids and their association shifts. Spectrochim. Acta 1958, 12, 162–168. (29) Richards, R. E.; Thompson, H. W. Spectroscopic studies of the amide linkage. J. Chem. Soc. 1947, 1248–1259. (30) Kniseley, R. N.; Fassel, V. A.; Farquhar, E. L.; Gray, L. S. Infrared spectra of nitrogen containing compounds: benzamide. Spectrochim. Acta 1962, 18, 1217–1229. (31) Dollish, F. R.; Fateley, W. G.; Bentley, F. F. Characteristic Raman Frequencies of Organic Compounds; John Wiley & Sons: New York, 1974. (32) Kim, Y.; Machida, K. Vibrational spectra, normal vibrations and infrared intensities of six isotopic spectra benzoic acids. Spectrochim. Acta 1986, 42A, 881–889. (33) Pagannone, M.; Fornari, B.; Mattei, G. Molecular structure and orientation of chemisorbed aromatic carboxylic acids: surface enhanced raman spectrum of benzoic acid adsorbed on silver sol. Spectrochim. Acta 1987, 43A, 621–625. (34) Findlay, A. The Phase Rule and its Applications; Dover Publications: New York, 1938; pp 105-108.

CG801397T

Vibrational Spectroscopic Studies of Cocrystals and Salts. 1. The

Recommend Documents