Study of polymorphism in imatinib mesylate: A quantum chemical approach using electronic and vibrational spectra

Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 103 (2013) 325–332

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Study of polymorphism in imatinib mesylate: A quantum chemical approach using electronic and vibrational spectra Anubha Srivastava a, B.D. Joshi a, Poonam Tandon a,⇑, A.P. Ayala b, A.K. Bansal c, Damián Grillo d a

Department of Physics, University of Lucknow, University Road, Lucknow, Uttar Pradesh 226 007, India Departamento de Física, Universidade Federal do Ceará, C.P. 6030, 60.455-900 Fortaleza, CE, Brazil c Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar, Punjab 160 062, India d Departamento Física de la Materia Condensada, Gerencia de Investigación y Aplicaciones, Comisión Nacional de Energía Atómica, Av. Gral. Paz 1499, 1650 San Martín, Buenos Aires, Argentina b

h i g h l i g h t s

g r a p h i c a l a b s t r a c t

" A detailed vibrational spectroscopic

"

"

"

"

investigation of b-form of imatinib mesylate has been presented. These data are supported by quantum mechanical calculations using DFT/B3LYP/6-311G(d,p) method. The vibrational shifts observed due to polymorphic changes have been discussed. UV–vis spectroscopic studies along with HOMO–LUMO analysis of both polymorphs (a and b) were performed. The absorption spectrum has also been calculated in methanol environment using IEF-PCM model.

a r t i c l e

i n f o

Article history: Received 9 May 2012 Received in revised form 18 October 2012 Accepted 25 October 2012 Available online 10 November 2012 Keywords: Imatinib mesylate Polymorphism Raman Infrared UV–vis spectroscopy Quantum mechanical calculations

a b s t r a c t Imatinib mesylate, 4-(4-methyl-piperazin-1-ylmethyl)-N-u[4-methyl-3-(4-pyridin-3-yl)pyrimidine-2ylamino)phenyl]benzamide methanesulfonate is a therapeutic drug that is approved for the treatment of chronic myelogeneous leukemia (CML) and gastrointestinal stromal tumors (GIST). It is known that imatinib mesylate exists in two polymorphic forms a and b. However, b-form is more stable than the a-form. In this work, we present a detailed vibrational spectroscopic investigation of b-form by using FT-IR and FT-Raman spectra. These data are supported by quantum mechanical calculations using DFT employing 6-311G(d,p) basis set, which allow us to characterize completely the vibrational spectra of this compound. The FT-IR spectrum of a-form has also been discussed. The importance of hydrogen-bond formation in the molecular packing arrangements of both forms has been examined with the vibrational shifts observed due to polymorphic changes. The red shift of the NH stretching bands in the infrared spectrum from the computed wavenumber indicates the weakening of the NH bond. The UV–vis spectroscopic studies along with the HOMO–LUMO analysis of both polymorphs (a and b) were performed and their chemical activity has been discussed. The TD-DFT method was used to calculate the electronic absorption spectra in the gas phase as well as in the solvent environment using IEF-PCM model and 631G basis set. Finally, the results obtained complements to the experimental findings. Ó 2012 Elsevier B.V. All rights reserved.

⇑ Corresponding author. Tel.: +91 522 2782653; fax: +91 522 2740840. E-mail addresses: [email protected], [email protected] (P. Tandon). 1386-1425/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.saa.2012.10.066

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Introduction Imatinib is an Abl tyrosine kinase inhibitor of the 2-pheynalamine pyrimidine class that was created using the structure of the adenosine triphosphate (ATP) binding site of the Abl protein kinase. It may also have therapeutic potential for the treatment of diseases that involve platelet-derived growth factor receptor (PDGF-R) activation [1–3]. Imatinib mesylate (ImM) is an anti-cancer agent that inhibits the Bcr–Abl tyrosine kinase, the constitutive abnormal tyrosine kinase created by Philadelphia chromosome abnormality in chronic myelogeneous leukemia (CML) [4,5] and thus represents the frontline therapy for CML [6]. The chemical structure of ImM (C29 H32 N7 Oþ  CH3 SO 3 ) is shown in Fig. 1 [7]. Imatinib is a milestone in small-molecule drug discovery and molecular targeted therapies [7]. It displays excellent efficacy and minimal side effects in clinical studies with CML patients [8,9]. The efficacy and specificity of ImM has been confirmed and extended by several laboratories [10,11]. Imatinib therapy must be a forerunner of other targeted therapies of the future [12]. As it is well known, that polymorphic forms of a drug substance differ in internal solid-state structure, but not in chemical structure. Various drug regulatory agencies consider different forms of an active substance as the same active substance in case of generic medicinal products. As a generic drug ImM (Imatib) is distributed in the a-polymorphic form, whereas the polymorphic form in the marketed innovator product is the b-form as GleevecÒ [13,14]. Because of better flow properties, the b-form has the advantage over the a-form thus improving its processability. This crystal form has the further advantage of being thermodynamically more stable at temperatures below 140 °C. Finally, the b-form is less hygroscopic than the a-crystal form and thus better for storage purposes [15]. Despite the fact that ImM polymorphism is well known, the electronic structure and vibrational spectra of ImM have not been reported so far. As a result, in this communication, we have discussed the conformational polymorphism of ImM on the basis of the available structural data, infrared spectroscopy, Raman spectroscopy, and quantum mechanical calculations. Vibrational spectroscopic methods are well-established tools for the characterization of active pharmaceutical ingredients (APIs) in the solid state because hydrogen bonding patterns and other ‘‘weak’’ interactions differ among polymorphic forms and the effected functional groups display shifts in the energy of the vibrational modes. Now a days, density functional theory (DFT) [16] calculations are being commonly used in order to obtain accurate normal mode descriptions in terms of the potential energy distributions (PEDs) and also provide a promising cost-effective tool for calculating the effect of hydrogen bonding on vibrational modes of biomolecules [17]. Thus, FT-IR and FT-Raman spectra of b-form were recorded and a detailed interpretation has been done on the basis of the PED. The molecular geometry and vibrational modes associated with the hydrogen bonding interactions of a and b-forms have been identified and discussed in terms of the crystalline structure which could give in-depth information of the structure–property relationships of ImM solid state forms. An approximate assignment of prominent modes of a-form has been proposed on the basis of PEDs of b-form, in order to point out some important differences between them. Polymorphic changes have also been discussed by comparing FT-IR spectra of both the forms.

The UV–vis spectra of both the forms were measured in methanol solution. The solvent effects have been incorporated using timedependent density functional theory (TD-DFT) [18,19] in combination with the integral equation formalism-polarized continuum model (IEF-PCM) [20–22], and the results are in good agreement with the experimental measurements. Experimental details Infrared spectra of ImM were recorded on a Bruker TENSOR 27 FT-IR spectrometer with a spectral resolution of 4 cm1 in the region 400–4000 cm1. KBr pellets of solid samples were prepared from mixtures of 200 mg KBr with 1 mg of sample in a laboratory press. FT-Raman spectra were recorded from the original samples on a Bruker IFS55 EQUINOX spectrometer equipped with a Nd:YAG laser (1064 nm excitation line) and a liquid nitrogen cooled Ge detector in the region 200–3400 cm1. Typical spectra were acquired by accumulating 1024 scans at a spectral resolution of 2 cm1. The absorption spectrum of ImM was recorded in the range 200–800 nm using a Specord 200 UV–vis Spectrophotometer equipped with a 10 mm quartz cell. The UV pattern is taken from a 1  105 M solution of ImM dissolved in methanol solvent. Computational details For meeting the requirements of both accuracy and computing economy, theoretical methods and basis sets should be considered. DFT [16] has proved to be extremely useful in treating electronic structure of molecules. The basis set 6-311G(d,p) augmented by ‘d’ polarization functions on heavy atoms and ‘p’ polarization functions on hydrogen atoms were used [23,24]. Based on these points, the density functional three parameter hybrid model (DFT/B3LYP) [25–27] was adopted to calculate the properties of the studied molecule. All the calculations were performed using the Gaussian 09 program package [28] with the default convergence criteria without any constraint on the geometry [29]. Geometries of the ImM polymorphs were first optimized with full relaxation on the potential energy surfaces, without symmetry constraints and the resultant geometries were used as inputs for further calculations. The optimized structures were compared with experimental results using CHEM3D software by superimposing them and minimizing the root square distance between selected atoms [30]. The normal mode analysis was performed and the PED was calculated along the internal coordinates using localized symmetry [31,32]. For this purpose a complete set of 225 internal coordinates were defined using Pulay’s recommendations [31]. The vibrational assignments of the normal modes were made on the basis of the PED calculated by using the program GAR2PED [33]. Visualization and confirmation of calculated data were done by using the CHEMCRAFT program [34]. Raman and infrared theoretical spectra were calculated using a pure Lorentzian band profile (FWHM = 8 cm1) with our own software. The graphical presentation of the calculated Raman and IR spectra were made using GaussView program [35]. Results and discussion Geometric structure

Fig. 1. Structural formula of ImM.

Geometry optimization calculations of a and b forms were started taking the molecular conformation from the X-ray crystal structure [7] as the initial geometry and by considering ImM polymorphs in two counterparts; imatinib+ and mesylate ions.

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The results of these calculations have been labeled as conformers A and B, respectively. The ground state optimized structure of conformer B is shown in Supporting Fig. S1 (for the atom numbering scheme adopted in this study). The atom numbering scheme in both the conformers are same. Both conformations have relatively different geometries. Total energies obtained for conformers A and B after complete geometry optimizations by an accurate DFT [16] calculations are 2247.1028 and 2247.1020 Hartree, respectively. This refers the formation energy of the conformer, not predicting the packing energy of the polymorphs in the crystal in structure. From these energy differences we can predict that conformer A is slightly more stable than the B one. The crystal structures [7] of a and b forms were compared by superimposing rings R1, R2 and R3 using a least-squares algorithm that minimizes the distances between the corresponding non-hydrogen atoms as shown in Supporting Fig. S2(a). These molecules exhibit quite different conformations. The main conformational differences are associated with the torsions C25AC23AN67AC23, C25AC27AN69AC34 and C38AC40AC45AN71. In the similar way the optimized (A) and experimental (a) [7] conformations were compared as shown in Supporting Fig. S2(b). It is noted that the main difference is in the torsion angle C25AC24AN67AC23. Comparison of the optimized (B) and experimental (b) [7] molecular conformations show that the main conformational differences are evident when inspecting the torsions C25AC27AN69AC34 and C13AC15AC18AC19. Due to the variation in the torsion C25AC27AN69AC34, a small deviation is associated in methylbenzene ring (ring R3) as depicted in Supporting Fig. S2(c). These differences are due to the conformational flexibility of imatinib which is also reflected in the crystal structure of its polymorphs. The optimized and experimental values of the most relevant torsion angles are shown in Supporting Table S1. There are no conformational changes associated with all the rings in both the forms and it may be observed that rings R1, R2 and R3 of conformers A or B are similar to a or b forms, respectively. On the other hand, by superimposing rings R4 and R5, a similar agreement is observed as shown in Supporting Fig. S3(a–c), also confirms that the torsions around the bonds C27AN69 and C24AN67 play a very important role in the conformational polymorphism of ImM. The hydrogen bonding motifs in the two forms are also essentially different due to quite different molecular conformations of the imatinib+ ion and hence molecules in each crystal form are associated with different intramolecular interactions to stabilize their molecular conformation. A comparison of the selective torsion angles of conformers A and B is given in Supporting Table S1. The torsion angles of ±60°, between 0° and ±90°, between 30° and 150° or 30° and 150°, 0° and ±30° or ±150° and 180°, between 0° and ±30° and between 30° and 90° or 30° and 90° are called gauche, syn (s), periplanar (p), clinal, synperiplanar or syn- or cisconformation (sp) and synclinal or gauche or skew (sc), respectively [36,37]. In a-form a weak hydrogen bond is determined by C25AH26  O74, giving a +sp character to C25AC27AN69AC34. In conformer A this torsion is changed to sp character. This interaction is not observed in b-form and this torsion angle exhibits a sc character. However, in conformer B this is observed in +sp character. Whereas, in b-form a weak intramolecular hydrogen bond determined by C16AH17  N65, giving to C16AC15AC18AN65 a +sp character, still in conformer B it is found in sp character. This interaction is not observed in a-form and the torsion angle has +sc character, consequently in conformer A it is found in +sp character. Imatinib and mesylate ions are linked with each other by intermolecular hydrogen bond N72AH73  O5 in the isolated state. However, in crystal packing of both polymorphs chains of dimers are connected via mesylate ion by forming intermolecular hydrogen bonds and these intermolecular interactions are quite different in both polymorphs [7]. These differences in the crystal packing of

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a and b forms may explain why b-form exhibits a lower solubility (and is more stable) than a-form. We are not going in detail of intermolecular hydrogen bonds as we are considering here only an isolated molecule. A comparison of the geometries of the possible hydrogen bonds of conformers A and B in the isolated state with a and b forms in the crystal structure [7] is given in the Supporting Table S2. The intermolecular (between imatinib+ and mesylate ion) and intramolecular distances (as discussed above) of isolated conformers of both the forms show a small shift from the experimental one [7] because the calculations have been actually done on a single molecule in the gaseous state contrary to the experimental values recorded in the solid state and in the presence of intermolecular interactions. Absorption spectra and solvent effect The UV–vis absorption spectrum of ImM (b-form) recorded in methanol solvent is presented in Fig. 2. There are no changes observed in the spectra of both the forms in the solution. It shows two strong transitions at 238 nm and 277 nm. The solvent effect has been calculated using TD-DFT method [18,19] and IEF-PCM model [20–22] employing 6-31G basis. The computed results state that the first excited state originates from the HOMO (highest occupied molecular orbital) to LUMO (lowest unoccupied molecular orbital) transition that corresponds to the kmax absorption band in the UV–vis spectrum. From the calculations in the gas phase as well as in the solvent phase it is assigned that the frontier level HOMO has the molecular orbital number 156 with ‘A’ symmetry and the LUMO has the molecular orbital number 157 with the same ‘A’ symmetry of both the forms. In an attempt to understand the nature of electronic transitions, positions of experimental and calculated absorption peaks (kmax’s), vertical excitation energies, oscillator strengths (f) and assignments of the transitions of the conformers A and B have been calculated and the results are presented in Table 1. In conformer A, the first dipole-allowed transition is calculated at 252 nm (H-7 ? L) in the gas phase with strong oscillator strength of 0.3396. Another strong transition is at 296 nm (H ? L + 2) with oscillator strength of 0.2921. In the case of the methanol environment, strong transitions are observed at 255 nm (H-5 ? L) and 282 nm (H-2 ? L + 1) with strong oscillator strengths of 0.3236 and 0.4144, respectively. In a similar manner for conformer B, the first dipole-allowed transition is calculated at 227 nm (H-7 ? L) in the gas phase with strong oscillator strength of 0.5233. Another strong transition is at 306 nm (H ? L + 2) with oscillator strength of 4.0482. In the case of methanol environment, strong transitions are observed at 230

Fig. 2. UV–vis absorption spectrum of ImM (b-form).

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Table 1 Electronic transitions, absorption peaks kmax (in nm), oscillator strength (f) and assignments of the transitions of conformers A and B. Conformers

Excited state

Experimental (ImM) methanol kmax (nm)

Calculated Gas Phase

Transition type/ assignments

Methanol

kmax (nm)

E (eV)

Oscillator strength (f)

Excitation transition

kmax (nm)

E(eV)

Oscillator strength (f)

Excitation transition

A

1 2

238 277

252 296

4.9120 4.1859

0.3396 0.2921

(H-7 ? L) (H ? L + 2)

255 282

4.8640 4.4034

0.3236 0.4144

(H-5 ? L) (H-2 ? L + 1)

p ? p⁄ p ? p⁄

B

1 2

238 277

227 306

5.4659 4.0482

0.5233 0.2691

(H ? L + 6) (H ? L + 1)

230 300

5.3835 4.1375

0.4156 0.3954

(H-4 ? L + 1) (H ? L + 1)

p ? p⁄ p ? p⁄

nm (H-5 ? L) and 300 nm (H-2 ? L + 1) with strong oscillator strengths of 0.4156 and 0.3954, respectively. The HOMO–LUMO plots (in the gas phase) with frontier orbital gap DE of conformers A and B are shown in Supporting Figs. S4 and S5, respectively. As predicted from the curve the calculated value of DE for conformer A is lower than that of B, therefore, showing higher chemical activity of conformer A than the B one. In the HOMO, the charge density is mainly accumulated on the methylbenzene ring, aminopyrimidine ring, and peptide group fragment. However, in the case of LUMO, more charge density moves to the aminopyrimidine and pyridine rings in both the conformers. Some shifts are observed between the theoretical and experimental values. This shifting is due to the high polarity of methanol and hence there is a high chance of solvent–solute specific interaction. The specific interaction of solvent solute H-bonding causes the absorption to red shift in the kmax. However, it is to be noted that the experimental peaks are closer to the solvent phase rather than gas phase values in almost all the cases. Vibrational assignments The total number of atoms in this molecule is 77; hence, it gives 225 (3n  6) normal modes. The molecular conformation obtained from the crystalline structure, as well as the one yielded by geometry optimization, exhibits no special symmetries, and hence the molecule belongs to the C1 point group. As a consequence, all the 225 fundamental vibrations of the free molecule belong to the A irreducible representation and are both IR and Raman active. The Raman scattering cross section, orj/oX, which are proportional to Raman intensity may be calculated from the Raman scattering amplitude and predicted wavenumbers for each normal mode using the relationship [38,39]:

@ rj ¼ @X

!0  4 1  24 p4 @ m0  mj h h iA Sj hcm 8p2 cmj 45 1  exp kT j

where Sj and mj are the scattering activities and the predicted frequencies (in cm1), respectively, of the jth normal mode, m0 is the Raman exciting frequency (in cm1), and h, c, and k are universal constants. The calculated Raman and infrared intensities are used to convolve each predicted vibrational mode with a Lorentzian line shape (FWHM = 8 cm1) to produce simulated spectra. The wavenumbers of all the observed bands as well as their assignment of conformer B based on the PED calculations are collected in Supporting Table S3, where the contributions are organized according to the main molecular groups of ImM. None of the predicted vibrational spectra has any imaginary wavenumber, implying that the optimized geometry is located at the local lowest point on the potential energy surface. List of some selected prominent and intense modes are given in Table 2 due to the lack of space.

Vibrational wavenumbers It is well known that DFT [16] potential systematically overestimates the vibrational wavenumbers. These discrepancies are corrected either by computing anharmonic corrections explicitly or by introducing a scaled field [40] or by directly scaling the calculated wavenumbers with a proper factor [41]. The vibrational wavenumbers calculated by B3LYP method, have been calibrated by considering systematic errors by the wavenumber linear scaling (WLS) procedure of Yoshida et al. [42] by using the expression [mobs/mcal = (1.0087  0.0000163  mcal) cm1]. The wavenumber-linear scaling method with this relationship predicts vibrational wavenumbers with high accuracy and is applicable to a large number of compounds, except for those where the effect of dispersion forces is significant. A comparison of the wavenumbers calculated with DFT [16] method shows very good agreement with observed values due to the inclusion of electron correlation, approximate treatment of basis set deficiencies and anharmonicity. All the calculated vibrational wavenumbers reported in this study are the scaled values. The observed FT-IR spectra of a-form and simulated theoretical spectra of conformer A are presented in Fig. 3. Also, the observed FTRaman and FT-IR spectra of b-form and simulated theoretical spectra of conformer B are compared in Fig. 4 and Supporting Fig. S6, respectively. Both of simulated spectra are calculated at the B3LYP/6-311G(d,p) level of theory. The intramolecular vibrations of a drug molecule can be affected by changes in molecular conformation and molecular bonding. Although the differences between the two forms are spread out over almost the entire spectral range yet, some of the differences between the two polymorphs can be associated with the distinct hydrogen-bond network and molecular conformations as discussed in ‘Geometric structure’ which explains the wavenumber shifts. Out of the several internal coordinates that may be present in the PED distribution shown in Table 2 (or Supporting Table S3), we have discussed here only the prominent modes that are involved in the hydrogen-bond interactions and also the modes that reflect polymorphic changes in a and b forms.

N-methylpiperazine ring (ring R1) vibrations Piperazine ring contains one CH3 group connected to nitrogen. The CH3 group has several modes associated with it such as symmetric/asymmetric stretches, bends, rocks and torsional modes. Assignments of these modes are summarized in Supporting Table S3. Symmetric stretching of CH3, R1[ms(CH3)] is calculated at 2921 cm1 in conformer B. Asymmetric stretching vibration of CH3, R1[ma(CH3)] is observed at 3010 cm1 in the Raman and at 2991 cm1 in the IR spectra of b-form and calculated at 3000 cm1 in conformer B. Intensity of this mode is weak in both the calculated and observed spectra. Another one is observed at 3015 cm1 in the IR spectra of b-form and occurs at the same

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Table 2 Some prominent and intense theoretical (conformer B) and experimental (b-form) vibrational wavenumbers (in cm1) of ImM. Unscaled DFT

Scaled DFT

Raman

IR

Assignment (%PED)a

3628 3606 3238 3216 3203 3188 3173 3166 3163 3149 3149 3133 3124 3110 3105 3089 3086 3065 3054 3045 3036 3033 2952 2944 2169 1741 1652 1608 1593 1558 1547 1481 1448 1443 1418 1408 1352 1352 1333 1327 1227 1216 1206 1197 1112 1092 1050 1040 998 988 941 939 812 567 555 188 80 30 17 38 25 36

3445 3426 3095 3075 3064 3050 3036 3031 3028 3015 3014 3000 2992 2980 2975 2960 2958 2938 2929 2921 2913 2909 2836 2829 2111 1706 1622 1580 1566 1532 1522 1458 1426 1421 1398 1388 1334 1334 1316 1310 1213 1202 1193 1185 1101 1082 1041 1031 990 981 935 933 809 567 555 189 80 36 17 38 25 36

– – 3104 3071 – 3056 3035 – –

3420 3341 3101 3084 3069 – 3028 – – 3015 3009 2991 2990 – – 2959 2947 2936 2932 – – 2900 2833 2831 – 1657 1620 – 1574 1535 1533 1452 1423 1418 1389 1373 1339 1337 1315 1313 1211 – 1182 1169 1099 1097 1050 1038 – 982 943 922 804 561 550 – – – – – – –

m(N69H)(100) m(N67H)(100) R3[m(CH)](99) R4[m(CH)](96) R2[m(CH)](99) R5[m(CH)](97) R3[m(CH)](99) ma(C1H3)(100) ma(C1H3)(100) R1[ma(CH3)](98) R5[m(CH)](98) R1[ma(CH3)](99) R1[ma(C54H2)](99) R1[ma(C51H2)](99) R3[ma(CH3)](100) R3[ma(CH3)](100) R1[ma(C48H2)(95) ms(C1H3)(100) R1[ms(C51H2) + ms(CH3) + ms(C54H2)(93) R1[ms(CH3) + ms(C51H2) + ms(C54H2)(95) ma(C45H2)(96) R3[ms(CH3)](99) R1[ms(C48H2)](94) ms(C45H2)(94) R1[m(N72H73)](81) + m(O5H)(17) m(C@O)(72) + q(C@O)(7)+m(C34N69)(5) R2[m(CC) + da + din(CH)](87) R2[m(CC) + d0 a](79) R4[m(CC) + m(CN) + din(CH)](39) + R5[m(CC) + din(CH)](22) R3[m(C27N69) + din(CH) + m(CC)](31) + q(N69H)(21) + m(C34N69)(9) + q(N67H)(5) R3[din(CH) + m(CC)](28) + q(N67H)(10) + q(N69H)(7) + R4[m(C23N67)](7)

3010 3000 2998 2979 2965 – 2948 2932 – 2921 2880 2836 2832 – 1656 1609 1571 1555 1536 1534 1451 1426 1424 – 1388 – – 1318 1305 1218 1205 1202 1183 1094 1081 1042 1040 994 977 946 944 803 558 551 190 82 – – – – –

R1[d(C51H2) + d(C54H2) + d0 a(CH3)](91) R5[din(CH) + m(CN) + m(CC)](32) + R4[m(CN) + din(CH)](15) + R1[x(C57H2)](5) R4[din(CH) + m(C23N67) + m(CN)](29) + R5[din(CH) + m(CN)](14) + R3[m(CC)](5) R3[ds(CH3) + m(CC) + din(CH)](38) + R4[din(CH)](15) + q(N67H)(10) R3[ds(CH3) + m(CC)](75) R3[m(CC) + m(C27N69)](42) + ds(C1H3)(24) ds(C1H3)(56) + R3[m(CC)](16) R2[din(CH) + m(CC)](85) R1[c(C57H2) + c(C48H2) + c(C54H2) + c(C51H2) + x(C51H2)](54) R2[m(C40C45) + m(CC) + dtrig + din(CH)](57) + m(S@O)(19) R1[c(C57H2) + q0 (CH3) + c(C48H2) + c(C45H2) + q(CH3) + q(C48H2) + m(CN)](62) R1[q + q0 (CH3) + q(C57H2) + dtrig + m(C45 N) + q(NC60H) + q(C48H2)](54) R2[din(CH) + m(C40C45) + m(CC)](70) R1[m(C60 N) + q0 (CH3) + m(C45 N) + q(C54H2) + q(C51H2) + m(CN)](58) m(S@O)(53) + R1[q(C57H2) + m(N72H73) + q(C54H2)](13) + m(SO)(11) + q0 (C1H3)(5) R1[q(C48H2) + m(CN) + q(C57H2) + q(CH3) + m(CC) + q(C54H2)](76) R5[dtrig + m(CC)](82) R4[oop(CH)](80) q0 + q(C1H3)(53) + m(S@O)(15) + m(SO)(11) m(SO)(63) + (q0 + q)(C1H3)(12) R3[oop(CH) + R3[puck](76) R3[oop(CH) + oop(C27N69) + sa](74) oop[(N69H)](29) + s(C34N69)(26) + s(C27N69)(10) + R3[da](6) oop[(N69H)](14) + R3[da](13) + d(C@O)(10) + q(C@O)(6) + s(C34N69)(6) m(O5H)(26) + q(SC)(8) + R1[din(NC45)](7) + R4[sa](5) s(C34C35)(42) + s(C27N69)(14) + s(C40C45)(7) s(C40C45)(30) + s(C27N69)(15) + s(O5S)(13) + d(C45CN)(6) + d(SNO5)(5) s(C24N67)(31) + d(N67H)(8) + s(C27N69)(8) + R1[oop(NC45)](5) + d(C45CN)(5) s(C15C18)(30) + s(N72O5)(13) + s(O5S)(7) + s(C23N67)(5) s(C23N67)(26) + s(C15C18)(22) + oop(N67H)(20) s(C40C45)(30) + s(C27N69)(15) + s(O5S)(13) + d(C45CN)(6) + d(SNO5)(5)

Proposed assignments and potential energy distribution (PED) for vibrational normal modes. Types of vibration: m, stretching; d, deformation (bending), scissoring; oop, out-of-plane bending; x, wagging; c, twisting; q, rocking; s, torsion. a Potential energy distribution (contribution P 5).

wavenumber in conformer B. The stretching vibrations of methylene groups are located as a very complex band spread over the 2800–3000 cm1 region. The asymmetric stretching vibration of C57H2 appears at 2949 cm1 in conformer B. The symmetric stretching mode of C57H2 is intended at 2859 cm1 in conformer

B and matches well with the Raman and IR wavenumbers of b-form. It is to be noted in the FT-IR spectra of a and b form that no changes observed in ring R1 modes as in crystal structure [7] this ring exhibit a similar conformation in both of these forms.

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Fig. 3. Observed (a-form) and calculated (scaled) IR absorption spectra of conformer A in the region, 3600–2600 and 2000–400 cm1.

Fig. 4. Observed (b-form) and calculated (scaled) Raman scattering spectra of conformer B in the region, 3600–2700 and 1800–200 cm1. (Inset shows Raman spectra in the region 200–40 cm1.)

Benzamide ring (ring R2) vibrations The strong band of NAH stretching extends from 3400 to 3100 cm1, with the centre of the band at 3370 cm1 [43]. Upon hydrogen bonding, the NAH stretching considerably downshifts and broadens [44]. The heteroaromatic structure shows the presence of CAH stretching vibrations in the range 3000–3100 cm1 which is the characteristic region for the ready identification of CAH stretching vibrations [45]. If the CAH bond is adjacent to an aromatic ring, the CAH stretching frequency and absorption between 3100 cm1 and 3000 cm1 can be expected [46]. These modes of NAH and CAH stretching can be seen in Figs. 3 and 4 and Supporting Fig. S6. However, not all the observed bands are associated with fundamental vibrations, since some overtones and combinations of the low energy modes originating in anharmonic effects usually present in this region. The CAH stretches are calculated at 3025 cm1 and 3049 cm1 in conformer B and also at the same values in conformer A. In-plane vibration of CAH of the ring mixed with CAC stretching occur at 1316 cm1 in conformer B and predicted at 1318 cm1 in the Raman and at 1315 cm1 in IR spectra of b-form. Out-of-plane vibration of CAH of the ring highly mixed with asymmetric torsion of the ring and

oop (CC34) mode has been calculated at 870 cm1 in conformer B. It is observed at 871 cm1 in the Raman and at 881 cm1 in the IR spectra of b-form. This mode is calculated at 893 cm1 in conformer A with the remarkable shifting from the conformer B and observed at 887 cm1 in the IR spectrum of a-form. This shifting is associated with the conformational changes around CC34 bond. Methylbenzene ring (ring R3) vibrations The CAH stretching vibrations in ring are usually strong in both the Raman and IR spectra. The CAH wavenumber of the ring is assigned at 3104 cm1 in the Raman and at 3101 cm1 in IR spectra of b-form. It is calculated to be 3095 cm1 in conformer B, and thus coincides well with the observed bands. The asymmetric stretching mode, R3[ma(CH3)] is assigned to the observed peaks at 2965 cm1 in the Raman and at 2959 cm1 in the IR spectra of b-form. The corresponding calculated value is at 2960 cm1 in conformer B. Similarly, symmetric stretching mode, R3[ms(CH3)] of conformer B is calculated at 2909 cm1 and matches well with the observed value of b-form. In conformer A, it is calculated at 2882 cm1. Outof-plane vibration of C27N69 and C24N67 modes are calculated to

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be 607 cm1 in conformer B and coincide well with the observed FTRaman and FT-IR wavenumbers of b-form. Whereas, in conformer A it corresponds to the band at 626 cm1 and matches satisfactorily with the IR wavenumber of a-form. This shifting in both the conformers is attributed to the conformational changes around the torsions C25AC27AN69AC34 and C25AC24AN67AC23. Aminopyrimidine ring (ring R4) vibrations The stretching mode of CN band is calculated at 1308 cm1 in conformer B and assigned to the Raman band at 1302 cm1 and IR band at 1312 cm1 in b-form. It is highly mixed mode. Out-ofplane deformation of CAH mixed with oop(C23N67) mode and asymmetric torsion of the ring R4 is calculated at 704 cm1 in conformer B and corresponds to the peak at the same value in the Raman and at 696 cm1 in the IR spectra of b-form. This mode is calculated at 762 cm1 in conformer A and observed at 773 cm1 in the IR spectrum of a-form. This shifting is also associated with the conformational change about torsion N66AC23AN67AC24. The in - plane deformation of CAH mixed with stretching vibration of m(C23N67) mode appear at 1421 cm1 in conformer B as strong band and matches well with the Raman band at 1424 cm1 and low intense IR band at 1418 cm1 of b-form. Pyridine ring (ring R5) vibrations The CAC stretching mixed with CAN stretching and asymmetric deformation of the ring occur at 1604 cm1 in conformer B and is in good agreement with the observed bands at 1596 cm1 in the Raman and at 1597 cm1 in IR spectra of b-form. Asymmetric deformation of the ring is calculated at 628 cm1 in conformer B corresponding to the observed Raman peak at 624 cm1 of b-form. Asymmetric torsion of the ring is calculated at 413 cm1 in conformer B and assigned to the peak at 416 cm1 in the Raman and at 405 cm1 in the IR spectra of b-form. Another mode of asymmetric torsion corresponds to the peak at 240 cm1 in the Raman spectra of b-form and calculated at 249 cm1 in conformer B. It is to be noted that, there are not many polymorphic changes observed in pyridine ring modes of both the forms. Peptide group vibrations Three NAH groups and one carbonyl group are present in the molecule. The stretching mode of N69AH, m(N69H) is calculated at the wavenumber 3445 cm1 in conformer B corresponding to the observed band at 3420 cm1 in the IR spectrum of b-form. The red shifting of this wavenumber in the FT-IR spectra supports the intermolecular N69AH. . .N64 (N64 in dimer) interaction in crystal structure of b-form [7]. The detection of the red shift in the IR spectrum is regarded as the ‘‘signature’’ of the hydrogen bonding [43]. As expected, this mode is a pure stretching mode, and as evident from the PED column they are almost contributing 100%. The major vibrational spectral effect of the intermolecular amide hydrogen bonding can be found in the NAH stretching mode. The band around 3426 cm1 is contributing to N67AH stretch in conformer B and observed at 3341 cm1 in the IR spectra of b-form. Again this shifting is due to another intermolecular hydrogen bond between N67AH. . .O7 (O7 in dimer) in crystal structure of b-form [7]. These shifting may also be observed while comparing the modes of conformer A with a-form. The stretching vibration of NH+ ion, R1[m(N72H73)] combined with O5H ion is calculated at 2111 cm1 and 2056 cm1 in conformers B and A, respectively, because the wavenumbers of NAH and OAH ions shift to the lower wavenumber values than the free NAH and OAH wavenumber values. The calculated wavenumber at 555 cm1 in conformer B corresponds to the out-of-plane deformation of N69AH assigned at 551 cm1 in the Raman and at 550 cm1 in IR spectra of b-form, whereas it is calculated at 565 cm1 in

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conformer A and assigned to the peak at 555 cm1 in the IR spectrum of a-form. The carbonyl (C@O) stretching wavenumber has been extensively studied by infrared spectroscopy [47]. This multiple bonded group is highly polar and therefore gives rise to an intense infrared absorption band in the region 1700–1800 cm1 [47]. In the present case, one can expect only one C@O stretching vibration corresponding to the C34AO74 mode. The observed medium intense band at 1656 cm1 in the FT-Raman and a most intense infrared absorption at 1657 cm1 in b-form is assigned to C@O stretching vibration, which shows moderate agreement with that obtained with the B3LYP method at 1706 cm1 for conformer B. This shifting is because the carbonyl group is linked with N69AH group via peptide bond and N69AH being involved in intermolecular hydrogen bonding as discussed above. In a similar manner it is found at 1714 cm1 in conformer A and observed at 1661 cm1 in the FTIR spectrum of a-form. This shifting explains the phenomenon of intramolecular hydrogen bonding C25AH26. . .O74 as well as intermolecular hydrogen bonding N69H. . .N66 (N66 in dimer) in crystal structure of a-form [7], as carbonyl group linked with N69 via peptide bond. O3S-CH3 group (mesylate ion) vibrations The stretching mode of SO2 group, m(S@O) is calculated at 1082 cm1 with high intensity in conformer B and coincides well with weak intense IR peak at 1081 cm1 and the Raman peak of same intensity at 1097 cm1 in the b-form. Another high intense stretching band of SO2 group, m(SO) is calculated at 935/926 cm1 in conformer B/A and observed as weak peak at 946/934 cm1 in the FT-IR spectra of b/a form. Deformation motion of O5S@O6, d(O5S@O6) appears at 504 cm1 and assigned to the peak at 502 cm1 in the Raman spectra. A high intense peak of asymmetric deformation of C1H3 is calculated at 1460 cm1 in conformer A and assigned to the low intense peak at 1447 cm1 in the FT-IR spectrum of a-form. Comparison of the observed IR spectra of a and b forms show that the modes of both the forms do not show large deviations except for the modes of the moieties which are involved in hydrogen bonding or associated with conformational changes as discussed above. The stretching vibration of CC34 coupled with m(C34N69) is calculated at 1245 cm1 in conformer B and shifted to 1225 cm1 in b-form. This shifting is because of the conformational changes around these bonds in going from one form to the other. The outof-plane vibration of C27N69 coupled with C24N67 is observed at 600/582 cm1 in the FT-IR spectra of b/a form. It is to be noticed that there are also some torsion angles which differ in both the forms in going from isolated state (conformers A or B) to solid state (a and b forms) except those which are related to conformational changes in the crystal structure. For example, the main torsion which is affected in going from conformer A to a-form is C25AC24AN67AC23 which is calculated at 14 cm1 in conformer A. Similarly, the main torsion angles which have been altered in going from conformer B to b-form are C25AC27AN69AC34 and C13AC15AC18AC19. These are calculated at 36/80 cm1 and 38/25 cm1, respectively in conformer B. In going from a to b-form the main torsion angles which have been changed are N66AC23AN67AC24, C25AC27AN69AC34 and C38AC40AC45AN71. These are calculated at 31/25 cm1, 89/ 80 cm1 and 39/36 cm1 in the conformers A/B, respectively. Our results show that these types of modes (deformations and torsions of the ImM molecule) are expected in the very low wavenumber region, probably below 100 cm1, as shown in Fig. 4 (in inset). The extended spectral range allows us to observe the lattice and skeleton vibrational modes, which are expected to be directly related to the crystal structure. On the other hand, the lattice modes associated with the translations and librations of the whole molecule lie below 50 cm1 and can only be observed by dispersive

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Raman (in a subtractive spectrometer), far-infrared, or terahertz spectroscopy. Conclusions Geometry optimization of a and b forms of ImM resulted in conformers A and B, respectively. Polymorphism in ImM has been studied and it is observed that a and b forms can be distinguished easily due to the differences in their molecular conformation, hydrogen bonding, and unique vibrational peaks. A complete and consistent assignment of the 225 vibrational modes of conformer B were performed both at HF and DFT level of theories and compared with the FT-Raman and FT-IR spectra. We have found the conformational polymorphism in ImM is mainly due to the rotation around the bond C27AN69. In particular, the capability of measuring skeleton and lattice vibrations has played a very important role to study the conformational polymorphism of ImM. Quantum mechanical calculations confirm that the interand intramolecular hydrogen bonding can be associated with the observed conformational changes and also presence of different hydrogen bonds in both the studied forms of ImM affects the vibrational wavenumbers of some characteristic bands. The difference between the observed and scaled wavenumber values of most of the fundamentals of conformer B is quite small. However, the difference between the observed and scaled wavenumber values of the NH and C@O group fundamentals are quite large in both the conformers. It is due to the presence of the hydrogen bonding interactions in the solid state, which is mainly reflected in the IR spectra. The UV–vis spectrum of ImM was measured in methanol solution and a comparison was made with the theoretical results obtained in the gas phase as well as in methanol environment. The HOMO–LUMO transition clearly explicates charge transfer interaction from aminopyrimidine and pyridine rings to the methylbenzene, aminopyrimidine ring and peptide group fragment. Also the lower value of frontier molecular orbital gap of conformer A in comparison to the B one predicts the higher chemical activity of a-form in comparison to the b one. Overall, there is a good correlation between the theoretical and experimental data, notwithstanding that the DFT calculations were based upon isolated molecules in the gas phase. Acknowledgements A.S. thanks CSIR (New Delhi) for financial assistance in the form of a Research Associateship. Also, the financial support from the CNPq and DST under Indo-Brazil project is gratefully acknowledged.

[7] [8] [9]

[10] [11] [12] [13]

[14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28]

[29] [30] [31] [32] [33] [34] [35] [36]

Appendix A. Supplementary material

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Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.saa.2012.10.066.

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