Investigation into tautomeric polymorphism of 2-thiobarbituric acid using experimental vibrational spectroscopy combined with DFT theoretical simulation

Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 204 (2018) 99–104

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Investigation into tautomeric polymorphism of 2-thiobarbituric acid using experimental vibrational spectroscopy combined with DFT theoretical simulation Qiqi Wang a, Jiadan Xue b, Yaguo Wang a, Shunji Jin a, Qi Zhang a, Yong Du a,⁎ a b

Centre for THz Research, China Jiliang University, Hangzhou 310018, China Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou 310018, China

a r t i c l e

i n f o

Article history: Received 4 April 2018 Received in revised form 4 June 2018 Accepted 10 June 2018 Available online 11 June 2018 Keywords: 2-Thiobarbituric acid Tautomeric polymorphism Terahertz time-domain spectroscopy Raman spectroscopy Density functional theory

a b s t r a c t Vibrational modes of 2-thiobarbituric acid (TBA) tautomeric polymorphs (form I, II and IV) were characterized by terahertz time-domain spectroscopy (THz-TDS) and Raman spectral techniques. The experimental results indicate that both vibrational spectroscopy techniques could be used to recognize the above TBA three tautomeric forms clearly. Experimental THz spectral results show that each of TBA tautomeric polymorphs has distinctive fingerprint peaks in the terahertz region. Raman spectra also show similar results about differences of TBA tautomeric polymorphs, but not significant as that of terahertz spectra since Raman-active vibrational modes are mostly from intra-molecular interaction of various functional groups within the specific molecule while that of terahertz region is more sensitive to inter-molecular interaction within crystalline unit cells. In addition, density functional theory (DFT) was used to simulate the optimized structures and vibrational modes of these three TBA tautomeric forms above. The characteristic vibrational modes of TBA polymorphs are assigned comparing the simulated DFT results with experimental vibrational spectra. The results provide fundamental benchmark for the study of pharmaceutical polymorphism based on both Raman and terahertz vibrational spectroscopic techniques combined with theoretical simulations. © 2018 Elsevier B.V. All rights reserved.

1. Introduction Polymorphism of active pharmaceutical ingredients (APIs), which is the ability of APIs to crystallize in two or even more crystalline phases with different crystal structures, has become an important branch in the research of pharmaceutical formulation and development [1–5]. Lots of pharmaceuticals have been reported to have more than one polymorphic form [2, 3]. Polymorphism plays an important role in affecting many of the physical and/or chemical properties of pharmaceutical compounds such as density, solubility, hardness, melting point, bioavailability etc. and consequently could profoundly influence the manufacturing process, long-term stability and also performance of drug products [6–8]. Polymorphic transformations of most drug compounds have been reported to be easily influenced by several factors such as pressure, solvent and heat during APIs manufacturing and storing processes [9, 10]. Consequently, characterization and detection of polymorphs play an essential role in pharmaceutical research and development fields. 2-Thiobarbituric acid (TBA) belongs to a family of materials which act as central nervous system depressants in therapeutic use and ⁎ Corresponding author. E-mail address: [email protected] (Y. Du).

https://doi.org/10.1016/j.saa.2018.06.034 1386-1425/© 2018 Elsevier B.V. All rights reserved.

could be widely used for sedation and hypnosis [11]. In the molecule of TBA, the presence of imino, methylene, carbonyl, hydroxyl group and thione bond allows the existence of various inter-molecular hydrogen bonds and possible tautomers [12]. Calas [13] first used single-crystal X-ray diffraction (SC-XRD) to find out form I (FI). According to Chierotti's research [14, 15], TBA includes several kinds of polymorphs, which are labeled as FII, III and IV meanwhile FI is raw material for commercial available. Chierotti [14] used SC-XRD and solid-state NMR to study FII and FIV polymorphs of TBA. Martin [16] reported that Raman spectroscopy was used to distinguish the different forms (FI, II) of TBA. Recently, Bakalska [17] used TD-DFT calculations and experimental investigation on the mechanism of the photo-induced tautomerism of TBA. As a good model pharmaceutical compound, TBA could be chosen to investigate corresponding different crystal structures due to its typical tautomeric polymorphism. Regarding as the structure, TBA has been shown as the possible tautomeric keto or enol form [15]. The structure of TBA tautomeric keto and enol forms could be shown as isomer A and isomer B in Fig. 1. Some studies suggest that isomer A and isomer B of TBA is the most stable among its all isomers in the gas-phase or in solution [17]. Energy difference between isomer A and isomer B is about 11 kcal/mol in the gasphase, however, the corresponding value is around 2 kcal/mol in the aqueous-phase [18]. Isomer A and isomer B of TBA show important

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Q. Wang et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 204 (2018) 99–104

isomer A (keto)

isomer B (enol)

Fig. 1. Possible positions of hydrogen bond donor and acceptor in keto isomer A and enol isomer B of TBA.

inter-molecular hydrogen bonds from the point of view of the structure (shown in Fig. 1, “↑”represents hydrogen bond donor positions and “↓”indicates the possible positions of the hydrogen bond acceptor). The structure of FI is regarded as isomer A, and the structure of FII is regarded as isomer B, while that of FIV is consisted of hybridization between isomer A and isomer B though hydrogen bonds [14]. The

Fig. 3. Terahertz absorption spectra of TBA FI (a), II (b), IV (c) polymorphs in the range of 0.2–1.6 THz.

structural features of each crystal form were characterized by powdercrystal X-ray diffraction (PXRD). Vibrational spectroscopy has been regarded as a pretty useful tool for APIs solid-state characterization, and its main research objective is focus on functional vibration modes within and between molecules. Among them, Raman spectroscopy is based on light scattering effect and applied in analyzing intra-molecular vibration and rotation information of molecules and structures of materials [19–21]. Meanwhile, the emerging terahertz time-domain spectroscopy (THz-TDS) is pretty sensitive to the weak inter-molecular interactions, skeleton vibration for molecules, and also dipole transitions at low-frequency vibrational region. THz-TDS has advantages of nondestructive and fast detection and has been used to directly investigate the collective vibrations and the whole structure and interactions of chemical materials [22, 23]. In this work, THz-TDS and Raman vibrational spectroscopic techniques were used for the characterization of TBA tautomeric polymorphs named as FI, II and IV. In addition, quantum chemical density functional theory (DFT) calculation was chosen to optimize most possible structures and simulate the vibrational frequencies of TBA tautomeric polymorphs in order to help understand experimental THz and Raman spectral observations. Combined experimental spectroscopic results with DFT simulation calculations, rich information about different molecular structures and also intra- and/or inter-molecular interactions of the TBA tautomeric polymorphs could be obtained successfully.

2. Materials and Methods 2.1. Chemicals and Sample Preparation Raw material, 2-thiobarbituric acid (TBA, characterized as FI) was purchased from Sigma Aldrich (≥98% purity) and used without further purification. FII: TBA raw material (0.25 g) was dissolved and stirred gently until a saturated solution in hot ethanol (20 ml). Then the solution was evaporated slowly at room temperature under a fume hood for around two weeks and then the light yellow solid powder was obtained. Table 1 Chemical compositions and THz characteristic peaks of TBA polymorphs.

Fig. 2. Molecular structures of FI (a), F II (b) and two kinds of possible structures of FIV TBA polymorphs (form a shown in c, and form b shown in d).

TBA polymorphs

Chemical composition

Characteristic peak/THz

FI FII FIV

Isomer A Isomer B Isomer A, isomer B

1.02 0.65, 1.22, 1.40 0.65, 1.02, 1.41

Q. Wang et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 204 (2018) 99–104

101

Fig. 4. Comparisons of THz spectrum between the experimental result (a) of TBA FIV polymorph and theoretical results of form a (b) and form b (c).

FIV:TBA raw material (0.25 g) was dissolved and stirred gently until a saturated solution in hot acetonitrile (20 ml). Then the solution was evaporated slowly at room temperature under a fume hood for around three weeks and obtained white granule. 2.2. Apparatus and Procedure Raman spectra were obtained using Fourier Transform Raman spectrometer Nicolet Raman 960 (Thermo Nicolet, CA, USA) with diode pumped 1064 nm solid-state laser as the near-IR source. Spectra were acquired over 250 scans at 2 cm−1 resolution over the wave-number range 150–3500 cm−1 with a laser operating power 150 mW. Total analysis time per sample was of the order of 3 min intervals. Z2 measurement system (Zomega, NY, USA) was adopted in THzTDS. Femtosecond pulse system (Spectra Physics, USA) was used as excitation light source in the frequency 80 MHz with pulse width 100 fs and center wavelength at 780 nm. The samples were measured at room temperature and the relative humidity of the sample cavity was always kept below 3% by purging nitrogen gas during measurements, in order to reduce the effect about strong absorption of atmospheric water.

Fig. 5. Raman spectra of TBA FI (red line), FII (black line), FIV (blue line) polymorphs ranging from 200 to 900 cm−1 (A) and 900–1800 cm−1 (B). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

2.3. Theoretical Calculations Quantum chemistry theoretical calculations were performs to simulate the structures of TBA polymorphs FI, II and IV by Gaussian 03 software program [24]. DFT geometry optimization was carried out with the B3LYP method [25–27]. Reliability of B3LYP functional in calculations of the ground-state geometries had been widely assessed previously [28].The geometry and vibrational frequencies of all the three TBA tautomeric polymorphs were calculated based on 6-31G(d, p) Table 2 Vibrational modes assignment for THz characteristic peaks of FIV TBA polymorph. No.

Experiment/THz

Theory/THz

Assignment of vibrational modes

a

0.65

0.41 (0.44)

b

1.02

0.47 (0.44) 0.89

c

1.41

1.35

\ \C22H20H21 torsion Isomer A and isomer B molecular out of plane bending \ \C22H20H21 torsion \ \C22H20H21 torsion Isomer A and isomer B molecular out of plane bending \ \C22H20H21 torsion Isomer A and isomer B molecular in plane bending

Fig. 6. Comparisons of Raman spectra between experimental (black line) and simulated (red line) results of TBA FI (A) and FII (B) polymorphs. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

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Q. Wang et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 204 (2018) 99–104 Table 4 Vibrational modes assignment for Raman characteristic peaks of FII TBA polymorph. Mode Theoretical Raman Mode assignment wavenumber/cm−1 wavenumber/cm−1

Fig. 7. Comparisons of Raman spectra between experimental (black line) and simulated (red line) results of TBA FIV polymorph. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

and the calculated wavenumbers were scales with a factor of 0.96 when using the B3LYP method [29]. According to TBA the tautomeric of the keto or enol form, FI is keto form shown in Fig. 2(a) while FII is enol form shown in Fig. 2(b) [14]. Two kinds of possible structures of TBA form IV could be formed as following. Theoretical structure (form a) could be shown in Fig. 2(c), in which the first hydrogen bond is consisted of C6_S13 and H14\\N15, and the second hydrogen bond is consisted of C17_S19 and N2\\H7. Meanwhile, theoretical structure (form b) could be found in Fig. 2(d), where the first hydrogen bond is consisted of N5\\12H and O18_C16, and the second hydrogen bond is consisted of H14\\N15 and C4_O11. 3. Results and Discussion THz spectra results of TBA tautomeric polymorphs FI, II and IV are shown in Fig. 3 and their THz characteristic peaks are shown in Table 1. In this diagram, it could be seen that FI has only one characteristic peaks at 1.02 THz, meanwhile FII has three peaks at around 0.65, 1.22, 1.40 THz and FIV has three absorption bands at 0.65, 1.02, 1.41 THz. From Fig. 2 and Table 1, it can be clearly seen that the absorption peak of FIV is different from the linear superposition of the characteristic peaks of FI and FII. FII has a broad peak at 1.22 THz, while FIV has no peak at this point, thus it is judged that FIV is not a simple physical

ν1

238

–

ν2 ν3 ν4 ν5 ν6 ν7

345 379 435 490 568 597

– 400 448 490 588 600

ν8

701

705

ν9 ν10 ν11

752 892 981

– – 999

ν12 ν13 ν14

1151 1178 1307

1156 1171/1178 1284

ν15 ν16

1361 1433

1373 1430

ν17

1528

1558

ν18

1627

1627

ν19

1735

1720

ρ(S13C6, H7N2, H12N5, O11C4) ρ(O11C4,\ \OH) ω(H12N5, H7N2) Def R Def R ρ(H7N2, O11C4, H10C13) ω(H1O7, H3N5, H2N8, C12H13) ω(H7N2, H3N5, C3H10, O11C4) ρ(C3H10, H12N5) θ(S13C6, N5C4, C3C4) θ(N5C6, N2C6), ρ(H7N2, H3N5, C3H10) ρ(H7N2, H3N5), θ(S13C6) θ(N5C6), δ(H9O8C1, C1C3H10) θ(O8C1), δ(H12N5C4, C3C4H10) ρ(\ \OH, C3H10, H7N2, H3N5) θ(N5C6, N2C6), ρ(H7N2, H3N5, C3H10,\ \OH) Def R, ρ(H7N2, H3N5, C3H10, \ \OH) Def R, θ(N2C1, N2C6, S13C6), ρ(\ \OH, H7N2, C3H10) θ(C1C3), ρ(C3H10, H7N2)

θ-Stretching, ρ-in plane bending vibration, ω-out of plane bending vibration, δ-scissor, τtorsion, Def-deformation.

mixture of F I and FII, and both isomer A and isomer B consists of network of hydrogen bonds. And it indicates that THz spectroscopic technology could be an effective identification of TBA tautomeric polymorphs and also provides obvious fingerprint characteristics for their different solid-state crystalline molecular structures. These apparent differences could be explained reasonably by theoretical calculations which were as effective ways to bridge the observed vibrational modes and molecular structures. In the work, isomer A is used to simulate the structure of FI of TBA, while isomer B is used to simulate that of FII. And two kinds of possible structures of FIV are chosen to be simulated from connecting isomer A with isomer B through hydrogen bonds. The simulated THz spectra provided by DFT calculation are plotted against the experimental THz spectra of FIV shown in Fig. 4 respectively. In Fig. 4, the simulated frequencies of FIV theoretical structure (form a) has characteristic peaks in the position 0.41, 0.47, 0.89 and 1.35 THz,

Table 3 Vibrational modes assignment for Raman characteristic peaks of FI TBA polymorph. Mode

Theoretical wavenumber/cm−1

Experimental wavenumber/cm−1

Mode assignment

ν1 ν2 ν3 ν4 ν5 ν6 ν7 ν8 ν9 ν10 ν11 ν12 ν13 ν14 ν15 ν16 ν17 ν18

249 348 445 542 579 603 634 687 921 1001 1125 1224 1335 1421 1510 1650 1689 1721

– – 450 531 585 606 640 687 933 1010 1151/1168 1220/1239 1350/1376 1431/1450 1539 1645 1680 1717

ρ(S19C17) Def R Def R Def R, ρ(O18C16, O24C23, H14N15, H26N25) Def R, ρ(O18C16, H14N15, H26N25,\ \C22H20H21) ω(H14N15, H26N25, S19C17), τ(C22H20H21) ω(H14N15, H26N25) ρ(H14N15, N15C17, N25C17) Def R ρ(H14N15, H26N25), θ(S19C17) θ(S19C17), ρ(H14N15, H26N25) Def R θ(N25C17, N15C16), τ(H26N25C23, H14N15C16) τ(H14N15, H26N25, N15C16, N25C23) τ(H14N15, H26N25), θ(S19C17) ρ(\ \C22H20H21) θ(O18C16,O24C23), τ(\ \C22H20H21) θ(O18C16,O24C23), ρ(\ \C22H20H21)

θ-Stretching, ρ-in plane bending vibration, ω-out of plane bending vibration, δ-scissor, τ-torsion, Def-deformation.

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which is in a higher agreement with the experimental spectra result, at 0.65, 1.02 and 1.41 THz respectively. The FIV theoretical structure (form b) has a big difference with the experimental result. So, the theoretical structure (form a) is regarded as FIV structure. The result is consistent with single-crystal X-ray diffraction's result [14]. Compared with N\\H…O_C hydrogen bond shown in Fig. 2(d), the N\\H…S\\H hydrogen bond in Fig. 2(c) is likely to appear at inter-molecular interaction [30]. Compared to experimental results, the obvious difference may due to the reason that our calculation are based on the single molecular structure and ignore inter-molecular forces within solid-state crystalline unit cells. Also, the following factors, temperature effect of experiments (room temperature at around 298 K) and simulations (at 0 K), humidity of the ambient environment etc. need to be taken into consideration as well [31–33]. Vibrations of molecules in the terahertz frequency region are mainly due to the deformation vibration, bending vibration and distortion etc., produced by collective vibrational modes contribution [34]. Different vibrations make contributions to these peaks appearing at different positions. Though the dynamic observation of Gaussian-View, the vibrational mode assignments of TBA FIV could be obtained (shown in Table 2). For FIV, the observed characteristic peak at 0.65 THz is produced by the calculation at 0.41 and 0.47 THz, which mainly originates from \\C22H20H21 torsion of isomer A shown in Fig. S1(a). The Table 5 Vibrational modes assignment for Raman characteristic peaks of FIV TBA polymorph. Raman Mode assignment Mode Theoretical wavenumber/cm−1 wavenumber/cm−1 ν1

254

274

ν2 ν3

316 369

– 400

ν4 ν5 ν6 ν7 ν8

442 454 491 507 556

448 463 494 519 584

ν9

575

597

ν10 ν11 ν12

612 639 723

618 648 701

ν13 ν14 ν15

880 948 1010

933 – 1015

ν16

1148

1148

ν17 ν18

1167 1188

1158 1190

ν19 ν20 ν21

1226 1293 1395

1247 1284 1346/1364/1383

ν22

1417

1426

ν23

1463

1485

ν24

1553

1531

ν25

1586

–

ν26

1710

1691

ω(O8H9), δ(N2C613S, N15C17S19), ρ(C4O10, C16O18) ω(N2H7, O8H9) Def R2, θ(C17S19, O18C16C22, O24C23C22) Def R2 Def R1 Def R2, δ(\ \C22H20H21) Def R1, ρ(N2H7, N5H12) Def R2, ρ(C16O18, C23O24), τ(\ \C22H20H21) Def R1, δ(N5C4O16, N2C1O8), ρ(C3H10, N5H12,\ \OH) ω(C1O8, C3H10, C6S13) δ(N15C17N25) ω(N2H7, N5H12, C3H10, C25H26) δ(C3H10) δ(\ \C22H20H21) ρ(N5H12, C3H10, N2H7, H14N15), θ(C17S19) θ(C17S19), ρ(N5H12), τ(C17N25H26) ρ(N5H12, N2H7) τ(\ \C22H20H21), ρ(C3H10, O8H9) Def R1, ρ(N2H7, N5H12, O8H9) τ(C1N2H7,C3H10), θ(C1O8) ρ(N2H7, C3H10, N5H12, H14N15, N25H26, C1O8H9) ρ(N2H7, C3H10, N5H12, C6S13, H14N15, C17S19, N25H26), δ(C17N25H26, \ \C22H20H21) ρ(C3H10, N5H12, N25H26), θ(C1N2, C4O11, N5C6) ρ(N2H7, N5H12, H14N15, N25H26), θ(C17S19) ρ(N2H7, N5H12, H14N15, N25H26) θ(C1C3), ρ(C3H10, N2H7, C1N2), δ(C1N2H7)

θ-Stretching, ρ-in plane bending vibration, ω-out of plane bending vibration, δ-scissor, τtorsion, Def-deformation.

103

Fig. 8. Optimized structure of TBA FIV polymorph based on theoretical simulation (with typical bond lengths depicted on the corresponding side).

observed peak at 1.02 THz is attributed to out of plane bending vibration of isomer A and isomer B and\\C22H20H21 torsion, belong to isomer A shown in Fig. S1(b). The relative broad peak at 1.41 THz is made up of contributions from both in plane bending vibration of isomer A and isomer B and\\C22H20H21 torsion shown in Fig. S1(c). THz spectra and vibrational mode assignments of TBA tautomeric polymorph shows the molecular vibrations involve most of the atoms and even collective vibration of the whole molecule, which are not show in the following Raman spectral result. It has also reflected some advantages of THz spectroscopy in detecting pharmaceutical polymorphs. Raman spectra mainly represent intra-molecular vibrations of pharmaceutical molecules. These vibrations can be often affected by changes in molecular conformation and molecular functional groups. Solid-state Raman scattering spectra of TBA tautomeric polymorphs (FI,II and IV) are shown in Fig. 4. Although the difference is not so significant, some peaks are relatively obvious to be recognized. FI has two strong peaks at 585 and 606 cm−1, while FII has a strong peak at 588 cm−1 with a small sharp peak at 600 cm−1. And FIV has a strong peak at 584 cm−1 with a small peak at 597 cm−1. The other difference of the Raman spectra for FIV have several unique bands at 1190, 1158, 1148 cm−1 and exhibits markedly different from that of FI at 1182, 1168, 1182 cm−1 and of FII at 1156, 1171, 1178 cm−1 (Fig. 5). Theoretical DFT calculations of Raman spectra could reveal the vibrational modes of TBA tautomeric polymorphs, and were shown in Figs. 6 and 7. The characteristic vibration bands of TBA polymorphs are listed in Tables 3, 4 and 5 with band assignments detailedly. The principal differences are related to those functional groups mostly participating in intra-molecular associations within the molecule and these characterized vibrational bands could be chosen for identifying different pharmaceutical polymorphs. Martin et al. [16] used Raman spectroscopy to describe some differences between FI and FII, but vibrational mode assignments are not completed in Martin's work. In this work, several differences in Raman spectra of TBA FI and FII are consistent with those results shown in Martin's work [16]. Meanwhile, the vibrational mode assignments are completely analyzed in this work, and keto/enol isomerization and also possible hydrogen-bond effects between keto/enol

Table 6 Typical changes of characteristic bond lengths of TBA polymorphs FI,II and IV. Chemical bond

N2\ \C6 N5\ \C6 N2\ \H7 C6_S13 N15\ \C17 N25\ \C17 N15\ \H14 C17_S19

Bond length/Å FI

FII

FIV

– – – – 1.377 1.377 1.014 1.665

1.380 1.364 1.012 1.657 – – – –

1.370 1.355 1.024 1.683 1.359 1.371 1.035 1.681

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Q. Wang et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 204 (2018) 99–104

forms are mainly analyzed and combined with the differences of three TBA tautomeric polymorphs. In the region of 400–900 cm−1, the strong peak of TBA FI at 585 cm−1 and the peak of FII at 588 cm−1 have been influenced by in plane bending vibrations of N\\H. As for TBA FIV, the peak shift to 597 cm−1 is mainly caused by deformation of isomer B. At the high wavenumbers, 900–1800 cm−1, the peak in position 1013 cm−1 of FIV in experimental results is mainly caused by stretching modes of C_S and in plane bending vibration of N\\H, both belong to isomer A and in plane bending vibration from N\\H in isomer B. And regarding as the peak at 1426 cm−1 of FIV, this characteristic peak is originated from in plane bending vibrations from N\\H and C_S, both belong to isomer A, and in plane bending vibration from N\\H, belong to isomer B. So it is clear to know that two characteristic peaks at 1013 cm−1 and 1426 cm−1 of FIV appear for the reason of the hydrogen bonding effects between isomer A and isomer B. In the other hand, the change of typical bond lengths is one of the most important factors which can help to understand the corresponding molecular structure. Fig. 8 shows typical bond length changes of TBA FIV based on the DFT optimized structure. And Table 6 reflects the change of characteristic bond lengths of TBA FI, II and IV. By the influence of hydrogen bonds between keto/enol forms, the bonds N15\\H14 and C17_S19 of FI, would increase their bonds from 1.014 Å and 1.665 Å to 1.035 Å and 1.681 Å, while the bonds N2\\H7 of FII increase to 1.024 Å from the original length 1.012 Å upon forming FIV. The three bonds make major contributions to vibrations of peaks in the position 1013 cm−1 and 1426 cm−1. According to the vibrational of peaks assignments and the changing of bond length, it will be more convenient to understand reasons of other peak's appearance and/or disappearance [20]. And other bonds, N15\\C17, N25\\C17 from isomer A (FI) and N5\\C6, N2\\C6 from isomer B (FII) decrease along with formation of FIV. Effects of hydrogen bond lead to the structure change of TBA polymorphs and result in apparent differences shown in the corresponding Raman spectra in Fig. 7. From above spectra analysis, Raman and THz spectroscopy could distinguish TBA tautomeric polymorphs. Combining the Raman and THz spectroscopy together could help to make it better to analyze structures of such pharmaceutical polymorphs and corresponding inter-molecular hydrogen bonding effects. What's more, THz spectroscopy, due to the high sensibility and also clearly reflecting both collective vibrational modes and inter-molecular interaction within crystalline pharmaceutical compounds, has been widely applied in pharmaceutical, chemical, material fields and so on. 4. Conclusions Using Raman and THz spectroscopy, we have recorded the vibrational spectra of TBA tautomeric polymorphs. Both of the two vibrational spectra were simulated by DFT calculation, producing theoretical spectral simulations and vibrational mode assignments for three TBA tautomeric polymorphs. THz-TDS technology is more easily distinguish polymorphs difference, because THz spectra are mainly dependent on the contribution from collective vibrational modes of different crystalline materials. The result offers us the unique means and benchmark to identify and characterize the different polymorphic drugs and verify THz-TDS technology superiority in drug polymorphic detection.

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