Journal of Spectroscopy
Volume 2018 (2018), Article ID 8573014, 12 pages
https://doi.org/10.1155/2018/8573014

Research Article

FT-IR, Laser-Raman, UV-Vis, and NMR Spectroscopic Studies of Antidiabetic Molecule Nateglinide

Tuba Özdemir Öge

Vocational School of Health Services, Bartın University, 74100 Bartın, Turkey

Correspondence should be addressed to Tuba Özdemir Öge; tozdemir@bartin.edu.tr

Received 5 June 2018; Accepted 26 August 2018; Published 24 September 2018

Academic Editor: Rizwan Hasan Khan

Copyright © 2018 Tuba Özdemir Öge. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

The quantum chemical calculations and spectroscopic and theoretical characterizations of nateglinide molecule, a derivative of meglitinide and an oral antidiabetic drug, were performed using FT-IR, Laser-Raman, and NMR chemical shift and UV-Vis analysis methods. The other parameters including geometric structures, optimized geometry, vibrational frequencies, dipole moments, infrared and Raman intensities, and HOMO and LUMO energies of nateglinide molecules were studied using the density functional theory. In addition, the ¹³C and ¹H NMRs were calculated using Gaussian 09 program with the DFT/B3LYP method at the 6-31G + (d, p) basis set. TD-DFT calculations were performed to examine the electronic transitions including orbital energies, absorption wavelengths, oscillator strengths, and excitation energies in methanol. The research was performed to provide detailed spectroscopic information of antidiabetic nateglinide molecule’s monomer conformations.

1. Introduction

Meglitinides (glitinides) are insulin secretagogues, and they stimulate insulin release from pancreas [1–3]. Nateglinide, a derivative of meglitinide, is an oral antidiabetic drug used for the treatment of type II diabetes mellitus. Nateglinide lowers the blood glucose levels by stimulating insulin secretion from the pancreas. The structure name of nateglinide is (−)-N-[(trans-4-isopropylcyclohexane) carbonyl]-D-phenylalanine [4–7]. The chemical formula of nateglinide used in the present study is C₁₉H₂₇NO₃. The CAS and MDL numbers are 105816-04-4 and MFCD00875706, respectively. The molecular weight of nateglinide is 317.42 g/mol. The synonyms of nateglinide are given as Fastic, N-[(trans-4-isopropylcyclohexyl)carbonyl]-D-phenylalanine, Starlix, and Starsis in [8].

Jain et al. carried out a work on spectrophotometric determination of nateglinide in bulk and tablet dosage forms [9]. Babu et al. investigated nateglinide with visible spectrophotometry and spectrophotometric methods [10, 11]. Bruni et al. developed a method for the quantification of the polymorphic purity of nateglinide in mixtures formed by polymorphs H and B [12]. Guardado-Mendoza et al. explained that nateglinide and repaglinide are effective in reducing postprandial glucose excursion and HbA1c levels from 0.8% to 1% in T2DM [13]. Rani et al. described two spectrophotometric methods for the determination of nateglinide [14]. Goyal et al. determined the crystal structure and crystallographic parameters of experimentally crystallized polymorphs of nateglinide. Crystallographic parameters of nateglinide polymorphs were given as Form H, Form B, Form MS, and Form S (space groups are P-1, C2, P-4, and P-42C), and the forms were found to exist in triclinic, monoclinic, tetragonal, and tetragonal, correspondingly [15]. Remko [16] used the methods of theoretical chemistry to elucidate the molecular properties of the hypoglycemic sulfonylureas and glinides (acetohexamide, tolazamide, tolbutamide, chlorpropamide, gliclazide, glimepiride, glipizide, glibenclamide, nateglinide, and repaglinide) which are known as antidiabetic molecules. The geometry and energy of these drugs were computed using the Becke3LYP/6-31G + (d, p) method. Karakaya et al. [17] investigated the vibrational and structural properties of tolazamide molecule. Ozdemir and Gokce studied the glimepiride molecule as a sulfonylurea compound using FT-IR, Raman and NMR spectroscopy, and DFT theory [18].

Few studies have been encountered on investigation of nateglinide molecule, which is effectively used against diabetes mellitus. In this regard, the present research was carried out to perform a detailed theoretical and experimental investigation of nateglinide, which is the active ingredient of an antidiabetic drug commonly prescribed as Starlix, using spectroscopic analyses such as FT-IR, Laser-Raman, UV-Vis, and NMR. In the present study, density functional theory study was theoretically performed to obtain the vibrational wavenumbers, FT-IR, Laser-Raman, and NMR chemical shifts and UV-Vis of nateglinide molecule. The recorded experimental data were supported with the computed parameters using theoretical methods at DFT/B3LYP/6-31G + (d, p) level. The obtained theoretical and experimental results were used to give detailed information of the molecular electronic structure of nateglinide.

2. Experimental and Computational Procedures

Nateglinide was purchased from Sigma-Aldrich Corporation in powder form. The melting point of nateglinide is in the range of 137°C–141°C. The chemical name of nateglinide (NTG) is N-(trans-4-isopropylcyclohexyl carbonyl)-D-phenylalanine. This molecule is almost insoluble in water, and highly soluble in methylene and methanol chloride. It shows polymorphism [19]. The optimized monomer structures of antidiabetic molecule are given in Figure 1. The FT-IR spectrum of nateglinide molecule was recorded within 400–4000 cm⁻¹ region at room temperature, using the potassium bromide (KBr) pellet, on a Fourier-transform infrared spectrometer in the solid phase of the sample as shown in Figure 2. The Laser-Raman spectrum was recorded at room temperature in 100–4000 cm⁻¹ region as shown in Figure 3. The ¹H and ¹³C NMR chemical shift spectra of the compound solved in dimethyl sulfoxide (DMSO-d6) were recorded with TMS as the internal standard using the Premium Compact NMR device at 600 MHz frequency and 14.1 Tesla field power. The chemical shifts were reported at ppm level as given in Figures 4 and 5. The ultraviolet visible spectrum of nateglinide dissolved in methanol was recorded using a UV-Vis spectrophotometer in 200–400 nm range at room temperature as given in Figure 6.

(a)

(b)

Figure 1: The optimized monomer structures of antidiabetic molecule nateglinide: (a) Monomer 1; (b) Monomer 2. Monomer 1: 6-31 + G(d, p); E(RB3LYP) = −1020.83682668 a.u.; dipole moment = 5.1216 debye; Monomer 2: 6–31 + G(d, p); E(RB3LYP) = −1020.83864468 a.u.; dipole moment = 2.3479 debye.

(a)

(b)

Figure 2: The experimental IR spectrum of nateglinide (a) and simulated IR spectra of nateglinide for Monomer 1 and for Monomer 2 (b).

(a)

(b)

Figure 3: The experimental Laser-Raman spectrum of nateglinide (a) and simulated Raman spectra of nateglinide for Monomer 1 and for Monomer 2 (b).

Figure 4: The experimental ¹³C NMR chemical shift spectra of nateglinide.

Figure 5: The experimental ¹H NMR chemical shift spectra of nateglinide.

Figure 6: The experimental UV-Vis analysis of antidiabetic molecule nateglinide in methanol.

B3LYP (Becke, three-parameter, Lee–Yang–Parr) level with 6-31G + (d, p) basis set was used to compute the electronic structure properties of nateglinide molecule [20, 21]. Vibrational wavenumbers, geometric parameters, and molecular properties were calculated using Gaussian 09W software and GaussView5 molecular visualization program on a computer system [22–24]. Veda 4 program was used to compute the potential energy distribution of vibrational wavenumbers as given in Table 1 [25]. The major contributions for the computed electronic wavelengths were obtained by GaussSum 3.0 program as listed in Table 2 [26].

Table 1: The experimental and computed vibrational wavenumbers and vibrational assignments of nateglinide results.

Assignment (PED%)
Molecular formula: C₁₉H₂₇NO₃
Exp. freq. (cm⁻¹)
The computed parameters for Monomer 2

IR
Raman
Freq.
Scaled freq.
IIR
SRaman

νsO₂H₃(100)

3748
3613
78.26
226.52

νsN₅H₆(100)

3639
3508
32.33
56.46

νsC₉H₁₀(17) + νsC₁₁H₁₂(44+ νsC₁₃H₁₄(32)
3289
3285
3206
3091
15.57
292.02

νsC₁₃H₁₄(39) + νsC₁₅H₁₆(10)

3195
3079,98
29.04
42.71

νsC₁₅H₁₆(18)

3186
3071
8.57
107.31

νsC₁₃H₁₄(22) + νsC₁₅H₁₆(67)
3063
3063
3176
3062
3.57
57.71

νsC₇H₈(68) + νsC₉H₁₀(23)
3029

3171
3057
7.64
33.74

νsC₁₈H₁₉(64) + νsC₁₈H₂₀(35)

2937
3044
2934
22.81
112.46

νsC₄₃H₄₄(28) + νsC₄₃H₄₅(32) + νsC₄₃H₄₆(28)
2925

3031
2922
36.09
53.34

νsC₃₃H₃₄(93)
2859
2860
2975
2868
16.76
44.91

νsO₁C₂₃(86)
1711

1811
1746
279.97
16.72

νsO₄C₂₄(83)
1647
1647
1733
1671
224.63
6.75

νsC₉C₇(12) + νsC₁₅C₁₃(26)

1607
1654
1594
4.06
36.96

νsC₁₁C₉(29) + νsC₁₇C₇(22) + δC₁₅C₁₃C₁₁(12)
1541

1633
1574
1.19
8.95

νsN₅C₂₄(19) + δH₆N₅C₂₄(50)
1497

1542
1486
257.57
2.00

δH₈C₇C₉(15) + δH₁₀C₉C₁₁(18) + δH₁₄C₁₃C₁₁(18) + δH₁₆C₁₅C₁₇(16) + δC₁₃C₁₁C₉(10)
1471

1534
1479
10.80
0.38

δH₄₄C₄₃H₄₆(20) + δH₄₆C₄₃H₄₅(15) + δH₄₈C₄₇H₅₀(20) + δH₄₉C₄₇H₄₈(24)

1462
1513
1459
8.37
10.34

δH₃₂C₃₀H₃₁ (29) + δH₃₇C₃₅H₃₆ (31)

1440
1490
1436
0.69
8.01

δH₁₂C₁₁C₉ (18) + δH₂₀C₁₈H₁₉ (25)
1424

1487
1433
7.34
4.42

δH₄₄C₄₃H₄₆(13) + δH₄₅C₄₃H₄₄(10) + δH₄₈C₄₇H₅₀(17) + δH₄₉C₄₇H₄₈(15) + δH₅₀C₄₇H₄₉(15)
1388

1430
1379
9.88
0.76

δH₃₄C₃₃H₃₅(11) + δH₄₅C₄₃H₄₄(11) + δH₄₆C₄₃H₄₅(13)
1367

1411
1360
8.04
0.36

νsO₂C₂₃(12) + νsO₂₃C₂₁(10) + δH₂₂C₂₁C₂₃(23)
1339
1339
1391
1341
138.92
6.34

νsC₉C₇(11) + νsC₁₃C₁₁(13) + νsC₁₅C₁₃(12)+ δH₈C₇C₉(16) + δH₁₂C₁₁C₉(10) + δH₁₆C₁₅C₁₇(19)

1311
1361
1312
1.08
2.19

δH₃O₂C₂₃(15) + τH₂₀C₁₈C₁₇C₁₅(24) + τH₂₂C₂₁C₂₃O₂(17)
1290

1339
1291
12.17
6.90

δH₂₆C₂₅C₃₈(23)

1268
1314
1267
2.01
1.47

δH₃O₂C₂₃(13) + δH₂₂C₂₁C₂₃(28)
1243
1243
1276
1230
11.37
6.35

δH₂₂C₂₁C₂₃(10)
1213
1210
1260
1215
35.96
7.82

δH₆N₅C₂₄(11) + δH₁₉C₁₈C₁₇(17) + τH₂₂C₂₁C₂₃O₂(13)
1187
1182
1224
1180
10.33
12.41

νsC₁₅C₁₃(11) + δH₈C₇C₉(17) + δH₁₀C₉C₁₁(16) + δH₁₄C₁₃C₁₁(21) + δH₁₆C₁₅C₁₇(17)+
1157
1155
1207
1164
0.71
3.24

νsO₂C₂₃(18) + νsN₅C₂₁(35)
1113

1131
1090
150.02
7.17

νsC₉C₇(19) + νsC₁₅C₁₃(16) + δH₈C₇C₉(10) + δH₁₂C₁₁C₉(12)
1081
1080
1110
1070
6.74
4.44

νsC₂₇C₂₅(15) + νsC₃₀C₂₇(11) + νsC₃₈C₃₅(11)
1034
1037
1089
1050
1.62
3.31

νsC₃₈C₃₅(20)
1003
1003
1038
1001
2.60
14.97

τH₁₀C₉C₁₁C₁₃(16) + τH₁₂C₁₁C₉C₇(31) + τH₁₄C₁₃C₁₁C₉(26) + τH₁₆C₁₅C₁₇C₁₈(10)
962

1001
965
0.10
0.23

τH₈C₇C₉C₁₁(14) + τH₁₀C₉C₁₁C₁₃(25) + τH₁₄C₁₃C₁₁C₉(18) + τH₁₆C₁₅C₁₇C₁₈(18)

948
981
946
0.53
0.73

νsC₄₇C₄₁(10) + τH₄₉C₄₇C₄₁C₃₃(10)
933

966
931
4.13
6.27

τH₁₆C₁₅C₁₇C₁₈(10)
914
911
942
908
14.03
1.89

τH₈C₇C₉C₁₁(11) + τH₁₂C₁₁C₉C₇(13) + τH₁₆C₁₅C₁₇C₁₈(10)
884
880
918
885
0.46
3.67

τH₈C₇C₉C₁₁(26) + τH₁₀C₉C₁₁C₁₃(23) + τH₁₄C₁₃C₁₁C₉(24) + τH₁₆C₁₅C₁₇C₁₈(26)
825

856
825
0.33
0.73

δC₁₃C₁₁C₉(23)
794
790
831
801
1.83
3.28

τC₁₇C₇C₉C₁₁(10)
752
754
766
738
34.94
2.67

τO₄C₂₅N₅C₂₄(25) + τO₁C₂₁O₂C₂₃(10)
721
720
757
730
9.88
1.25

νsC₂₁C₁₈(10) + δC₁₃C₁₁C₉(10) + τO₁C₂₁O₂C₂₃(36)
698

733
707
13.36
10.82

τH₈C₇C₉C₁₁(13) + τC₁₃C₁₁C₉C₇(13) + τC₁₅C₁₃C₁₁C₉(19) + τC₁₇C₇C₉C₁₁(22)
677

709
683
39.63
0.27

δO₁C₂₃O₂(41)
577
625
655
631
29.30
8.83

δC₁₇C₇C₉(11)
557

580
559
8.75
2.77

γC₄₁C₃₀C₃₅C₃₃(12)
458
458
472
455
7.50
2.39

δN₅C₂₁C₁₈(10)
424

444
428
2.74
0.98

τH₈C₇C₉C₁₁(12) + τC₁₃C₁₁C₉C₇(19) + τC₁₅C₁₃C₁₁C₉(36)

406
414
399
0.11
0.03

δO₂C₂₃C₂₁(14)

261
286
276
5.95
0.70

τC₃₈C₃₅C₃₃C₃₀(12)

227
241
232
1.00
0.31

s, symmetric; as, asymmetric; ν, stretching; δ, in-plane bending; τ, torsion; γ, out-of-plane bending; ds, scissoring and symmetric bending; ρ, rocking; t, twisting; , wagging; IIR, IR intensity (km/mol); SRaman, Raman scattering activity; PED, potential energy distribution; W, wavenumber (cm⁻¹); T, transmittance (%). R²=0.9981 for Monomer 1 and R²=0.9980 for Monomer 2 for IR wavenumbers.

Table 2: The experimental and computed UV-Vis parameters and electronic transitions in methanol of nateglinide.

The experimental parameters
Calculated parameter for Monomer 2
The calculated parameters for Monomer 1 (td = (nstates = 6) B3LYP/6–31 + G(d, p) scrf = (cpcm,solvent = methanol) maxdis k  = 22 GB geom = connectivity)

 (nm)
Transitions
 (nm)
 (nm)
Excitation energy (eV)
Oscillator strength
Major contributions [31]

 ⟶ 
236.49
236.51
5.2421
0.0046
H-1->LUMO (35%), HOMO->L + 1 (41%) H-2->LUMO (3%), H-1->L + 1 (4%), H-1->L + 2 (5%), HOMO->LUMO (9%)

 ⟶ 
228.64
228.14
5.4345
0.0144
H-3->LUMO (50%), H-3->L + 2 (18%) H-7->LUMO (2%), H-7->L + 2 (2%), H-6->LUMO (3%), H-6->L + 2 (3%), H-1->LUMO (4%), HOMO->LUMO (7%)

 ⟶ 
219.7
221.79
5.5902
0.0065
H-2->L + 2 (25%), H-2->L + 4 (39%) H-2->LUMO (3%), H-2->L + 3 (5%), H-2->L + 5 (6%), H-1->L + 2 (4%), H-1->L + 4 (5%)

 ⟶ 
216.37
219.16
5.6571
0.0741
HOMO->LUMO (66%) H-3->LUMO (6%), H-2->LUMO (6%), H-2->L+ 4 (2%), H-1->L + 1 (5%), HOMO->L+ 1 (6%), HOMO->L + 2 (3%)

212
 ⟶ 
212.63
216.85
5.7175
0.0120
H-2->LUMO (67%), H-1->LUMO (12%) H-3->LUMO (6%), H-2->L + 4 (5%), HOMO->LUMO (2%)

 ⟶ 
210.78
207.28
5.9814
0.0257
H-1->LUMO (13%), H-1->L + 1 (18%), HOMO->L + 2 (50%) H-2->LUMO (4%), H-1->L + 2 (6%)

3. Results and Discussion

3.1. Geometric Structure

The experimental data explain the crystallographic structure of nateglinide [27], and these findings were compared with the calculated results as given in Table 3. The other geometric parameters such as bond lengths, bond angles, and torsion angles with the corresponding literature information are given in Table 3. Zero-point, relative energy values, and dipole moments are given in Table 4. Tessler and Goldberg investigated bis(nateglinide) hydronium chloride, in addition to its self-assembly into extended polymeric arrays with O-H⋯O, N-H⋯Cl, and O-H⋯Cl hydrogen bonds. The title compound contains four dissimilar moieties which are conformationally different in the asymmetric unit [27].

Table 3: The optimized molecular geometric parameters of nateglinide.

Bond lengths (Å)
X-ray [27]
Values
Bond lengths (Å)
X-ray [27]
Values
Bond angles (°)
Values
X-ray [27]
Bond angles (°)
Values
X-ray [27]

C11-C13
1.352
1.398
C24-C25
1.495
1.530
C11-C13-H14
120.102
119.116
C25-C38-C35
111.408
110.700

C13-C15
1.413
1.395
C25-C38
1.537
1.546
C15-C13-H14
119.705
119.160
C38-C35-C33
112.186
112.617

C9-C11
1.360
1.396
C35-C38
1.524
1.537
C9-C11-H12
120.254
120.606
C35-C33-C30
109.752
110.312

C7-C9
1.404
1.398
C33-C35
1.527
1.542
C13-C11-H12
120.199
120.467
C33-C30-C27
112.163
112.776

C7-C17
1.374
1.401
C33-C30
1.522
1.542
C13-C15-H16
119.437
120.306
H28-C27-H29
107.285
108.188

C15-C17
1.392
1.403
C27-C30
1.527
1.539
C11-C9-H10
120.189
119.550
C27-C25-H26
108.092
106.800

C17-C18
1.524
1.514
C25-C27
1.532
1.539
C17-C15-H16
119.745
120.288
H39-C38-H40
107.036
108.165

C18-C21
1.526
1.558
C33-C41
1.542
1.554
C7-C9-H10
119.774
119.650
C35-C33-H34
106.915
106.334

C21-C23
1.522
1.525
C41-C47
1.493
1.539
C17-C7-H8
119.457
119.513
H37-C35-H36
106.559
107.896

C23=O1
1.231
1.213
C41-C43
1.543
1.539
C17-C18-H20
110.141
108.536
H31-C30-H32
106.523
107.730

C23=O2
1.308
1.353
C24=O4
1.252
1.230
C17-C18-H19
109.619
108.510
C33-C41-H42
105.779
106.849

O2-H3
0.909
0.973
N5-H6
0.927
1.010
C21-C18-H19
108.662
108.488
H44-C43-H45
107.793
109.495

C21-N5
1.460
1.447
C24=N5
1.332
1.372
C21-C18-H20
107.531
108.534
C41-C43-H46
110.750
109.459

Dihedral angles (°)

C23-C21-H22
108.860
107.886
H42-C41-C47
107.149
106.767

H10-C9-C7-C17
179.820
179.844

N5-C21-H22
106.696
107.947
C41-C47-H50
111.618
109.518

H10-C9-C11-C13
−179.816
178.624

C24-N5-H6
119.107
121.393
H49-C47-H48
107.337
109.401

H16-C15-C13-C11
−179.772
178.229

C23-O2-H3
107.493
106.777
C25-C24-O4
120.642
121.732

C9-C7-C17-C18
−179.489
−179.882

O4-C24-N5
121.982
119.602
C24-C25-C27
117.171
116.594

C21-C23-O2-H3
−177.502
178.064

O1-C23-O2
122.883
124.478
C24-C25-C38
109.582
109.451

C21-N5-C24-C25
−174.757
−170.842

N5-C24-C25
117.375
118.654
C25-C27-C30
110.933
109.665

C25-C38-C35-H36
−65.703
−65.679

[27] L. Tessler, I. Goldberg., bis(nateglinide) hydronium chloride, and its unique self-assembly into extended polymeric arrays via O-H⋯O, N-H⋯Cl, and O-H⋯Cl hydrogen bonds. Acta Cryst. C61 (2005) 738–740.

Table 4: Zero point, relative energy and dipole moment of nateglinide.

Conformers
Zero-point energy (Hartree/particle)
Relative energy (kcal/mole)
Dipole moment (debye)

Monomer 1
−1020.402782
0.99582
5.1216

Monomer 2
−1020.404370
2.3479

The C-C bond lengths of the title molecule were calculated at the interval of 1.395–1.558 Å, while they were recorded between 1.352 and 1.543 Å in the literature [27]. The C-N bond lengths of the title molecule were calculated at 1.447 Å and 1.372 Å, while they were recorded at 1.460 Å and 1.332 in the literature [27]. In this research, the C-H bond lengths of the title molecule were calculated at the interval of 1.086–1.103 Å. The calculated C11-C13, C13-C15, C9-C11, C7-C9, C7-C17, C15-C17, C17-C18, C18-C21, C21-C23, C24-C25, C25-C38, C35-C38, C33-C35, C33-C30, C27-C30, C25-C27, C33-C41, C41-C47, and C41-C43 bond lengths for nateglinide are 1.398 Å, 1.395 Å, 1.396 Å, 1.398 Å, 1.401 Å, 1.403 Å, 1.514 Å, 1.558 Å, 1.525 Å, 1.530 Å, 1.546 Å, 1.537 Å, 1.542 Å, 1.542 Å, 1.539 Å, 1.539 Å, 1.554 Å, 1.539 Å, and 1.539 Å, respectively. The calculated bond angles of C24-C25-C27, C24-C25-C38, C25-C27-C30, C25-C38-C35, C38-C35-C33, C35-C33-C30, and C33-C30-C27 are 117.171°, 109.582°, 110.933°, 111.408°, 112.186°, 109.752°, and 112.163°, respectively, in this study. The calculated dihedral angle of C9-C7-C17-C18 is −179.489°.

Jain et al. studied the monomers, dimers, and tetramers of nateglinide to understand the conformational properties. Nateglinide molecule contains two strong hydrogen bond donors as N–H/O–H and two strong acceptors as 2 × C = O [28]. As in the present research, two conformations come into prominence, namely, N-A and N-C. These two differ from others by the relative position of hydrogen in the carboxylic group and by torsional angle across C2–C3–N4–C5 (−169.17° in N-A and −118.57° in N-C). Likewise, the torsional angles of Monomer 1 and Monomer 2 were calculated −169.15007° and −120.87747°, respectively, in the present research.

3.2. Vibrational Frequency Analyses

In the following discussion, nateglinide is experimentally examined using FT-IR, Laser-Raman, UV-Vis spectroscopy, and NMR. The observed and calculated vibrational frequencies, observed and calculated FT-IR intensities, Raman scattering activities, and vibrational assignments of the title molecule are given in Table 1. Nateglinide consists of 50 atoms, and accordingly, it has 144 modes of vibrations according to the relation 3N-6 (for N = 50). In the present research, C-H, C-O, O-H, N-H, and C-C vibrations were examined. As shown in Figures 2 and 3 and Table 1, the experimental and calculated vibrational wavenumbers are in good agreement.

The computations of harmonic wavenumbers, IR intensities, and Raman activities were performed with the DFT/B3LYP/6-31G + (d, p) level. Scaling factors were used for theoretical vibrational wavenumbers. The computed vibrational wavenumbers were scaled as 0.964 for frequencies at the B3LYP/6-31G + (d, p) basis set [29]. The experimental and simulated IR and Raman spectra of the title compound are given in Figures 2 and 3, respectively.

The characteristic bond of nateglinide was observed at 1647 cm⁻¹ with–C=O functional group, 1715 cm⁻¹ with –COOH functional group, 2859–3064 cm⁻¹ with –CH2 functional group, and 3308 cm⁻¹ with –NH functional group [30]. The C=O peak was observed at 1650 cm⁻¹ with an intensity of 333.887 D (10–40 esu²·cm²) [31]. The C=O stretching vibration of nateglinide was observed at 1711 (IR), 1647 (IR)−1647 (R) cm⁻¹, and 1339 (IR)–1339 (R), and the computed scaled wavenumber values for this band were obtained at 1746 cm⁻¹, 1671 cm⁻¹, and 1341 cm⁻¹.

NH stretching peaks appear at 3585.48 cm⁻¹ and 3710.51 cm⁻¹ [31]. In the present case, NH stretching modes are calculated at 3508 cm⁻¹.

The peaks at 2921.26 cm⁻¹–3147.88 cm⁻¹ range have the highest intensity of 122.03 D (10⁻⁴⁰ esu²·cm²) due to C-H (aromatic) single stretching and OH sharp peak for the infrared spectrum. There is strong symmetric stretching between carbon and hydrogen (νCH) at 2800–3000 cm⁻¹ frequency range for the Raman spectrum [31]. The C-H aromatic stretching vibration and C-H aliphatic stretching vibrations are at 3074 cm⁻¹, 2933 cm⁻¹, and 2860.88 cm⁻¹ [32]. The C-H stretching bands in molecule were observed at 3289, 3063 cm⁻¹, 3029 cm⁻¹, 2925 cm⁻¹, and 2859 cm⁻¹ in the FT-IR spectrum and at 3285 cm⁻¹, 3063 cm⁻¹, 2937 cm⁻¹, and 2860 cm⁻¹ in the Laser-Raman spectrum. These bands were computed at 3091 cm⁻¹, 3079.98 cm⁻¹, 3071 cm⁻¹, 3062 cm⁻¹, 3057 cm⁻¹, 2934 cm⁻¹, 2922 cm⁻¹, and 2868 cm⁻¹ in our calculations.

The O-H stretching band in the title molecule was computed at 3613 cm⁻¹ in the FT-IR spectrum. The OH in-plane bending vibrations (δHOC) were experimentally obtained at 1290 cm⁻¹ (IR) (cal. with 15% contribution of PED) and 1243(IR)–1243(R) (cal. with 13% contribution of PED) cm⁻¹. The OH in-plane bending vibrations (δHOC) were calculated at 1291 cm⁻¹ (IR) and 1230 cm⁻¹ (IR). The OH out-of-plane bending mode (τHOCC) was observed at 1290 cm⁻¹ (IR) and 1187 cm⁻¹ (IR)–1182 cm⁻¹ (R), whereas it was computed at 1291 cm⁻¹ and 1180 cm⁻¹ with 17% and 13% contribution of PED, respectively.

3.3. ¹H and ¹³C NMR Chemical Shift Analyses

The experimental shielding ranges for ¹H NMR and ¹³C NMR are given as 0–13 ppm and 0–180  ppm, respectively. ¹H and ¹³C NMR chemical shift calculated with gauge-including atomic orbital (GIAO) approach using Gaussian 09 software shows good agreement with the experimental chemical shift. Figures 4 and 5 show the experimental ¹H and ¹³C NMR chemical shift spectra of nateglinide. The experimental ¹H and ¹³C chemical shift values measured in DMSO-d₆ solvent and the chemical shift values calculated at the DFT/B3LYP/6-31G + (d, p) level in DMSO solvent are shown in Tables 5 and 6.

Table 5: The experimental and computed ¹H NMR isotropic chemical shifts (with respect to TMS, all values in ppm) of nateglinide.

(in DMSO-d₆)
Monomer 1 (in DMSO)
Monomer 2 (in DMSO)
(in DMSO-d₆)
Manomer 1 (in DMSO)
Manomer 2 (in DMSO)

12.58

1.76
1.78-H42
1.88-H37

8.16-H8
8.09-H16
1.68
1.67-H31
1.83-H26

8.07-H10
7.89-H10
1.66
1.67-H28
1.65-H32

7.93–7.92
7.95-H14
7.84-H14
1.63
1.61-H34
1.55-H29

7.24–7.36
7.83-H12
7.78-H12
1.51
1.54-H29
1.51-H34

7.15–7.19
7.80-H16
7.70-H8

1.50-H32
1.50-H31

7.05–7.10
6.92-H3
7.10-H3

1.49-H39
1.31-H39

6.16-H6
6.20-H6
1.35
1.35-H37
1.23-H44

4.36–4.49
4.55-H22
5.76-H22

1.25-H44
1.23-H36

3.01–3.15
3.48-H19
3.71-H20

1.19-H46
1.21-H49

2.80–2.84
2.93-H20
2.67-H19

1.13-H49
1.19-H46

2.59
2.17-H26
2.05-H40

1.10-H45
1.08-H45

2.00–2.02
2.15-H40
1.94-H42
0.91, 0.87
0.86-H48
0.96-H48

1.97-H36
1.88-H28
0.69, 0.70
0.81-H50
0.81-H50

R² = 0.9932 and RMSD = 0.237831578 ppm for Monomer 1 and R² = 0.9709 and RMSD = 0.403748 ppm for Monomer 2.

Table 6: The experimental and computed ¹³C NMR isotropic chemical shifts (with respect to TMS, all values in ppm) of nateglinide.

(in DMSO-d₆)
Monomer 1 (in DMSO)
Monomer 2 (in DMSO)
(in DMSO-d₆)
(in DMSO)
Monomer 2 (in DMSO)

175.54
163.551-C24
161.592-C23
43.27, 44.25
39.6492-C25
39.5256-C25

173.68
161.646-C23
161.179-C24
37.15
36.5275-C33
36.7221-C33

138.23
124.208-C17
124.354-C17
32.76
30.134-C18
33.2255-C18

129.53
115.937-C9
116.639-C7
29.63
27.5208-C41
27.5424-C41

128.48
115.795-C15
115.406-C15
29.48
25.2552-C38
25.943-C38

126.73
115.334-C13
114.909-C9
28.98
24.9742-C30
24.3689-C30

114.87-C7
114.799-C13
20.07
21.5326-C27
21.083-C27

113.289-C11
112.649-C11

18.302-C35
17.7894-C35

53.47
50.3871-C21
44.1719-C21

12.926-C43
13.0837-C43

7.0408-C47
6.1516-C47

R² = 0.9985 and RMSD = 8.615417071 ppm for Monomer 1 and R² = 0.9981 and RMSD = 9.136034 ppm for Monomer 2.

¹H chemical shift values for Monomer 1 were computed at the intervals of 0.8078–8.1579 ppm in DMSO. ¹H chemical shift values for Monomer 2 were computed at the intervals of 0.8144–8.089 ppm in DMSO. The experimental chemical shifts of ¹H are measured in the range of 0.69–12.58 ppm. The largest deviation between the calculated and experimental ¹H NMR chemical shifts (δexp–δcal.) was obtained for H16 with 0.6135 ppm, whereas the smallest deviation was found for H37 with 0.0009 ppm for Monomer 1. The largest deviation between the calculated and experimental ¹H NMR chemical shifts (δexp–δcal.) was obtained for H22 with 1.4 ppm, whereas the smallest deviation was found for H34 with 0.0028 ppm for Monomer 2.

The ¹³C chemical shifts for Monomer 1 were calculated in the range of 7.0408–163.551 ppm in DMSO ppm, and the ¹³C chemical shifts for Monomer 2 were calculated in the range of 6.1516–161.592 ppm, while they were experimentally recorded in the range of 20.07–175.54 ppm. The largest deviation between the calculated and experimental ¹³C NMR chemical shifts (dexp–dcal.) was obtained for C17 with 14.022 ppm, whereas the smallest deviation was found for C33 with 0.6225 ppm for Monomer 1. The largest deviation between the calculated and experimental ¹³C NMR chemical shifts (dexp–dcal.) was obtained for C23 with 13.948 ppm, whereas the smallest deviation was found for C33 with 0.4279 ppm for Monomer 2.

3.4. UV-Vis Analyses

The obtained and simulated UV-Vis spectrum of nateglinide dissolved in methanol was recorded in the region of 190–350 nm. UV-Vis calculation was performed in methanol using the TD-DFT method with Gaussian 09W software and GaussView5 molecular visualization program. The measured and simulated UV-Vis electronic absorption spectra are given in Figures 6 and 7. Additionally, the experimental and computed electronic absorption wavelengths, electronic transitions, oscillator strengths, excitation energies, and major contributions are listed Table 2. Rajasekaran et al. determined a method in which the absorbance of pure drug and tablet extract in 95% ethanol was measured at 210 nm [33]. Xavier studied the UV detector response of NTG and found the best result at 210 nm [19]. In this research, the wavelength recorded at 212  nm in the experimental UV-Vis spectrum can be assigned to n ⟶ σ∗ transition. The calculated wavelength corresponding to this experimental value was obtained at 216.85 nm with 5.7175 eV value of excitation energy and 0.0120 value of oscillator strength for Monomer 1. The other computed wavelengths are given as 236.51 nm, 228.14 nm, 221.79 nm, 219.16 nm, 216.85 nm, and 207.28 nm. The experimental and computed wavelengths and electronic transitions are in good harmony. The calculated wavelength corresponding to this experimental value was obtained at 212.63 nm with 5.8310 eV value of excitation energy and 0.0133 value of oscillator strength for Monomer 2. The other computed wavelengths are given as 228.64 nm, 219.70 nm, 216.37 nm, 212.63 nm, and 210.78 nm.

Figure 7: The simulated UV-Vis analysis of nateglinide in methanol, Monomer 1 and Monomer 2.

3.5. HOMO-LUMO Analyses

The computed molecular energies for Monomer I and Monomer II were obtained as E = −1020.83682668 a.u. and E = −1020.83864468 a.u., respectively. The calculated dipole moments are 5.1216 and 2.3479 debye for Monomer I and Monomer II, respectively. By considering Monomer II, the structural, spectroscopic (IR, Raman, NMR, and UV-Vis), and HOMO-LUMO analyses for nateglinide were performed using theoretical computational methods. The relative energy between the two monomers is considerably low, and it has a value of −0.99582 kcal/mole. Owing to its more stable structure, dipole moment of monomer 2 is lower than monomer 1. The simulated HOMO and LUMO surfaces, energy values, and their shapes for the title molecule are given in Figure 8. The calculated HOMO and LUMO energy values were computed as −6.9449 eV and −0.8923 eV for Monomer 1 and −6.8336 eV and −0.8101 eV for Monomer 2 at the DFT/B3LYP/6-31G + (d, p) level, respectively.

(a)

(b)

(c)

(d)

Figure 8: The HOMO and LUMO energy plots of nateglinide molecule. (a) Monomer 1: HOMO = −6.9449 eV. (b) Monomer 1: LUMO = −0.8923 eV. (c) Monomer 2: HOMO = −6.8336 eV. (d) Monomer 2: LUMO = −0.8101 eV.

4. Conclusion

The structural, spectroscopic (IR, Laser-Raman, NMR, and UV-Vis), and HOMO-LUMO analyses for nateglinide were performed using theoretical computational methods. The computed spectral properties were compared with the experimental data. After the conformational analysis, two molecular geometric forms at the lowest energies were optimized with the DFT/B3LYP/6-31G + (d, p) level. The results can be summarized as follows:

(i)The linear correlation coefficient (R²) value between the calculated and experimental [27] molecular geometric parameters was found as 0.975 for bond lengths (Å) and 0.9605 for bond angles (°), respectively, as given in Table 3.(ii)As a result of the performed analyses, the linear correlation coefficient (R²) values between the experimental and computed vibrational frequencies of Monomer 1 and Monomer 2 for IR wavenumbers were found as R² = 0.9981 and R² = 0.9980, respectively.(iii)The R² and RMSD values between the experimental and computed ¹H NMR chemical shifts were found as 0.9932 and 0.24 ppm for Monomer 1 and as 0.9709 and 0.40 ppm for Monomer 2, respectively. The R² and RMSD values between the experimental and computed ¹³C NMR chemical shifts were found as 0.9985 and 8.62 ppm for Monomer 1 and as 0.9981 and 9.14 ppm for Monomer 2, respectively.(iv)The major contributions for Monomer 1 were found as H-2->LUMO (67%), H-1->LUMO (12%) H-3->LUMO (6%), H-2->L + 4 (5%), and HOMO->LUMO (2%) for 216.85 nm wavelength. The major contributions for Monomer 2 were found as H-3->LUMO (64%), H-1->LUMO (10%) H-1->L + 2 (6%), HOMO->LUMO (3%), and HOMO->L + 1 (4%) for 212.63 nm wavelength.

Data Availability

The data used to support the findings of this study are available from the corresponding author upon request.

Additional Points

(i) The optimized molecular geometry and molecular parameters of nateglinide molecule were investigated. (ii) Molecular structure of nateglinide molecule was studied using DFT. (iii) The complete assignments were performed on the basis of the PED. (iv) The vibrational wavenumbers (FT-IR and Laser-Raman) and UV-Vis spectroscopy were studied using experimental and theoretical methods. (v) The experimental and computed proton and carbon-13 NMR chemical shifts were determined. (vi) All the results were compared with experimental (FT-IR, FT-Raman, UV-Vis, and NMR) spectra.

Conflicts of Interest

The author declares that there are no conflicts of interest.

Acknowledgments

This work was supported by Bartin University Research Fund Project under the Project no. 2017-FEN-A-005. The author thanks Cankiri Karatekin University Research Center for NMR, FT-IR, and UV-Vis analysis and Niğde Ömer Halisdemir University Center Research Laboratory for Laser-Raman analysis. The valuable help of Assoc. Prof. Dr. Halil Gökçe, Assoc. Prof. Dr. Halil Oturak, Asst. Prof. Adnan Sağlam, Asst. Prof. Firdevs Banu Özdemir, Pharmaceutist Ali Ünsal Keskiner, and Res. Asst. Mecit Öge is also acknowledged.

References

Novartis, Starlix® (nateglinide) tablets, http://www.pharma.us.novartis.com/product/pi/pdf/Starlix.pdf/, 2013.

N. Nordisk, “Prandin® (repaglinide) tablets,” July 2018, http://www.novo-pi.com/prandin.pdf/.

J. S. Grant and L. J. Graven, “Progressing from metformin to sulfonylureas or meglitinides,” Workplace Health and Safety, vol. 64, no. 9, pp. 433–439, 2016.

J. F. McLeod, “Clinical pharmacokinetics of nateglinide,” Clinical Pharmacokinetics, vol. 43, no. 2, pp. 97–120, 2004.

N. R. Pani, L. K. Nath, S. Acharya, and B. Bhuniya, “Application of DSC, IST, and FTIR study in the compatibility testing of nateglinide with different pharmaceutical excipients,” Journal of Thermal Analysis and Calorimetry, vol. 108, no. 1, pp. 219–226, 2012.

R. Landgraf, “Meglitinide analogues in the treatment of type 2 diabetes mellitus,” Drugs & Aging, vol. 17, no. 5, pp. 411–425, 2000.

R. E. Pratley, J. E. Foley, and B. E. Dunning, “Rapid acting insulinotropic agents: restoration of early insulin secretion as a physiologic approach to improve glucose control,” Current Pharmaceutical Design, vol. 7, no. 14, pp. 1375–1397, 2001.

https://www.sigmaaldrich.com/catalog/product/usp/1457607?lang=en&region=TR&cm_sp=Insite-_-prodRecCold_xviews-_-prodRecCold10-2, April 2018.

S. Jain, A. Bhandari, and S. Purohit, “Spectrophotometric determination of nateglinide in bulk and tablet dosage forms,” Asian Journal of Pharmaceutics, vol. 3, no. 3, 2009.

G. R. Babu, A. L. Rao, S. L. Surekha, T. Kalapraveen, and P. S. Rao, “Spectrophotometric methods for estimation of Nateglinide in bulk drug and its dosage form,” International Journal of Pharmaceutical, Chemical And Biological Sciences, vol. 3, no. 4, pp. 1160–1164, 2013.

G. R. Babu, A. L. Rao, S. L. Surekha, T. Kalapraveen, and P. S. Rao, “Quantitative estimation of nateglinide in pharmaceutical dosage forms by visible spectrophotometry,” IJRPC, vol. 3, no. 4, pp. 803–807, 2013.

G. Bruni, V. Berbenni, C. Milanese et al., “Determination of the nateglinide polymorphic purity through dsc,” Journal of Pharmaceutical and Biomedical Analysis, vol. 54, no. 5, pp. 1196–1199, 2011.

R. Guardado-Mendoza, A. Prioletta, L. M. Jiménez-Ceja, A. Sosale, and F. Folli, “State of the art paper the role of nateglinide and repaglinide, derivatives of meglitinide, in the treatment of type 2 diabetes mellitus,” Archives of Medical Science, vol. 5, pp. 936–943, 2013.

A. P. Rani, C. B. Sekaran, N. Archana, P. S. Teja, and B. Aruna, “Vis-spectrophotometric methods for the determination of nateglinide,” International Journal of Chemical Sciences, vol. 7, no. 3, pp. 1642–1652, 2009.

P. Goyal, D. Rani, and R. Chadha, “Exploring structural aspects of nateglinide polymorphs using powder x-ray diffraction,” International Journal of Pharmacy and Pharmaceutical Sciences, vol. 9, no. 10, pp. 119–127, 2017.

M. Remko, “Theoretical study of molecular structure, pKa, lipophilicity, solubility, absorption, and polar surface area of some hypoglycemic agents,” Journal of Molecular Structure: THEOCHEM, vol. 897, no. 1–3, pp. 73–82, 2009.

M. Karakaya, Y. Sert, M. Kürekçi, B. Eskiyurt, and Ç. Çırak, “Theoretical and experimental investigations on vibrational and structural properties of tolazamide,” Journal of Molecular Structure, vol. 1095, pp. 87–95, 2015.

T. Özdemir and H. Gökce, “FT-IR, Raman, and NMR spectroscopy and DFT theory of Glimepiride molecule as a Sulfonylurea compound,” Journal of Applied Spectroscopy, vol. 85, no. 3, pp. 560–572, 2018.

C. M. Xavier, “Analytical studies on some anti-diabetic drugs,” Ph.D. thesis, University of Mysore, Mysore, Karnataka, India, 2015.

A. D. Becke, “Density-functional thermochemistry. III. The role of exact exchange,” Journal of Chemical Physics, vol. 98, no. 7, pp. 5648–5652, 1993.

C. Lee, W. Yang, and R. G. Parr, “Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density,” Physical Review B, vol. 37, no. 2, pp. 785–789, 1988.

A. Frish, A. B. Nielsen, and A. J. Holder, Gauss View User Manual, Gaussian Inc., Pittsburg, PA, USA, 2001.

M. J. Frisch, G. W. Trucks, H. B. Schlegel et al., Gaussian 09, Revision, A.1, Gaussian Inc., Wallingford, CT, USA, 2009.

Gaussian Website, Visualizing Molecules & Reactions with Gaussview 5, August 2016, http://www.gaussian.com/g_prod/gv5.htm.

M. H. Jamr’oz, “Vibrational energy distribution analysis VEDA4,” Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, vol. 114, pp. 220–230, 2004.

M. O’boyle, A. L. Tenderholt, and K. M. Langner, “Cclib: a library for package-independent computational chemistry algorithms,” Journal of Computational Chemistry, vol. 29, no. 5, pp. 839–845, 2008.

L. Tessler and I. Goldberg, “Bis(nateglinide) hydronium chloride, and its unique self-assembly into extended polymeric arrays via O-H...O, N-H...Cl and O-H...Cl hydrogen bonds,” Acta Crystallographica Section C Crystal Structure Communications, vol. 61, no. 12, pp. 738–740, 2005.

V. Jain, D. K. Dhaked, Y. Kasetti, and P. V. Bharatam, “Computational study on the conformational preferences in nateglinide,” Journal of Physical Organic Chemistry, vol. 25, no. 8, pp. 649–657, 2012.

https://cccbdb.nist.gov/vibscalejust.asp, March 2018.

N. Pandey, A. N. Sah, and K. Mahara, “Formulation and evaluation of floating microspheres of nateglinide,” International Journal of Pharma Sciences aand Research, vol. 7, no. 11, pp. 453–464, 2016.

M. Sa’id, A. S. Bayero, and U. L. Ali, “Determination of infrared, raman, (¹H and ¹³C)-Nmr spectra and density of state of nateglinide oral antidiabetic drug,” International Journal of Nanomedicine and Nanosurgery, vol. 4, no. 1, 2018.

A. Patil, B. G. Desai, H. N. Shivakumar, and Purvang, “enhancement of nateglinide solubility and dissolution rate,” Research Journal of Pharmacy and Technology, vol. 4, no. 7, pp. 1159–1164, 2011.

A. Rajasekaran, S. Murugesan, M. K. A. Hathi et al., “Spectrophotometric and chromatographic assay of Nateglinide,” Indian Journal Pharmaceutical Sciences, vol. 66, p. 806, 2004.