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Cocrystallization is a phenomenon widely used to enhance the biological and physicochemical properties of active pharmaceutical ingredients (APIs). The present study deals with the synthesis of a cocrystal of coumarin-3-carb­oxy­lic acid (2-oxochromene-3-carb­oxy­lic acid, C10H6O4), a synthetic analogue of the naturally occurring anti­oxidant coumarin, with thio­urea (CH4N2S) using the neat grinding method. The purity and homogeneity of the coumarin-3-carb­oxy­lic acid–thio­urea (1/1) cocrystal was confirmed by single-crystal X-ray diffraction, FT–IR analysis and thermal stability studies based on differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Detailed geometry analysis via density functional theory (DFT) demonstrated that the 1:1 cocrystal stoichiometry is sustained by N—H...O hydrogen bonding between the amine (–NH2) groups of thio­urea and the carbonyl group of coumarin. The synthesized cocrystal exhibited potent anti­oxidant activity (IC50 = 127.9 ± 5.95 µM) in a DPPH radical scavenger assay in vitro in com­parison with the standard N-acetyl-L-cysteine (IC50 = 111.6 ± 2.4 µM). The promising results of the present study highlight the significance of cocrystallization as a crystal engineering tool to improve the efficacy of pharmaceutical ingredients.

Supporting information

cif

Crystallographic Information File (CIF) https://doi.org/10.1107/S205322962200081X/ov3156sup1.cif
Contains datablocks I, global

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S205322962200081X/ov3156Isup2.hkl
Contains datablock I

pdf

Portable Document Format (PDF) file https://doi.org/10.1107/S205322962200081X/ov3156sup3.pdf
X-ray data table, detailed methodologies of biological activities evaluation, Figs. S1 to S8

cml

Chemical Markup Language (CML) file https://doi.org/10.1107/S205322962200081X/ov3156Isup4.cml
Supplementary material

CCDC reference: 2075608

Computing details top

Data collection: APEX3 (Bruker, 2016); cell refinement: SAINT (Bruker, 2016); data reduction: SAINT (Bruker, 2016); program(s) used to solve structure: SHELXT2014 (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2018 (Sheldrick, 2015b); molecular graphics: SHELXTL (Bruker, 2016), ORTEP-3 for Windows (Farrugia, 2012) and Mercury (Macrae et al., 2020); software used to prepare material for publication: SHELXTL (Bruker, 2016), PLATON (Spek, 2020).

2-Oxochromene-3-carboxylic acid–thiourea (1/1) top
Crystal data top
C10H6O4·CH4N2SF(000) = 552
Mr = 266.27Dx = 1.512 Mg m3
Monoclinic, P21/nCu Kα radiation, λ = 1.54178 Å
a = 11.0390 (4) ÅCell parameters from 7384 reflections
b = 6.7554 (2) Åθ = 4.8–68.3°
c = 15.6951 (4) ŵ = 2.57 mm1
β = 91.905 (1)°T = 293 K
V = 1169.78 (6) Å3Block, colourless
Z = 40.20 × 0.08 × 0.05 mm
Data collection top
Bruker APEX-II CCD
diffractometer
1837 reflections with I > 2σ(I)
φ and ω scansRint = 0.054
Absorption correction: multi-scan
(Blessing, 1995)
θmax = 68.3°, θmin = 4.8°
Tmin = 0.627, Tmax = 0.882h = 1313
14985 measured reflectionsk = 88
2131 independent reflectionsl = 1818
Refinement top
Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: mixed
R[F2 > 2σ(F2)] = 0.037H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.102 w = 1/[σ2(Fo2) + (0.0538P)2 + 0.4417P]
where P = (Fo2 + 2Fc2)/3
S = 1.05(Δ/σ)max < 0.001
2131 reflectionsΔρmax = 0.31 e Å3
184 parametersΔρmin = 0.36 e Å3
0 restraintsExtinction correction: SHELXL2018 (Sheldrick, 2015b), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
Primary atom site location: dualExtinction coefficient: 0.0070 (7)
Special details top

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Refinement. A fine crystal of suitable size was selected and mounted on a Bruker D8 Venture Single-crystal X-ray diffraction (SC-XRD) instrument, fitted with a Photon (100) detector with CMOS technology. The crystal was irradiated with graphite-monochromated Cu Kα radiation (λ = 1.54178 Å) at 298 K. The SAINT program (Bruker, 2016) was used for data integration and reduction, while dual-space methods were employed to determine the structure (SHELXT2014/5, Sheldrick, 2015a) followed by full-matrix least-squares refinement up to the final refinement (SHELXL2018/3, Sheldrick, 2015b).

An extinction correction has been applied, which shows coefficient value to be 0.0068 (7). X-Ray structures were obtained by using the ORTEP program (Farrugia, 2012). Interactions were analysed with the help of PLATON (Spek, 2009). MERCURY (Macrae et al., 2020) was used to plot the crystal packing diagram, and generate molecular graphics of the interactions.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
S10.52560 (5)0.12316 (7)0.22997 (3)0.0425 (2)
O10.23789 (11)0.76206 (18)0.57140 (7)0.0329 (3)
O20.32849 (13)0.4796 (2)0.59563 (8)0.0414 (4)
O30.42709 (12)0.2827 (2)0.45638 (8)0.0381 (3)
O40.38776 (17)0.4288 (3)0.33155 (9)0.0553 (5)
N10.54529 (16)0.0809 (3)0.37445 (10)0.0364 (4)
N20.6478 (2)0.2027 (3)0.26301 (12)0.0552 (6)
C10.38209 (16)0.4166 (3)0.41498 (11)0.0318 (4)
C20.31493 (16)0.5869 (3)0.45029 (11)0.0288 (4)
C30.27019 (16)0.7320 (3)0.39856 (11)0.0306 (4)
H30.2796130.7213170.3400760.037*
C40.20913 (16)0.9007 (3)0.43099 (11)0.0294 (4)
C50.16299 (18)1.0564 (3)0.38025 (13)0.0368 (4)
H50.1698161.0515730.3213810.044*
C60.10799 (18)1.2152 (3)0.41703 (14)0.0408 (5)
H60.0770901.3174800.3831230.049*
C70.09836 (18)1.2235 (3)0.50517 (14)0.0399 (5)
H70.0614581.3323510.5296510.048*
C80.14259 (17)1.0730 (3)0.55682 (13)0.0365 (4)
H80.1361151.0791190.6156860.044*
C90.19660 (16)0.9135 (3)0.51880 (11)0.0294 (4)
C100.29784 (15)0.5981 (3)0.54205 (11)0.0289 (4)
C110.57597 (16)0.0651 (3)0.29395 (11)0.0313 (4)
H1A0.506 (2)0.014 (4)0.3975 (14)0.040 (6)*
H1B0.571 (2)0.178 (4)0.4077 (15)0.050 (7)*
H2A0.677 (2)0.302 (4)0.2940 (19)0.070 (8)*
H4A0.427 (3)0.340 (4)0.3099 (18)0.070 (9)*
H2B0.672 (3)0.190 (4)0.210 (2)0.076 (9)*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
S10.0654 (4)0.0365 (3)0.0260 (3)0.0120 (2)0.0069 (2)0.00480 (18)
O10.0424 (7)0.0335 (7)0.0230 (6)0.0026 (5)0.0036 (5)0.0006 (5)
O20.0566 (9)0.0394 (8)0.0282 (7)0.0044 (6)0.0023 (6)0.0085 (6)
O30.0450 (8)0.0377 (7)0.0319 (7)0.0093 (6)0.0034 (6)0.0041 (6)
O40.0813 (12)0.0587 (10)0.0266 (7)0.0364 (9)0.0095 (7)0.0036 (7)
N10.0448 (10)0.0371 (9)0.0278 (8)0.0047 (8)0.0079 (7)0.0066 (7)
N20.0774 (14)0.0577 (12)0.0313 (10)0.0305 (11)0.0144 (9)0.0107 (9)
C10.0334 (9)0.0351 (10)0.0272 (9)0.0007 (8)0.0026 (7)0.0010 (7)
C20.0278 (9)0.0316 (9)0.0271 (9)0.0022 (7)0.0015 (7)0.0002 (7)
C30.0323 (10)0.0353 (10)0.0240 (8)0.0030 (7)0.0007 (7)0.0007 (7)
C40.0297 (9)0.0295 (9)0.0287 (9)0.0031 (7)0.0019 (7)0.0002 (7)
C50.0424 (11)0.0348 (10)0.0330 (9)0.0029 (8)0.0043 (8)0.0040 (8)
C60.0409 (11)0.0298 (10)0.0510 (12)0.0008 (8)0.0082 (9)0.0043 (9)
C70.0363 (10)0.0318 (10)0.0516 (12)0.0000 (8)0.0006 (9)0.0075 (9)
C80.0370 (10)0.0371 (10)0.0355 (10)0.0021 (8)0.0020 (8)0.0074 (8)
C90.0283 (9)0.0296 (9)0.0300 (9)0.0052 (7)0.0012 (7)0.0004 (7)
C100.0300 (9)0.0298 (9)0.0271 (9)0.0050 (7)0.0019 (7)0.0021 (7)
C110.0332 (9)0.0341 (9)0.0267 (9)0.0014 (8)0.0018 (7)0.0012 (7)
Geometric parameters (Å, º) top
S1—C111.7024 (18)C2—C31.356 (3)
O1—C101.377 (2)C2—C101.461 (2)
O1—C91.383 (2)C3—C41.426 (2)
O2—C101.201 (2)C3—H30.9300
O3—C11.211 (2)C4—C91.392 (2)
O4—C11.316 (2)C4—C51.405 (3)
O4—H4A0.82 (3)C5—C61.370 (3)
N1—C111.323 (2)C5—H50.9300
N1—H1A0.86 (2)C6—C71.392 (3)
N1—H1B0.88 (3)C6—H60.9300
N2—C111.325 (3)C7—C81.379 (3)
N2—H2A0.88 (3)C7—H70.9300
N2—H2B0.89 (3)C8—C91.377 (3)
C1—C21.486 (2)C8—H80.9300
C10—O1—C9123.23 (13)C6—C5—H5119.8
C1—O4—H4A114 (2)C4—C5—H5119.8
C11—N1—H1A119.4 (14)C5—C6—C7119.99 (18)
C11—N1—H1B122.7 (15)C5—C6—H6120.0
H1A—N1—H1B118 (2)C7—C6—H6120.0
C11—N2—H2A122.8 (18)C8—C7—C6121.14 (18)
C11—N2—H2B118.4 (19)C8—C7—H7119.4
H2A—N2—H2B119 (3)C6—C7—H7119.4
O3—C1—O4123.29 (17)C9—C8—C7118.16 (18)
O3—C1—C2125.39 (16)C9—C8—H8120.9
O4—C1—C2111.31 (16)C7—C8—H8120.9
C3—C2—C10119.77 (16)C8—C9—O1117.34 (16)
C3—C2—C1120.86 (16)C8—C9—C4122.44 (17)
C10—C2—C1119.37 (15)O1—C9—C4120.21 (16)
C2—C3—C4122.08 (16)O2—C10—O1115.39 (15)
C2—C3—H3119.0O2—C10—C2127.80 (17)
C4—C3—H3119.0O1—C10—C2116.80 (15)
C9—C4—C5117.93 (17)N1—C11—N2117.97 (18)
C9—C4—C3117.83 (16)N1—C11—S1122.29 (15)
C5—C4—C3124.23 (17)N2—C11—S1119.73 (14)
C6—C5—C4120.33 (18)
O3—C1—C2—C3178.48 (18)C7—C8—C9—C40.8 (3)
O4—C1—C2—C31.2 (3)C10—O1—C9—C8177.31 (16)
O3—C1—C2—C101.1 (3)C10—O1—C9—C43.3 (2)
O4—C1—C2—C10179.26 (17)C5—C4—C9—C80.9 (3)
C10—C2—C3—C41.8 (3)C3—C4—C9—C8177.91 (17)
C1—C2—C3—C4177.74 (16)C5—C4—C9—O1178.47 (15)
C2—C3—C4—C90.2 (3)C3—C4—C9—O12.8 (2)
C2—C3—C4—C5178.91 (17)C9—O1—C10—O2179.72 (15)
C9—C4—C5—C60.2 (3)C9—O1—C10—C21.2 (2)
C3—C4—C5—C6178.46 (18)C3—C2—C10—O2177.57 (18)
C4—C5—C6—C70.4 (3)C1—C2—C10—O22.9 (3)
C5—C6—C7—C80.5 (3)C3—C2—C10—O11.4 (2)
C6—C7—C8—C90.1 (3)C1—C2—C10—O1178.22 (15)
C7—C8—C9—O1178.55 (16)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
C8—H8···S1i0.932.983.6742 (19)132
N1—H1A···O30.86 (2)2.23 (3)3.082 (2)172 (2)
N1—H1B···O2ii0.88 (3)2.32 (3)3.062 (2)142 (2)
N1—H1B···O3ii0.88 (3)2.25 (2)2.991 (2)142 (2)
N2—H2A···O2ii0.88 (3)2.11 (3)2.907 (2)150 (3)
N2—H2B···O1iii0.89 (3)2.37 (3)3.224 (2)162 (3)
O4—H4A···S10.82 (3)2.23 (3)3.0466 (16)170 (3)
Symmetry codes: (i) x1/2, y+3/2, z+1/2; (ii) x+1, y, z+1; (iii) x+1/2, y+1/2, z1/2.
Hardness and softness values of CU and CU:TH top
Moleculeν (hardness)σ (softness)
CU0.087311.461
CU:TH0.032730.581
Biological activities of CU, TH and CU:TH top
DPPH radical scavenging (IC50 in µM±SEM)Antileishmanial activity L. major promastigotes (IC50 in µg ml-1±SEM)Cytotoxic activity 3T3 cell normal fibroblast cell Line (IC50 in µM±SEM)
Sample
Coumarin-3-carboxylic acid (CU)NA27.24±0.89NA
Thiourea (TH)NA86.06±0.6NA
CU:TH cocrystal127.9±5.95NANA
CU:TH (1:1 mixture)128.18±2.5190.03±0.73NA
Standard
N-Acetyl-L-cysteine111.6±2.4--
Amphotericin B-3.145±0.005-
Miltefosine-15.5±0.03-
Cycloheximide--0.8±0.1
 

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