A tolbutamide–metformin salt based on anti­diabetic drug combinations: synthesis, crystal structure analysis and pharmaceutical properties

A drug–drug anhydrous pharmaceutical salt containing tolbutamide {systematic name: 3-butyl-1-[(4-methyl­benzene)­sulfon­yl]urea, TOL, C₁₂H₁₈N₂O₃S} and metformin (systematic name: 1-carbamimidamido-N,N-di­methyl­meth­ani­mid­amide, MET, C₄H₁₁N₅) was created based on anti­diabetic drug combinations to overcome the poor pharmaceutical properties of the parent drugs. Proton transfer and the proportion of the two components were confirmed by ¹H NMR spectroscopy and single-crystal X-ray diffraction analysis. Comprehensive char­acterization of the new pharmaceutical salt crystal, 2-[(di­methyl­amino)(iminium­yl)meth­yl]guanidine (butyl­carbamo­yl)[(4-methyl­benzene)­sulfon­yl]aza­nide, C₄H₁₂N₅⁺·C₁₂H₁₇N₂O₃S⁻, was performed and showed enhancement of the pharmaceutical properties, such as lower hygroscopicity and greater accelerated stability than the parent drug MET, and higher solubility and dissolution rate than TOL. The property alterations were correlated with the crystal packing features and potential hydrogen-bonding sites through observed changes in the crystal structures.

Computing details

Data collection: CrystalClear; cell refinement: CrystalClear; data reduction: CrystalClear; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009).

2-[(Dimethylamino)(iminiumyl)methyl]guanidine (butylcarbamoyl)[(4-methylbenzene)sulfonyl]azanide

Crystal data

C4H12N5^+·C12H17N2O3S^−	F(000) = 856
Mr = 399.52	Dx = 1.318 Mg m^−3
Monoclinic, P21/n	Mo Kα radiation, λ = 0.71073 Å
a = 7.9854 (16) Å	Cell parameters from 4643 reflections
b = 28.569 (6) Å	θ = 2.1–27.9°
c = 8.8257 (18) Å	µ = 0.19 mm^−1
β = 91.61 (3)°	T = 113 K
V = 2012.7 (7) Å^3	Prism, colorless
Z = 4	0.2 × 0.18 × 0.12 mm

Data collection

Bruker P4 diffractometer	2731 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.044
ω scans	θmax = 25.0°, θmin = 2.4°
Absorption correction: multi-scan crystalclear	h = −9→9
Tmin = 0.845, Tmax = 1	k = −34→33
11884 measured reflections	l = −10→10
3432 independent reflections

Refinement

Refinement on F^2	10 restraints
Least-squares matrix: full	Hydrogen site location: mixed
R[F^2 > 2σ(F^2)] = 0.058	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.158	w = 1/[σ^2(Fo^2) + (0.0778P)^2 + 2.1553P] where P = (Fo^2 + 2Fc^2)/3
S = 1.06	(Δ/σ)max = 0.001
3432 reflections	Δρmax = 1.27 e Å^−3
269 parameters	Δρmin = −0.43 e Å^−3

Special details

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. Single crystal X-ray diffraction measurements were conducted on a Bruker P4 CCD Diffractometer using Mo-Kα radiation (λ = 0.71073 Å) with a graphite monochromator. Data were collected at 113 K. Integration and scaling of the intensity data were accomplished using the CrystalClear program. Direct methods were used to solve structures and a full-matrix least-squares technique was used for refinement using the SHELXL-2014 program package ?(Sheldrick, 2008)?. The non-hydrogen atoms were refined with anisotropic displacement parameters and hydrogen atoms were refined with isotropic displacement parameters.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
S1	0.47284 (9)	0.13845 (2)	1.04996 (9)	0.0220 (2)
O1T	0.4979 (3)	0.12443 (7)	1.2061 (2)	0.0278 (5)
O2T	0.3195 (2)	0.16442 (7)	1.0148 (2)	0.0284 (5)
O3T	0.4981 (2)	0.05449 (7)	0.7272 (2)	0.0262 (5)
N1T	0.4961 (3)	0.09297 (8)	0.9505 (3)	0.0226 (6)
N2T	0.3559 (4)	0.12253 (9)	0.7313 (3)	0.0321 (6)
H2T	0.316 (4)	0.1448 (9)	0.792 (3)	0.039*
N3M	0.7861 (3)	0.00927 (10)	0.5740 (3)	0.0284 (6)
H3MA	0.720 (3)	0.0161 (11)	0.651 (2)	0.034*
H3MB	0.8878 (19)	−0.0014 (11)	0.600 (3)	0.034*
N2M	0.6038 (3)	0.04984 (9)	0.4214 (3)	0.0254 (6)
H2MA	0.572 (4)	0.0671 (10)	0.342 (2)	0.030*
H2MB	0.547 (3)	0.0547 (10)	0.5058 (18)	0.030*
N1M	0.8676 (3)	0.02491 (8)	0.3319 (3)	0.0226 (5)
N4M	0.6831 (3)	0.02084 (8)	0.1181 (3)	0.0234 (6)
H4MA	0.629 (3)	0.0393 (9)	0.051 (3)	0.028*
H4MB	0.616 (3)	0.0037 (9)	0.175 (3)	0.028*
N5M	0.9413 (3)	0.05601 (8)	0.1026 (3)	0.0242 (6)
C5T	0.6403 (3)	0.17640 (9)	1.0066 (3)	0.0217 (6)
C4T	0.7928 (4)	0.17119 (10)	1.0826 (4)	0.0301 (7)
H4T	0.8057	0.1488	1.1616	0.036*
C3T	0.9271 (4)	0.19900 (11)	1.0422 (4)	0.0385 (9)
H3T	1.0318	0.1954	1.0947	0.046*
C2T	0.9120 (4)	0.23168 (11)	0.9278 (4)	0.0376 (8)
C7T	0.7571 (4)	0.23720 (11)	0.8539 (4)	0.0371 (8)
H7T	0.7443	0.2598	0.7756	0.045*
C6T	0.6214 (4)	0.21003 (11)	0.8933 (4)	0.0324 (8)
H6T	0.5157	0.2144	0.8432	0.039*
C1T	1.0606 (5)	0.26109 (15)	0.8827 (6)	0.0656 (14)
H1TA	1.1552	0.2552	0.9534	0.098*
H1TB	1.0304	0.2943	0.8860	0.098*
H1TC	1.0924	0.2527	0.7797	0.098*
C8T	0.4514 (3)	0.08964 (9)	0.8011 (3)	0.0216 (6)
C9T	0.3067 (5)	0.12049 (12)	0.5711 (4)	0.0394 (8)
H9TA	0.2740	0.0881	0.5442	0.047*
H9TB	0.4033	0.1293	0.5092	0.047*
C10T	0.1632 (4)	0.15283 (14)	0.5356 (4)	0.0425 (9)
H10A	0.1446	0.1550	0.4244	0.051*
H10B	0.1896	0.1846	0.5745	0.051*
C11T	0.0027 (6)	0.13424 (19)	0.6099 (6)	0.0712 (14)
H11A	−0.0028	0.0999	0.5944	0.085*
H11B	0.0129	0.1399	0.7204	0.085*
C12T	−0.1518 (6)	0.1543 (2)	0.5547 (6)	0.0925 (19)
H12A	−0.1452	0.1885	0.5617	0.139*
H12B	−0.2440	0.1430	0.6159	0.139*
H12C	−0.1719	0.1452	0.4487	0.139*
C1M	0.7506 (3)	0.02820 (9)	0.4386 (3)	0.0218 (6)
C2M	0.8268 (3)	0.03473 (9)	0.1872 (3)	0.0208 (6)
C3M	1.0929 (4)	0.07661 (11)	0.1691 (4)	0.0319 (7)
H3MC	1.0841	0.0778	0.2796	0.048*
H3MD	1.1069	0.1084	0.1297	0.048*
H3ME	1.1899	0.0575	0.1429	0.048*
C4M	0.9226 (4)	0.05920 (12)	−0.0618 (3)	0.0316 (7)
H4MC	0.8608	0.0319	−0.1005	0.047*
H4MD	1.0336	0.0601	−0.1065	0.047*
H4ME	0.8610	0.0878	−0.0891	0.047*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
S1	0.0222 (4)	0.0232 (4)	0.0208 (4)	0.0016 (3)	0.0041 (3)	0.0006 (3)
O1T	0.0354 (12)	0.0302 (11)	0.0181 (12)	−0.0002 (9)	0.0030 (9)	0.0031 (8)
O2T	0.0228 (11)	0.0317 (11)	0.0308 (13)	0.0060 (9)	0.0035 (9)	0.0005 (9)
O3T	0.0318 (11)	0.0251 (10)	0.0220 (12)	0.0002 (8)	0.0065 (9)	−0.0002 (8)
N1T	0.0236 (13)	0.0225 (12)	0.0218 (15)	0.0003 (10)	0.0012 (10)	0.0006 (10)
N2T	0.0439 (16)	0.0310 (14)	0.0208 (16)	0.0112 (12)	−0.0071 (12)	−0.0012 (11)
N3M	0.0227 (13)	0.0447 (15)	0.0181 (15)	0.0036 (11)	0.0038 (11)	0.0061 (11)
N2M	0.0260 (13)	0.0346 (14)	0.0158 (14)	0.0052 (11)	0.0051 (11)	0.0028 (11)
N1M	0.0209 (12)	0.0297 (13)	0.0172 (14)	0.0002 (10)	0.0034 (10)	0.0052 (10)
N4M	0.0225 (13)	0.0274 (13)	0.0203 (15)	−0.0007 (10)	0.0003 (10)	0.0044 (10)
N5M	0.0233 (13)	0.0300 (13)	0.0195 (14)	−0.0014 (10)	0.0050 (10)	0.0033 (10)
C5T	0.0242 (15)	0.0219 (14)	0.0192 (17)	0.0008 (11)	0.0035 (12)	−0.0031 (11)
C4T	0.0268 (16)	0.0261 (15)	0.037 (2)	0.0010 (12)	0.0004 (14)	0.0040 (13)
C3T	0.0248 (17)	0.0327 (17)	0.058 (3)	0.0001 (13)	−0.0018 (16)	0.0047 (16)
C2T	0.0338 (18)	0.0258 (16)	0.054 (2)	−0.0028 (13)	0.0099 (17)	0.0018 (15)
C7T	0.044 (2)	0.0283 (16)	0.039 (2)	−0.0033 (14)	0.0045 (16)	0.0113 (14)
C6T	0.0333 (17)	0.0314 (16)	0.032 (2)	−0.0001 (13)	−0.0037 (14)	0.0045 (13)
C1T	0.040 (2)	0.048 (2)	0.109 (4)	−0.0108 (18)	0.011 (2)	0.025 (2)
C8T	0.0198 (14)	0.0241 (14)	0.0210 (17)	−0.0041 (11)	0.0034 (12)	0.0029 (11)
C9T	0.054 (2)	0.0404 (19)	0.024 (2)	0.0098 (16)	−0.0075 (16)	0.0016 (14)
C10T	0.044 (2)	0.057 (2)	0.027 (2)	0.0157 (17)	−0.0051 (16)	0.0066 (16)
C11T	0.065 (3)	0.092 (4)	0.056 (3)	0.008 (3)	0.000 (2)	0.003 (3)
C12T	0.056 (3)	0.153 (6)	0.068 (4)	−0.006 (3)	−0.003 (3)	−0.032 (4)
C1M	0.0198 (14)	0.0236 (14)	0.0221 (17)	−0.0027 (11)	0.0021 (12)	−0.0008 (11)
C2M	0.0218 (14)	0.0201 (13)	0.0207 (16)	0.0032 (11)	0.0042 (12)	−0.0003 (11)
C3M	0.0269 (17)	0.0368 (17)	0.032 (2)	−0.0057 (13)	0.0026 (14)	0.0060 (14)
C4M	0.0337 (17)	0.0417 (18)	0.0198 (18)	0.0044 (14)	0.0088 (14)	0.0070 (13)

Geometric parameters (Å, º)

S1—O1T	1.444 (2)	C3T—C2T	1.378 (5)
S1—O2T	1.457 (2)	C2T—C7T	1.391 (5)
S1—N1T	1.582 (2)	C2T—C1T	1.517 (5)
S1—C5T	1.771 (3)	C7T—H7T	0.9500
O3T—C8T	1.260 (3)	C7T—C6T	1.385 (5)
N1T—C8T	1.359 (4)	C6T—H6T	0.9500
N2T—H2T	0.896 (10)	C1T—H1TA	0.9800
N2T—C8T	1.348 (4)	C1T—H1TB	0.9800
N2T—C9T	1.458 (4)	C1T—H1TC	0.9800
N3M—H3MA	0.892 (10)	C9T—H9TA	0.9900
N3M—H3MB	0.892 (10)	C9T—H9TB	0.9900
N3M—C1M	1.335 (4)	C9T—C10T	1.498 (5)
N2M—H2MA	0.888 (10)	C10T—H10A	0.9900
N2M—H2MB	0.892 (10)	C10T—H10B	0.9900
N2M—C1M	1.330 (4)	C10T—C11T	1.550 (6)
N1M—C1M	1.348 (4)	C11T—H11A	0.9900
N1M—C2M	1.339 (4)	C11T—H11B	0.9900
N4M—H4MA	0.895 (10)	C11T—C12T	1.434 (7)
N4M—H4MB	0.895 (10)	C12T—H12A	0.9800
N4M—C2M	1.344 (4)	C12T—H12B	0.9800
N5M—C2M	1.343 (4)	C12T—H12C	0.9800
N5M—C3M	1.455 (4)	C3M—H3MC	0.9800
N5M—C4M	1.457 (4)	C3M—H3MD	0.9800
C5T—C4T	1.382 (4)	C3M—H3ME	0.9800
C5T—C6T	1.392 (4)	C4M—H4MC	0.9800
C4T—H4T	0.9500	C4M—H4MD	0.9800
C4T—C3T	1.389 (4)	C4M—H4ME	0.9800
C3T—H3T	0.9500
O1T—S1—O2T	115.95 (13)	H1TB—C1T—H1TC	109.5
O1T—S1—N1T	106.65 (13)	O3T—C8T—N1T	119.0 (3)
O1T—S1—C5T	106.93 (13)	O3T—C8T—N2T	119.4 (3)
O2T—S1—N1T	114.27 (13)	N2T—C8T—N1T	121.6 (3)
O2T—S1—C5T	106.08 (13)	N2T—C9T—H9TA	109.4
N1T—S1—C5T	106.34 (13)	N2T—C9T—H9TB	109.4
C8T—N1T—S1	124.3 (2)	N2T—C9T—C10T	111.2 (3)
C8T—N2T—H2T	116 (2)	H9TA—C9T—H9TB	108.0
C8T—N2T—C9T	123.3 (3)	C10T—C9T—H9TA	109.4
C9T—N2T—H2T	121 (2)	C10T—C9T—H9TB	109.4
H3MA—N3M—H3MB	115.6 (17)	C9T—C10T—H10A	109.7
C1M—N3M—H3MA	118.3 (18)	C9T—C10T—H10B	109.7
C1M—N3M—H3MB	122.7 (18)	C9T—C10T—C11T	109.7 (3)
H2MA—N2M—H2MB	115.7 (16)	H10A—C10T—H10B	108.2
C1M—N2M—H2MA	125.2 (17)	C11T—C10T—H10A	109.7
C1M—N2M—H2MB	116.2 (18)	C11T—C10T—H10B	109.7
C2M—N1M—C1M	119.8 (2)	C10T—C11T—H11A	108.4
H4MA—N4M—H4MB	114.4 (15)	C10T—C11T—H11B	108.4
C2M—N4M—H4MA	120.9 (18)	H11A—C11T—H11B	107.4
C2M—N4M—H4MB	115.2 (18)	C12T—C11T—C10T	115.6 (4)
C2M—N5M—C3M	122.0 (3)	C12T—C11T—H11A	108.4
C2M—N5M—C4M	122.0 (3)	C12T—C11T—H11B	108.4
C3M—N5M—C4M	115.9 (2)	C11T—C12T—H12A	109.5
C4T—C5T—S1	119.3 (2)	C11T—C12T—H12B	109.5
C4T—C5T—C6T	119.9 (3)	C11T—C12T—H12C	109.5
C6T—C5T—S1	120.7 (2)	H12A—C12T—H12B	109.5
C5T—C4T—H4T	120.3	H12A—C12T—H12C	109.5
C5T—C4T—C3T	119.3 (3)	H12B—C12T—H12C	109.5
C3T—C4T—H4T	120.3	N3M—C1M—N1M	117.6 (3)
C4T—C3T—H3T	119.2	N2M—C1M—N3M	117.0 (3)
C2T—C3T—C4T	121.6 (3)	N2M—C1M—N1M	125.4 (3)
C2T—C3T—H3T	119.2	N1M—C2M—N4M	123.6 (3)
C3T—C2T—C7T	118.6 (3)	N1M—C2M—N5M	118.3 (3)
C3T—C2T—C1T	121.0 (3)	N5M—C2M—N4M	117.9 (3)
C7T—C2T—C1T	120.4 (3)	N5M—C3M—H3MC	109.5
C2T—C7T—H7T	119.7	N5M—C3M—H3MD	109.5
C6T—C7T—C2T	120.7 (3)	N5M—C3M—H3ME	109.5
C6T—C7T—H7T	119.7	H3MC—C3M—H3MD	109.5
C5T—C6T—H6T	120.1	H3MC—C3M—H3ME	109.5
C7T—C6T—C5T	119.8 (3)	H3MD—C3M—H3ME	109.5
C7T—C6T—H6T	120.1	N5M—C4M—H4MC	109.5
C2T—C1T—H1TA	109.5	N5M—C4M—H4MD	109.5
C2T—C1T—H1TB	109.5	N5M—C4M—H4ME	109.5
C2T—C1T—H1TC	109.5	H4MC—C4M—H4MD	109.5
H1TA—C1T—H1TB	109.5	H4MC—C4M—H4ME	109.5
H1TA—C1T—H1TC	109.5	H4MD—C4M—H4ME	109.5
S1—N1T—C8T—O3T	169.4 (2)	C4T—C3T—C2T—C1T	−178.7 (4)
S1—N1T—C8T—N2T	−11.9 (4)	C3T—C2T—C7T—C6T	−0.7 (5)
S1—C5T—C4T—C3T	176.1 (2)	C2T—C7T—C6T—C5T	−0.9 (5)
S1—C5T—C6T—C7T	−175.6 (3)	C6T—C5T—C4T—C3T	−1.5 (5)
O1T—S1—N1T—C8T	166.8 (2)	C1T—C2T—C7T—C6T	179.2 (3)
O1T—S1—C5T—C4T	28.6 (3)	C8T—N2T—C9T—C10T	163.3 (3)
O1T—S1—C5T—C6T	−153.8 (2)	C9T—N2T—C8T—O3T	−2.0 (4)
O2T—S1—N1T—C8T	37.3 (3)	C9T—N2T—C8T—N1T	179.4 (3)
O2T—S1—C5T—C4T	152.9 (2)	C9T—C10T—C11T—C12T	−164.5 (4)
O2T—S1—C5T—C6T	−29.5 (3)	C1M—N1M—C2M—N4M	−42.1 (4)
N1T—S1—C5T—C4T	−85.0 (3)	C1M—N1M—C2M—N5M	144.0 (3)
N1T—S1—C5T—C6T	92.6 (3)	C2M—N1M—C1M—N3M	166.7 (3)
N2T—C9T—C10T—C11T	−69.0 (4)	C2M—N1M—C1M—N2M	−15.1 (4)
C5T—S1—N1T—C8T	−79.3 (2)	C3M—N5M—C2M—N1M	−12.2 (4)
C5T—C4T—C3T—C2T	−0.1 (5)	C3M—N5M—C2M—N4M	173.5 (3)
C4T—C5T—C6T—C7T	2.0 (5)	C4M—N5M—C2M—N1M	166.8 (3)
C4T—C3T—C2T—C7T	1.2 (5)	C4M—N5M—C2M—N4M	−7.5 (4)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N2T—H2T···O2T	0.90 (1)	2.05 (2)	2.796 (3)	140 (3)
N3M—H3MA···O3T	0.89 (1)	2.21 (2)	2.994 (3)	147 (2)
N3M—H3MB···N1M^i	0.89 (1)	2.13 (1)	3.026 (3)	178 (3)
N2M—H2MA···O1T^ii	0.89 (1)	2.11 (1)	2.962 (3)	162 (3)
N2M—H2MB···O3T	0.89 (1)	2.00 (1)	2.853 (3)	159 (2)
N4M—H4MA···N1T^ii	0.90 (1)	2.05 (1)	2.923 (3)	164 (3)
N4M—H4MB···O3T^iii	0.90 (1)	2.09 (1)	2.950 (3)	161 (3)
C3M—H3MD···O2T^iv	0.98	2.56	3.400 (4)	143

Symmetry codes: (i) −x+2, −y, −z+1; (ii) x, y, z−1; (iii) −x+1, −y, −z+1; (iv) x+1, y, z−1.