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Furosemide (Fur) is a BCS class IV diuretic drug with low bioavailability due to its poor solubility and poor membrane permeability. Triamterene (Tri) is a potassium-sparing diuretic with low bioavailability due to its poor solubility. Here, a novel drug–drug salt composed of Tri and Fur was successfully synthesized. Tri–Fur was comprehensively characterized with single-crystal X-ray and powder X-ray diffraction techniques, thermogravimetric analysis, differential scanning calorimetry and dynamic vapor sorption. The apparent equilibrium solubility (in pH 2.0 buffer) of Tri–Fur is improved compared with Fur and a physical mixture of Tri with equimolar Fur by 15.3-fold and 12.2-fold enhancements, respectively. Its intrinsic dissolution rate (in pH 2.0 buffer) is also higher than for a Fur component with an enhancement of 9.5-fold. This study provides a valuable insight into the formation of dual pharmaceutical salts and demonstrates that Tri–Fur can be a potential alternative formulation.

Supporting information

cif

Crystallographic Information File (CIF) https://doi.org/10.1107/S2052520618013185/aw5014sup1.cif
Contains datablock I

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S2052520618013185/aw5014Isup2.hkl
Contains datablock I

pdf

Portable Document Format (PDF) file https://doi.org/10.1107/S2052520618013185/aw5014sup3.pdf
Supplementary material

CCDC reference: 1850982

Computing details top

Cell refinement: SAINT v8.34A (Bruker, 2013); data reduction: SAINT v8.34A (Bruker, 2013); program(s) used to solve structure: XT (Sheldrick, 2015); program(s) used to refine structure: XL (Sheldrick, 2008); molecular graphics: Olex2 (Dolomanov et al., 2009); software used to prepare material for publication: Olex2 (Dolomanov et al., 2009).

(I) top
Crystal data top
C12H10ClN2O5S·C12H12N7Z = 2
Mr = 584.01F(000) = 604
Triclinic, P1Dx = 1.592 Mg m3
a = 7.522 (5) ÅMo Kα radiation, λ = 0.71073 Å
b = 8.110 (5) ÅCell parameters from 1237 reflections
c = 20.892 (14) Åθ = 2.8–23.4°
α = 92.574 (16)°µ = 0.30 mm1
β = 98.836 (17)°T = 220 K
γ = 103.844 (16)°Plate, clear light yellow
V = 1218.2 (14) Å30.2 × 0.1 × 0.05 mm
Data collection top
Bruker APEX-II CCD
diffractometer
3062 reflections with I > 2σ(I)
φ and ω scansRint = 0.059
Absorption correction: multi-scan
SADABS-2014/5 (Bruker,2014/5) was used for absorption correction. wR2(int) was 0.0630 before and 0.0500 after correction. The Ratio of minimum to maximum transmission is 0.8893. The λ/2 correction factor is 0.00150.
θmax = 27.5°, θmin = 2.0°
Tmin = 0.663, Tmax = 0.746h = 99
11115 measured reflectionsk = 1010
5465 independent reflectionsl = 2626
Refinement top
Refinement on F2Primary atom site location: dual
Least-squares matrix: fullHydrogen site location: mixed
R[F2 > 2σ(F2)] = 0.059H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.193 w = 1/[σ2(Fo2) + (0.1P)2]
where P = (Fo2 + 2Fc2)/3
S = 0.95(Δ/σ)max < 0.001
5465 reflectionsΔρmax = 0.47 e Å3
367 parametersΔρmin = 0.52 e Å3
18 restraints
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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
S10.04809 (13)0.19447 (11)0.23218 (5)0.0270 (3)
Cl10.03699 (17)0.12973 (13)0.08124 (5)0.0426 (3)
O30.2495 (4)0.4148 (3)0.34541 (12)0.0283 (6)
O10.3799 (4)0.5831 (3)0.27590 (13)0.0304 (6)
O40.0120 (4)0.1770 (3)0.30147 (13)0.0345 (7)
O50.2343 (4)0.2578 (3)0.19956 (15)0.0387 (7)
N10.4676 (4)0.6688 (4)0.44060 (15)0.0256 (7)
H10.38700.59650.41190.031*
N50.5253 (4)0.8569 (4)0.60343 (15)0.0237 (7)
N60.2575 (4)0.6314 (4)0.51236 (15)0.0243 (7)
N20.6727 (4)0.7027 (4)0.36951 (15)0.0308 (8)
H2A0.78000.74790.35880.037*
H2B0.58840.63000.34210.037*
N30.7686 (4)0.8551 (4)0.46776 (15)0.0271 (7)
N70.0527 (4)0.6111 (4)0.58343 (17)0.0342 (8)
H7A0.03180.54640.55360.041*
H7B0.02540.63530.62120.041*
O20.2262 (5)0.5043 (5)0.00237 (16)0.0560 (9)
N80.3545 (5)0.4663 (4)0.15552 (16)0.0306 (8)
H80.37270.55830.18120.037*
N40.8582 (4)1.0072 (4)0.56636 (16)0.0347 (8)
H4A0.96521.05240.55550.042*
H4B0.83541.03550.60440.042*
N90.0673 (5)0.3235 (4)0.2108 (2)0.0331 (8)
H9A0.067 (6)0.330 (5)0.166 (2)0.040*
H9B0.158 (6)0.337 (6)0.234 (2)0.040*
C90.4239 (5)0.7071 (4)0.49943 (18)0.0221 (8)
C130.2168 (5)0.3006 (4)0.23675 (18)0.0207 (8)
C160.2844 (5)0.4406 (4)0.28978 (18)0.0221 (8)
C10.3518 (5)0.8092 (5)0.68864 (18)0.0235 (8)
C180.1225 (5)0.1436 (4)0.25235 (18)0.0225 (8)
H180.10780.13000.29580.027*
C100.5547 (5)0.8223 (4)0.54300 (17)0.0222 (8)
C110.7309 (5)0.8963 (5)0.52540 (18)0.0254 (8)
C200.0483 (5)0.0049 (4)0.20667 (18)0.0237 (8)
C170.2466 (5)0.3200 (4)0.17205 (18)0.0233 (8)
C60.4470 (5)0.9648 (5)0.72208 (19)0.0254 (8)
H60.50401.05390.69910.031*
C140.1601 (5)0.1834 (5)0.12496 (19)0.0279 (9)
H140.16930.19660.08100.033*
C50.4591 (5)0.9904 (5)0.78730 (19)0.0284 (9)
H50.52671.09560.80930.034*
C120.6381 (5)0.7442 (5)0.42689 (18)0.0245 (8)
C80.2235 (5)0.6729 (5)0.57135 (18)0.0243 (8)
C70.3661 (5)0.7812 (4)0.61950 (17)0.0214 (8)
C210.0625 (5)0.0310 (5)0.14233 (19)0.0264 (8)
C20.2652 (5)0.6801 (5)0.72306 (19)0.0279 (9)
H20.19930.57410.70120.034*
C40.3717 (5)0.8614 (5)0.8215 (2)0.0313 (9)
H40.37790.87950.86660.038*
C30.2760 (5)0.7072 (5)0.7892 (2)0.0322 (9)
H30.21730.61950.81250.039*
C190.3682 (6)0.5853 (5)0.05015 (19)0.0307 (9)
C150.4424 (6)0.4799 (5)0.09744 (19)0.0311 (9)
H15A0.42480.36530.07640.037*
H15B0.57620.52860.11060.037*
C240.4107 (8)0.7501 (6)0.0430 (3)0.0567 (14)
H240.50640.83400.06870.068*
C220.1797 (8)0.6319 (9)0.0334 (3)0.0685 (16)
H220.08350.61340.06940.082*
C230.2832 (9)0.7764 (8)0.0114 (3)0.0694 (16)
H230.27730.88150.02770.083*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
S10.0227 (5)0.0214 (5)0.0346 (6)0.0002 (4)0.0076 (4)0.0005 (4)
Cl10.0565 (7)0.0351 (6)0.0291 (6)0.0049 (5)0.0009 (5)0.0095 (4)
O30.0297 (15)0.0285 (14)0.0241 (15)0.0003 (11)0.0104 (12)0.0024 (11)
O10.0309 (15)0.0245 (14)0.0298 (16)0.0029 (11)0.0022 (12)0.0013 (11)
O40.0380 (16)0.0304 (15)0.0311 (16)0.0051 (12)0.0146 (13)0.0036 (12)
O50.0176 (14)0.0318 (15)0.059 (2)0.0027 (11)0.0015 (14)0.0091 (14)
N10.0176 (16)0.0298 (17)0.0236 (18)0.0059 (12)0.0051 (13)0.0017 (14)
N50.0189 (16)0.0268 (16)0.0230 (17)0.0001 (12)0.0052 (13)0.0004 (13)
N60.0178 (16)0.0286 (17)0.0241 (17)0.0016 (12)0.0088 (13)0.0002 (13)
N20.0195 (16)0.0392 (19)0.0267 (19)0.0090 (14)0.0111 (14)0.0079 (15)
N30.0222 (16)0.0319 (18)0.0216 (17)0.0036 (13)0.0038 (14)0.0024 (14)
N70.0198 (17)0.047 (2)0.0288 (19)0.0072 (14)0.0087 (14)0.0056 (16)
O20.048 (2)0.071 (2)0.042 (2)0.0081 (18)0.0029 (17)0.0050 (18)
N80.041 (2)0.0237 (16)0.0292 (19)0.0044 (14)0.0188 (16)0.0031 (14)
N40.0265 (18)0.045 (2)0.0237 (18)0.0094 (15)0.0090 (15)0.0068 (15)
N90.031 (2)0.0272 (18)0.043 (2)0.0119 (15)0.0038 (18)0.0044 (17)
C90.0169 (18)0.0261 (19)0.022 (2)0.0010 (14)0.0051 (15)0.0016 (15)
C130.0158 (17)0.0220 (18)0.025 (2)0.0049 (14)0.0042 (15)0.0001 (15)
C160.0173 (18)0.0210 (18)0.026 (2)0.0030 (14)0.0021 (16)0.0024 (15)
C10.0182 (18)0.0263 (19)0.025 (2)0.0029 (14)0.0057 (16)0.0026 (16)
C180.0195 (18)0.0231 (18)0.024 (2)0.0028 (14)0.0050 (16)0.0011 (15)
C100.0220 (19)0.0217 (18)0.020 (2)0.0005 (14)0.0052 (15)0.0005 (15)
C110.0215 (19)0.0268 (19)0.024 (2)0.0023 (15)0.0048 (16)0.0032 (16)
C200.0202 (18)0.0242 (19)0.027 (2)0.0041 (14)0.0073 (16)0.0011 (15)
C170.027 (2)0.0228 (19)0.022 (2)0.0094 (15)0.0047 (16)0.0055 (15)
C60.024 (2)0.0252 (19)0.027 (2)0.0039 (15)0.0097 (17)0.0022 (16)
C140.033 (2)0.029 (2)0.023 (2)0.0106 (17)0.0044 (17)0.0050 (16)
C50.030 (2)0.0241 (19)0.029 (2)0.0029 (16)0.0065 (18)0.0041 (16)
C120.0217 (19)0.0254 (19)0.023 (2)0.0009 (15)0.0047 (16)0.0030 (16)
C80.0180 (18)0.030 (2)0.025 (2)0.0032 (15)0.0084 (16)0.0048 (16)
C70.0192 (18)0.0235 (18)0.0194 (19)0.0008 (14)0.0042 (15)0.0019 (15)
C210.027 (2)0.027 (2)0.023 (2)0.0048 (15)0.0031 (17)0.0040 (16)
C20.027 (2)0.029 (2)0.027 (2)0.0037 (16)0.0094 (17)0.0008 (16)
C40.032 (2)0.040 (2)0.023 (2)0.0090 (18)0.0072 (18)0.0021 (18)
C30.031 (2)0.031 (2)0.033 (2)0.0021 (17)0.0093 (18)0.0104 (18)
C190.035 (2)0.035 (2)0.023 (2)0.0068 (18)0.0095 (18)0.0025 (17)
C150.033 (2)0.038 (2)0.024 (2)0.0077 (18)0.0108 (18)0.0106 (18)
C240.080 (3)0.040 (2)0.049 (3)0.010 (2)0.014 (2)0.010 (2)
C220.060 (3)0.102 (4)0.054 (3)0.040 (3)0.005 (2)0.024 (3)
C230.097 (4)0.072 (3)0.059 (3)0.046 (3)0.028 (3)0.031 (3)
Geometric parameters (Å, º) top
S1—O41.425 (3)C13—C161.488 (5)
S1—O51.422 (3)C13—C181.381 (5)
S1—N91.600 (4)C13—C171.413 (5)
S1—C201.749 (4)C1—C61.388 (5)
Cl1—C211.726 (4)C1—C71.476 (5)
O3—C161.246 (4)C1—C21.387 (5)
O1—C161.278 (4)C18—H180.9400
N1—H10.8700C18—C201.388 (5)
N1—C91.361 (5)C10—C111.428 (5)
N1—C121.361 (4)C20—C211.386 (5)
N5—C101.344 (5)C17—C141.407 (5)
N5—C71.309 (4)C6—H60.9400
N6—C91.329 (4)C6—C51.355 (5)
N6—C81.341 (5)C14—H140.9400
N2—H2A0.8700C14—C211.373 (5)
N2—H2B0.8700C5—H50.9400
N2—C121.311 (5)C5—C41.385 (5)
N3—C111.325 (5)C8—C71.439 (5)
N3—C121.324 (5)C2—H20.9400
N7—H7A0.8700C2—C31.377 (6)
N7—H7B0.8700C4—H40.9400
N7—C81.330 (4)C4—C31.371 (6)
O2—C191.359 (5)C3—H30.9400
O2—C221.383 (6)C19—C151.467 (5)
N8—H80.8700C19—C241.319 (6)
N8—C171.359 (4)C15—H15A0.9800
N8—C151.464 (5)C15—H15B0.9800
N4—H4A0.8700C24—H240.9400
N4—H4B0.8700C24—C231.429 (8)
N4—C111.313 (5)C22—H220.9400
N9—H9A0.93 (5)C22—C231.264 (8)
N9—H9B0.80 (4)C23—H230.9400
C9—C101.370 (5)
O4—S1—N9105.9 (2)N8—C17—C13121.2 (3)
O4—S1—C20106.70 (17)N8—C17—C14120.8 (3)
O5—S1—O4118.97 (18)C14—C17—C13118.0 (3)
O5—S1—N9107.02 (19)C1—C6—H6119.4
O5—S1—C20110.05 (18)C5—C6—C1121.2 (3)
N9—S1—C20107.70 (18)C5—C6—H6119.4
C9—N1—H1120.2C17—C14—H14119.6
C9—N1—C12119.7 (3)C21—C14—C17120.9 (4)
C12—N1—H1120.2C21—C14—H14119.6
C7—N5—C10118.5 (3)C6—C5—H5120.0
C9—N6—C8116.2 (3)C6—C5—C4119.9 (4)
H2A—N2—H2B120.0C4—C5—H5120.0
C12—N2—H2A120.0N2—C12—N1117.1 (3)
C12—N2—H2B120.0N2—C12—N3118.9 (3)
C12—N3—C11118.1 (3)N3—C12—N1124.0 (3)
H7A—N7—H7B120.0N6—C8—C7121.2 (3)
C8—N7—H7A120.0N7—C8—N6117.4 (3)
C8—N7—H7B120.0N7—C8—C7121.4 (3)
C19—O2—C22105.3 (4)N5—C7—C1115.5 (3)
C17—N8—H8117.7N5—C7—C8119.7 (3)
C17—N8—C15124.6 (3)C8—C7—C1124.8 (3)
C15—N8—H8117.7C20—C21—Cl1121.0 (3)
H4A—N4—H4B120.0C14—C21—Cl1117.5 (3)
C11—N4—H4A120.0C14—C21—C20121.5 (3)
C11—N4—H4B120.0C1—C2—H2120.0
S1—N9—H9A112 (3)C3—C2—C1119.9 (4)
S1—N9—H9B122 (3)C3—C2—H2120.0
H9A—N9—H9B118 (4)C5—C4—H4120.1
N1—C9—C10118.2 (3)C3—C4—C5119.8 (4)
N6—C9—N1119.0 (3)C3—C4—H4120.1
N6—C9—C10122.8 (3)C2—C3—H3119.8
C18—C13—C16117.7 (3)C4—C3—C2120.5 (4)
C18—C13—C17118.9 (3)C4—C3—H3119.8
C17—C13—C16123.4 (3)O2—C19—C15117.3 (4)
O3—C16—O1122.8 (3)C24—C19—O2109.5 (4)
O3—C16—C13119.7 (3)C24—C19—C15133.2 (4)
O1—C16—C13117.5 (3)N8—C15—C19113.3 (3)
C6—C1—C7118.5 (3)N8—C15—H15A108.9
C2—C1—C6118.7 (4)N8—C15—H15B108.9
C2—C1—C7122.4 (3)C19—C15—H15A108.9
C13—C18—H18118.5C19—C15—H15B108.9
C13—C18—C20122.9 (3)H15A—C15—H15B107.7
C20—C18—H18118.5C19—C24—H24126.6
N5—C10—C9121.2 (3)C19—C24—C23106.7 (5)
N5—C10—C11119.5 (3)C23—C24—H24126.6
C9—C10—C11119.1 (3)O2—C22—H22124.4
N3—C11—C10120.9 (3)C23—C22—O2111.3 (5)
N4—C11—N3119.0 (3)C23—C22—H22124.4
N4—C11—C10120.2 (3)C24—C23—H23126.5
C18—C20—S1119.6 (3)C22—C23—C24107.1 (5)
C21—C20—S1123.0 (3)C22—C23—H23126.5
C21—C20—C18117.3 (3)
 

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