A drug–drug cocrystal and a co-amorphous form, prepared from honokiol and ligustrazine, inspired by Chinese patent medicine

A drug–drug cocrystal created with two antithrombotic-active ingredients from herbs, honokiol (HON) and ligustrazine (TMP, 1:1), was synthesized and characterized. The structure of HON–TMP (1:1) was determined by single-crystal X-ray diffraction. Then co-amorphous HON–TMP was prepared by honey-assisted grinding, which was inspired by a grinding process for a Chinese patent medicine-Shijunzi honey pill. This co-amorphous drug–drug cocrystal (20% honey) exhibits improved solubility over HON and a significantly reduced sublimation tendency than TMP.

Computing details

(I)

Crystal data

C18H18O2·2(C4H6N)	Z = 2
Mr = 402.52	F(000) = 432
Triclinic, P1	Dx = 1.176 Mg m^−3
a = 8.0045 (5) Å	Mo Kα radiation, λ = 0.71073 Å
b = 9.2035 (6) Å	Cell parameters from 1966 reflections
c = 15.821 (1) Å	θ = 2.6–25.5°
α = 90.211 (2)°	µ = 0.07 mm^−1
β = 102.112 (2)°	T = 170 K
γ = 93.805 (2)°	Block, colourless
V = 1136.88 (13) Å^3	0.12 × 0.08 × 0.05 mm

Data collection

D8 VENTURE diffractometer	2504 reflections with I > 2σ(I)
φ and ω scans	Rint = 0.078
Absorption correction: multi-scan SADABS-2016/2 (Bruker,2016/2) was used for absorption correction. wR2(int) was 0.0910 before and 0.0614 after correction. The Ratio of minimum to maximum transmission is 0.9094. The λ/2 correction factor is Not present.	θmax = 26.4°, θmin = 2.2°
Tmin = 0.678, Tmax = 0.745	h = −9→10
13033 measured reflections	k = −11→11
4620 independent reflections	l = −19→19

Refinement

Refinement on F^2	Primary atom site location: dual
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.069	H-atom parameters constrained
wR(F^2) = 0.175	w = 1/[σ^2(Fo^2) + (0.0507P)^2 + 0.6051P] where P = (Fo^2 + 2Fc^2)/3
S = 1.06	(Δ/σ)max = 0.003
4620 reflections	Δρmax = 0.36 e Å^−3
277 parameters	Δρmin = −0.26 e Å^−3
0 restraints

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.

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

	x	y	z	Uiso*/Ueq
O2	0.7872 (3)	0.7071 (2)	0.30418 (12)	0.0443 (6)
H2	0.849753	0.778956	0.328024	0.066*
O1	0.1798 (3)	0.2572 (2)	0.32208 (14)	0.0461 (6)
H1	0.239946	0.205196	0.358250	0.069*
N2	0.9480 (3)	0.9087 (2)	0.42915 (15)	0.0318 (6)
N1	0.3864 (3)	0.0782 (3)	0.44324 (15)	0.0350 (6)
C20	0.9122 (4)	1.0494 (3)	0.42433 (18)	0.0298 (7)
C10	0.6020 (4)	0.6474 (3)	0.16905 (18)	0.0284 (7)
C5	0.3147 (4)	0.5449 (3)	0.18896 (18)	0.0315 (7)
H5	0.263994	0.611822	0.147290	0.038*
C21	1.0341 (4)	0.8584 (3)	0.50411 (19)	0.0319 (7)
C6	0.2077 (4)	0.4489 (3)	0.22482 (19)	0.0333 (7)
C25	0.5872 (4)	0.0593 (3)	0.57552 (18)	0.0343 (7)
C24	0.4726 (4)	0.1387 (3)	0.51810 (19)	0.0335 (7)
C4	0.4926 (4)	0.5471 (3)	0.21150 (18)	0.0288 (7)
C11	0.5646 (4)	0.6655 (3)	0.07937 (18)	0.0334 (7)
H11	0.466584	0.612748	0.046065	0.040*
C3	0.5635 (4)	0.4490 (3)	0.27314 (18)	0.0324 (7)
H3	0.684449	0.448158	0.290369	0.039*
C15	0.7472 (4)	0.7264 (3)	0.21658 (18)	0.0335 (7)
C13	0.8053 (4)	0.8330 (3)	0.08633 (19)	0.0379 (8)
H13	0.874881	0.896600	0.058792	0.045*
C2	0.4609 (4)	0.3532 (3)	0.30952 (19)	0.0354 (7)
H2A	0.512007	0.286657	0.351328	0.043*
C1	0.2851 (4)	0.3523 (3)	0.28618 (19)	0.0336 (7)
C12	0.6633 (4)	0.7564 (3)	0.03679 (18)	0.0351 (7)
C14	0.8478 (4)	0.8187 (3)	0.17508 (19)	0.0368 (7)
H14	0.945973	0.872006	0.207830	0.044*
C19	0.8116 (4)	1.0984 (3)	0.33986 (19)	0.0390 (8)
H19A	0.816193	1.027247	0.294304	0.058*
H19B	0.860492	1.193423	0.325777	0.058*
H19C	0.692227	1.106585	0.344183	0.058*
C7	0.0157 (4)	0.4447 (3)	0.1960 (2)	0.0431 (8)
H7A	−0.036205	0.439627	0.247565	0.052*
H7B	−0.016214	0.536140	0.165924	0.052*
C22	1.0677 (4)	0.6992 (3)	0.5067 (2)	0.0452 (9)
H22A	1.022568	0.654451	0.449434	0.068*
H22B	1.011017	0.650785	0.549177	0.068*
H22C	1.191296	0.688939	0.523032	0.068*
C23	0.4427 (4)	0.2941 (3)	0.5377 (2)	0.0460 (9)
H23A	0.356420	0.330286	0.490615	0.069*
H23B	0.550115	0.354521	0.543444	0.069*
H23C	0.402151	0.298394	0.591933	0.069*
C16	0.6186 (5)	0.7704 (3)	−0.06066 (19)	0.0447 (8)
H16A	0.711661	0.732971	−0.085256	0.054*
H16B	0.512648	0.708705	−0.083832	0.054*
C26	0.6846 (5)	0.1228 (4)	0.6605 (2)	0.0525 (9)
H26A	0.751603	0.048088	0.693044	0.079*
H26B	0.603995	0.156861	0.693789	0.079*
H26C	0.761895	0.204809	0.650223	0.079*
C8	−0.0554 (5)	0.3195 (4)	0.1376 (3)	0.0605 (11)
H8	−0.044127	0.225586	0.161951	0.073*
C17	0.5928 (6)	0.9210 (4)	−0.0895 (2)	0.0672 (12)
H17	0.494063	0.962818	−0.078378	0.081*
C18	0.6904 (7)	1.0020 (4)	−0.1282 (2)	0.0909 (16)
H18A	0.790894	0.965425	−0.140823	0.109*
H18B	0.661771	1.098086	−0.144023	0.109*
C9	−0.1286 (6)	0.3235 (6)	0.0596 (3)	0.0953 (16)
H9A	−0.143456	0.414494	0.031825	0.114*
H9B	−0.169420	0.235556	0.028203	0.114*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O2	0.0569 (16)	0.0441 (13)	0.0263 (12)	−0.0195 (11)	0.0034 (11)	−0.0011 (10)
O1	0.0348 (13)	0.0504 (14)	0.0540 (15)	−0.0026 (11)	0.0129 (11)	0.0197 (11)
N2	0.0313 (15)	0.0311 (13)	0.0317 (14)	−0.0050 (11)	0.0057 (12)	−0.0016 (11)
N1	0.0398 (16)	0.0340 (14)	0.0326 (15)	−0.0024 (12)	0.0119 (13)	0.0037 (12)
C20	0.0290 (17)	0.0298 (16)	0.0305 (16)	−0.0022 (13)	0.0071 (14)	−0.0002 (13)
C10	0.0294 (17)	0.0271 (15)	0.0286 (15)	0.0005 (13)	0.0064 (14)	−0.0018 (12)
C5	0.0343 (19)	0.0252 (15)	0.0348 (17)	0.0045 (13)	0.0060 (14)	−0.0001 (13)
C21	0.0319 (18)	0.0292 (15)	0.0347 (17)	−0.0032 (13)	0.0086 (15)	0.0037 (13)
C6	0.0288 (18)	0.0347 (16)	0.0372 (18)	0.0019 (13)	0.0085 (14)	0.0013 (14)
C25	0.0370 (19)	0.0369 (17)	0.0297 (16)	−0.0057 (14)	0.0112 (14)	0.0019 (14)
C24	0.0385 (19)	0.0304 (16)	0.0357 (18)	−0.0054 (14)	0.0197 (15)	0.0019 (14)
C4	0.0339 (18)	0.0255 (15)	0.0271 (15)	−0.0020 (13)	0.0078 (14)	−0.0041 (12)
C11	0.0346 (18)	0.0318 (16)	0.0322 (17)	−0.0015 (13)	0.0046 (14)	0.0001 (13)
C3	0.0268 (17)	0.0362 (16)	0.0333 (17)	−0.0004 (13)	0.0051 (14)	0.0006 (13)
C15	0.0411 (19)	0.0332 (16)	0.0258 (16)	−0.0004 (14)	0.0073 (14)	0.0019 (13)
C13	0.046 (2)	0.0341 (17)	0.0361 (18)	−0.0043 (15)	0.0161 (16)	0.0024 (14)
C2	0.0333 (19)	0.0373 (17)	0.0371 (18)	0.0037 (14)	0.0099 (15)	0.0086 (14)
C1	0.0307 (18)	0.0323 (16)	0.0402 (18)	−0.0011 (13)	0.0136 (15)	0.0056 (14)
C12	0.046 (2)	0.0324 (16)	0.0280 (16)	0.0008 (15)	0.0101 (15)	−0.0001 (13)
C14	0.0352 (19)	0.0361 (17)	0.0376 (18)	−0.0068 (14)	0.0071 (15)	0.0012 (14)
C19	0.041 (2)	0.0392 (17)	0.0352 (18)	0.0027 (15)	0.0052 (15)	0.0031 (14)
C7	0.0313 (19)	0.0413 (18)	0.058 (2)	0.0052 (15)	0.0108 (17)	0.0025 (16)
C22	0.055 (2)	0.0304 (17)	0.048 (2)	0.0031 (15)	0.0066 (18)	0.0027 (15)
C23	0.055 (2)	0.0356 (18)	0.051 (2)	0.0036 (16)	0.0202 (18)	0.0017 (15)
C16	0.056 (2)	0.047 (2)	0.0295 (17)	−0.0078 (17)	0.0098 (16)	0.0005 (15)
C26	0.064 (3)	0.056 (2)	0.035 (2)	−0.0046 (19)	0.0062 (18)	−0.0053 (16)
C8	0.038 (2)	0.067 (3)	0.072 (3)	0.0079 (19)	0.001 (2)	0.003 (2)
C17	0.106 (3)	0.065 (3)	0.037 (2)	0.032 (2)	0.022 (2)	0.0071 (19)
C18	0.168 (5)	0.055 (3)	0.051 (3)	0.003 (3)	0.028 (3)	0.013 (2)
C9	0.077 (4)	0.119 (4)	0.078 (4)	0.008 (3)	−0.010 (3)	−0.001 (3)

Geometric parameters (Å, º)

O2—H2	0.8400	C2—H2A	0.9500
O2—C15	1.370 (3)	C2—C1	1.378 (4)
O1—H1	0.8400	C12—C16	1.516 (4)
O1—C1	1.380 (3)	C14—H14	0.9500
N2—C20	1.344 (3)	C19—H19A	0.9800
N2—C21	1.341 (3)	C19—H19B	0.9800
N1—C25^i	1.339 (4)	C19—H19C	0.9800
N1—C24	1.338 (4)	C7—H7A	0.9900
C20—C21^ii	1.388 (4)	C7—H7B	0.9900
C20—C19	1.496 (4)	C7—C8	1.480 (5)
C10—C4	1.487 (4)	C22—H22A	0.9800
C10—C11	1.400 (4)	C22—H22B	0.9800
C10—C15	1.400 (4)	C22—H22C	0.9800
C5—H5	0.9500	C23—H23A	0.9800
C5—C6	1.394 (4)	C23—H23B	0.9800
C5—C4	1.392 (4)	C23—H23C	0.9800
C21—C22	1.506 (4)	C16—H16A	0.9900
C6—C1	1.394 (4)	C16—H16B	0.9900
C6—C7	1.507 (4)	C16—C17	1.474 (5)
C25—C24	1.395 (4)	C26—H26A	0.9800
C25—C26	1.500 (4)	C26—H26B	0.9800
C24—C23	1.507 (4)	C26—H26C	0.9800
C4—C3	1.389 (4)	C8—H8	0.9500
C11—H11	0.9500	C8—C9	1.251 (5)
C11—C12	1.385 (4)	C17—H17	0.9500
C3—H3	0.9500	C17—C18	1.292 (5)
C3—C2	1.374 (4)	C18—H18A	0.9500
C15—C14	1.392 (4)	C18—H18B	0.9500
C13—H13	0.9500	C9—H9A	0.9500
C13—C12	1.386 (4)	C9—H9B	0.9500
C13—C14	1.383 (4)
C15—O2—H2	109.5	C13—C14—C15	120.2 (3)
C1—O1—H1	109.5	C13—C14—H14	119.9
C21—N2—C20	119.2 (2)	C20—C19—H19A	109.5
C24—N1—C25^i	118.8 (3)	C20—C19—H19B	109.5
N2—C20—C21^ii	120.2 (3)	C20—C19—H19C	109.5
N2—C20—C19	116.8 (3)	H19A—C19—H19B	109.5
C21^ii—C20—C19	123.0 (3)	H19A—C19—H19C	109.5
C11—C10—C4	121.1 (3)	H19B—C19—H19C	109.5
C11—C10—C15	117.2 (2)	C6—C7—H7A	109.0
C15—C10—C4	121.7 (2)	C6—C7—H7B	109.0
C6—C5—H5	118.5	H7A—C7—H7B	107.8
C4—C5—H5	118.5	C8—C7—C6	112.9 (3)
C4—C5—C6	122.9 (3)	C8—C7—H7A	109.0
N2—C21—C20^ii	120.6 (3)	C8—C7—H7B	109.0
N2—C21—C22	117.1 (3)	C21—C22—H22A	109.5
C20^ii—C21—C22	122.3 (3)	C21—C22—H22B	109.5
C5—C6—C7	121.5 (3)	C21—C22—H22C	109.5
C1—C6—C5	117.5 (3)	H22A—C22—H22B	109.5
C1—C6—C7	120.9 (3)	H22A—C22—H22C	109.5
N1^i—C25—C24	120.8 (3)	H22B—C22—H22C	109.5
N1^i—C25—C26	117.3 (3)	C24—C23—H23A	109.5
C24—C25—C26	121.9 (3)	C24—C23—H23B	109.5
N1—C24—C25	120.4 (3)	C24—C23—H23C	109.5
N1—C24—C23	118.1 (3)	H23A—C23—H23B	109.5
C25—C24—C23	121.5 (3)	H23A—C23—H23C	109.5
C5—C4—C10	121.2 (2)	H23B—C23—H23C	109.5
C3—C4—C10	121.5 (3)	C12—C16—H16A	108.8
C3—C4—C5	117.3 (2)	C12—C16—H16B	108.8
C10—C11—H11	118.4	H16A—C16—H16B	107.7
C12—C11—C10	123.3 (3)	C17—C16—C12	113.7 (3)
C12—C11—H11	118.4	C17—C16—H16A	108.8
C4—C3—H3	119.5	C17—C16—H16B	108.8
C2—C3—C4	120.9 (3)	C25—C26—H26A	109.5
C2—C3—H3	119.5	C25—C26—H26B	109.5
O2—C15—C10	117.7 (2)	C25—C26—H26C	109.5
O2—C15—C14	121.8 (3)	H26A—C26—H26B	109.5
C14—C15—C10	120.5 (3)	H26A—C26—H26C	109.5
C12—C13—H13	119.4	H26B—C26—H26C	109.5
C14—C13—H13	119.4	C7—C8—H8	116.4
C14—C13—C12	121.3 (3)	C9—C8—C7	127.3 (4)
C3—C2—H2A	119.5	C9—C8—H8	116.4
C3—C2—C1	120.9 (3)	C16—C17—H17	116.6
C1—C2—H2A	119.5	C18—C17—C16	126.9 (4)
O1—C1—C6	117.8 (3)	C18—C17—H17	116.6
C2—C1—O1	121.8 (2)	C17—C18—H18A	120.0
C2—C1—C6	120.4 (2)	C17—C18—H18B	120.0
C11—C12—C13	117.7 (3)	H18A—C18—H18B	120.0
C11—C12—C16	121.2 (3)	C8—C9—H9A	120.0
C13—C12—C16	121.2 (3)	C8—C9—H9B	120.0
C15—C14—H14	119.9	H9A—C9—H9B	120.0

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