Binary polymorphic cocrystals: an update on the available literature in the Cambridge Structural Database, including a new polymorph of the pharmaceutical 1:1 cocrystal theophylline–3,4-di­hydroxy­benzoic acid

An analysis and classification of the 2925 neutral binary organic cocrystals in the Cambridge Structural Database is reported, focusing specifically on those both showing polymorphism and containing an active pharmaceutical ingredient (API). The search was confined to mol­ecules having only C, H, N, O, S and halogens atoms. It was found that 400 out of 2925 cocrystals can be classified as pharmaceutical cocrystals, containing at least one API, and that of those, 56 can be classified as being polymorphic cocrystals. In general, the total number of polymorphic cocrystal systems of any type stands at 125. In addition, a new polymorph of the pharmaceutical cocrystal theophylline–3,4-di­hydroxy­benzoic acid (1/1), C₇H₈N₄O₂·C₇H₆O₄, is reported.

Computing details

Data collection: APEX3 (Bruker, 2016); cell refinement: SAINT-Plus (Bruker, 2016); data reduction: SAINT-Plus and XPREP (Bruker, 2016); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015b); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012) and DIAMOND (Brandenburg & Berndt, 1999); software used to prepare material for publication: WinGX (Farrugia, 2012).

1,3-Dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione–\ 3,4-dihydroxybenzoic acid (1/1)

Crystal data

C7H8N4O2·C7H6O4	F(000) = 1392
Mr = 334.29	Dx = 1.564 Mg m^−3
Orthorhombic, Pbca	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ac 2ab	Cell parameters from 2293 reflections
a = 6.7095 (3) Å	θ = 2.7–26.1°
b = 13.7764 (6) Å	µ = 0.13 mm^−1
c = 30.7205 (15) Å	T = 173 K
V = 2839.6 (2) Å^3	Needle, colourless
Z = 8	0.39 × 0.12 × 0.07 mm

Data collection

Bruker D8 Venture Photon CCD area detector diffractometer	2037 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.078
ω scans	θmax = 28.0°, θmin = 2.7°
Absorption correction: multi-scan (SADABS; Bruker, 2016)	h = −7→8
Tmin = 0.9, Tmax = 0.93	k = −15→18
16271 measured reflections	l = −40→33
3425 independent reflections

Refinement

Refinement on F^2	0 constraints
Least-squares matrix: full	Hydrogen site location: mixed
R[F^2 > 2σ(F^2)] = 0.048	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.123	w = 1/[σ^2(Fo^2) + (0.0522P)^2 + 0.1208P] where P = (Fo^2 + 2Fc^2)/3
S = 1.00	(Δ/σ)max < 0.001
3425 reflections	Δρmax = 0.23 e Å^−3
235 parameters	Δρmin = −0.22 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
C1	0.0994 (3)	0.32118 (14)	0.44979 (6)	0.0262 (4)
C2	0.0882 (3)	0.25119 (14)	0.41703 (7)	0.0284 (5)
H2A	0.0994	0.1844	0.4243	0.034*
C3	0.0612 (3)	0.27805 (14)	0.37428 (6)	0.0261 (4)
C4	0.0513 (3)	0.37639 (15)	0.36375 (6)	0.0271 (5)
C5	0.0679 (3)	0.44622 (15)	0.39604 (7)	0.0289 (5)
H5	0.0644	0.5131	0.3886	0.035*
C6	0.0897 (3)	0.41878 (14)	0.43916 (6)	0.0280 (5)
H6	0.098	0.4667	0.4613	0.034*
C7	0.1120 (3)	0.28559 (15)	0.49508 (7)	0.0297 (5)
O1	0.1156 (2)	0.35457 (10)	0.52520 (5)	0.0364 (4)
O2	0.1167 (2)	0.19924 (10)	0.50402 (4)	0.0382 (4)
O3	0.0427 (2)	0.21297 (11)	0.34084 (5)	0.0360 (4)
O4	0.0248 (2)	0.40593 (11)	0.32176 (5)	0.0348 (4)
H1	0.110 (4)	0.3251 (19)	0.5541 (10)	0.076 (9)*
H3	0.019 (4)	0.158 (2)	0.3509 (9)	0.065 (9)*
H4	0.010 (3)	0.3559 (18)	0.3048 (8)	0.047 (7)*
C8	0.0013 (3)	0.32810 (14)	0.20646 (7)	0.0281 (5)
C9	0.0680 (3)	0.26456 (14)	0.13184 (6)	0.0256 (5)
C10	0.0673 (3)	0.36317 (14)	0.11910 (6)	0.0246 (4)
C11	0.0771 (3)	0.50195 (14)	0.08572 (7)	0.0297 (5)
H11	0.0893	0.5486	0.0631	0.036*
C12	0.0389 (3)	0.43805 (13)	0.14759 (6)	0.0243 (4)
C13	−0.0421 (3)	0.50175 (15)	0.22021 (7)	0.0344 (5)
H13A	0.054	0.5546	0.2161	0.052*
H13B	−0.0367	0.4791	0.2504	0.052*
H13C	−0.1766	0.5253	0.2137	0.052*
C14	0.0475 (4)	0.15563 (15)	0.19476 (7)	0.0418 (6)
H14A	−0.0889	0.1322	0.1992	0.063*
H14B	0.1179	0.1565	0.2227	0.063*
H14C	0.1172	0.1124	0.1745	0.063*
N2	0.0909 (2)	0.40652 (12)	0.07910 (6)	0.0260 (4)
N1	0.0444 (2)	0.52539 (12)	0.12736 (5)	0.0281 (4)
N3	0.0070 (2)	0.42191 (11)	0.19112 (5)	0.0273 (4)
N4	0.0419 (2)	0.25433 (11)	0.17660 (5)	0.0282 (4)
O5	−0.0369 (2)	0.30865 (10)	0.24435 (4)	0.0363 (4)
O6	0.0889 (2)	0.19269 (10)	0.10814 (4)	0.0315 (4)
H2	0.105 (3)	0.3749 (15)	0.0526 (7)	0.034 (6)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0259 (11)	0.0303 (11)	0.0223 (10)	−0.0017 (8)	−0.0017 (8)	0.0014 (8)
C2	0.0325 (12)	0.0241 (10)	0.0285 (12)	−0.0020 (8)	0.0003 (9)	0.0036 (9)
C3	0.0285 (11)	0.0251 (11)	0.0248 (11)	−0.0022 (8)	0.0014 (8)	−0.0022 (8)
C4	0.0264 (11)	0.0321 (12)	0.0226 (11)	−0.0005 (9)	0.0008 (8)	0.0030 (8)
C5	0.0314 (11)	0.0265 (11)	0.0288 (12)	−0.0019 (9)	0.0018 (9)	0.0040 (9)
C6	0.0311 (11)	0.0265 (11)	0.0264 (11)	−0.0022 (8)	0.0003 (9)	−0.0029 (8)
C7	0.0312 (12)	0.0317 (12)	0.0264 (11)	−0.0027 (9)	−0.0012 (9)	−0.0023 (9)
O1	0.0530 (10)	0.0336 (9)	0.0226 (8)	−0.0042 (7)	−0.0025 (7)	−0.0008 (7)
O2	0.0589 (10)	0.0288 (9)	0.0269 (8)	−0.0012 (7)	−0.0018 (7)	0.0041 (6)
O3	0.0579 (10)	0.0260 (8)	0.0243 (8)	−0.0044 (7)	0.0001 (7)	−0.0010 (6)
O4	0.0515 (10)	0.0305 (9)	0.0224 (8)	−0.0009 (7)	−0.0009 (7)	0.0020 (7)
C8	0.0295 (12)	0.0292 (12)	0.0257 (11)	0.0002 (8)	−0.0004 (9)	−0.0023 (9)
C9	0.0272 (11)	0.0269 (11)	0.0227 (11)	−0.0008 (8)	−0.0004 (8)	−0.0005 (8)
C10	0.0243 (11)	0.0276 (11)	0.0220 (11)	−0.0008 (8)	0.0001 (8)	0.0000 (8)
C11	0.0354 (12)	0.0256 (11)	0.0282 (12)	−0.0022 (9)	−0.0001 (9)	0.0020 (9)
C12	0.0247 (10)	0.0257 (11)	0.0225 (11)	0.0000 (8)	0.0000 (8)	0.0011 (8)
C13	0.0458 (14)	0.0324 (12)	0.0249 (12)	0.0020 (10)	0.0012 (10)	−0.0052 (9)
C14	0.0621 (16)	0.0308 (12)	0.0324 (13)	0.0028 (11)	0.0047 (11)	0.0097 (9)
N2	0.0335 (10)	0.0249 (9)	0.0197 (9)	−0.0006 (7)	0.0012 (7)	0.0005 (7)
N1	0.0338 (10)	0.0269 (10)	0.0235 (9)	−0.0008 (7)	0.0000 (7)	−0.0009 (7)
N3	0.0336 (10)	0.0257 (9)	0.0227 (9)	0.0020 (7)	0.0006 (7)	−0.0010 (7)
N4	0.0364 (10)	0.0243 (9)	0.0238 (9)	0.0001 (7)	0.0005 (7)	0.0017 (7)
O5	0.0500 (10)	0.0373 (9)	0.0218 (8)	−0.0004 (7)	0.0036 (7)	0.0023 (7)
O6	0.0449 (9)	0.0243 (8)	0.0255 (8)	0.0014 (6)	−0.0001 (7)	−0.0023 (6)

Geometric parameters (Å, º)

C1—C6	1.385 (3)	C9—O6	1.237 (2)
C1—C2	1.396 (3)	C9—N4	1.393 (3)
C1—C7	1.478 (3)	C9—C10	1.414 (3)
C2—C3	1.377 (3)	C10—C12	1.366 (3)
C2—H2A	0.95	C10—N2	1.375 (2)
C3—O3	1.369 (2)	C11—N2	1.333 (2)
C3—C4	1.394 (3)	C11—N1	1.337 (2)
C4—O4	1.364 (2)	C11—H11	0.95
C4—C5	1.386 (3)	C12—N1	1.355 (2)
C5—C6	1.385 (3)	C12—N3	1.372 (2)
C5—H5	0.95	C13—N3	1.455 (2)
C6—H6	0.95	C13—H13A	0.98
C7—O2	1.221 (2)	C13—H13B	0.98
C7—O1	1.327 (2)	C13—H13C	0.98
O1—H1	0.98 (3)	C14—N4	1.470 (3)
O3—H3	0.83 (3)	C14—H14A	0.98
O4—H4	0.87 (2)	C14—H14B	0.98
C8—O5	1.222 (2)	C14—H14C	0.98
C8—N3	1.376 (2)	N2—H2	0.93 (2)
C8—N4	1.396 (3)
C6—C1—C2	119.88 (18)	C12—C10—C9	123.28 (18)
C6—C1—C7	123.14 (18)	N2—C10—C9	131.62 (18)
C2—C1—C7	116.92 (18)	N2—C11—N1	113.28 (18)
C3—C2—C1	120.61 (18)	N2—C11—H11	123.4
C3—C2—H2A	119.7	N1—C11—H11	123.4
C1—C2—H2A	119.7	N1—C12—C10	111.89 (17)
O3—C3—C2	123.48 (18)	N1—C12—N3	126.53 (17)
O3—C3—C4	117.25 (17)	C10—C12—N3	121.58 (17)
C2—C3—C4	119.27 (18)	N3—C13—H13A	109.5
O4—C4—C5	118.70 (18)	N3—C13—H13B	109.5
O4—C4—C3	121.03 (18)	H13A—C13—H13B	109.5
C5—C4—C3	120.28 (18)	N3—C13—H13C	109.5
C6—C5—C4	120.23 (19)	H13A—C13—H13C	109.5
C6—C5—H5	119.9	H13B—C13—H13C	109.5
C4—C5—H5	119.9	N4—C14—H14A	109.5
C1—C6—C5	119.68 (18)	N4—C14—H14B	109.5
C1—C6—H6	120.2	H14A—C14—H14B	109.5
C5—C6—H6	120.2	N4—C14—H14C	109.5
O2—C7—O1	122.72 (19)	H14A—C14—H14C	109.5
O2—C7—C1	122.44 (18)	H14B—C14—H14C	109.5
O1—C7—C1	114.83 (18)	C11—N2—C10	106.50 (17)
C7—O1—H1	109.6 (16)	C11—N2—H2	127.0 (13)
C3—O3—H3	109.6 (19)	C10—N2—H2	126.3 (13)
C4—O4—H4	110.1 (16)	C11—N1—C12	103.23 (16)
O5—C8—N3	122.56 (18)	C12—N3—C8	119.35 (16)
O5—C8—N4	120.50 (18)	C12—N3—C13	120.76 (16)
N3—C8—N4	116.94 (18)	C8—N3—C13	119.55 (17)
O6—C9—N4	120.95 (17)	C9—N4—C8	126.83 (17)
O6—C9—C10	127.34 (18)	C9—N4—C14	117.70 (17)
N4—C9—C10	111.71 (17)	C8—N4—C14	115.39 (16)
C12—C10—N2	105.10 (17)
C6—C1—C2—C3	−2.1 (3)	C9—C10—C12—N3	−0.6 (3)
C7—C1—C2—C3	175.13 (19)	N1—C11—N2—C10	−0.5 (2)
C1—C2—C3—O3	−177.88 (18)	C12—C10—N2—C11	0.4 (2)
C1—C2—C3—C4	2.0 (3)	C9—C10—N2—C11	−180.0 (2)
O3—C3—C4—O4	−0.2 (3)	N2—C11—N1—C12	0.3 (2)
C2—C3—C4—O4	179.92 (18)	C10—C12—N1—C11	0.0 (2)
O3—C3—C4—C5	179.71 (18)	N3—C12—N1—C11	−179.32 (19)
C2—C3—C4—C5	−0.2 (3)	N1—C12—N3—C8	178.51 (18)
O4—C4—C5—C6	178.33 (18)	C10—C12—N3—C8	−0.7 (3)
C3—C4—C5—C6	−1.6 (3)	N1—C12—N3—C13	5.2 (3)
C2—C1—C6—C5	0.3 (3)	C10—C12—N3—C13	−174.00 (18)
C7—C1—C6—C5	−176.72 (19)	O5—C8—N3—C12	−176.01 (19)
C4—C5—C6—C1	1.5 (3)	N4—C8—N3—C12	4.1 (3)
C6—C1—C7—O2	178.58 (19)	O5—C8—N3—C13	−2.6 (3)
C2—C1—C7—O2	1.5 (3)	N4—C8—N3—C13	177.46 (17)
C6—C1—C7—O1	−0.7 (3)	O6—C9—N4—C8	−174.58 (18)
C2—C1—C7—O1	−177.82 (17)	C10—C9—N4—C8	5.6 (3)
O6—C9—C10—C12	178.5 (2)	O6—C9—N4—C14	2.2 (3)
N4—C9—C10—C12	−1.6 (3)	C10—C9—N4—C14	−177.62 (17)
O6—C9—C10—N2	−1.0 (4)	O5—C8—N4—C9	173.09 (19)
N4—C9—C10—N2	178.82 (19)	N3—C8—N4—C9	−7.0 (3)
N2—C10—C12—N1	−0.2 (2)	O5—C8—N4—C14	−3.8 (3)
C9—C10—C12—N1	−179.88 (17)	N3—C8—N4—C14	176.12 (17)
N2—C10—C12—N3	179.09 (17)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1···O6^i	0.98 (3)	1.68 (3)	2.636 (2)	164 (2)
O3—H3···N1^ii	0.83 (3)	1.99 (3)	2.824 (2)	177 (3)
O4—H4···O3	0.87 (2)	2.27 (2)	2.725 (2)	113 (2)
O4—H4···O5	0.87 (2)	1.99 (3)	2.761 (2)	147 (2)
N2—H2···O2^iii	0.93 (2)	1.81 (2)	2.734 (2)	172.9 (19)

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