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.
Supporting information
CCDC reference: 1451221
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-1
H-purine-2,6-dione–\
3,4-dihydroxybenzoic acid (1/1)
top
Crystal data top
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) Å3 | Needle, colourless |
Z = 8 | 0.39 × 0.12 × 0.07 mm |
Data collection top
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 top
Refinement on F2 | 0 constraints |
Least-squares matrix: full | Hydrogen site location: mixed |
R[F2 > 2σ(F2)] = 0.048 | H atoms treated by a mixture of independent and constrained refinement |
wR(F2) = 0.123 | w = 1/[σ2(Fo2) + (0.0522P)2 + 0.1208P] where P = (Fo2 + 2Fc2)/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 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 | 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 (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
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) top
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) top
D—H···A | D—H | H···A | D···A | D—H···A |
O1—H1···O6i | 0.98 (3) | 1.68 (3) | 2.636 (2) | 164 (2) |
O3—H3···N1ii | 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···O2iii | 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. |
Summary of CSD analysis topTotal number of binary cocrystal structures | 2925 |
Total number of pharmaceutical cocrystal structures | 400/2925 (13.6%) |
Pharmaceutical cocrystals containing a GRAS compound | 145/400 |
Pharmaceutical cocrystals containing a non-GRAS compound | 211/400 |
Pharmaceutical cocrystals consisting of two drug compounds | 44/400 |
Total number of polymorphic pharmaceutical cocrystal combinations | 56/400 (14.0%) |
Total number of polymorphic cocrystal structures | 239/2925 (8.2 %) |
Total number of polymorphic cocrystal systems | 125 |
Details of caffeine cocrystal systems (unique combinations) that are
polymorphic topCo-former | CSD refcodes | Polymorphism Type (Packing/conformational/synthon) |
4-Chloro-3-nitrobenzoic acid | DIPHUH, DIPHUH01 | P |
Glutaric acid | EXUQUJ, EXUQUJ01 | P/C |
Maleic acid | GANYEA, GANYEA01 | P/C/S |
Mesaconic acid | HOLWAI, HOLWAI01, HOLWAI02. | P/C |
Citric acid | KIGKER, KIGKER01 | P/S/C |
Theophylline | NEHJER, NEHJER01 | P |
Trifluoroacetic acid | VAWKUA, VAWKUA01 | P |
Pterostilbene | YABHAM, YABHAM01 | P |