Buy article online - an online subscription or single-article purchase is required to access this article.
The structure of a previously unreported polymorph of anhydrous theophylline (1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione), C7H8N4O2, has been determined at 100 K and shown to have monoclinic symmetry with Z' = 2. The structure is named form IV and experimental observation indicates that this is the stable form of the material. The molecular packing consists of discrete hydrogen-bonded dimers similar to that observed in the monohydrate structure. The structure of form I has also been determined and consists of hydrogen-bonded chains.
Supporting information
CCDC references: 862237; 862238
Anhydrous theophylline purchased from Sigma Aldrich UK was identified as form
(II) and used as received. To prepare form (IV), a saturated solution of
theophylline was prepared by suspending excess form (II) in a 9:1, methanol
(HPLC gradient grade): water solvent mixture for 1 h at 318 K and then
filtering with a syringe filter of 0.45 µm size. The filtered solution was
cooled to room temperature. After 1 h, needle-like crystals were observed
which were held in contact with the mother liquor for 2 months. Over this
period, the morphology of the crystals was observed to change, with hexagonal
plates being observed after several days, indicating the solvent-mediated
transformation to form (IV). Form (I) could not be obtained by solution
methods and was prepared by heating form (II) in glass vials at 538-541 K for
2 h. The crystals undergo solid-state conversion and in doing so the parent
crystal laminates to produce very fine needles of form (I). The quality of the
crystals was poor and contained cracks and defects introduced during the phase
transition.
The positions of the H atoms of form (IV) were refined freely with their
U values riding on those of their carrier atoms. The H atoms of form
(I) were constrained with N—H, C1—H1 and C—H(methyl) distances of 0.88,
0.95 and 0.98 Å, respectively, with their U values again riding.
The quality of form (I) crystals, which were obtained by solid-state
conversion, was poor. The best crystal was selected from several samples but
it was not possible to obtain a high-quality crystal without defects. The
dimensions of the crystals were such that data collection was only just
possible. The crystal diffracted poorly and reflection intensity was extremely
weak so that a scan time greater than 30 h produced 90% completion. Further
collection was not possible due to the quality and size of the crystal.
For both compounds, data collection: COLLECT (Hooft, 1998); cell refinement: HKL SCALEPACK (Otwinowski & Minor, 1997); data reduction: HKL DENZO and SCALEPACK (Otwinowski & Minor, 1997); program(s) used to solve structure: SIR92 (Altomare et al., 1994); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997); software used to prepare material for publication: WinGX publication routines (Farrugia, 1999).
(IV) 3,7-dihydro-1,3-dimethyl-1
H-purine-2,6-dione
top
Crystal data top
C7H8N4O2 | F(000) = 752 |
Mr = 180.17 | Dx = 1.555 Mg m−3 |
Monoclinic, P21/c | Mo Kα radiation, λ = 0.71073 Å |
Hall symbol: -P 2ybc | Cell parameters from 3844 reflections |
a = 7.7055 (1) Å | θ = 2–26° |
b = 13.0010 (2) Å | µ = 0.12 mm−1 |
c = 15.7794 (3) Å | T = 100 K |
β = 103.224 (1)° | Plate, colourless |
V = 1538.85 (4) Å3 | 0.25 × 0.2 × 0.08 mm |
Z = 8 | |
Data collection top
Nonius KappaCCD area-detector diffractometer | 3023 independent reflections |
Radiation source: Enraf–Nonius FR590 | 2275 reflections with I > 2σ(I) |
Graphite monochromator | Rint = 0.075 |
Detector resolution: 9 pixels mm-1 | θmax = 26°, θmin = 3.1° |
CCD rotation images, thick slices scans | h = 0→9 |
Absorption correction: multi-scan (Blessing, 1989) | k = 0→16 |
Tmin = 0.971, Tmax = 0.991 | l = −19→18 |
35162 measured reflections | |
Refinement top
Refinement on F2 | Secondary atom site location: difference Fourier map |
Least-squares matrix: full | Hydrogen site location: inferred from neighbouring sites |
R[F2 > 2σ(F2)] = 0.050 | All H-atom parameters refined |
wR(F2) = 0.138 | w = 1/[σ2(Fo2) + (0.0683P)2 + 1.0567P] where P = (Fo2 + 2Fc2)/3 |
S = 1.07 | (Δ/σ)max < 0.001 |
3023 reflections | Δρmax = 0.25 e Å−3 |
300 parameters | Δρmin = −0.32 e Å−3 |
0 restraints | Extinction correction: SHELXL, Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4 |
Primary atom site location: structure-invariant direct methods | Extinction coefficient: 0.0035 (14) |
Crystal data top
C7H8N4O2 | V = 1538.85 (4) Å3 |
Mr = 180.17 | Z = 8 |
Monoclinic, P21/c | Mo Kα radiation |
a = 7.7055 (1) Å | µ = 0.12 mm−1 |
b = 13.0010 (2) Å | T = 100 K |
c = 15.7794 (3) Å | 0.25 × 0.2 × 0.08 mm |
β = 103.224 (1)° | |
Data collection top
Nonius KappaCCD area-detector diffractometer | 3023 independent reflections |
Absorption correction: multi-scan (Blessing, 1989) | 2275 reflections with I > 2σ(I) |
Tmin = 0.971, Tmax = 0.991 | Rint = 0.075 |
35162 measured reflections | |
Refinement top
R[F2 > 2σ(F2)] = 0.050 | 0 restraints |
wR(F2) = 0.138 | All H-atom parameters refined |
S = 1.07 | Δρmax = 0.25 e Å−3 |
3023 reflections | Δρmin = −0.32 e Å−3 |
300 parameters | |
Special details top
Geometry. All s.u.'s (except the s.u. in the dihedral angle between two l.s. planes) are
estimated using the full covariance matrix. The cell s.u.'s are taken into
account individually in the estimation of s.u.'s in distances, angles and
torsion angles; correlations between s.u.'s in cell parameters are only used
when they are defined by crystal symmetry. An approximate (isotropic)
treatment of cell s.u.'s is used for estimating s.u.'s involving l.s. planes. |
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top | x | y | z | Uiso*/Ueq | |
C1 | 0.3212 (3) | 0.50420 (17) | 0.63506 (14) | 0.0266 (5) | |
C2 | 0.2328 (3) | 0.52543 (15) | 0.49470 (13) | 0.0215 (4) | |
C3 | 0.1953 (3) | 0.52080 (16) | 0.40273 (14) | 0.0234 (5) | |
C4 | 0.0124 (3) | 0.67913 (15) | 0.40692 (13) | 0.0218 (4) | |
C5 | 0.1655 (3) | 0.59992 (15) | 0.53948 (13) | 0.0217 (4) | |
C6 | 0.0417 (3) | 0.6053 (2) | 0.26781 (14) | 0.0309 (5) | |
C7 | −0.0217 (3) | 0.75327 (19) | 0.54468 (16) | 0.0288 (5) | |
C11 | 0.4273 (3) | 0.22393 (17) | 0.29313 (14) | 0.0255 (5) | |
C12 | 0.5243 (3) | 0.20659 (15) | 0.43310 (13) | 0.0212 (4) | |
C13 | 0.5653 (3) | 0.21345 (16) | 0.52510 (13) | 0.0227 (5) | |
C14 | 0.7217 (3) | 0.04496 (16) | 0.52199 (13) | 0.0227 (5) | |
C15 | 0.5764 (3) | 0.12563 (15) | 0.38935 (13) | 0.0216 (4) | |
C16 | 0.7207 (3) | 0.12615 (18) | 0.66041 (14) | 0.0266 (5) | |
C17 | 0.7376 (3) | −0.03938 (17) | 0.38541 (15) | 0.0262 (5) | |
N1 | 0.2190 (2) | 0.58844 (14) | 0.62739 (12) | 0.0258 (4) | |
N2 | 0.3339 (2) | 0.46310 (14) | 0.55842 (11) | 0.0250 (4) | |
N3 | 0.0856 (2) | 0.60140 (13) | 0.36367 (11) | 0.0232 (4) | |
N4 | 0.0553 (2) | 0.67640 (13) | 0.49658 (11) | 0.0226 (4) | |
N11 | 0.5177 (2) | 0.13552 (14) | 0.30143 (11) | 0.0260 (4) | |
N12 | 0.4254 (2) | 0.26962 (14) | 0.36910 (11) | 0.0235 (4) | |
N13 | 0.6660 (2) | 0.12947 (13) | 0.56479 (11) | 0.0227 (4) | |
N14 | 0.6739 (2) | 0.04496 (13) | 0.43192 (11) | 0.0233 (4) | |
O1 | 0.2495 (2) | 0.45574 (12) | 0.35749 (10) | 0.0286 (4) | |
O2 | −0.08478 (19) | 0.74583 (11) | 0.36696 (10) | 0.0277 (4) | |
O11 | 0.5225 (2) | 0.28330 (11) | 0.56969 (9) | 0.0282 (4) | |
O12 | 0.8084 (2) | −0.02497 (11) | 0.56285 (10) | 0.0284 (4) | |
H1 | 0.381 (3) | 0.4730 (17) | 0.6924 (15) | 0.021 (5)* | |
H2 | 0.401 (4) | 0.402 (2) | 0.5508 (19) | 0.055 (9)* | |
H6A | −0.006 (5) | 0.537 (3) | 0.245 (2) | 0.081 (11)* | |
H6B | 0.152 (5) | 0.618 (2) | 0.246 (2) | 0.064 (9)* | |
H6C | −0.041 (5) | 0.664 (3) | 0.247 (3) | 0.094 (13)* | |
H7A | 0.007 (4) | 0.740 (2) | 0.606 (2) | 0.053 (8)* | |
H7B | 0.017 (4) | 0.822 (3) | 0.5344 (19) | 0.057 (9)* | |
H7C | −0.149 (5) | 0.752 (2) | 0.523 (2) | 0.061 (9)* | |
H11 | 0.364 (3) | 0.2532 (19) | 0.2357 (17) | 0.036 (7)* | |
H12 | 0.374 (4) | 0.338 (2) | 0.373 (2) | 0.056 (9)* | |
H16A | 0.682 (4) | 0.062 (2) | 0.6818 (18) | 0.042 (7)* | |
H16B | 0.848 (4) | 0.130 (2) | 0.6808 (18) | 0.046 (8)* | |
H16C | 0.667 (4) | 0.191 (2) | 0.6834 (17) | 0.041 (7)* | |
H17A | 0.688 (3) | −0.0299 (17) | 0.3207 (16) | 0.024 (6)* | |
H17B | 0.866 (4) | −0.039 (2) | 0.3948 (18) | 0.043 (7)* | |
H17C | 0.701 (3) | −0.108 (2) | 0.4056 (16) | 0.038 (7)* | |
Atomic displacement parameters (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
C1 | 0.0278 (11) | 0.0261 (11) | 0.0249 (11) | 0.0002 (9) | 0.0039 (9) | 0.0019 (9) |
C2 | 0.0198 (10) | 0.0200 (10) | 0.0240 (10) | −0.0005 (8) | 0.0037 (8) | 0.0011 (8) |
C3 | 0.0194 (9) | 0.0226 (11) | 0.0272 (11) | −0.0008 (8) | 0.0035 (8) | 0.0000 (8) |
C4 | 0.0198 (10) | 0.0217 (10) | 0.0237 (10) | −0.0010 (8) | 0.0044 (8) | −0.0002 (8) |
C5 | 0.0207 (10) | 0.0202 (10) | 0.0233 (10) | −0.0027 (8) | 0.0033 (8) | 0.0010 (8) |
C6 | 0.0362 (13) | 0.0348 (13) | 0.0207 (11) | 0.0079 (11) | 0.0042 (9) | −0.0006 (10) |
C7 | 0.0325 (13) | 0.0268 (12) | 0.0273 (12) | 0.0075 (10) | 0.0075 (10) | −0.0033 (9) |
C11 | 0.0264 (11) | 0.0266 (11) | 0.0220 (11) | −0.0010 (9) | 0.0027 (9) | −0.0003 (9) |
C12 | 0.0209 (10) | 0.0197 (10) | 0.0219 (10) | −0.0008 (8) | 0.0027 (8) | 0.0016 (8) |
C13 | 0.0195 (10) | 0.0224 (10) | 0.0262 (11) | −0.0011 (8) | 0.0050 (8) | 0.0010 (8) |
C14 | 0.0216 (10) | 0.0207 (10) | 0.0255 (11) | −0.0023 (8) | 0.0046 (8) | 0.0001 (8) |
C15 | 0.0225 (10) | 0.0198 (10) | 0.0216 (10) | −0.0030 (8) | 0.0028 (8) | 0.0008 (8) |
C16 | 0.0298 (12) | 0.0279 (12) | 0.0211 (11) | 0.0028 (10) | 0.0040 (9) | 0.0027 (9) |
C17 | 0.0289 (12) | 0.0228 (11) | 0.0276 (12) | 0.0035 (9) | 0.0079 (9) | −0.0028 (9) |
N1 | 0.0276 (9) | 0.0248 (9) | 0.0239 (9) | 0.0004 (8) | 0.0032 (7) | 0.0021 (7) |
N2 | 0.0255 (9) | 0.0226 (9) | 0.0253 (10) | 0.0025 (8) | 0.0024 (7) | 0.0032 (7) |
N3 | 0.0245 (9) | 0.0225 (9) | 0.0213 (9) | 0.0026 (7) | 0.0026 (7) | 0.0011 (7) |
N4 | 0.0250 (9) | 0.0188 (9) | 0.0239 (9) | 0.0021 (7) | 0.0052 (7) | −0.0002 (7) |
N11 | 0.0266 (9) | 0.0257 (10) | 0.0241 (9) | 0.0015 (8) | 0.0022 (7) | −0.0002 (7) |
N12 | 0.0233 (9) | 0.0219 (9) | 0.0235 (9) | 0.0010 (7) | 0.0019 (7) | 0.0010 (7) |
N13 | 0.0248 (9) | 0.0220 (9) | 0.0215 (9) | 0.0025 (7) | 0.0054 (7) | 0.0015 (7) |
N14 | 0.0253 (9) | 0.0220 (9) | 0.0219 (9) | 0.0015 (7) | 0.0040 (7) | −0.0013 (7) |
O1 | 0.0301 (8) | 0.0273 (8) | 0.0273 (8) | 0.0055 (6) | 0.0045 (6) | −0.0031 (6) |
O2 | 0.0270 (8) | 0.0252 (8) | 0.0287 (8) | 0.0050 (6) | 0.0017 (6) | 0.0024 (6) |
O11 | 0.0349 (8) | 0.0245 (8) | 0.0247 (8) | 0.0051 (6) | 0.0060 (6) | −0.0027 (6) |
O12 | 0.0307 (8) | 0.0239 (8) | 0.0294 (8) | 0.0051 (6) | 0.0045 (7) | 0.0036 (6) |
Geometric parameters (Å, º) top
C1—N1 | 1.338 (3) | C11—N12 | 1.341 (3) |
C1—N2 | 1.346 (3) | C11—H11 | 1.00 (3) |
C1—H1 | 1.00 (2) | C12—C15 | 1.368 (3) |
C2—C5 | 1.369 (3) | C12—N12 | 1.386 (3) |
C2—N2 | 1.384 (3) | C12—C13 | 1.416 (3) |
C2—C3 | 1.415 (3) | C13—O11 | 1.239 (3) |
C3—O1 | 1.239 (3) | C13—N13 | 1.401 (3) |
C3—N3 | 1.398 (3) | C14—O12 | 1.221 (2) |
C4—O2 | 1.222 (2) | C14—N14 | 1.384 (3) |
C4—N4 | 1.378 (3) | C14—N13 | 1.407 (3) |
C4—N3 | 1.408 (3) | C15—N11 | 1.363 (3) |
C5—N1 | 1.362 (3) | C15—N14 | 1.373 (3) |
C5—N4 | 1.380 (3) | C16—N13 | 1.471 (3) |
C6—N3 | 1.473 (3) | C16—H16A | 0.97 (3) |
C6—H6A | 1.00 (4) | C16—H16B | 0.96 (3) |
C6—H6B | 1.00 (3) | C16—H16C | 1.04 (3) |
C6—H6C | 1.00 (4) | C17—N14 | 1.465 (3) |
C7—N4 | 1.460 (3) | C17—H17A | 1.01 (2) |
C7—H7A | 0.96 (3) | C17—H17B | 0.96 (3) |
C7—H7B | 0.97 (3) | C17—H17C | 1.01 (3) |
C7—H7C | 0.96 (4) | N2—H2 | 0.97 (3) |
C11—N11 | 1.334 (3) | N12—H12 | 0.98 (3) |
| | | |
N1—C1—N2 | 113.95 (19) | O12—C14—N13 | 121.20 (19) |
N1—C1—H1 | 123.6 (12) | N14—C14—N13 | 117.01 (18) |
N2—C1—H1 | 122.5 (12) | N11—C15—C12 | 111.93 (18) |
C5—C2—N2 | 104.83 (18) | N11—C15—N14 | 125.94 (18) |
C5—C2—C3 | 123.17 (19) | C12—C15—N14 | 122.12 (18) |
N2—C2—C3 | 131.99 (19) | N13—C16—H16A | 110.1 (16) |
O1—C3—N3 | 120.46 (18) | N13—C16—H16B | 111.8 (16) |
O1—C3—C2 | 127.12 (19) | H16A—C16—H16B | 107 (2) |
N3—C3—C2 | 112.41 (18) | N13—C16—H16C | 107.0 (15) |
O2—C4—N4 | 121.51 (18) | H16A—C16—H16C | 113 (2) |
O2—C4—N3 | 121.70 (18) | H16B—C16—H16C | 107 (2) |
N4—C4—N3 | 116.79 (17) | N14—C17—H17A | 108.8 (13) |
N1—C5—C2 | 112.71 (18) | N14—C17—H17B | 111.7 (16) |
N1—C5—N4 | 125.97 (19) | H17A—C17—H17B | 107 (2) |
C2—C5—N4 | 121.32 (18) | N14—C17—H17C | 110.7 (15) |
N3—C6—H6A | 108 (2) | H17A—C17—H17C | 111.1 (19) |
N3—C6—H6B | 110.4 (18) | H17B—C17—H17C | 108 (2) |
H6A—C6—H6B | 107 (3) | C1—N1—C5 | 102.51 (18) |
N3—C6—H6C | 110 (2) | C1—N2—C2 | 105.99 (18) |
H6A—C6—H6C | 114 (3) | C1—N2—H2 | 125.9 (18) |
H6B—C6—H6C | 107 (3) | C2—N2—H2 | 128.1 (18) |
N4—C7—H7A | 112.0 (18) | C3—N3—C4 | 126.40 (17) |
N4—C7—H7B | 111.7 (19) | C3—N3—C6 | 116.89 (17) |
H7A—C7—H7B | 109 (2) | C4—N3—C6 | 116.71 (17) |
N4—C7—H7C | 107.7 (19) | C4—N4—C5 | 119.88 (17) |
H7A—C7—H7C | 110 (2) | C4—N4—C7 | 119.05 (17) |
H7B—C7—H7C | 107 (3) | C5—N4—C7 | 121.04 (18) |
N11—C11—N12 | 113.96 (19) | C11—N11—C15 | 103.02 (17) |
N11—C11—H11 | 123.5 (15) | C11—N12—C12 | 105.83 (18) |
N12—C11—H11 | 122.5 (15) | C11—N12—H12 | 122.9 (18) |
C15—C12—N12 | 105.25 (17) | C12—N12—H12 | 130.9 (18) |
C15—C12—C13 | 122.90 (18) | C13—N13—C14 | 126.32 (17) |
N12—C12—C13 | 131.80 (19) | C13—N13—C16 | 118.72 (17) |
O11—C13—N13 | 120.63 (18) | C14—N13—C16 | 114.96 (17) |
O11—C13—C12 | 127.04 (19) | C15—N14—C14 | 119.31 (17) |
N13—C13—C12 | 112.33 (18) | C15—N14—C17 | 122.36 (17) |
O12—C14—N14 | 121.79 (19) | C14—N14—C17 | 118.26 (17) |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
N2—H2···O11 | 0.97 (3) | 1.80 (3) | 2.736 (2) | 163 (3) |
N12—H12···O1 | 0.98 (3) | 1.80 (3) | 2.759 (2) | 168 (3) |
C1—H1···N11i | 1.00 (2) | 2.29 (2) | 3.266 (3) | 165 (2) |
C11—H11···O2ii | 1.00 (3) | 2.38 (3) | 3.222 (3) | 141 (2) |
Symmetry codes: (i) x, −y+1/2, z+1/2; (ii) −x, y−1/2, −z+1/2. |
(I) 3,7-dihydro-1,3-dimethyl-1
H-purine-2,6-dione
top
Crystal data top
C7H8N4O2 | F(000) = 376 |
Mr = 180.17 | Dx = 1.51 Mg m−3 |
Orthorhombic, Pna21 | Mo Kα radiation, λ = 0.71073 Å |
Hall symbol: P 2c -2n | Cell parameters from 817 reflections |
a = 13.158 (2) Å | θ = 2–26° |
b = 15.630 (3) Å | µ = 0.12 mm−1 |
c = 3.854 (1) Å | T = 100 K |
V = 792.6 (3) Å3 | Prism, colourless |
Z = 4 | 0.25 × 0.06 × 0.03 mm |
Data collection top
Nonius KappaCCD area-detector diffractometer | 764 independent reflections |
Radiation source: Enraf–Nonius FR590 | 462 reflections with I > 2σ(I) |
Graphite monochromator | Rint = 0.040 |
Detector resolution: 9 pixels mm-1 | θmax = 25.4°, θmin = 3.1° |
CCD rotation images, thick slices scans | h = −15→15 |
Absorption correction: multi-scan (SORTAV; Blessing, 1989) | k = −18→18 |
Tmin = 0.972, Tmax = 0.997 | l = −4→4 |
1246 measured reflections | |
Refinement top
Refinement on F2 | Secondary atom site location: difference Fourier map |
Least-squares matrix: full | Hydrogen site location: inferred from neighbouring sites |
R[F2 > 2σ(F2)] = 0.088 | H-atom parameters constrained |
wR(F2) = 0.202 | w = 1/[σ2(Fo2) + (0.01P)2 + 3.50P] where P = (Fo2 + 2Fc2)/3 |
S = 0.98 | (Δ/σ)max = 0.005 |
764 reflections | Δρmax = 0.34 e Å−3 |
120 parameters | Δρmin = −0.30 e Å−3 |
1 restraint | Absolute structure: Flack (1983), no. Friedel pairs? |
Primary atom site location: structure-invariant direct methods | Absolute structure parameter: −10 (10) |
Crystal data top
C7H8N4O2 | V = 792.6 (3) Å3 |
Mr = 180.17 | Z = 4 |
Orthorhombic, Pna21 | Mo Kα radiation |
a = 13.158 (2) Å | µ = 0.12 mm−1 |
b = 15.630 (3) Å | T = 100 K |
c = 3.854 (1) Å | 0.25 × 0.06 × 0.03 mm |
Data collection top
Nonius KappaCCD area-detector diffractometer | 764 independent reflections |
Absorption correction: multi-scan (SORTAV; Blessing, 1989) | 462 reflections with I > 2σ(I) |
Tmin = 0.972, Tmax = 0.997 | Rint = 0.040 |
1246 measured reflections | |
Refinement top
R[F2 > 2σ(F2)] = 0.088 | H-atom parameters constrained |
wR(F2) = 0.202 | Δρmax = 0.34 e Å−3 |
S = 0.98 | Δρmin = −0.30 e Å−3 |
764 reflections | Absolute structure: Flack (1983), no. Friedel pairs? |
120 parameters | Absolute structure parameter: −10 (10) |
1 restraint | |
Special details top
Geometry. All s.u.'s (except the s.u. in the dihedral angle between two l.s. planes) are
estimated using the full covariance matrix. The cell s.u.'s are taken into
account individually in the estimation of s.u.'s in distances, angles and
torsion angles; correlations between s.u.'s in cell parameters are only used
when they are defined by crystal symmetry. An approximate (isotropic)
treatment of cell s.u.'s is used for estimating s.u.'s involving l.s. planes. |
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top | x | y | z | Uiso*/Ueq | |
C1 | −0.0241 (7) | 0.4035 (6) | 0.658 (3) | 0.064 (3) | |
H1 | −0.0622 | 0.4514 | 0.5809 | 0.077* | |
C2 | 0.0194 (6) | 0.2682 (5) | 0.772 (3) | 0.052 (2) | |
C3 | 0.0271 (6) | 0.1808 (6) | 0.807 (4) | 0.061 (3) | |
C4 | 0.1886 (6) | 0.2116 (5) | 1.116 (3) | 0.055 (3) | |
C5 | 0.0913 (6) | 0.3256 (6) | 0.895 (3) | 0.052 (2) | |
C6 | 0.1345 (7) | 0.0626 (5) | 1.058 (3) | 0.069 (3) | |
H6A | 0.2063 | 0.0537 | 1.1142 | 0.104* | |
H6B | 0.1171 | 0.0296 | 0.8497 | 0.104* | |
H6C | 0.0923 | 0.0435 | 1.2523 | 0.104* | |
C7 | 0.2524 (6) | 0.3593 (5) | 1.190 (3) | 0.061 (3) | |
H7A | 0.2713 | 0.3464 | 1.4305 | 0.091* | |
H7B | 0.2232 | 0.4169 | 1.1783 | 0.091* | |
H7C | 0.313 | 0.3565 | 1.0426 | 0.091* | |
N1 | 0.0697 (5) | 0.4080 (5) | 0.828 (2) | 0.060 (2) | |
N2 | −0.0530 (5) | 0.3202 (4) | 0.621 (2) | 0.062 (2) | |
H2 | −0.1087 | 0.3025 | 0.5166 | 0.074* | |
N3 | 0.1159 (5) | 0.1552 (5) | 0.992 (3) | 0.062 (2) | |
N4 | 0.1776 (5) | 0.2970 (5) | 1.070 (2) | 0.057 (2) | |
O1 | −0.0350 (4) | 0.1251 (4) | 0.705 (2) | 0.067 (2) | |
O2 | 0.2641 (4) | 0.1825 (4) | 1.281 (3) | 0.070 (2) | |
Atomic displacement parameters (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
C1 | 0.060 (5) | 0.065 (6) | 0.069 (9) | 0.001 (4) | 0.000 (6) | −0.003 (6) |
C2 | 0.040 (4) | 0.061 (5) | 0.056 (7) | 0.002 (4) | −0.008 (5) | −0.005 (5) |
C3 | 0.048 (5) | 0.071 (6) | 0.064 (8) | 0.004 (5) | 0.003 (6) | 0.001 (6) |
C4 | 0.047 (5) | 0.058 (5) | 0.059 (8) | −0.004 (4) | 0.005 (5) | 0.002 (5) |
C5 | 0.049 (5) | 0.067 (5) | 0.042 (7) | −0.004 (4) | −0.003 (4) | −0.002 (5) |
C6 | 0.081 (6) | 0.058 (5) | 0.069 (9) | 0.008 (5) | 0.002 (7) | 0.001 (6) |
C7 | 0.056 (5) | 0.063 (5) | 0.062 (8) | −0.010 (4) | −0.003 (5) | −0.004 (5) |
N1 | 0.058 (4) | 0.064 (5) | 0.058 (6) | 0.004 (4) | 0.009 (4) | 0.001 (4) |
N2 | 0.062 (4) | 0.064 (4) | 0.059 (6) | −0.002 (4) | −0.001 (5) | −0.002 (5) |
N3 | 0.054 (4) | 0.066 (5) | 0.068 (7) | −0.001 (4) | 0.004 (5) | 0.000 (5) |
N4 | 0.049 (4) | 0.070 (5) | 0.053 (6) | 0.002 (4) | 0.001 (4) | 0.007 (5) |
O1 | 0.056 (3) | 0.070 (4) | 0.077 (6) | −0.008 (3) | −0.003 (4) | −0.010 (4) |
O2 | 0.052 (3) | 0.080 (4) | 0.079 (6) | 0.004 (3) | −0.015 (4) | 0.006 (5) |
Geometric parameters (Å, º) top
C1—N2 | 1.364 (10) | C5—N1 | 1.345 (11) |
C1—N1 | 1.399 (11) | C5—N4 | 1.393 (10) |
C1—H1 | 0.95 | C6—N3 | 1.489 (10) |
C2—C3 | 1.376 (12) | C6—H6A | 0.98 |
C2—N2 | 1.381 (11) | C6—H6B | 0.98 |
C2—C5 | 1.388 (11) | C6—H6C | 0.98 |
C3—O1 | 1.257 (10) | C7—N4 | 1.460 (10) |
C3—N3 | 1.426 (13) | C7—H7A | 0.98 |
C4—O2 | 1.265 (11) | C7—H7B | 0.98 |
C4—N4 | 1.354 (10) | C7—H7C | 0.98 |
C4—N3 | 1.387 (11) | N2—H2 | 0.88 |
| | | |
N2—C1—N1 | 110.1 (8) | H6A—C6—H6C | 109.5 |
N2—C1—H1 | 124.9 | H6B—C6—H6C | 109.5 |
N1—C1—H1 | 124.9 | N4—C7—H7A | 109.5 |
C3—C2—N2 | 132.6 (8) | N4—C7—H7B | 109.5 |
C3—C2—C5 | 123.9 (9) | H7A—C7—H7B | 109.5 |
N2—C2—C5 | 103.5 (7) | N4—C7—H7C | 109.5 |
O1—C3—C2 | 127.6 (9) | H7A—C7—H7C | 109.5 |
O1—C3—N3 | 119.6 (8) | H7B—C7—H7C | 109.5 |
C2—C3—N3 | 112.8 (8) | C5—N1—C1 | 103.2 (7) |
O2—C4—N4 | 120.4 (8) | C1—N2—C2 | 109.0 (8) |
O2—C4—N3 | 119.1 (8) | C1—N2—H2 | 125.5 |
N4—C4—N3 | 120.5 (8) | C2—N2—H2 | 125.5 |
N1—C5—C2 | 114.2 (8) | C4—N3—C3 | 124.0 (8) |
N1—C5—N4 | 124.9 (8) | C4—N3—C6 | 116.5 (8) |
C2—C5—N4 | 120.9 (8) | C3—N3—C6 | 119.5 (8) |
N3—C6—H6A | 109.5 | C4—N4—C5 | 117.8 (8) |
N3—C6—H6B | 109.5 | C4—N4—C7 | 122.9 (8) |
H6A—C6—H6B | 109.5 | C5—N4—C7 | 119.3 (7) |
N3—C6—H6C | 109.5 | | |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
N2—H2···O2i | 0.88 | 1.92 | 2.743 (11) | 155 |
C1—H1···N1ii | 0.95 | 2.41 | 3.267 (12) | 150 |
Symmetry codes: (i) x−1/2, −y+1/2, z−1; (ii) −x, −y+1, z−1/2. |
Experimental details
| (IV) | (I) |
Crystal data |
Chemical formula | C7H8N4O2 | C7H8N4O2 |
Mr | 180.17 | 180.17 |
Crystal system, space group | Monoclinic, P21/c | Orthorhombic, Pna21 |
Temperature (K) | 100 | 100 |
a, b, c (Å) | 7.7055 (1), 13.0010 (2), 15.7794 (3) | 13.158 (2), 15.630 (3), 3.854 (1) |
α, β, γ (°) | 90, 103.224 (1), 90 | 90, 90, 90 |
V (Å3) | 1538.85 (4) | 792.6 (3) |
Z | 8 | 4 |
Radiation type | Mo Kα | Mo Kα |
µ (mm−1) | 0.12 | 0.12 |
Crystal size (mm) | 0.25 × 0.2 × 0.08 | 0.25 × 0.06 × 0.03 |
|
Data collection |
Diffractometer | Nonius KappaCCD area-detector diffractometer | Nonius KappaCCD area-detector diffractometer |
Absorption correction | Multi-scan (Blessing, 1989) | Multi-scan (SORTAV; Blessing, 1989) |
Tmin, Tmax | 0.971, 0.991 | 0.972, 0.997 |
No. of measured, independent and observed [I > 2σ(I)] reflections | 35162, 3023, 2275 | 1246, 764, 462 |
Rint | 0.075 | 0.040 |
(sin θ/λ)max (Å−1) | 0.617 | 0.603 |
|
Refinement |
R[F2 > 2σ(F2)], wR(F2), S | 0.050, 0.138, 1.07 | 0.088, 0.202, 0.98 |
No. of reflections | 3023 | 764 |
No. of parameters | 300 | 120 |
No. of restraints | 0 | 1 |
H-atom treatment | All H-atom parameters refined | H-atom parameters constrained |
Δρmax, Δρmin (e Å−3) | 0.25, −0.32 | 0.34, −0.30 |
Absolute structure | ? | Flack (1983), no. Friedel pairs? |
Absolute structure parameter | ? | −10 (10) |
Hydrogen-bond geometry (Å, º) for (IV) top
D—H···A | D—H | H···A | D···A | D—H···A |
N2—H2···O11 | 0.97 (3) | 1.80 (3) | 2.736 (2) | 163 (3) |
N12—H12···O1 | 0.98 (3) | 1.80 (3) | 2.759 (2) | 168 (3) |
C1—H1···N11i | 1.00 (2) | 2.29 (2) | 3.266 (3) | 165 (2) |
C11—H11···O2ii | 1.00 (3) | 2.38 (3) | 3.222 (3) | 141 (2) |
Symmetry codes: (i) x, −y+1/2, z+1/2; (ii) −x, y−1/2, −z+1/2. |
Hydrogen-bond geometry (Å, º) for (I) top
D—H···A | D—H | H···A | D···A | D—H···A |
N2—H2···O2i | 0.88 | 1.92 | 2.743 (11) | 155 |
C1—H1···N1ii | 0.95 | 2.41 | 3.267 (12) | 150 |
Symmetry codes: (i) x−1/2, −y+1/2, z−1; (ii) −x, −y+1, z−1/2. |
Subscribe to Acta Crystallographica Section C: Structural Chemistry
The full text of this article is available to subscribers to the journal.
If you have already registered and are using a computer listed in your registration details, please email
support@iucr.org for assistance.
Theophylline, (1), is a bronchodilator used to treat asthma in an oral dosage form. The hydration behaviour and solid-state chemistry have been studied (Wikstroem et al., 2008; Amado et al., 2007) and it is known to exist as a monohydrate form (Sun et al. 2002); three anhydrous polymorphs, forms (I), (II) and (III), have also been reported (Ebisuzaki et al., 1997; Suzuki et al.,1989; Matsuo & Matsuoka, 2007). Theophylline has been shown to convert between the monohydrate and anhydrous form (II) dependent on the humidity or water activity of the solvent environment (Zhu et al.,1996). The pharmaceutical properties of both the anhydrous and monohydrate material have been studied and shown to differ (Phadnis & Suryanarayanan, 1997).
The monohydrate, form (M), has a channel hydrate structure which has been shown to lose water to produce form (II) anhydrous material (Zhu et al.,1996; Ticehurst et al., 2002). The monohydrate packing [Sun et al., 2002; Cambridge Structural Database (CSD; Allen, 2002) refcode THEOPH01] consists of hydrogen-bonded dimer pairs which link via further hydrogen bonding with water molecules to form chains.
Form (II) occurs when the monohydrate loses water, either in low humidity or at temperatures above 353 K. The form (II) structure has been determined (Ebisuzaki et al., 1997; CSD refcode BAPLOT01) and consists of two bifurcated C—H···O hydrogen bonds and one N—H···N hydrogen bond. The molecules join via these bonds to form chains. Unlike the monohydrate, there are no discrete dimers present in the crystal structure of form (II).
Form (I) is reported to be the stable form at higher temperatures. Its powder pattern has been presented in the literature (Suzuki et al.,1989), but its structure has not been previously reported.
Form (III) is a highly metastable form and rapidly converts to form (II). Its powder pattern has been reported (Matsuo & Matsuoka 2007) but its structure has not been obtained due to its metastable nature.
Recently, a fourth anhydrous polymorph of theophylline was identified (Seton et al., 2010). Form (IV) occurs as a result of slow, solvent-mediated conversion from form (II) or form (I), and is therefore identified as the most thermodynamically stable anhydrous polymorph of theophylline. Form (IV) can be identified from its plate-like hexagonal morphology, distinct from the elongated morphology observed in particles of forms (I), (II) and the monohydrate. On heating, form (IV) does not melt but undergoes solid-state conversion to form (II) at 483–513 K (Khamar et al. , 2011). This paper presents the structure of this previously unreported anhydrous polymorph of theophylline, and the structure of the high-temperature anhydrous polymorph, form (I).
The structure of form (IV) is monoclinic and, unlike the other anhydrous polymorphs, has two molecules in its asymmetric unit, as shown in Fig. 1. These two molecules form a dimer pair with an R22(10) motif by forming hydrogen bonds between N2—H2···O11 and N12—H12···O1. A short contact is formed by donation via C11—H11···O2[-x, -1/2+y,-1/2-z] and a second by accepting via N11 a short contact from C1—H1[x, -1/2-y, -1/2+z]. These short contacts link the dimers into a two-dimensional network parallel to the (100) plane.
The hydrogen-bonding pattern of the basic nitrogen (N in imidazole ring) is interesting. It is a good acceptor according to Etter's rules (Etter, 1990), but due to insufficient donors, only one of the N atoms of the asymmetric unit, N11, is involved in a contact and not N1. These short contacts link the dimers into chains, and chains of dimers stack in layers related by an inversion centre as displayed in Fig. 2. This dimerization is similar to the packing motif observed in the monohydrate structure and in a number of co-crystals of theophylline (Trask et al., 2006) and may account for the thermodynamic stability of the structure compared with the chain motif of form (II).
Both form (I) and form (II) are known to immediately convert to the monohydrate on contact with water (Suzuki et al., 1989) and therefore the monohydrate structure is considered to be the most thermodynamically stable structure for the theophylline molecule in an aqueous environment. It is not unreasonable therefore that the dimer-based structure of form (IV), containing the same dimer pair motif as the monohydrate, is the most thermodynamically stable of the observed anhydrous forms. It has been observed that, like forms (I) and (II), form (IV) will convert to the monohydrate on contact with water, further stability being conferred by the hydrogen bonding of the dimer pairs with the water molecules.
The asymmetric unit of the high-temperature polymorph, form (I), is shown in Fig. 3. The structure consists of extended chains formed by hydrogen bonding between N2—H2 and O2[-1/2+x, 1/2-y, -1+z] as shown in Fig. 4. Chains are joined by a weak contact from C1—H1···N1[-x, 1-y, -1/2+z] which has the effect of generating a three-dimensional network. The hydrogen-bonded chains run parallel to the (201) plane and are stacked with a π–π interaction.