Polymorphs of anhydrous theophylline: stable form IV consists of dimer pairs and metastable form I consists of hydrogen-bonded chains

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.

Comment

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 the compound is known to exist as a monohydrate form (form M; Sun et al., 2002), and three anhydrous polymorphs, viz. 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 depending 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).

Monohydrate form M has a channel hydrate structure which has been shown to lose water, either in low humidity or at temperatures above 353 K, 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.

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 reported previously.

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 owing 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 (Bernstein et al., 1995) via N2—H2⋯O11 and N12—H12⋯O1 hydrogen bonds. A short contact is formed by donation via C11—H11⋯O2(−x, y − , −z + ) and a second by accepting via N11 at (x, −y + , z + ) a short contact from C1—H1. These short contacts link the dimers into a two-dimensional network parallel to the (110) plane. In addition, there are π–π stacking interactions between the fused rings of pairs of molecules of the same unique type (atoms O1 to C8). The centroid–centroid distance between the five-membered and opposing six-membered rings is 3.3686 (12) Å, with an interplanar angle of 0.17 (11)°.

The hydrogen-bonding pattern of the basic nitro­gen (N in the imidazole ring) is inter­esting. It is a good acceptor according to Etter's rules (Etter, 1990), but because of insufficient donors, only atom N11 of the asymmetric unit 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 cocrystals 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 forms I and 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(− + x, , −1 + z), as shown in Fig. 4. Chains are joined by a weak contact from C1—H1⋯N1(−x, 1 − y, − + 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 between the fused rings of adjacent molecules related by translation along the c axis. The centroid–centroid distance between the strictly parallel five-membered rings is 3.854 (7) Å, with an offset of 1.871 Å, and between the six-membered rings the centroid–centroid distance is 3.703 (6) Å.

Figure 1 A view of the two independent mol­ecules in the asymmetric unit of form IV. Displacement ellipsoids are drawn at the 50% probability level and H atoms are shown as spheres of arbitrary radii.

Figure 2 (a) The structure of form IV is built from hydrogen-bonded dimers which are linked via close contacts to form extended chains. The chains form close contacts with each other to make an extended network structure. (b) The rings of the mol­ecule also stack in a π–π fashion.

Figure 3 The asymmetric unit of form I. Displacement ellipsoids are drawn at the 50% probability level and H atoms are shown as spheres with arbitrary radii.

Figure 4 A projection of form I down the c axis, showing the chain motif. Hydrogen bonds are indicated by broken lines. The chains are discrete, having no hydrogen bonds linking them.

Experimental

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 methanol–water mixture (9:1 v/v) 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 two 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; they contained cracks and defects introduced during the phase transition.

Form IV

Crystal data

• C₇H₈N₄O₂

• M_r = 180.17

• Monoclinic, P 2₁ /c

• a = 7.7055 (1) Å

• b = 13.0010 (2) Å

• c = 15.7794 (3) Å

• β = 103.224 (1)°

• V = 1538.85 (4) ų

• Z = 8

• Mo Kα radiation

• μ = 0.12 mm⁻¹

• T = 100 K

• 0.25 × 0.2 × 0.08 mm

Data collection

• Nonius KappaCCD area-detector diffractometer

• Absorption correction: multi-scan (SORTAV; Blessing, 1989) T_min = 0.971, T_max = 0.991

• 35162 measured reflections

• 3023 independent reflections

• 2275 reflections with I > 2σ(I)

• R_int = 0.075

Refinement

• R[F² > 2σ(F²)] = 0.050

• wR(F²) = 0.138

• S = 1.07

• 3023 reflections

• 300 parameters

• All H-atom parameters refined

• Δρ_max = 0.25 e Å⁻³

• Δρ_min = −0.32 e Å⁻³

Table 1
Hydrogen-bond geometry (Å, °) for IV

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⋯N11^i	1.00 (2)	2.29 (2)	3.266 (3)	165 (2)
C11—H11⋯O2^ii	1.00 (3)	2.38 (3)	3.222 (3)	141 (2)
Symmetry codes: (i) ; (ii) .

Form I

Crystal data

• C₇H₈N₄O₂

• M_r = 180.17

• Orthorhombic, P n a 2₁

• a = 13.158 (2) Å

• b = 15.630 (3) Å

• c = 3.854 (1) Å

• V = 792.6 (3) ų

• Z = 4

• Mo Kα radiation

• μ = 0.12 mm⁻¹

• T = 100 K

• 0.25 × 0.06 × 0.03 mm

Data collection

• Nonius KappaCCD area-detector diffractometer

• Absorption correction: multi-scan (SORTAV; Blessing, 1989) T_min = 0.972, T_max = 0.997

• 1246 measured reflections

• 764 independent reflections

• 462 reflections with I > 2σ(I)

• R_int = 0.040

Refinement

• R[F² > 2σ(F²)] = 0.088

• wR(F²) = 0.202

• S = 0.98

• 764 reflections

• 120 parameters

• 1 restraint

• H-atom parameters constrained

• Δρ_max = 0.34 e Å⁻³

• Δρ_min = −0.30 e Å⁻³

• Absolute structure: Flack (1983), 482 Friedel pairs

• Flack parameter: −10 (10)

Table 2
Hydrogen-bond geometry (Å, °) for form I

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N2—H2⋯O2^i	0.88	1.92	2.743 (11)	155
C1—H1⋯N1^ii	0.95	2.41	3.267 (12)	150
Symmetry codes: (i) ; (ii) .

The positions of the H atoms of form IV were refined freely with freely refined individual isotropic displacement parameters. 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 U_iso(H) = 1.5U_eq(C) for the methyl groups and 1.2U_eq(C,N) otherwise.

The quality of the 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: SCALEPACK (Otwinowski & Minor, 1997); data reduction: DENZO (Otwinowski & Minor, 1997) and SCALEPACK; 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 (Farrugia, 1999).

Supporting information

S1. Comment

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.

Related literature

For related literature, see: Allen (2002); Amado et al. (2007); Ebisuzaki et al. (1997); Etter (1990); Matsuo & Matsuoka (2007); Phadnis & Suryanarayanan (1997); Seton et al. (2010); Sun et al. (2002); Suzuki et al. (1989); Ticehurst et al. (2002); Trask et al. (2006); Wikstroem et al. (2008); Zhu et al. (1996).

S2. Experimental

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.

S3. Refinement

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.

Computing details

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).

Figures

	Fig. 1. A view of the two independent molecules in the asymmetric unit of form (IV) showing hydrogen bonding to form the dimer. Displacement ellipsoids are drawn at the 50% probability level and H atoms are shown as spheres of arbitrary radii.
	Fig. 2. The structure of form (IV) is built from hydrogen-bonded dimers [visible in (a)] which are linked via close contacts to form extended chains. The chains form close contacts with each other to make an extended network structure. The rings of the molecule also stack in a π –π fashion (b).
	Fig. 3. The asymmetric unit of form (I). The displacement ellipsoids are drawn at the 50% probability level and H atoms are drawn as spheres with arbitrary radii.
	Fig. 4. A projection of form (I) down the c axis (a) and the b axis (b) showing the chain motif. Hydrogen bonds are indicated by broken lines. The chains are discrete, having no hydrogen bonds linking them.

(IV) 3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione

Crystal data

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) Å^3	0.25 × 0.2 × 0.08 mm
Z = 8

Data collection

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

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.050	All H-atom parameters refined
wR(F^2) = 0.138	w = 1/[σ^2(Fo^2) + (0.0683P)^2 + 1.0567P] where P = (Fo^2 + 2Fc^2)/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+0.001xFc^2λ^3/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.0035 (14)

Special details

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 (Ų)

	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 (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
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)

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)

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···N11^i	1.00 (2)	2.29 (2)	3.266 (3)	165 (2)
C11—H11···O2^ii	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-1H-purine-2,6-dione

Crystal data

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) Å^3	Prism, colourless
Z = 4	0.25 × 0.06 × 0.03 mm

Data collection

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

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.088	H-atom parameters constrained
wR(F^2) = 0.202	w = 1/[σ^2(Fo^2) + (0.01P)^2 + 3.50P] where P = (Fo^2 + 2Fc^2)/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)

Special details

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 (Ų)

	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 (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
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)

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)

D—H···A	D—H	H···A	D···A	D—H···A
N2—H2···O2^i	0.88	1.92	2.743 (11)	155
C1—H1···N1^ii	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.