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Acta Crystallogr Sect E Struct Rep Online. 2009 September 1; 65(Pt 9): o2126–o2127.
Published online 2009 August 8. doi:  10.1107/S1600536809031031
PMCID: PMC2970150

Theophylline–gentisic acid (1/1)

Abstract

In the title 1:1 cocrystal, C7H8N4O2·C7H6O4, the anti-asthmatic drug theophylline (systematic name: 1,3-dimethyl-7H-purine-2,6-dione) and a non-steroidal anti-inflammatory drug, gentisic acid (systematic name: 2,5-dihydroxy­benzoic acid) crystallize together, forming two-dimensional hydrogen-bonded sheets involving N—H(...)O and O—H(...)N hydrogen bonds. The overall crystal packing features π–π stacking inter­actions [centroid–centroid distance = 3.348 (1) Å]. The cocrystal described herein belongs to the class of pharmaceutical cocrystals involving two active pharmaceutical ingredients which has been relatively unexplored to date.

Related literature

For characterization of the title cocrystal by Fourier Transform Infrared Spectroscopy, see: Childs et al. (2007 [triangle]). For a detailed study on theophylline monohydrate see: Khankari & Grant (1995 [triangle]). For recent cocrystals of the theophylline, see: Trask et al. (2006 [triangle]); Lu et al. (2008 [triangle]). For recent cocrystals involving two or more active pharmaceutical ingredients, see: Aitipamula et al. (2009 [triangle]); Bhatt et al. (2009 [triangle]); Vishweshwar et al. (2005 [triangle]); Caira (2007 [triangle]); Childs (2007 [triangle]); Childs et al. (2007 [triangle]); Fleischman et al. (2003 [triangle]); Shan & Zaworotko (2008 [triangle]).

An external file that holds a picture, illustration, etc.
Object name is e-65-o2126-scheme1.jpg

Experimental

Crystal data

  • C7H8N4O2·C7H6O4
  • M r = 334.29
  • Triclinic, An external file that holds a picture, illustration, etc.
Object name is e-65-o2126-efi1.jpg
  • a = 7.0989 (14) Å
  • b = 8.0543 (16) Å
  • c = 13.034 (3) Å
  • α = 86.08 (3)°
  • β = 81.27 (3)°
  • γ = 74.14 (3)°
  • V = 708.3 (3) Å3
  • Z = 2
  • Mo Kα radiation
  • μ = 0.13 mm−1
  • T = 110 K
  • 0.24 × 0.22 × 0.13 mm

Data collection

  • Rigaku Saturn CCD area-deterctor diffractometer
  • Absorption correction: multi-scan (Blessing, 1995 [triangle]) T min = 0.971, T max = 0.984
  • 10245 measured reflections
  • 3478 independent reflections
  • 3302 reflections with I > 2σ(I)
  • R int = 0.021

Refinement

  • R[F 2 > 2σ(F 2)] = 0.046
  • wR(F 2) = 0.127
  • S = 1.08
  • 3478 reflections
  • 235 parameters
  • H atoms treated by a mixture of independent and constrained refinement
  • Δρmax = 0.36 e Å−3
  • Δρmin = −0.33 e Å−3

Data collection: CrystalClear (Rigaku, 2008 [triangle]); cell refinement: CrystalClear; data reduction: CrystalClear; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 [triangle]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 [triangle]); molecular graphics: X-SEED (Barbour, 2001 [triangle]); software used to prepare material for publication: SHELXTL (Sheldrick, 2008 [triangle]) and PLATON (Spek, 2009 [triangle]).

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536809031031/pb2002sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536809031031/pb2002Isup2.hkl

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Acknowledgments

This work was supported by the Institute of Chemical and Engineering Sciences of A*STAR (Agency for Science, Technology and Research), Singapore.

supplementary crystallographic information

Comment

Theophylline (1,3-dimethyl-7H-purine-2,6-dione) is a drug used in the treatment of respiratory diseases such as asthma. It has been reported that theophylline forms a monohydrate as a function of relative humidity and poses challenges in the formultion stages (Khankari and Grant, 1995). Using the cocrystallization as an aid to improve the physical stability, several theophylline cocrystals with dicarboxylic acids have been prepared and studied for their physical stability (Trask et al., 2006, Childs et al., 2007). Cocrystals which involve two or more active pharmaceutical ingredients (APIs) are relatively unexplored solid forms of APIs which have potential relevance in the context of combination drugs for pharmaceutical drug development (Aitipamula et al., 2009, Bhatt et al., 2009). We have recently reported trimorphs of a pharmaceutical cocrystal involving two APIs, namely ethenzamide (2-ethoxybenzamide), and gentisic acid and shown that the dissolution rate of the cocrystal polymorphs improved by two times when compared to the parent ethenzamide (Aitipamula et al., 2009). In the present paper, we report a 1:1 cocrystal of theophylline with gentisic acid and analyzed the hydrogen bonding.

The crystal structure of the title cocrystal contains each one molecule of theophylline and gentisic acid in the asymmetric unit (Fig. 1). In the structure, two molecules of theophylline which are related by an inversion centre form a dimer involving N—H···O hydrogen bonds (Table 1). Hydroxy atom O5 of the gentisic acid acts as an intramolecular O—H···O hydrogen bond donor to the carbonyl of carboxyl group and also involves in a bifurcated O—H···O hydrogen bond to atom O3 at (-x, -y + 1, -z) (Fig. 2). Hydroxy atom O4 acts as a hydrogen bond donor to atom N2 of the theophylline at (-x, -y + 2, -z + 1), thus generating chains of alternating dimers of theophylline and gentisic acid running parallel to [21–1]. In addition, there is a C—H···O hydrogen bond between C4 of the theophylline and O5 of the gentisic acid. The 5-hydroxyl group (O6) of the gentisic acid acts as a hydrogen bond donor to atom O2 of the theophylline at (1 + x, -1 + y, 1 + z), thus generating a hydrogen bonded sheet parallel to the (21–1) plane (Fig. 2). The crystal structure is further stabilized by a π-π interaction involving pyrimidine ring of theophylline and phenyl ring of gentisic acid: Cg1···Cg2 (x, y, z) = 3.348 (1) Å, where Cg1 and Cg2 denote the centroids of N3/C2/N4/C1/C5/C3 of the theophylline and C8—C13 of the gentisic acid, respectively (Fig. 3).

Zaworotko and co-workers distinguished between two types of hydrogen bonding possibilities in cocrystal structures depending on whether the interacting complementary functional groups are the same or different (Fleischman et al., 2003). In type I, an API forms hydrogen bonds like in pure structure, e.g. dimers, catemers, etc. (homosynthons) and such units are connected by cocrystal former spacer, and in type II, both the API and cocrystal former involve in heterosynthon formation. The title cocrystal belongs to type I, in which both the theophylline and gentisic acid molecules form dimers involving homosynthons, and such dimers are connected via O—H···O hydrogen bonds (Fig. 2).

Experimental

Equimolar quantities of theophylline and gentisic acid (purchased from Aldrich) were dissolved in methanol upon heating. The solution was set aside to crystallize providing crystals that belong to a 1:1 cocrystal. Crystal suitable for single-crystal X-ray diffraction were selected directly from the sample as prepared.

Refinement

H atoms bonded to N and O atoms were located in a difference map and allowed to ride on their parent atoms in the refinement cycles. Other H atoms were positioned geometrically and refined using a riding model.

Figures

Fig. 1.
The molecular structures of theophylline and gentisic acid, with atom labels and 50% probability displacement ellipsoids for non-H atoms.
Fig. 2.
Part of the crystal structure of the title cocrystal, showing formation of a hydrogen bonded sheet in the (21–1) plane.
Fig. 3.
Part of the crystal structure of the title cocrystal, showing the π-π stacking interaction between two layers.

Crystal data

C7H8N4O2·C7H6O4Z = 2
Mr = 334.29F(000) = 348
Triclinic, P1Dx = 1.567 Mg m3
Hall symbol: -P 1Melting point: 513 K
a = 7.0989 (14) ÅMo Kα radiation, λ = 0.71073 Å
b = 8.0543 (16) ÅCell parameters from 2156 reflections
c = 13.034 (3) Åθ = 2.6–31.0°
α = 86.08 (3)°µ = 0.13 mm1
β = 81.27 (3)°T = 110 K
γ = 74.14 (3)°Needle, yellow
V = 708.3 (3) Å30.24 × 0.22 × 0.13 mm

Data collection

Rigaku Saturn CCD area-deterctor diffractometer3478 independent reflections
Radiation source: fine-focus sealed tube3302 reflections with I > 2σ(I)
graphiteRint = 0.021
ω scansθmax = 28.3°, θmin = 2.6°
Absorption correction: multi-scan (Blessing, 1995)h = −9→7
Tmin = 0.971, Tmax = 0.984k = −10→10
10245 measured reflectionsl = −17→17

Refinement

Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.046Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.127H atoms treated by a mixture of independent and constrained refinement
S = 1.08w = 1/[σ2(Fo2) + (0.0749P)2 + 0.2093P] where P = (Fo2 + 2Fc2)/3
3478 reflections(Δ/σ)max < 0.001
235 parametersΔρmax = 0.36 e Å3
0 restraintsΔρmin = −0.33 e Å3
0 constraints

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.
Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2)

xyzUiso*/Ueq
O50.17595 (15)0.25838 (12)0.08234 (7)0.0256 (2)
O30.01074 (15)0.59680 (12)0.09419 (7)0.0271 (2)
O40.00547 (15)0.72663 (12)0.24149 (7)0.0271 (2)
O60.30321 (16)0.26347 (12)0.48941 (7)0.0294 (2)
C80.14294 (17)0.42610 (14)0.23596 (9)0.0181 (2)
C130.17542 (18)0.42529 (15)0.33978 (9)0.0199 (2)
H130.13530.52780.37570.024*
C140.04741 (18)0.58978 (15)0.18344 (9)0.0202 (2)
C100.29140 (18)0.11806 (15)0.23356 (10)0.0217 (3)
H100.32970.01450.19880.026*
C110.32413 (19)0.11938 (15)0.33503 (10)0.0220 (3)
H110.38510.01690.36790.026*
C90.20119 (18)0.27073 (15)0.18233 (9)0.0195 (2)
C120.26646 (19)0.27340 (15)0.38900 (9)0.0213 (2)
O20.28704 (13)0.57656 (11)0.56702 (7)0.0221 (2)
O10.50287 (14)0.39024 (11)0.87972 (7)0.0244 (2)
N30.23273 (15)0.78018 (12)0.68830 (8)0.0181 (2)
N40.39267 (15)0.48739 (12)0.72414 (8)0.0187 (2)
N20.19067 (16)0.97032 (13)0.83320 (8)0.0207 (2)
C10.41682 (17)0.51168 (15)0.82663 (9)0.0186 (2)
C20.30251 (17)0.61332 (15)0.65492 (9)0.0176 (2)
C50.33462 (17)0.68618 (15)0.85505 (9)0.0183 (2)
C30.24950 (17)0.81358 (15)0.78778 (9)0.0177 (2)
N10.32986 (16)0.76825 (13)0.94525 (8)0.0206 (2)
C60.1586 (2)0.91951 (15)0.61444 (9)0.0232 (3)
H6A0.05021.00500.64950.035*
H6B0.11460.87330.55930.035*
H6C0.26260.97160.58620.035*
C70.4852 (2)0.31464 (15)0.68265 (10)0.0251 (3)
H7A0.38790.25080.68800.038*
H7B0.58930.25510.72170.038*
H7C0.53910.32500.61110.038*
C40.24348 (19)0.93614 (15)0.92880 (9)0.0225 (3)
H40.22241.01980.97810.027*
H50.111 (3)0.366 (3)0.0573 (16)0.048 (6)*
H60.289 (3)0.372 (3)0.5139 (16)0.046 (5)*
H4A−0.063 (4)0.834 (3)0.2064 (19)0.069 (7)*
H10.383 (3)0.714 (3)1.0054 (15)0.040 (5)*

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
O50.0382 (5)0.0190 (4)0.0179 (4)−0.0011 (4)−0.0094 (4)−0.0033 (3)
O30.0373 (5)0.0208 (4)0.0222 (4)−0.0018 (4)−0.0123 (4)−0.0001 (3)
O40.0395 (5)0.0152 (4)0.0233 (4)0.0025 (4)−0.0105 (4)−0.0035 (3)
O60.0512 (6)0.0186 (4)0.0205 (5)−0.0070 (4)−0.0162 (4)0.0000 (3)
C80.0198 (5)0.0149 (5)0.0192 (5)−0.0026 (4)−0.0049 (4)−0.0002 (4)
C130.0244 (6)0.0155 (5)0.0195 (5)−0.0034 (4)−0.0053 (4)−0.0021 (4)
C140.0229 (5)0.0157 (5)0.0212 (5)−0.0024 (4)−0.0045 (4)−0.0017 (4)
C100.0277 (6)0.0142 (5)0.0221 (6)−0.0019 (4)−0.0052 (5)−0.0035 (4)
C110.0278 (6)0.0157 (5)0.0218 (6)−0.0030 (4)−0.0071 (5)0.0006 (4)
C90.0222 (5)0.0190 (5)0.0171 (5)−0.0037 (4)−0.0047 (4)−0.0028 (4)
C120.0285 (6)0.0189 (5)0.0181 (5)−0.0066 (5)−0.0073 (4)−0.0006 (4)
O20.0307 (5)0.0190 (4)0.0158 (4)−0.0032 (3)−0.0069 (3)−0.0023 (3)
O10.0324 (5)0.0177 (4)0.0206 (4)−0.0001 (3)−0.0089 (4)0.0008 (3)
N30.0235 (5)0.0142 (4)0.0157 (5)−0.0018 (4)−0.0061 (4)−0.0003 (3)
N40.0251 (5)0.0134 (4)0.0163 (5)−0.0011 (4)−0.0061 (4)−0.0016 (4)
N20.0265 (5)0.0158 (5)0.0185 (5)−0.0018 (4)−0.0055 (4)−0.0027 (4)
C10.0216 (5)0.0174 (5)0.0164 (5)−0.0041 (4)−0.0033 (4)−0.0007 (4)
C20.0204 (5)0.0156 (5)0.0160 (5)−0.0027 (4)−0.0034 (4)−0.0008 (4)
C50.0224 (5)0.0168 (5)0.0150 (5)−0.0029 (4)−0.0047 (4)−0.0013 (4)
C30.0206 (5)0.0160 (5)0.0163 (5)−0.0034 (4)−0.0039 (4)−0.0016 (4)
N10.0282 (5)0.0170 (5)0.0152 (5)−0.0016 (4)−0.0060 (4)−0.0018 (4)
C60.0318 (6)0.0166 (5)0.0203 (5)−0.0023 (5)−0.0092 (5)0.0020 (4)
C70.0359 (7)0.0131 (5)0.0236 (6)0.0010 (5)−0.0083 (5)−0.0040 (4)
C40.0288 (6)0.0171 (5)0.0196 (6)−0.0010 (4)−0.0054 (5)−0.0039 (4)

Geometric parameters (Å, °)

O5—C91.3561 (14)N3—C21.3754 (15)
O5—H50.92 (2)N3—C61.4649 (15)
O3—C141.2245 (15)N4—C21.3957 (15)
O4—C141.3199 (15)N4—C11.4055 (14)
O4—H4A0.99 (3)N4—C71.4682 (15)
O6—C121.3658 (14)N2—C41.3444 (15)
O6—H60.92 (2)N2—C31.3629 (15)
C8—C91.4052 (16)C1—C51.4179 (16)
C8—C131.4060 (16)C5—C31.3733 (16)
C8—C141.4817 (17)C5—N11.3792 (14)
C13—C121.3828 (17)N1—C41.3408 (16)
C13—H130.9300N1—H10.95 (2)
C10—C111.3783 (16)C6—H6A0.9600
C10—C91.3983 (17)C6—H6B0.9600
C10—H100.9300C6—H6C0.9600
C11—C121.3984 (17)C7—H7A0.9600
C11—H110.9300C7—H7B0.9600
O2—C21.2306 (14)C7—H7C0.9600
O1—C11.2321 (15)C4—H40.9300
N3—C31.3710 (14)
C9—O5—H5109.4 (13)O1—C1—N4120.78 (11)
C14—O4—H4A113.1 (14)O1—C1—C5127.75 (11)
C12—O6—H6111.2 (13)N4—C1—C5111.46 (10)
C9—C8—C13119.63 (11)O2—C2—N3121.22 (11)
C9—C8—C14120.17 (11)O2—C2—N4121.22 (10)
C13—C8—C14120.20 (11)N3—C2—N4117.56 (10)
C12—C13—C8120.56 (11)C3—C5—N1105.65 (10)
C12—C13—H13119.7C3—C5—C1122.98 (10)
C8—C13—H13119.7N1—C5—C1131.26 (11)
O3—C14—O4123.21 (11)N2—C3—N3126.79 (11)
O3—C14—C8122.79 (11)N2—C3—C5110.99 (10)
O4—C14—C8114.00 (10)N3—C3—C5122.21 (11)
C11—C10—C9120.70 (11)C4—N1—C5106.66 (10)
C11—C10—H10119.7C4—N1—H1128.1 (12)
C9—C10—H10119.7C5—N1—H1125.2 (12)
C10—C11—C12120.60 (11)N3—C6—H6A109.5
C10—C11—H11119.7N3—C6—H6B109.5
C12—C11—H11119.7H6A—C6—H6B109.5
O5—C9—C10116.96 (10)N3—C6—H6C109.5
O5—C9—C8123.97 (11)H6A—C6—H6C109.5
C10—C9—C8119.07 (11)H6B—C6—H6C109.5
O6—C12—C13123.61 (11)N4—C7—H7A109.5
O6—C12—C11116.95 (11)N4—C7—H7B109.5
C13—C12—C11119.44 (11)H7A—C7—H7B109.5
C3—N3—C2118.91 (10)N4—C7—H7C109.5
C3—N3—C6121.52 (10)H7A—C7—H7C109.5
C2—N3—C6119.35 (10)H7B—C7—H7C109.5
C2—N4—C1126.83 (10)N1—C4—N2112.63 (11)
C2—N4—C7116.29 (10)N1—C4—H4123.7
C1—N4—C7116.70 (10)N2—C4—H4123.7
C4—N2—C3104.07 (10)

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
N1—H1···O1i0.95 (2)1.85 (2)2.8000 (16)177.2 (17)
O6—H6···O20.92 (2)1.83 (2)2.7478 (14)173.9 (18)
O5—H5···O3ii0.92 (2)2.24 (2)2.8503 (16)122.6 (17)
O5—H5···O30.92 (2)1.87 (2)2.6617 (15)142.3 (19)
O4—H4A···N2iii0.99 (3)1.68 (3)2.6596 (16)171 (2)

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

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: PB2002).

References

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