Theophylline-gentisic acid (1/1).

In the title 1:1 cocrystal, C(7)H(8)N(4)O(2)·C(7)H(6)O(4), 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-dihydroxy-benzoic 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 inter-actions [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 ▶). For a detailed study on theophylline monohydrate see: Khankari & Grant (1995 ▶). For recent cocrystals of the theophylline, see: Trask et al. (2006 ▶); Lu et al. (2008 ▶). For recent cocrystals involving two or more active pharmaceutical ingredients, see: Aitipamula et al. (2009 ▶); Bhatt et al. (2009 ▶); Vishweshwar et al. (2005 ▶); Caira (2007 ▶); Childs (2007 ▶); Childs et al. (2007 ▶); Fleischman et al. (2003 ▶); Shan & Zaworotko (2008 ▶).

Experimental

Crystal data

C7H8N4O2·C7H6O4

M = 334.29

Triclinic,

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

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

C7H8N4O2·C7H6O4	Z = 2
Mr = 334.29	F(000) = 348
Triclinic, P1	Dx = 1.567 Mg m−3
Hall symbol: -P 1	Melting point: 513 K
a = 7.0989 (14) Å	Mo Kα radiation, λ = 0.71073 Å
b = 8.0543 (16) Å	Cell parameters from 2156 reflections
c = 13.034 (3) Å	θ = 2.6–31.0°
α = 86.08 (3)°	µ = 0.13 mm−1
β = 81.27 (3)°	T = 110 K
γ = 74.14 (3)°	Needle, yellow
V = 708.3 (3) Å3	0.24 × 0.22 × 0.13 mm

Rigaku Saturn CCD area-deterctor diffractometer	3478 independent reflections
Radiation source: fine-focus sealed tube	3302 reflections with I > 2σ(I)
graphite	Rint = 0.021
ω scans	θmax = 28.3°, θmin = 2.6°
Absorption correction: multi-scan (Blessing, 1995)	h = −9→7
Tmin = 0.971, Tmax = 0.984	k = −10→10
10245 measured reflections	l = −17→17

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

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.

	x	y	z	Uiso*/Ueq
O5	0.17595 (15)	0.25838 (12)	0.08234 (7)	0.0256 (2)
O3	0.01074 (15)	0.59680 (12)	0.09419 (7)	0.0271 (2)
O4	0.00547 (15)	0.72663 (12)	0.24149 (7)	0.0271 (2)
O6	0.30321 (16)	0.26347 (12)	0.48941 (7)	0.0294 (2)
C8	0.14294 (17)	0.42610 (14)	0.23596 (9)	0.0181 (2)
C13	0.17542 (18)	0.42529 (15)	0.33978 (9)	0.0199 (2)
H13	0.1353	0.5278	0.3757	0.024*
C14	0.04741 (18)	0.58978 (15)	0.18344 (9)	0.0202 (2)
C10	0.29140 (18)	0.11806 (15)	0.23356 (10)	0.0217 (3)
H10	0.3297	0.0145	0.1988	0.026*
C11	0.32413 (19)	0.11938 (15)	0.33503 (10)	0.0220 (3)
H11	0.3851	0.0169	0.3679	0.026*
C9	0.20119 (18)	0.27073 (15)	0.18233 (9)	0.0195 (2)
C12	0.26646 (19)	0.27340 (15)	0.38900 (9)	0.0213 (2)
O2	0.28704 (13)	0.57656 (11)	0.56702 (7)	0.0221 (2)
O1	0.50287 (14)	0.39024 (11)	0.87972 (7)	0.0244 (2)
N3	0.23273 (15)	0.78018 (12)	0.68830 (8)	0.0181 (2)
N4	0.39267 (15)	0.48739 (12)	0.72414 (8)	0.0187 (2)
N2	0.19067 (16)	0.97032 (13)	0.83320 (8)	0.0207 (2)
C1	0.41682 (17)	0.51168 (15)	0.82663 (9)	0.0186 (2)
C2	0.30251 (17)	0.61332 (15)	0.65492 (9)	0.0176 (2)
C5	0.33462 (17)	0.68618 (15)	0.85505 (9)	0.0183 (2)
C3	0.24950 (17)	0.81358 (15)	0.78778 (9)	0.0177 (2)
N1	0.32986 (16)	0.76825 (13)	0.94525 (8)	0.0206 (2)
C6	0.1586 (2)	0.91951 (15)	0.61444 (9)	0.0232 (3)
H6A	0.0502	1.0050	0.6495	0.035*
H6B	0.1146	0.8733	0.5593	0.035*
H6C	0.2626	0.9716	0.5862	0.035*
C7	0.4852 (2)	0.31464 (15)	0.68265 (10)	0.0251 (3)
H7A	0.3879	0.2508	0.6880	0.038*
H7B	0.5893	0.2551	0.7217	0.038*
H7C	0.5391	0.3250	0.6111	0.038*
C4	0.24348 (19)	0.93614 (15)	0.92880 (9)	0.0225 (3)
H4	0.2224	1.0198	0.9781	0.027*
H5	0.111 (3)	0.366 (3)	0.0573 (16)	0.048 (6)*
H6	0.289 (3)	0.372 (3)	0.5139 (16)	0.046 (5)*
H4A	−0.063 (4)	0.834 (3)	0.2064 (19)	0.069 (7)*
H1	0.383 (3)	0.714 (3)	1.0054 (15)	0.040 (5)*

	U11	U22	U33	U12	U13	U23
O5	0.0382 (5)	0.0190 (4)	0.0179 (4)	−0.0011 (4)	−0.0094 (4)	−0.0033 (3)
O3	0.0373 (5)	0.0208 (4)	0.0222 (4)	−0.0018 (4)	−0.0123 (4)	−0.0001 (3)
O4	0.0395 (5)	0.0152 (4)	0.0233 (4)	0.0025 (4)	−0.0105 (4)	−0.0035 (3)
O6	0.0512 (6)	0.0186 (4)	0.0205 (5)	−0.0070 (4)	−0.0162 (4)	0.0000 (3)
C8	0.0198 (5)	0.0149 (5)	0.0192 (5)	−0.0026 (4)	−0.0049 (4)	−0.0002 (4)
C13	0.0244 (6)	0.0155 (5)	0.0195 (5)	−0.0034 (4)	−0.0053 (4)	−0.0021 (4)
C14	0.0229 (5)	0.0157 (5)	0.0212 (5)	−0.0024 (4)	−0.0045 (4)	−0.0017 (4)
C10	0.0277 (6)	0.0142 (5)	0.0221 (6)	−0.0019 (4)	−0.0052 (5)	−0.0035 (4)
C11	0.0278 (6)	0.0157 (5)	0.0218 (6)	−0.0030 (4)	−0.0071 (5)	0.0006 (4)
C9	0.0222 (5)	0.0190 (5)	0.0171 (5)	−0.0037 (4)	−0.0047 (4)	−0.0028 (4)
C12	0.0285 (6)	0.0189 (5)	0.0181 (5)	−0.0066 (5)	−0.0073 (4)	−0.0006 (4)
O2	0.0307 (5)	0.0190 (4)	0.0158 (4)	−0.0032 (3)	−0.0069 (3)	−0.0023 (3)
O1	0.0324 (5)	0.0177 (4)	0.0206 (4)	−0.0001 (3)	−0.0089 (4)	0.0008 (3)
N3	0.0235 (5)	0.0142 (4)	0.0157 (5)	−0.0018 (4)	−0.0061 (4)	−0.0003 (3)
N4	0.0251 (5)	0.0134 (4)	0.0163 (5)	−0.0011 (4)	−0.0061 (4)	−0.0016 (4)
N2	0.0265 (5)	0.0158 (5)	0.0185 (5)	−0.0018 (4)	−0.0055 (4)	−0.0027 (4)
C1	0.0216 (5)	0.0174 (5)	0.0164 (5)	−0.0041 (4)	−0.0033 (4)	−0.0007 (4)
C2	0.0204 (5)	0.0156 (5)	0.0160 (5)	−0.0027 (4)	−0.0034 (4)	−0.0008 (4)
C5	0.0224 (5)	0.0168 (5)	0.0150 (5)	−0.0029 (4)	−0.0047 (4)	−0.0013 (4)
C3	0.0206 (5)	0.0160 (5)	0.0163 (5)	−0.0034 (4)	−0.0039 (4)	−0.0016 (4)
N1	0.0282 (5)	0.0170 (5)	0.0152 (5)	−0.0016 (4)	−0.0060 (4)	−0.0018 (4)
C6	0.0318 (6)	0.0166 (5)	0.0203 (5)	−0.0023 (5)	−0.0092 (5)	0.0020 (4)
C7	0.0359 (7)	0.0131 (5)	0.0236 (6)	0.0010 (5)	−0.0083 (5)	−0.0040 (4)
C4	0.0288 (6)	0.0171 (5)	0.0196 (6)	−0.0010 (4)	−0.0054 (5)	−0.0039 (4)

O5—C9	1.3561 (14)	N3—C2	1.3754 (15)
O5—H5	0.92 (2)	N3—C6	1.4649 (15)
O3—C14	1.2245 (15)	N4—C2	1.3957 (15)
O4—C14	1.3199 (15)	N4—C1	1.4055 (14)
O4—H4A	0.99 (3)	N4—C7	1.4682 (15)
O6—C12	1.3658 (14)	N2—C4	1.3444 (15)
O6—H6	0.92 (2)	N2—C3	1.3629 (15)
C8—C9	1.4052 (16)	C1—C5	1.4179 (16)
C8—C13	1.4060 (16)	C5—C3	1.3733 (16)
C8—C14	1.4817 (17)	C5—N1	1.3792 (14)
C13—C12	1.3828 (17)	N1—C4	1.3408 (16)
C13—H13	0.9300	N1—H1	0.95 (2)
C10—C11	1.3783 (16)	C6—H6A	0.9600
C10—C9	1.3983 (17)	C6—H6B	0.9600
C10—H10	0.9300	C6—H6C	0.9600
C11—C12	1.3984 (17)	C7—H7A	0.9600
C11—H11	0.9300	C7—H7B	0.9600
O2—C2	1.2306 (14)	C7—H7C	0.9600
O1—C1	1.2321 (15)	C4—H4	0.9300
N3—C3	1.3710 (14)
C9—O5—H5	109.4 (13)	O1—C1—N4	120.78 (11)
C14—O4—H4A	113.1 (14)	O1—C1—C5	127.75 (11)
C12—O6—H6	111.2 (13)	N4—C1—C5	111.46 (10)
C9—C8—C13	119.63 (11)	O2—C2—N3	121.22 (11)
C9—C8—C14	120.17 (11)	O2—C2—N4	121.22 (10)
C13—C8—C14	120.20 (11)	N3—C2—N4	117.56 (10)
C12—C13—C8	120.56 (11)	C3—C5—N1	105.65 (10)
C12—C13—H13	119.7	C3—C5—C1	122.98 (10)
C8—C13—H13	119.7	N1—C5—C1	131.26 (11)
O3—C14—O4	123.21 (11)	N2—C3—N3	126.79 (11)
O3—C14—C8	122.79 (11)	N2—C3—C5	110.99 (10)
O4—C14—C8	114.00 (10)	N3—C3—C5	122.21 (11)
C11—C10—C9	120.70 (11)	C4—N1—C5	106.66 (10)
C11—C10—H10	119.7	C4—N1—H1	128.1 (12)
C9—C10—H10	119.7	C5—N1—H1	125.2 (12)
C10—C11—C12	120.60 (11)	N3—C6—H6A	109.5
C10—C11—H11	119.7	N3—C6—H6B	109.5
C12—C11—H11	119.7	H6A—C6—H6B	109.5
O5—C9—C10	116.96 (10)	N3—C6—H6C	109.5
O5—C9—C8	123.97 (11)	H6A—C6—H6C	109.5
C10—C9—C8	119.07 (11)	H6B—C6—H6C	109.5
O6—C12—C13	123.61 (11)	N4—C7—H7A	109.5
O6—C12—C11	116.95 (11)	N4—C7—H7B	109.5
C13—C12—C11	119.44 (11)	H7A—C7—H7B	109.5
C3—N3—C2	118.91 (10)	N4—C7—H7C	109.5
C3—N3—C6	121.52 (10)	H7A—C7—H7C	109.5
C2—N3—C6	119.35 (10)	H7B—C7—H7C	109.5
C2—N4—C1	126.83 (10)	N1—C4—N2	112.63 (11)
C2—N4—C7	116.29 (10)	N1—C4—H4	123.7
C1—N4—C7	116.70 (10)	N2—C4—H4	123.7
C4—N2—C3	104.07 (10)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···O1i	0.95 (2)	1.85 (2)	2.8000 (16)	177.2 (17)
O6—H6···O2	0.92 (2)	1.83 (2)	2.7478 (14)	173.9 (18)
O5—H5···O3ii	0.92 (2)	2.24 (2)	2.8503 (16)	122.6 (17)
O5—H5···O3	0.92 (2)	1.87 (2)	2.6617 (15)	142.3 (19)
O4—H4A···N2iii	0.99 (3)	1.68 (3)	2.6596 (16)	171 (2)

Table 1

Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1⋯O1i	0.95 (2)	1.85 (2)	2.8000 (16)	177.2 (17)
O6—H6⋯O2	0.92 (2)	1.83 (2)	2.7478 (14)	173.9 (18)
O5—H5⋯O3ii	0.92 (2)	2.24 (2)	2.8503 (16)	122.6 (17)
O5—H5⋯O3	0.92 (2)	1.87 (2)	2.6617 (15)	142.3 (19)
O4—H4A⋯N2iii	0.99 (3)	1.68 (3)	2.6596 (16)	171 (2)

Symmetry codes: (i) ; (ii) ; (iii) .