Theophyl­line monohydrate

organic papers

o368

Acta Crystallographica Section E Structure Reports Online

ISSN 1600-5368

Theophylline monohydrate

Changquan Sun,a_{Deliang Zhou,}b

David J. W. Grantb_{* and}

Victor G. Young Jrc

a_{Pharmacia Corporation, 7207-259-277, 7001}

Portage Rd, Kalamazoo, MI 49001, USA, b_{Department of Pharmaceutics, College of}

Pharmacy, University of Minnesota, Weaver-Densford Hall, 308 Harvard Street SE, Minneapolis, MN 55455-0343, USA, and c_{Department of Chemistry, University of}

Minnesota, 207 Pleasant St. SE, Minneapolis, MN 55455, USA

Correspondence e-mail: [email protected]

Key indicators

Single-crystal X-ray study T= 173 K

Mean(C±C) = 0.003 AÊ Disorder in main residue Rfactor = 0.045 wRfactor = 0.125

Data-to-parameter ratio = 11.2

For details of how these key indicators were automatically derived from the article, see http://journals.iucr.org/e.

#2002 International Union of Crystallography Printed in Great Britain ± all rights reserved

The crystal structure of the title compound, 3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione monohydrate, C7H8N4O2H2O,

was determined by single-crystal X-ray diffractometry using direct methods. Water molecules in the crystals form in®nite chains, through hydrogen-bonded chains running through tunnels formed by surrounding theophylline molecules along the a axis. The water chains are also crosslinked through hydrogen bonds by hydrogen-bonded theophylline dimers, and form a two-dimensional hydrogen-bonded structure parallel to the ab plane. The previously reported structure [Suctor (1958),Acta Cryst.11, 83±87] in space groupP21, with

Z= 4, appears to be incorrect.

Comment

Theophylline, (I), is a common therapeutic agent for the treatment of asthma. It exists as two polymorphic anhydrates and as a monohydrate.

The change in the crystal structure of a drug, as a result of its solid-state hydration, alters many pharmaceutically important properties, such as solubility and tableting behavior (Khankari & Grant, 1995). The differences between the physical properties of theophylline anhydrate and mono-hydrate have been the subject of numerous studies (RodrõÂ-guez-Hornedo et al., 1992; Zhu et al., 1996; Phadnis & Suryanarayanan, 1997). Differences between the structures of crystals may provide an important fundamental understanding of the differences in the thermodynamic activities, mechanical behavior, and other important physicochemical properties of the different solid phases containing the same molecule (Payneet al., 1996; Nichols & Frampton, 1998; Sun & Grant, 2001). For these purposes, an accurate determination of the structure of a crystal is critical. The crystal structure of theophylline monohydrate has been reported previously (Suctor, 1958), with the reference code THEOPH in the Cambridge Structural Database (CSD; Allen & Kennard, 1993). However, this published crystal structure appears to be

incorrect (CSD, error message, April 2000;xandycoordinates of N7 and C8 should bexÿ1

2andyÿ12, respectively; similarly

for its H atoms and H10 of the water molecules). The present work shows that the space group of the previous crystal structure is notP21(Sutor, 1958) butP21/n(Table 1).

In the present structure, one H atom of the water molecule has two disordered sites with 50:50 occupancy (Fig. 1). The O1ÐH1Bbond points in the direction of the inversion center. This H atom is found at the correct distance to form a hydrogen bond with the water molecule related by the inversion center, which means that the H atom can not have full occupancy. The other half occupancy is found with H1C which forms a hydrogen bond with another symmetry-related water molecule (Table 2). The H atoms on C13 are disordered by a rotation of 60_{and the occupancy of the two sets is 64:36} (Table 2).

Two centrosymmetrically related theophylline molecules form a dimer through two hydrogen bonds in the crystal of theophylline monohydrate. The water molecules in the crystal form in®nite hydrogen-bonded chains, running through tunnels along theaaxis (Fig. 2). These chains are parallel and are crosslinked, through hydrogen bonds, by theophylline dimers (Fig. 2). Consequently, two-dimensional hydrogen-bonded layers, parallel to theabplane, are formed.

Experimental

Theophylline anhydrate powder (95 mg, Sigma Chemical Co., St. Louis, MO) was suspended in 10 ml of distilled water contained in a 20 ml glass vial. The vial was heated gradually until a clear solution was obtained. The solution was ®ltered through a 0.2 mm pore

membrane ®lter to remove residual particles. The ®ltrate was trans-ferred to another 20 ml glass vial. The vial was covered with aluminum foil with a circular hole of diameter 1.5 mm and was left undisturbed in a fume hood. Transparent needle-shaped crystals were obtained after slow evaporation of water for one month.

Crystal data

C7H8N4O2H2O

Mr= 198.19

Monoclinic,P21=n a= 4.468 (2) AÊ

b= 15.355 (5) AÊ

c= 13.121 (5) AÊ

= 97.792 (7)

V= 891.9 (6) AÊ3

Z= 4

Dx= 1.476 Mg mÿ3

MoKradiation Cell parameters from 514

re¯ections

= 2.1±25.0

= 0.12 mmÿ1

T= 173 (2) K Needle, light yellow 0.500.110.09 mm

Acta Cryst.(2002). E58, o368±o370 Sun, Zhou, Grant and Young Jr C₇H₈N₄O₂H₂O

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organic papers

Figure 1

The atomic numbering scheme of theophylline monohydrate, with displacement ellipsoids drawn at the 50% probability level. H atoms are drawn as spheres with arbitrary radii.

Figure 2

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Data collection

Bruker SMART CCD area-detector diffractometer

'and!scans

Absorption correction: multi-scan (SADABS; Blessing, 1995; Shel-drick, 2000)

Tmin= 0.985,Tmax= 0.989 5481 measured re¯ections

1554 independent re¯ections 1285 re¯ections withI> 2(I)

Rint= 0.031

max= 25.0

h=ÿ5!5

k=ÿ18!18

l=ÿ15!15

Re®nement

Re®nement onF2

R[F2_{> 2(F}2_{)] = 0.045}

wR(F2_{) = 0.125}

S= 1.01 1554 re¯ections 139 parameters

H atoms treated by a mixture of independent and constrained re®nement

w= 1/[2_(F

o2) + (0.063P)2

+ 0.7841P]

whereP= (Fo2+ 2Fc2)/3

(/)max= 0.001

max= 0.20 e AÊÿ3

min=ÿ0.19 e AÊÿ3

Table 1

Crystal data of theophylline monohydrate.

The present work Sutor (1958)a

Experimental temperature 173 (2) K 295 K

Crystal system monoclinic monoclinic

Space group P21/n P21

a 4.468 (2) 4.50

b 15.355 (5) 15.3

c 13.121 (5) 13.3

97.792 (7) 99.5

Volume 891.9 (6) 903.15

Z 4 4

Density 1.476 1.456

Notes: (a) theaandcaxes of this earlier crystal structure (Sutor, 1958) were assigned differently and have now been interchanged to match the assignment in the present work.

Table 2

Hydrogen-bonding geometry (AÊ,_).

DÐH A DÐH H A D A DÐH A

N7ÐH7A O10i _{0.88 1.90 2.763 (2) 168} O1ÐH1A N9 0.86 (2) 2.05 (3) 2.901 (3) 171 (3) O1ÐH1B O1ii _{0.86 (3) 1.92 (3) 2.726 (4) 156 (6)} O1ÐH1C O1iii _{0.85 (3) 2.01 (4) 2.744 (4) 143 (5)} Symmetry codes: (i)ÿx;2ÿy;1ÿz; (ii)ÿx;1ÿy;1ÿz; (iii)ÿ1ÿx;1ÿy;1ÿz.

Most H atoms were placed in ideal positions and re®ned as riding atoms with individual isotropic displacement parameters. Water H atoms were re®ned isotropically with OÐH distance restraints and individual isotropic displacement parameters

Data collection:SMART(Bruker, 2000); cell re®nement:SAINT (Bruker, 2000); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 1990); program(s) used to re®ne structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL/PC(Bruker, 1997); software used to prepare material for publication:SHELXTL/PC.

References

Allen, F. H. & Kennard, O. (1993).Chem. Des. Autom. News,8, 1, 31±37. Blessing, R. (1995).Acta Cryst.A51, 33±38.

Bruker (1997).SHELXTL/PC. Bruker AXS Inc., Madison, Wisconsin, USA. Bruker (2000).SMARTandSAINT. Bruker AXS Inc., Madison, Wisconsin,

USA.

Khankari, R. K. & Grant, D. J. W. (1995).Thermochim. Acta,248, 61±79. Nichols, G. & Frampton, C. S. (1998).J. Pharm. Sci.87, 684±693.

Payne, R. S., Roberts, R. J., Rowe, R. C., McPartlin, M. & Bashal, A. (1996).

Int. J. Pharm.145, 165±173.

Phadnis, N. V. & Suryanarayanan, R. (1997).J. Pharm. Sci.86, 1256. RodrõÂguez-Hornedo, N., Lechuga-Ballesteros, D. & Wu, H.-J. (1992).Int. J.

Pharm.85, 149±162.

Sheldrick, G. M. (1990).Acta Cryst.A46, 467±473.

Sheldrick, G. M. (1997).SHELXL97. University of GoÈttingen, Germany. Sheldrick, G. M. (2000).SADABS. Bruker AXS Inc., Madison, Wisconsin,

USA.

Sutor, D. J. (1958).Acta Cryst.11, 83±87.

Sun, C. & Grant, D. J. W. (2001).Pharm. Res.18, 274±280.

supporting information

sup-1 Acta Cryst. (2002). E58, o368–o370

supporting information

Acta Cryst. (2002). E58, o368–o370 [https://doi.org/10.1107/S1600536802002921]

Theophylline monohydrate

Changquan Sun, Deliang Zhou, David J. W. Grant and Victor G. Young

theophylline monohydrate

Crystal data

C7H8N4O2·H2O Mr = 198.19 Monoclinic, P21/n a = 4.468 (2) Å b = 15.355 (5) Å c = 13.121 (5) Å β = 97.792 (7)° V = 891.9 (6) Å3 Z = 4

F(000) = 416 Dx = 1.476 Mg m−3

Mo Kα radiation, λ = 0.71073 Å Cell parameters from 514 reflections θ = 2.1–25.0°

µ = 0.12 mm−1 T = 173 K

Needle, light yellow 0.50 × 0.11 × 0.09 mm

Data collection

Bruker CCD area-detector diffractometer

Radiation source: normal-focus sealed tube Graphite monochromator

π and ω scans

Absorption correction: multi-scan

(SADABS; Blessing, 1995; Sheldrick, 2000) Tmin = 0.985, Tmax = 0.989

5481 measured reflections 1554 independent reflections 1285 reflections with I > 2σ(I) Rint = 0.031

θmax = 25.0°, θmin = 2.1° h = −5→5

k = −18→18 l = −15→15

Refinement

Refinement on F2 Least-squares matrix: full R[F2 _{> 2σ(F}2_{)] = 0.045} wR(F2_{) = 0.125} S = 1.01 1554 reflections 139 parameters 6 restraints

Primary atom site location: structure-invariant direct methods

Secondary atom site location: difference Fourier map

Hydrogen site location: inferred from neighbouring sites

H atoms treated by a mixture of independent and constrained refinement

w = 1/[σ2_(F

o2) + (0.063P)2 + 0.7841P] where P = (Fo2 + 2Fc2)/3

(Δ/σ)max = 0.001 Δρmax = 0.20 e Å−3 Δρmin = −0.19 e Å−3

Special details

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sup-2 Acta Cryst. (2002). E58, o368–o370

Refinement. Refinement of F2 _{against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F}2_, conventional R-factors R are based on F, with F set to zero for negative F2_{. The threshold expression of F}2 _{> σ(F}2_{) 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₎

x y z Uiso*/Ueq Occ. (<1)

N1 0.5006 (4) 0.86445 (11) 0.70804 (13) 0.0248 (4)

C2 0.4946 (5) 0.77444 (14) 0.72914 (16) 0.0256 (5)

N3 0.2779 (4) 0.72580 (11) 0.67088 (13) 0.0253 (4)

C4 0.0840 (5) 0.76507 (14) 0.59422 (15) 0.0234 (5)

C5 0.1007 (5) 0.85251 (13) 0.57384 (16) 0.0236 (5)

C6 0.3118 (5) 0.90849 (14) 0.63115 (16) 0.0251 (5)

N7 −0.1274 (4) 0.86794 (11) 0.49419 (13) 0.0257 (4)

H7A −0.1748 0.9182 0.4641 0.031*

C8 −0.2629 (5) 0.79099 (14) 0.47166 (17) 0.0266 (5)

H8A −0.4280 0.7836 0.4186 0.032*

N9 −0.1431 (4) 0.72607 (12) 0.53104 (14) 0.0265 (4)

O10 0.3377 (4) 0.98801 (10) 0.61981 (12) 0.0329 (4)

C10 0.7207 (5) 0.91660 (16) 0.77636 (18) 0.0336 (6)

H10A 0.7800 0.9676 0.7390 0.050*

H10B 0.8995 0.8811 0.7992 0.050*

H10C 0.6288 0.9357 0.8363 0.050*

O12 0.6760 (4) 0.74234 (10) 0.79635 (12) 0.0343 (4)

C13 0.2595 (6) 0.63201 (15) 0.6900 (2) 0.0367 (6)

H13A 0.3540 0.6191 0.7602 0.055* 0.64 (3)

H13B 0.3651 0.6002 0.6408 0.055* 0.64 (3)

H13C 0.0471 0.6141 0.6819 0.055* 0.64 (3)

H13D 0.1568 0.6032 0.6284 0.055* 0.36 (3)

H13E 0.1457 0.6220 0.7478 0.055* 0.36 (3)

H13F 0.4637 0.6082 0.7068 0.055* 0.36 (3)

O1 −0.2597 (5) 0.54582 (11) 0.47253 (16) 0.0458 (5)

H1A −0.236 (7) 0.5979 (17) 0.495 (2) 0.069*

H1B −0.098 (8) 0.525 (3) 0.506 (4) 0.069* 0.50

H1C −0.378 (11) 0.529 (3) 0.515 (4) 0.069* 0.50

Atomic displacement parameters (Å2₎

U11 _U22 _U33 _U12 _U13 _U23

N1 0.0233 (9) 0.0224 (9) 0.0272 (10) 0.0010 (7) −0.0023 (7) −0.0012 (7)

C2 0.0245 (11) 0.0267 (11) 0.0254 (11) 0.0029 (9) 0.0026 (9) 0.0008 (9)

N3 0.0278 (10) 0.0188 (9) 0.0286 (10) 0.0015 (7) 0.0006 (8) 0.0028 (7)

C4 0.0236 (11) 0.0208 (11) 0.0256 (11) 0.0006 (8) 0.0023 (9) 0.0000 (8)

C5 0.0239 (11) 0.0198 (11) 0.0263 (11) 0.0035 (8) 0.0009 (9) 0.0009 (8)

C6 0.0260 (11) 0.0219 (12) 0.0274 (11) 0.0021 (9) 0.0036 (9) −0.0003 (9)

N7 0.0287 (10) 0.0187 (9) 0.0277 (10) 0.0020 (8) −0.0035 (8) 0.0005 (7)

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sup-3 Acta Cryst. (2002). E58, o368–o370

N9 0.0263 (10) 0.0216 (9) 0.0305 (10) −0.0015 (7) −0.0004 (8) −0.0006 (8)

O10 0.0394 (9) 0.0179 (8) 0.0388 (9) −0.0010 (7) −0.0044 (7) 0.0005 (7)

C10 0.0320 (13) 0.0310 (13) 0.0352 (13) −0.0011 (10) −0.0044 (10) −0.0072 (10)

O12 0.0338 (9) 0.0301 (9) 0.0357 (9) 0.0042 (7) −0.0067 (7) 0.0059 (7)

C13 0.0449 (15) 0.0193 (12) 0.0428 (14) 0.0011 (10) −0.0051 (11) 0.0056 (10)

O1 0.0525 (11) 0.0223 (9) 0.0585 (13) 0.0000 (8) −0.0069 (9) −0.0033 (8)

Geometric parameters (Å, º)

N1—C6 1.399 (3) C8—N9 1.332 (3)

N1—C2 1.411 (3) C8—H8A 0.95

N1—C10 1.474 (3) C10—H10A 0.98

C2—O12 1.218 (3) C10—H10B 0.98

C2—N3 1.371 (3) C10—H10C 0.98

N3—C4 1.375 (3) C13—H13A 0.98

N3—C13 1.466 (3) C13—H13B 0.98

C4—N9 1.359 (3) C13—H13C 0.98

C4—C5 1.373 (3) C13—H13D 0.98

C5—N7 1.378 (3) C13—H13E 0.98

C5—C6 1.415 (3) C13—H13F 0.98

C6—O10 1.237 (3) O1—H1A 0.86 (2)

N7—C8 1.342 (3) O1—H1B 0.86 (3)

N7—H7A 0.88 O1—H1C 0.85 (3)

C6—N1—C2 126.14 (17) N1—C10—H10C 109.5

C6—N1—C10 117.61 (18) H10A—C10—H10C 109.5

C2—N1—C10 116.21 (17) H10B—C10—H10C 109.5

O12—C2—N3 122.2 (2) N3—C13—H13A 109.5

O12—C2—N1 120.7 (2) N3—C13—H13B 109.5

N3—C2—N1 117.07 (18) H13A—C13—H13B 109.5

C2—N3—C4 119.77 (18) N3—C13—H13C 109.5

C2—N3—C13 119.43 (18) H13A—C13—H13C 109.5

C4—N3—C13 120.79 (18) H13B—C13—H13C 109.5

N9—C4—C5 111.59 (18) N3—C13—H13D 109.5

N9—C4—N3 126.68 (19) H13A—C13—H13D 141.1

C5—C4—N3 121.73 (19) H13B—C13—H13D 56.3

C4—C5—N7 105.18 (18) H13C—C13—H13D 56.3

C4—C5—C6 122.73 (19) N3—C13—H13E 109.5

N7—C5—C6 132.05 (19) H13A—C13—H13E 56.3

O10—C6—N1 120.45 (19) H13B—C13—H13E 141.1

O10—C6—C5 127.0 (2) H13C—C13—H13E 56.3

N1—C6—C5 112.51 (18) H13D—C13—H13E 109.5

C8—N7—C5 106.31 (17) N3—C13—H13F 109.5

C8—N7—H7A 126.8 H13A—C13—H13F 56.3

C5—N7—H7A 126.8 H13B—C13—H13F 56.3

N9—C8—N7 113.36 (19) H13C—C13—H13F 141.1

N9—C8—H8A 123.3 H13D—C13—H13F 109.5

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sup-4 Acta Cryst. (2002). E58, o368–o370

C8—N9—C4 103.57 (18) H1A—O1—H1B 96 (3)

N1—C10—H10A 109.5 H1A—O1—H1C 96 (3)

N1—C10—H10B 109.5 H1B—O1—H1C 96 (3)

H10A—C10—H10B 109.5

C6—N1—C2—O12 177.9 (2) N3—C4—C5—C6 −1.5 (3)

C10—N1—C2—O12 −4.4 (3) C2—N1—C6—O10 179.9 (2)

C6—N1—C2—N3 −2.0 (3) C10—N1—C6—O10 2.2 (3)

C10—N1—C2—N3 175.74 (18) C2—N1—C6—C5 0.7 (3)

O12—C2—N3—C4 −178.3 (2) C10—N1—C6—C5 −177.08 (18)

N1—C2—N3—C4 1.6 (3) C4—C5—C6—O10 −178.1 (2)

O12—C2—N3—C13 0.6 (3) N7—C5—C6—O10 −0.8 (4)

N1—C2—N3—C13 −179.49 (19) C4—C5—C6—N1 1.1 (3)

C2—N3—C4—N9 −179.3 (2) N7—C5—C6—N1 178.4 (2)

C13—N3—C4—N9 1.8 (3) C4—C5—N7—C8 −0.3 (2)

C2—N3—C4—C5 0.0 (3) C6—C5—N7—C8 −177.9 (2)

C13—N3—C4—C5 −178.9 (2) C5—N7—C8—N9 0.5 (3)

N9—C4—C5—N7 0.0 (2) N7—C8—N9—C4 −0.5 (2)

N3—C4—C5—N7 −179.40 (18) C5—C4—N9—C8 0.3 (2)

N9—C4—C5—C6 177.89 (19) N3—C4—N9—C8 179.7 (2)

Hydrogen-bond geometry (Å, º)

D—H···A D—H H···A D···A D—H···A

N7—H7A···O10i _{0.88 1.90 2.763 (2) 168}

O1—H1A···N9 0.86 (2) 2.05 (3) 2.901 (3) 171 (3)

O1—H1B···O1ii _{0.86 (3) 1.92 (3) 2.726 (4) 156 (6)}

O1—H1C···O1iii _{0.85 (3) 2.01 (4) 2.744 (4) 143 (5)}