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ISSN: 2056-9890

Lamotrigine ethanol monosolvate

aSchool of Chemistry, University of Bristol, Cantock's Close, Bristol, England BS8 1TS, England
*Correspondence e-mail: simon.hall@bristol.ac.uk

Edited by L. Fabian, University of East Anglia, England (Received 6 March 2018; accepted 13 April 2018; online 19 April 2018)

Lamotrigine is an active pharmaceutical ingredient used as a treatment for epilepsy and psychiatric disorders. Single crystals of an ethano­late solvate, C9H7Cl2N5·C2H5OH, were produced by slow evaporation of a saturated solution from anhydrous ethanol. Within the crystal structure, the lamotrigine mol­ecules form dimers through N—H⋯N hydrogen bonds involving the amine N atoms in the ortho position of the triazine group. These dimers are linked into a tape motif through hydrogen bonds involving the amine N atoms in the para position. The ethanol and lamotrigine are present in a 1:1 ratio in the lattice with the ethyl group of the ethanol mol­ecule exhibiting disorder with an occupancy ratio of 0.516 (14):0.484 (14).

1. Chemical context

Anti­convulsants are a group of drugs used principally in the treatment of epilepsy, which have also been shown to aid in the treatment of psychiatric conditions such as bipolar disorder. Although the drugs are effective when inside the body, many suffer from having low solubility and bioavailability. Prime examples of such drugs are carbamazepine (Uzunović et al., 2010[Uzunović, A., Vranić, E. & Hadžidedić, Š. (2010). Bosn. J. Basic Med. Sci. 10, 234-238.]), phenytoin (Widanapathirana et al., 2015[Widanapathirana, L., Tale, S. & Reineke, T. M. (2015). Mol. Pharm. 12, 2537-2543.]) and lamotrigine (Vai­thia­nathan et al., 2015[Vaithianathan, A., Raman, S., Jiang, W., Ting, Y. T., Kane, M. A. & Polli, J. E. (2015). Mol. Pharm. 12, 2436-2443.]), which are all categorised as BCS (biopharmaceutical classification system) class II (low solubility, high permeability).

In an attempt to increase the solubility of BCS class II drugs, extensive studies have been undertaken to produce crystal structures including the active pharmaceutical ingredients (APIs) with lower crystal lattice energies. In the case of lamotrigine, Cheney et al. (2010[Cheney, M. L., Shan, N., Healey, E. R., Hanna, M., Wojtas, L., Zaworotko, M. J., Sava, V., Song, S. & Sanchez-Ramos, J. R. (2010). Cryst. Growth Des. 10, 394-405.]) investigated the solubility of 10 novel forms, including salts, co-crystals and solvates, showing the possibility of creating many stable lamotrigine compounds. The structures of lamotrigine co-crystals and solvates are stabilized due to the large number of hydrogen bonds that can form with the 1,2,4-triazine-3,5-di­amine group.

[Scheme 1]

In this work, the structure for the ethano­late (I)[link], previously only obtained as a powder pattern (Garti et al., 2008[Garti, N., Berkovich, Y., Dolitzky, B. Z., Aronhime, J., Singer, C., Liebermann, A. & Gershon, N. (2008). US Patent Number. 7390807B2.]), is defined. This new structure determination affords a deeper insight into the different hydrogen-bonding networks that can form in the lamotrigine crystal.

2. Structural commentary

A displacement ellipsoid plot for lamotrigine ethano­late is shown in Fig. 1[link]. The central dihedral, C1—C6—C7—C8, sits at an angle of 63.5 (9)°, the flexibility of which allows for the inclusion of solvent mol­ecules to form hydrogen-bonding networks. Central dihedral angles for lamotrigine solvates are included in Table 1[link]. Fig. 2[link] shows the unit cell for (I)[link], which consists of eight lamotrigine mol­ecules and eight ethanol mol­ecules. The main motif within the structure is a lamotrigine dimer stabilized by two ethanol mol­ecules. Here the lamotrigine dimer forms using the amine N atoms in the ortho position of the triazine group.

Table 1
Chosen parameters for the comparison of lamotrigine alcohol solvates

Structure Central dihedral angle (°) Dimerization motif Density (g cm−1)
Methanol disolvate 63.7 (2) para 1.50
Ethanol monohydrate 67.6 (0) para 1.49
Methanol monosolvate 80.1 (5) ortho 1.45
Ethanol solvate (I) 63.5 (9) ortho 1.42
2-Propanol solvate 69.6 (8) ortho 1.36
Butan-1-ol solvate monohydrate 71.2 (1) para 1.34
[Figure 1]
Figure 1
A displacement ellipsoid plot of (I)[link], showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level.
[Figure 2]
Figure 2
The crystal packing of (I)[link], viewed along the c axis.

3. Supra­molecular features

In the crystal, adjacent in-plane lamotrigine dimers are linked via hydrogen bonding of the amines in the para position of the triazine group (Table 2[link]). Each dimer sits at an angle of 67.2 (5)° to the next closest dimer, measured with respect to the in-plane triazine rings, highlighted in Fig. 3[link].

Table 2
Hydrogen-bond geometry (Å, °)

D—H⋯A D—H H⋯A DA D—H⋯A
O1—H1A⋯N1 0.84 2.01 2.848 (7) 179
N4—H4A⋯N3i 0.88 2.10 2.972 (7) 172
N4—H4B⋯O1ii 0.88 2.14 2.841 (7) 137
N5—H5A⋯O1iii 0.88 2.16 3.014 (7) 163
N5—H5B⋯N2iv 0.88 2.14 2.987 (8) 161
Symmetry codes: (i) [-x+{\script{1\over 2}}, -y+{\script{3\over 2}}, -z]; (ii) [-x+{\script{1\over 2}}, y+{\script{1\over 2}}, -z+{\script{1\over 2}}]; (iii) [x, -y+1, z-{\script{1\over 2}}]; (iv) [-x+1, y, -z+{\script{1\over 2}}].
[Figure 3]
Figure 3
The bonding motif of adjacent lamotrigine dimers. The angle between the dimers was calculated using the planes of the indicated triazine rings.

4. Database survey

A database survey of the Cambridge Structural Database (CSD, version 5.38, last update May 2017; Groom et al., 2016[Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171-179.]) showed a list of 35 existing co-crystal/solvate structures for lamotrigine, including 6 structures incorporating alcohols, but no ethanol solvate. The most similar structure compositionally to (I)[link] is the ethanol solvate monohydrate (Cheney et al., 2010[Cheney, M. L., Shan, N., Healey, E. R., Hanna, M., Wojtas, L., Zaworotko, M. J., Sava, V., Song, S. & Sanchez-Ramos, J. R. (2010). Cryst. Growth Des. 10, 394-405.]); however, the arrangement contrasts quite dramatically, with the dimer formation of the lamotrigine mol­ecules using the amine N atoms in the para position, shown in Fig. 4[link]. This change in dimerization motif leads to a reduction in density of the lamotrigine ethano­late over the lamotrigine ethanol monohydrate by 5%.

[Figure 4]
Figure 4
(a) The dimerization motif in (I)[link], held together with the amines in the ortho position of the triazine group. The amine in the ortho and para positions are labelled with O and P, respectively. (b) The dimerization motif in the ethano­late hydrate structure, held together with the amines in the para position of the triazine group.

Analysis of the previously published lamotrigine alcohol solvates shows a trend between the alcohol chain length and whether the lamotrigine dimers form on the ortho or para group of the triazine. The two densest structures are the methanol disolvate (Hanna et al., 2009[Hanna, M., Shan, N. & Cheney, M. L. (2009). US Patent Number. 061513A1.]) and the ethanol solvate monohydrate, where lamotrigine dimers are connected via the amines in the para position of the triazine. Conversely, the methanol monosolvate (Janes et al., 1989[Janes, R. W., Lisgarten, J. N. & Palmer, R. A. (1989). Acta Cryst. C45, 129-132.]), iso­propanol solvate (Qian et al., 2009[Qian, Y., Lv, P. C., Shi, L., Fang, R. Q., Song, Z. C. & Zhu, H. L. (2009). J. Chem. Sci. 121, 463-470.]) and title compound form dimers from the amine on the ortho positions. The least dense structure is the butan-1-ol solvate monohydrate (Sridhar & Ravikumar, 2011[Sridhar, S. & Ravikumar, K. (2011). J. Chem. Crystallogr. 41, 1289-1300.]), which has similar arrangement to the dense structures, with the dimers held apart by the large butanol solvent mol­ecules. The densities of the lamotrigine structures are highlighted in Table 1[link].

5. Synthesis and crystallization

Lamotrigine (>98%, Acros Organics) was saturated in a solution of pure anhydrous ethanol (>99.5%, Sigma Aldrich) over several weeks. Crystals of lamotrigine ethano­late were produced via slow evaporation of 1 ml of the solution over 72 h.

6. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 3[link]. All of the hydrogen atoms were located geometrically (aromatic C—H = 0.95 Å, methyl C—H = 0.98 Å, ethyl C—H = 0.99 Å, O—H = 0.84 Å N—H= 0.88 Å) and refined using a riding model [aromatic, ethyl and amine Uiso(H) = 1.2 times parent atom Ueq, methyl and alcohol Uiso(H) = 1.5 times parent atom Ueq]. The ethanol solvent in the lattice is disordered over two positions; the occupancies of the two positions were refined with the sum set to equal 1, refining to give relative occupancies of 52:48. Restraints (SIMU 0.01 0.02) were applied to maintain sensible thermal displacement parameters for the carbon atoms.

Table 3
Experimental details

Crystal data
Chemical formula C9H7Cl2N5·C2H6O
Mr 302.16
Crystal system, space group Monoclinic, C2/c
Temperature (K) 100
a, b, c (Å) 21.2458 (15), 10.2320 (8), 14.8428 (11)
β (°) 118.808 (4)
V3) 2827.3 (4)
Z 8
Radiation type Mo Kα
μ (mm−1) 0.46
Crystal size (mm) 0.39 × 0.25 × 0.13
 
Data collection
Diffractometer Bruker APEXII CCD
Absorption correction Multi-scan (SADABS; Bruker, 2015[Bruker (2015). APEX2, SAINT and SADABS. Bruker AXS Inc., Madison, Wisconsin USA.])
Tmin, Tmax 0.602, 0.745
No. of measured, independent and observed [I > 2σ(I)] reflections 21376, 2925, 2634
Rint 0.053
(sin θ/λ)max−1) 0.629
 
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.098, 0.234, 1.41
No. of reflections 2925
No. of parameters 193
No. of restraints 48
H-atom treatment H-atom parameters constrained
Δρmax, Δρmin (e Å−3) 0.62, −0.87
Computer programs: APEX2 and SAINT (Bruker, 2015[Bruker (2015). APEX2, SAINT and SADABS. Bruker AXS Inc., Madison, Wisconsin USA.]), SHELXT (Sheldrick, 2015a[Sheldrick, G. M. (2015a). Acta Cryst. A71, 3-8.]), SHELXL (Sheldrick, 2015b[Sheldrick, G. M. (2015b). Acta Cryst. C71, 3-8.]) and Olex2 (Dolomanov et al., 2009[Dolomanov, O. V., Bourhis, L. J., Gildea, R. J., Howard, J. A. K. & Puschmann, H. (2009). J. Appl. Cryst. 42, 339-341.]).

Supporting information


Computing details top

Data collection: APEX2 (Bruker, 2015); cell refinement: SAINT (Bruker, 2015); data reduction: SAINT (Bruker, 2015); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL (Sheldrick, 2015b); molecular graphics: Olex2 (Dolomanov et al., 2009); software used to prepare material for publication: Olex2 (Dolomanov et al., 2009).

(I) top
Crystal data top
C9H7Cl2N5·C2H6OF(000) = 1248
Mr = 302.16Dx = 1.420 Mg m3
Monoclinic, C2/cMo Kα radiation, λ = 0.71073 Å
a = 21.2458 (15) ÅCell parameters from 7221 reflections
b = 10.2320 (8) Åθ = 2.2–26.4°
c = 14.8428 (11) ŵ = 0.46 mm1
β = 118.808 (4)°T = 100 K
V = 2827.3 (4) Å3Block, colourless
Z = 80.39 × 0.25 × 0.13 mm
Data collection top
Bruker APEXII CCD
diffractometer
2925 independent reflections
Radiation source: fine-focus sealed tube2634 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.053
φ and ω scansθmax = 26.6°, θmin = 2.2°
Absorption correction: multi-scan
(SADABS; Bruker, 2015)
h = 2626
Tmin = 0.602, Tmax = 0.745k = 1212
21376 measured reflectionsl = 1818
Refinement top
Refinement on F2Primary atom site location: dual
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.098H-atom parameters constrained
wR(F2) = 0.234 w = 1/[σ2(Fo2) + 59.8676P]
where P = (Fo2 + 2Fc2)/3
S = 1.41(Δ/σ)max < 0.001
2925 reflectionsΔρmax = 0.62 e Å3
193 parametersΔρmin = 0.87 e Å3
48 restraints
Special details top

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Refinement. The occupancies of the disordered atoms in the ethanol were refined with their sum set to equal 1. Restraints were applied to maintain sensible thermal and geometric parameters. The diffraction data showed slight splitting of some peaks but twinning could not be sensibly separated and modelled. However this may explain the large K values, slightly high second weight paramater and Fobs greater than Fcalc.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/UeqOcc. (<1)
Cl10.16117 (9)0.41684 (18)0.10486 (12)0.0254 (4)
Cl20.06655 (8)0.37527 (18)0.21033 (13)0.0256 (4)
O10.4106 (2)0.2925 (5)0.4111 (3)0.0192 (10)
H1A0.3978080.3578100.3719580.029*0.484 (14)
H1B0.3980270.3581210.3722840.029*0.516 (14)
N30.3251 (3)0.6534 (5)0.1015 (4)0.0136 (10)
N40.2195 (3)0.7095 (5)0.0967 (4)0.0145 (11)
H4A0.2086170.7572360.0418030.017*
H4B0.1895120.7050230.1217670.017*
N10.3666 (3)0.5147 (6)0.2792 (4)0.0177 (11)
N20.4130 (3)0.5288 (6)0.2425 (4)0.0185 (12)
N50.4347 (3)0.6032 (7)0.1152 (4)0.0293 (15)
H5A0.4220530.6461600.0576500.035*
H5B0.4772260.5658500.1475850.035*
C60.2549 (3)0.5427 (6)0.2790 (4)0.0144 (12)
C80.2808 (3)0.6445 (6)0.1415 (4)0.0133 (12)
C70.3022 (3)0.5648 (6)0.2321 (4)0.0142 (12)
C40.2351 (4)0.5649 (7)0.4253 (5)0.0191 (13)
H40.2513720.5934420.4938880.023*
C30.1697 (3)0.5029 (7)0.3727 (5)0.0193 (14)
H30.1402790.4910090.4040860.023*
C20.1470 (3)0.4581 (7)0.2738 (5)0.0176 (13)
C90.3894 (3)0.5948 (7)0.1536 (5)0.0189 (13)
C50.2772 (3)0.5859 (7)0.3788 (5)0.0188 (13)
H50.3218510.6301850.4154690.023*
C10.1893 (3)0.4782 (6)0.2273 (5)0.0152 (12)
C10B0.4570 (8)0.2138 (16)0.3909 (13)0.024 (3)0.484 (14)
H10A0.4352810.1973690.3160420.029*0.484 (14)
H10B0.4644110.1285240.4261190.029*0.484 (14)
C11B0.5275 (8)0.2819 (16)0.4283 (14)0.030 (4)0.484 (14)
H11A0.5199350.3659980.3930000.045*0.484 (14)
H11B0.5596890.2276340.4140260.045*0.484 (14)
H11C0.5491460.2966850.5025880.045*0.484 (14)
C10A0.4866 (8)0.2617 (17)0.4439 (12)0.030 (3)0.516 (14)
H10C0.5009140.1838600.4890870.036*0.516 (14)
H10D0.5169830.3357640.4844960.036*0.516 (14)
C11A0.5000 (8)0.2356 (15)0.3545 (12)0.030 (3)0.516 (14)
H11D0.4666040.1683890.3100750.045*0.516 (14)
H11E0.5495030.2051010.3804380.045*0.516 (14)
H11F0.4927150.3162050.3150820.045*0.516 (14)
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
Cl10.0342 (9)0.0289 (9)0.0201 (8)0.0150 (7)0.0189 (7)0.0098 (7)
Cl20.0144 (7)0.0370 (10)0.0260 (8)0.0077 (7)0.0102 (6)0.0040 (7)
O10.017 (2)0.024 (2)0.020 (2)0.0066 (18)0.0105 (18)0.0100 (19)
N30.010 (2)0.018 (3)0.011 (2)0.003 (2)0.004 (2)0.004 (2)
N40.011 (2)0.020 (3)0.012 (2)0.005 (2)0.006 (2)0.007 (2)
N10.016 (3)0.023 (3)0.016 (3)0.001 (2)0.010 (2)0.003 (2)
N20.010 (2)0.031 (3)0.015 (3)0.006 (2)0.007 (2)0.008 (2)
N50.017 (3)0.056 (4)0.019 (3)0.017 (3)0.012 (2)0.018 (3)
C60.015 (3)0.016 (3)0.013 (3)0.005 (2)0.008 (2)0.004 (2)
C80.014 (3)0.015 (3)0.012 (3)0.000 (2)0.007 (2)0.001 (2)
C70.009 (3)0.019 (3)0.014 (3)0.000 (2)0.006 (2)0.000 (2)
C40.025 (3)0.020 (3)0.013 (3)0.003 (3)0.010 (3)0.003 (3)
C30.021 (3)0.022 (3)0.023 (3)0.009 (3)0.018 (3)0.009 (3)
C20.014 (3)0.021 (3)0.019 (3)0.001 (3)0.009 (3)0.002 (3)
C90.015 (3)0.027 (4)0.017 (3)0.008 (3)0.010 (2)0.008 (3)
C50.015 (3)0.024 (3)0.015 (3)0.002 (3)0.006 (2)0.004 (3)
C10.019 (3)0.015 (3)0.012 (3)0.003 (2)0.009 (2)0.002 (2)
C10B0.020 (5)0.026 (5)0.028 (5)0.006 (5)0.013 (4)0.005 (5)
C11B0.020 (7)0.028 (7)0.044 (8)0.008 (6)0.017 (6)0.015 (6)
C10A0.017 (5)0.039 (6)0.031 (5)0.007 (5)0.011 (4)0.013 (5)
C11A0.030 (6)0.027 (7)0.040 (7)0.009 (6)0.021 (6)0.008 (6)
Geometric parameters (Å, º) top
Cl1—C11.735 (6)C8—C71.446 (8)
Cl2—C21.725 (6)C4—H40.9500
O1—H1A0.8400C4—C31.377 (9)
O1—H1B0.8400C4—C51.386 (9)
O1—C10B1.413 (15)C3—H30.9500
O1—C10A1.477 (14)C3—C21.384 (9)
N3—C81.335 (7)C2—C11.387 (8)
N3—C91.344 (8)C5—H50.9500
N4—H4A0.8800C10B—H10A0.9900
N4—H4B0.8800C10B—H10B0.9900
N4—C81.322 (8)C10B—C11B1.50 (2)
N1—N21.345 (7)C11B—H11A0.9800
N1—C71.304 (8)C11B—H11B0.9800
N2—C91.346 (8)C11B—H11C0.9800
N5—H5A0.8800C10A—H10C0.9900
N5—H5B0.8800C10A—H10D0.9900
N5—C91.336 (8)C10A—C11A1.51 (2)
C6—C71.490 (8)C11A—H11D0.9800
C6—C51.392 (9)C11A—H11E0.9800
C6—C11.391 (9)C11A—H11F0.9800
C10B—O1—H1A109.5N5—C9—N2116.5 (6)
C10A—O1—H1B109.5C6—C5—H5119.7
C8—N3—C9116.9 (5)C4—C5—C6120.6 (6)
H4A—N4—H4B120.0C4—C5—H5119.7
C8—N4—H4A120.0C6—C1—Cl1119.8 (5)
C8—N4—H4B120.0C2—C1—Cl1119.2 (5)
C7—N1—N2121.7 (5)C2—C1—C6120.9 (6)
N1—N2—C9116.9 (5)O1—C10B—H10A109.8
H5A—N5—H5B120.0O1—C10B—H10B109.8
C9—N5—H5A120.0O1—C10B—C11B109.3 (13)
C9—N5—H5B120.0H10A—C10B—H10B108.3
C5—C6—C7119.2 (6)C11B—C10B—H10A109.8
C1—C6—C7122.4 (5)C11B—C10B—H10B109.8
C1—C6—C5118.3 (6)C10B—C11B—H11A109.5
N3—C8—C7118.6 (5)C10B—C11B—H11B109.5
N4—C8—N3118.5 (5)C10B—C11B—H11C109.5
N4—C8—C7122.9 (5)H11A—C11B—H11B109.5
N1—C7—C6117.3 (5)H11A—C11B—H11C109.5
N1—C7—C8119.9 (5)H11B—C11B—H11C109.5
C8—C7—C6122.7 (5)O1—C10A—H10C109.0
C3—C4—H4119.8O1—C10A—H10D109.0
C3—C4—C5120.5 (6)O1—C10A—C11A112.8 (12)
C5—C4—H4119.8H10C—C10A—H10D107.8
C4—C3—H3120.2C11A—C10A—H10C109.0
C4—C3—C2119.6 (6)C11A—C10A—H10D109.0
C2—C3—H3120.2C10A—C11A—H11D109.5
C3—C2—Cl2119.3 (5)C10A—C11A—H11E109.5
C3—C2—C1120.0 (6)C10A—C11A—H11F109.5
C1—C2—Cl2120.7 (5)H11D—C11A—H11E109.5
N3—C9—N2125.6 (5)H11D—C11A—H11F109.5
N5—C9—N3117.9 (6)H11E—C11A—H11F109.5
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O1—H1A···N10.842.012.848 (7)179
N4—H4A···N3i0.882.102.972 (7)172
N4—H4B···O1ii0.882.142.841 (7)137
N5—H5A···O1iii0.882.163.014 (7)163
N5—H5B···N2iv0.882.142.987 (8)161
Symmetry codes: (i) x+1/2, y+3/2, z; (ii) x+1/2, y+1/2, z+1/2; (iii) x, y+1, z1/2; (iv) x+1, y, z+1/2.
Chosen parameters for the comparison of lamotrigine alcohol solvates top
StructureCentral dihedral angle (°)Dimerization motifDensity (g cm-1)
Methanol disolvate63.7 (2)para1.50
Ethanol monohydrate67.6 (0)para1.49
Methanol monosolvate80.1 (5)ortho1.45
Ethanol solvate (I)63.5 (9)ortho1.42
Isopropanol solvate69.6 (8)ortho1.36
Butan-1-ol solvate monohydrate71.2 (1)para1.34
 

Funding information

SRH, CLH and JP would like to thank MagnaPharm, a collaborative research project funded by the European Union's Horizon 2020 Research and Innovation programme (grant No. 736899), the Bristol Centre for Functional Nanomaterials (EP/G036780/1) and the Centre for Doctoral Training in Condensed Matter Physics (EP/L015544/1).

References

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