CRYSTAL GROWTH & DESIGN
Effect of the Counterion on the Solubility of Isostructural Pharmaceutical Lamotrigine Salts Judit Galcera* and Elies Molins Institut de Cie`ncia de Materials de Barcelona (ICMAB-CSIC), Campus UAB, 08193 Bellaterra, Spain
2009 VOL. 9, NO. 1 327–334
ReceiVed May 14, 2008; ReVised Manuscript ReceiVed August 4, 2008
ABSTRACT: Salt formation is an approach to improve the physicochemical properties of the solid forms of an active pharmaceutical ingredient. As the anticonvulsant drug Lamotrigine presents low water solubility, a set of its salts with four different counterions has been obtained, and the influence of the counterion on the salt properties has been investigated. Lamotrigine salts have been obtained from succinic acid, fumaric acid, DL-tartaric acid, and saccharin. Powder samples of each salt have been characterized by infrared spectroscopy, powder X-ray diffraction, and thermal methods. Single crystal structures of four of these salts have been solved from single crystal X-ray diffraction data. The salts crystallized in P21/c and P21/n space groups, being isostructural dicarboxylic acid salts of lamotrigine. Crystal structures of these salts are built up by hydrogen bond interactions of type N(+)-H · · · O(-), N-H · · · O(-), O-H · · · N, and N-H · · · O. The water solubility of these salts has been determined and appears directly related to the solubility of the precursor acid. The isostructural nature of the studied salts allows connection of their properties with those of the counterion involved. The importance of the counterion solubility on the final solubility of the salts is rationalized considering their crystal structures.
1. Introduction Solid forms of active pharmaceutical ingredients (APIs) are commonly used for marketed drug products due to their stability and easy handling. Accordingly, the pharmaceutical industry is deeply involved in the investigation of solids containing APIs with tailored physicochemical properties. It is very convenient to find the optimal API form during the developmental stage to avoid delays in further stages. Low solubilities are very common for new drugs obtained from targeted drug design, combinatorial chemistry, and high-throughput screening techniques. Approximately one-third of the new synthesized compounds in medicinal laboratories has an aqueous solubility of less than 10 µg/mL.1 Thus, solubility becomes a key physicochemical property to control in current drug development processes.2 To address problems related with solubility and other significant properties such as bioavailability, dissolution rate, or stability, new solid forms of APIs are extensively sought. This generally includes the search for single component (polymorphs) and multicomponent (solvates, salts, and cocrystals) molecular crystals,3 resulting in a set of structural variations of the same API that in some cases can be difficult to classify.4-6 Furthermore, the relations between the different solid crystalline forms and their properties are poorly understood and difficult to anticipate.7 Salt formation is a widespread multicomponent approach to improve water solubility of poorly soluble drugs since, in general, ionized species have greater solubility in water than uncharged species due to dipolar interactions of the ions with water. Nevertheless, the selection of the appropriate counterion is usually carried out mainly on an empirical basis.8 Only few attempts to establish relationships between the counterions and the aqueous solubility of the resulting salt have been reported.9-13 The main problem found is the difficulty to compare different crystal structures even containing similar counterions. Lamotrigine [3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine] is an anticonvulsant drug14 with low water solubility. Despite the fact * To whom correspondence should be addressed. Tel: +34 935801853. Fax: +34 935805729. E-mail:
[email protected].
that the crystal structures of three lamotrigine salts had been previously reported,15 their aqueous solubility and solid state properties were not investigated. In this work, a set of novel lamotrigine salts with dicarboxylic acids as counterions have been prepared to modify the water solubility of lamotrigine by a salt formation approach and to investigate relations between their solubility behavior and other properties of the salt and of the counterion involved. Four of these new phases have been isolated and characterized with powder X-ray diffraction (PXRD), differential scanning calorimetry-thermogravimetric analysis (DSC-TGA), infrared-attenuated total reflectance (IRATR), and single-crystal X-ray diffraction. Their corresponding solubilities have been determined and rationalized with respect to the counterions’ properties. The crystal structures of these salts have different compositions and identical packing motifs that are isostructural crystals.17 Kitaigorodskii16 earlier considered this phenomenon of “isomorphism in organic crystals”, claiming that it should be “different from that for inorganic compounds” because in organic crystals “strict geometrical similarity never occurs”.
2. Experimental Procedures Materials. The anhydrous crystalline form of lamotrigine was obtained as a complimentary sample from a local pharmaceutical company. All other chemicals (purity >99%) were purchased from Sigma Aldrich (Spain). Solvents (purity >99.5%) were purchased from Panreac Quı´mica, S. A., and were used as received. Sample Crystallization. All described compounds were obtained by dissolving specified quantities of lamotrigine and the corresponding acid in the appropriate solvent. Samples obtained by grinding experiments were not included in this publication because of undesired mixtures of phases and/or incomplete conversion of reactants. 2:1:2 Lamotrigine Hemisuccinate Dimethylsulfoxide (DMSO) Solvate (1a). A 1:1 mixture of lamotrigine (49.8 mg) and succinic acid (24.0 mg) was dissolved in DMSO by heating to 70 °C. The solution was allowed to cool and evaporate at room temperature. Crystals suitable for single-crystal X-ray diffraction analysis were obtained in 3 days. Despite the fact that the initial molar ratio is 1:1, the obtained ratio is 2:1. The remaining crystals obtained were filtered and used for subsequent analysis.
10.1021/cg8005025 CCC: $40.75 2009 American Chemical Society Published on Web 12/02/2008
328 Crystal Growth & Design, Vol. 9, No. 1, 2009
Galcera and Molins
Table 1. Crystallographic Data and Structure Refinement Parameters of Lamotrigine Salts 1a-3a identification
1a
1b
2a
3a
empirical formula formula weight T (K) crystal system space group a (Å) b (Å) c (Å) R (°) β (°) γ (°) volume (Å3) Z Fcalcd (g cm-3) µ (mm-1) crystal size (mm3) reflns collected unique reflns GOOF on F2 R1[I > 2σ(I)] wR2[I > 2σ(I)] largest diff. peak and hole (e Å-3)
(C9H7Cl2N5)2 C4H6O4 (C2H6OS)2 786.54 293(2) monoclinic P21/c 11.189(5) 10.705(6) 15.981(7) 90 109.35(4) 90 1806.0(15) 2 1.446 0.497 0.48 × 0.38 × 0.25 3292 3167 1.029 0.0512 0.1218 0.31 and -0.29
(C9H7Cl2N5)2 C4H6O4 (C3H6O)2 778.44 293(2) monoclinic P21/c 11.3190(10) 10.574(2) 15.836(2) 90 109.864(10) 90 1782.6(4) 2 1.450 0.394 0.46 × 0.41 × 0.27 2376 2307 0.916 0.0727 0.1617 0.25 and -0.23
(C9H7Cl2N5)2 C4H2O4 (C2H6OS)2 784.52 293(2) monoclinic P21/n 10.8470(19) 10.923(4) 15.877(4) 90 109.062(19) 90 1778.0(8) 2 1.465 0.504 0.21 × 0.18 × 0.06 3228 3111 0.989 0.0775 0.1166 0.31 and -0.33
(C9H7Cl2N5)2 C4H4O6 (C2H6OS)2 818.54 293(2) monoclinic P21/c 11.249(2) 11.033(1) 15.800(4) 90 108.40(1) 90 1860.7 (2) 2 1.461 0.489 0.39 × 0.21 × 0.15 3403 3272 1.052 0.0730 0.1279 0.24 and -0.21
2:1:2 Lamotrigine Hemisuccinate 1,3-Dioxolane Solvate (1b). Suitable crystals for single-crystal X-ray diffraction analysis were obtained from solvent diffusion of 1,3-dioxolane solutions of lamotrigine and succinic acid, with n-butyl acetate at the solvent interphase. 2:1:2 Lamotrigine Hemisuccinate Tetrahydrofuran (THF) Solvate (1c). An amount of lamotrigine (48.5 mg) was dissolved in THF by heating to reflux. A solution of succinic acid in THF was added, producing instantaneous precipitation of a fine powder (at mixture). The obtained precipitate was filtered and analyzed by IR-ATR and PXRD. 2:1:2 Lamotrigine Hemifumarate DMSO Solvate (2a). A 2:1 mixture of lamotrigine (50.1 mg) and fumaric acid (11.6 mg) was dissolved in a 1:3 DMSO-EtOH mixture by heating. The solution was allowed to cool in an ice bath; the obtained precipitate was filtered and analyzed. The pure phase of 2a was confirmed by PXRD, IRATR, and DSC-TGA analysis. Crystals suitable for single-crystal X-ray diffraction analysis were obtained from room temperature evaporation of the filtrated solution. 2:1:2 Lamotrigine Hemifumarate 1,3-Dioxolane Solvate (2b). A 2:1 mixture of lamotrigine (50.8 mg) and fumaric acid (11.8 mg) was stirred at room temperature for 1 h. The solution was filtered, and the powder sample obtained was analyzed by IR-ATR and PXRD to confirm salt formation. 2:1:2 Lamotrigine Hemifumarate THF Solvate (2c). An amount of lamotrigine (45.2 mg) was dissolved in THF by heating to reflux. A THF solution of fumaric acid was added with spontaneous precipitation at mixture. The powder sample filtrate was analyzed by IR-ATR and PXRD to confirm salt formation. 2:1:2 Lamotrigine D,L-Hemitartrate DMSO Solvate (3a). A 1:1 mixture of lamotrigine (50.2 mg) and D,L-tartaric acid (30.1 mg) was dissolved in DMSO at room temperature and allowed to evaporate. Crystals suitable for single-crystal X-ray diffraction analysis were obtained. The remaining crystals were filtered and used for subsequent analysis. Despite the initial molar ratio of 1:1, the obtained ratio was 2:1. 1:1 Lamotrigine Saccharinate (4). A 1:1 mixture of lamotrigine (50.3 mg) and saccharin (35.5 mg) was dissolved in THF at reflux temperature; addition of toluene to the solution produced instantaneous precipitation of a fine powder. The obtained precipitate was filtered and analyzed by IR-ATR and PXRD. Compound 4 was also obtained by precipitation from acetone. Unsolvated Forms. Vacuum drying at different temperatures of the solvated forms of all dicarboxylic acid salts produced new crystalline phases of the salts without solvent content, as confirmed by DSC-TGA and IR-ATR analysis. These phases were also obtained from suspensions of the reactants in different solvents. Attempts to produce single crystals suitable for X-ray analysis from different solvents resulted in fine powders of the unsolvated salts. PXRD. PXRD patterns of all samples were collected on a Siemens D5000 powder diffractometer using Cu KR radiation (λ ) 1.5406 Å),
at a voltage of 40 kV and an intensity of 35 mA. Samples were scanned between 4° and 50° of 2θ, at a scan rate of 0.02° 2θ s-1. The experimental PXRD patterns were compared with the simulated PXRD pattern from the corresponding single-crystal structure to ensure the pure phases of the powder samples used in subsequent analyses. Single-Crystal X-ray Diffraction. The single crystal diffraction data were collected at room temperature (293 K) on a CAD-4 diffractometer18 using Mo KR radiation (λ ) 0.71073 Å), at a voltage of 50 kV and an intensity of 20 mA. Cell parameters were obtained from refinement of 25 reflections collected from a random searching. Data reduction was performed with XCAD419 software. Data obtained were processed with the WinGX integrated system software package for single-crystal X-ray diffraction data solution, refinement, and analysis.20 Crystal structures of all compounds were solved by direct methods using SHELXS-9721 and were refined by full-matrix least-squares refinement on F2 using SHELXL-97.21 A mixed treatment of hydrogen atoms was adopted for each structure. H-atoms were refined with the isotropic displacement parameters when their location from difference Fourier maps was achieved. In other cases, the H-atoms were introduced in calculated positions and refined as riding on their bonded atoms with idealized geometries and with a restrained isotropic displacement parameter. Table 1 gives the crystal data, and Table 2 gives the hydrogen bond parameters. FT-IR-ATR Spectroscopy. IR-ATR spectra were recorded on a high-resolution spectrometer FT-IR Perkin-Elmer with an ATR accessory of diamond as the ATR crystal. The spectra were recorded in the 4000-400 cm-1 range. DSC and TGA. DSC analyses were performed using a Mettler Toledo DSC823 unit. The samples (2-5 mg) were encapsulated in aluminum pans (40 µL nominal volume) with pierced lids. A heating rate of 10 °C min-1 and nitrogen purge at 50 mL min-1 were employed for the temperature range 25-350 °C. The mass loss of the sample as a function of temperature (TGA) was determined using a Mettler Toledo TG50 unit. The samples were placed in pierced aluminum crucibles (100 µL nominal volume) and heated from 25 to 350 °C at 10 °C min-1. Nitrogen purge at 50 mL min-1 was employed. Solubility Determination. Solubility determination of compounds 1a, 2a, 3a, and 4 was performed using an isothermal technique by the addition of specified amounts of solvent in a specified ratio to a preweighted amount of sample (in a jacketed vessel, at a constant temperature bath) until complete dissolution of the compound was achieved. An amount of 0.2 mL of solvent was added with a syringe every 10 min with constant stirring to a preweighted amount of sample. When few amounts of undissolved material were observed, the elapsed time to the next solvent addition was increased, and the amount of solvent added was reduced. The solubility studies were done by triplicate, and the values were merged. The solubility of lamotrigine was also performed to validate the method obtaining the maximum deviation of 6% from the literature value.22
Isostructural Pharmaceutical Lamotrigine Salts
Crystal Growth & Design, Vol. 9, No. 1, 2009 329
Table 2. Hydrogen Bond Geometries of Compounds 1a, 1b, 2a, and 3a d(D-H) (Å)
D-H · · · A
d(H · · · A) (Å)
d(D · · · A) (Å)
