Structures of Polymorphic Agomelatine and Its Cocrystals with Acetic

Jan 6, 2011 - ABSTRACT: Two polymorphic structures of Form II and Form III of agomelatine were determined by single and powder. X-ray diffraction ...
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DOI: 10.1021/cg101234p

Structures of Polymorphic Agomelatine and Its Cocrystals with Acetic Acid and Ethylene Glycol

2011, Vol. 11 466–471

Sai-Li Zheng, Jia-Mei Chen,* Wei-Xiong Zhang, and Tong-Bu Lu* School of Pharmaceutical Sciences/School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou, 510275, China Received September 18, 2010; Revised Manuscript Received November 8, 2010

ABSTRACT: Two polymorphic structures of Form II and Form III of agomelatine were determined by single and powder X-ray diffraction, respectively, in which the agomelatine molecules are linked through the intermolecular hydrogen bonding interactions to form a one-dimensional (1D) chain, and the 1D chains are further packed through interchain π 3 3 3 π and C-H 3 3 3 π interactions to generate the three-dimensional (3D) structures. Two agomelatine cocrystals with acetic acid (1) and ethylene glycol (2) were synthesized, and their structures were determined by single and powder X-ray diffraction, respectively, in which the acetic acid molecules in 1 alternately link the agomelatine molecules to form 1D right-handed and left-handed helical chains, while the alternately linking of agomelatine molecules by ethylene glycol molecules in 2 generates the homochiral right-handed helical chains. After the formation of cocrystals of 1 and 2, the melting points dramatically decrease, and the solubility is approximately twice as large as that of Form II.

Scheme 1. Structure of Agomelatine

Introduction Polymorphism is defined as the ability of a molecule to adopt two or more crystal forms with different arrangements and/or conformations in the crystal lattice.1-3 Polymorphism is very common among pharmaceutical substances and is important in the pharmaceutical industry,4,5 as polymorphism significantly influences the pharmaceutical stability, dissolution rate, solubility, bioavailability, and manufacturability.6-8 In the past few decades, increasing numbers of pharmaceutical polymorphs have been reported in order to find a stable polymorph with better bioavailability. Recently, cocrystals have become a subject of growing interest in pharmaceutical science.9 For a given active pharmaceutical ingredient (API), its property can be tuned through cocrystallization with organic molecules via intermolecular hydrogen bonding or π 3 3 3 π stacking interactions; thus the bioavailability and stability of the API can be improved by tuning its solubility10-13 and the melting point14-16 through the cocrystallization. Agomelatine (N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide, see Scheme 1), a drug for treatment of severe depression, was first produced by Servier pharmaceutical company in 2009. Up to now, six polymorphic forms of agomelatine have been reported. Form I was primarily obtained from a biphasic (H2O-CHCl3) medium.17 Form II can be obtained from a mixture of ethanol and H2O.18 Form III can be obtained by slowly cooling after melting the agomelatine at 110 °C.19 Form IV was prepared by melting the compound at 110 °C rapidly, cooling to 50-70 °C, and then maintaining it for 5 h at 70 °C.20 Forms V and VI can be obtained by grinding21 and spray drying,22 respectively. However, only the structure of Form I has been reported so far.23 In order to understand the structural differences of the polymorphic forms of agomelatine, and to see if its physical *To whom correspondence should be addressed. Fax: þ86-20-84112921. E-mail: [email protected] (J.M.C.); [email protected] (T.-B.L.). pubs.acs.org/crystal

Published on Web 01/06/2011

properties such as the melting points and solubility can be tuned through cocrystals, two cocrystals of agomelatine with acetic acid (1) and ethylene glycol (2) were prepared, and their structures, melting points, and solubilities were investigated. Experimental Section General Remarks. Agomelatine was purchased from Nantong Chemical Co., Ltd. All the solvents employed were commercially available and used as received without further purification. Elemental analyses were determined using Elementar Vario EL elemental analyzer. The IR spectra were recorded in the 4000 to 400 cm-1 region using KBr pellets and a Bruker EQUINOX 55 spectrometer. Differential scanning calorimetry (DSC) was performed using a Netzsch DSC-204 instrument and aluminum sample pans in nitrogen atmosphere, with a heating rate of 10 °C/min. Form II. Agomelatine (0.100 g) was dissolved in a minimum of acetonitrile, and the solution was evaporated slowly at room temperature. After about 3 days, colorless crystals of Form II were obtained. Yield: 0.095 g, 95%. Anal. Calcd for C15H17NO2: C, 74.05; H, 7.04; N, 5.76%. Found: C, 74.00; H, 7.23; N, 5.84%. IR data (KBr, cm-1): 3244, 3073, 2998, 2964, 2941, 2871, 2837, 1640, 1625, 1598, 1548, 1509, 1471, 1435, 1367, 1343, 1302, 1251, 1215, 1183, 1160, 1131, 1100, 1030, 867, 834, 758, 732, 643, 612, 472. Form III. Form III was prepared according to the literature method.18 Yield, 98%. Anal. Calcd for C15H17NO2: C, 74.05; H, 7.04; N, 5.76%. Found: C, 73.95; H, 7.15; N, 5.84%. IR data (KBr, cm-1): 3250, 3078, 2996, 2972, 2935, 2863, 2837, 1638, 1598, 1562, 1510, 1470, 1437, 1371, 1297, 1252, 1215, 1183, 1160, 1132, 1097, 1031, 906, 863, 833, 755, 733, 698, 644, 612, 588, 550, 472, 449. Agomelatine Acetic Acid Cocrystal (1:1), 1. An acetic acid solution of agomelatine (0.100 g) was diffused with petroleum ether. After about 2 days, colorless prism-shaped crystals of 1 were isolated r 2011 American Chemical Society

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Table 1. Crystallographic Data and Details of Refinements for Form II and 1a

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Table 2. Crystallographic Data and Details of Refinements for Form III and 2a

compound

Form II

1

compound

Form III

2

formula Mr crystal system space group T (K) a (A˚) b (A˚) c (A˚) β (deg) V (A˚3) Z Dc (g 3 cm-3) μ (mm-1) F(000) reflections collected independent reflections Rint Rsigma data/restrains/parameters goodness-of-fit on F2 R1/wR2 [I > 2σ(I)] R1/wR2 (all data) largest diff. peak and hole (e 3 A˚-3)

C15H17NO2 243.30 monoclinic P21/c 293(2) 15.4300(12) 9.2934(7) 20.8558(13) 115.241(4) 2705.1(3) 8 1.195 0.079 1040 16426 5182 0.0542 0.0531 5182/0/330 1.036 0.0714/0.1988 0.1061/0.2273 0.576/-0.295

C17H21NO4 303.35 monoclinic P21/c 296(2) 12.5852(6) 8.8884(4) 17.8848(6) 124.586(2) 1647.1(1) 4 1.223 0.087 648 12268 3219 0.0263 0.0248 3219/0/208 1.164 0.0403/0.1293 0.0592/0.1569 0.272/-0.199

empirical formula Mr T (K) wavelength (A˚, Cu KR) crystal system space group a (A˚) b (A˚) c (A˚) β (o) V (A˚3) Z 2θ (o) step size (2θ) Rwp Rwp (without background) Rp

C15H17NO2 243.30 296(2) 1.540562 orthorhombic Pna21 9.202(2) 20.416(4) 7.208(2) 90 1354.2(6) 4 6-80 0.02° 0.0968 0.1366 0.0722

C17H23O4N 305.4 296(2) 1.540562 monoclinic P21 13.054(1) 7.347(1) 8.766(1) 95.177(2) 837.3(2) 2 5-70 0.02° 0.0608 0.0884 0.0444

Table 3. Hydrogen-Bonding Parameters of Agomelatine

)

)

R1 = Σ Fo| - |Fc /Σ|Fo|. wR2 = [Σ[w(Fo2 - Fc2)2]/Σw(Fo2)2]1/2, w = 1/[σ2(Fo)2 þ (aP)2 þ bP ], where P = [(Fo2) þ 2Fc2]/3. a

a Rwp = [w(cYsim(2θi) - Iexp(2i) þ Yback(2θi))2/Σw(Iexp(2θi))2]1/2, Rwp (without background) = [Σw(cYsim(2θi) - Iexp(2θi) þ Yback(2θi))2/ w(Iexp(2θi) - Yback(2θi))2]1/2, w = 1/Iexp(2θi), Rp = Σ|cYsim(2θi) Iexp(2θi) þ Yback(2θi)|/Σ|Iexp(2θi)|.

D-H 3 3 3 A Form IIa N1-H1 3 3 3 O4 N2-H2 3 3 3 O2A Form IIIb N2-H34 3 3 3 O4A 1c N1-H1 3 3 3 O4A O3-H3 3 3 3 O2 2d O39-H45 3 3 3 O38A N23B-H35B 3 3 3 O39 O38-H44 3 3 3 O30C O39D-H45D 3 3 3 O38

H3 3 3A (A˚)

D-H (A˚)

D3 3 3A (A˚)

D-H 3 3 3 A (deg)

2.005(1) 2.046(2)

0.860(2) 0.860(2)

2.86(3) 2.843(3)

171.7(1) 153.7(1)

2.2307(3) 0.8676(2) 2.8707(5) 1.99(2) 1.74(2)

0.90(2) 0.85(2)

2.882(2) 2.570(1)

1.6284(1) 2.1209(2) 1.7184(1) 1.6284(1)

0.9519(1) 0.8684(1) 0.9520(1) 0.9519(1)

2.5718(2) 2.9667(3) 2.6452(2) 2.5718(2)

130.47(1) 174(1) 165(3) 170.36(1) 164.460(9) 163.56(1) 170.36(1)

a Symmetry code: (A) x, 1 þ y, z. b Symmetry code: (A) x - 0.5, 0.5 y, z. c Symmetry code: (A) 1 - x, 0.5 þ y, 1.5 - z. d Symmetry code: (A) 1 - x, -0.5 þ y, -z; (B) -x - 1, -1.5 þ y, 1 - z; (C) x - 2, -1 þ y, z; (D) -1 - x, 0.5 þ y, -z.

Figure 1. The final Rietveld refinement plots of Form III (a) and 2 (b): experimental pattern (circles), calculated pattern (solid line), and difference profile (bottom solid line). Stick marks (|) at the bottom of the pattern indicate peak positions allowed by the unitcell parameters and space group. by filtration, washed with petroleum ether, and dried in air. Yield: 0.120 g, 96%. Anal. Calcd for C17H21NO4: C, 67.31; H, 6.98; N, 4.62%. Found: C, 67.67; H, 7.04; N, 4.70%. IR data (KBr, cm-1): 3252, 3079, 2998, 2973, 2936, 2865, 2837, 1918, 1637, 1599, 1562, 1510, 1471, 1437, 1371, 1345, 1299, 1253, 1215, 1183, 1160, 1132, 1098, 1031, 907, 864, 834, 755, 733, 698, 644, 612, 589, 550, 473, 450, 432.

Agomelatine Ethylene glycol Cocrystal (1:1), 2. A mixture of agomelatine (0.100 g) and ethylene glycol (0.120 g) was stirred at 110-130 °C for 5 h and cooled to 0 °C. The obtained white crystalline powder was collected in 98% yield. Anal. Calcd for C18H18NO6: C, 61.00; H, 7.96; N, 3.95%. Found: C, 61.08; H, 7.99; N, 4.04%. IR data (KBr, cm-1): 3258, 3083, 2997, 2971, 2939, 2864, 1917, 1636, 1598, 1563, 1509, 1469, 1441, 1372, 1343, 1306, 1253, 1215, 1182, 1161, 1132, 1096, 1060, 1029, 906, 891, 866, 833, 758, 735, 698, 648, 610, 591, 552, 473, 450, 433. Single Crystal X-ray Diffraction. The single crystal data for Form II and 1 were collected on a Rigaku R-AXIS Spider IP diffractometer with Mo-KR radiation (λ = 0.71073 A˚) by ω/2θ scanning at room temperature. Cell parameters were retrieved and refined using Rigaku RAPID AUTO (Rigaku, 1998, Ver2.30) software. The structures were solved by the direct methods using the SHELXS-97 program24 and refined by the full-matrix least-squares method on F2. All non-hydrogen atoms were refined with anisotropic displacement parameters. The hydrogen atoms were generated geometrically. Crystal data as well as details of data collection and refinements are summarized in Table 1. Selected hydrogen bonding distances and angles are listed in Table 3. Powder X-ray Diffraction. X-ray powder diffraction (XRPD) patterns for Form III and 2 were obtained on a Bruker D8 Advance with Cu KR radiation (40 kV, 40 mA). The powder sample was sideloaded on the glass holder carefully to reduce the preferred orientation, and the step-scanned X-ray powder diffraction data were

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Zheng et al. recorded in the range of 6-80° (2θ) for Form III, and 5-70° (2θ) for 2, with 0.02° 2θ step size and 4 s/step scan speed. Then various parameters, including Pseudo-Voigt profile parameters, background parameters, the cell constants, the zero point of the diffraction pattern, the position and orientation of motion groups and torsion angles, the global isotropic atom displacement parameter, the Berar-Baldinozzi asymmetry correction parameters, and the March-Dollase preferred orientation correction parameters, were optimized step by step to improve the agreement between the calculated and the experimental powder diffraction pattern, which was carried on the Reflex Powder Refinement module of Material Studio. The Rietveld refinement plots for Form III and 2 are shown in Figure 1, panels a and b, respectively. The obtained crystal data are listed in Table 2. Selected hydrogen bonding distances and angles are listed in Table 3. Powder Dissolution Experiments. Concentrations of 1 and 2 in water were determined by a Cary 50 UV spectrophotometry at 230 nm, and the absorbance values were related to solution concentrations using a calibration curve (ε = 4.87  104 M-1). The solids of Form II, 1 and 2 were milled to powder and sieved using standard mesh sieves to provide sample with approximate particle size ranges of 68-150 μm. In a typical experiment, a flask containing 100 mg of powder was added 50 mL of water, and the resulting mixture was stirred at 25 °C and 250 rpm. At each time, the solution was withdrawn from the flask and filtered through a 0.2 μm nylon filter. A 0.10 mL portion of the filtered aliquot was diluted to 10.0 mL with water and was measured with UV/vis spectrophotometry.

Results and Discussion

Figure 2. (a) The molecular structure of agomelatine in Form II. (b) Top view and (c) side view of 1D hydrogen bonding linked chain. (d) The 3D structure of agomelatine in Form II.

Crystal Structures. Single-crystal X-ray analysis reveals that the structure of Form II is similar to the reported structure of Form I (Figures 2a and S1),22 in which Form II crystallizes in the space group P21/n, with two independent agomelatine molecules in the asymmetric unit. As shown in Figure 2c, each agomelatine molecule links two adjacent agomelatine molecules through intermolecular hydrogen-bonding

Figure 3. (a) Side view and (b) top view of 1D hydrogen bonding linked chain in Form III. (c) The 3D structure of agomelatine in Form III.

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Figure 4. (a) The molecular structure of 1. (b) Side view of 1D hydrogen bonding linked right-handed helical chain. (c) The 1D right-handed and left-handed helical chains in 1. (d) The 1D righthanded and left-handed helical chains packed along the b axis.

interactions to form a one-dimensional (1D) infinite chain along the b axis, with the O 3 3 3 N distances of 2.846 and 2.857 A˚, respectively. These O 3 3 3 N distances are shorter than those found in Form I (2.850 and 2.927 A˚). The dihedral angle between two adjacent naphthalene rings within the chain is 105.2° (Figure 2b). The 1D chains are stacked further via interchain π 3 3 3 π and C-H 3 3 3 π interactions between the adjacent naphthalene ring to generate a three-dimensional (3D) structure (Figure 2d), with distances of 3.52 and 3.72 A˚, respectively. The structure of Form III was solved by the X-ray powder diffraction. It crystallizes in the space group Pna21. Similar to Form II, the agomelatine molecules in Form III are also linked through intermolecular hydrogen bonding interactions between the amide N atom in one agomelatine molecule and carbonyl O atom in the adjacent agomelatine molecule to form 1D chain (Figure 3a), with the O 3 3 3 N distance of 2.890 A˚. The dihedral angle between two adjacent naphthalene rings in Form III (89.8°) is smaller than that in Form II (Figure 3b). The 1D chains are further linked through the interchain C-H 3 3 3 π interactions of adjacent naphthalene

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rings to generate a 3D structure (Figure 3c), with a distance of 3.58 A˚. It is interesting to note that the structures of Form II and Form III are similar, and they are also similar to the reported structure of Form I (see Figure S1, Supporting Information), in which the agomelatine molecules are linked through the intermolecular hydrogen bonding interactions to form 1D chains. The different polymorphic forms of agomelatine (Forms I-III) are mainly caused by the different packing arrangements of 1D chains. In addition, there are no solvents in Forms I-III due to the strong interchain π 3 3 3 π and C-H 3 3 3 π interactions. In order to form agomelatine cocrystals, a molecule with hydrogen bond donor and acceptor is necessary so it can interact with agomelatine molecule through intermolecular hydrogen bonding interaction to form cocrystals. Thus, the solvents of dimethylformamide, water, glycerol, propanediol, xylitol, acetic acid, and ethylene glycol were used to cocrystallize with agomelatine, and two cocrystals of 1 and 2 were successfully obtained. As expected, the acetic acid molecules in 1 insert into the 1D chain of agomelatine molecules, in which each acetic acid molecule links two agomelatine molecules through two intermolecular hydrogen bonds (Figure 4a), and acetic acid molecules alternately link the agomelatine molecules to form a 1D right-handed helical chain (Figure 4b). However, the adjacent chains are arranged in the left-handed helicity; thus the structure of 1 is racemic and it crystallizes in centrosymmetric space group P21/c (Figure 4c). The 1D right-handed and left-handed helical chains are packed along the b axis to form a 3D structure (Figure 4d). Similar to 1, the ethylene glycol molecules in 2 also insert into the 1D chain of agomelatine molecules, and alternately link the agomelatine molecules through the intermolecular hydrogen bonding interactions to form 1D right-handed helical chain (Figure 5a,b). In contract to 1, the ethylene glycol molecules in 2 are linked together through intermolecular hydrogen bonding interactions to form a 1D left-handed helical chain (Figure 5c, green part). Thus, the right-handed helicity of the original formed 1D right-handed helical chain was uniformly transferred to the adjacent chain through the left-handed helical chains of (ethylene glycol)n to get a twodimensional (2D) chiral sheet (Figure 5c), in which all the 1D (agomelatine-ethylene glycol)n chains are arranged in the right-handed helicity. The 2D chiral chains are packed along the b axis to form a 3D homochrial structure of 2 (Figure 5d), with a chiral space group P21. The X-ray Powder Diffraction, DSC Analyses, and Powder Dissolution. XRPD was used to check the purity of Form II and 1. The results show that all the peaks displayed in the measured patterns at room temperature closely match to those in the simulated patterns generated from single-crystal diffraction data (see Figure S2, Supporting Information), indicating single phases of Form II and 1 were formed. In addition, successfully solving the structures of Form III and 2 from the X-ray powder diffraction patterns also indicates the formation of single phases of Form III and 2. The data of DSC analyses show the melting points at 99, 109, and 100 °C for Forms I, II, and III, respectively. After the formation of cocrystals with acetic acid and ethylene glycol, the melting points decrease dramatically to 76 and 68 °C for 1 and 2, respectively (Figure S3, Supporting Information). Powder dissolution profiles for Form II, 1, and 2 are shown in Figure 6. From Figure 6, it can be found that 1 and 2 dissolve more quickly than Form II, indicating the

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Figure 5. (a) The molecular structure of 2. (b) Side view of 1D hydrogen bonding linked right-handed helical chain. (c) A hydrogen bonding linked 2D sheet containing 1D left-handed helical chains of (ethylene glycol)n (green part) and 1D right-handed helical chains of (agomelatineethylene glycol)n (light blue and green). (d) 3D structure of 2 containing 2D sheets packed along the b axis.

filtered, and the results of XRPD analyses indicate that the solids of 1 and 2 transformed to Form I and Form III, respectively; this is attributed to the strong hydrophilic nature of acetic acid and ethylene glycol, and the acetic acid and ethylene glycol were extracted into water solution from 1 and 2. Conclusions

Figure 6. Powder dissolution profiles for Form II, 1 and 2.

dissolution rate becomes larger after formation of cocrystals of 1 and 2. In addition, the equilibrium solubility values of 1 and 2 are approximately twice as large as that of Form II, demonstrating that the solubility of API can be increased through the cocrystals. Since solubility and bioavailability are often related,11 the above results demonstrate that cocrystals may be used to tune the bioavailability of an API. After the dissolution experiments, the undissolved solids were

In summary, two structures of Form II and Form III of agomelatine, and its two cocrystals of 1 and 2 with acetic acid and ethylene glycol were determined by the single and powder X-ray diffraction. Both Form II and Form III possess similar hydrogen bond linked 1D chains of agomelatine molecules, and the different polymorphic forms of Form II and Form III are mainly caused by the different packing arrangements of 1D chains. After formation of cocrystals of 1 and 2, the agomelatine molecules are separated by acetic acid and ethylene glycol molecules. As the melting points of acetic acid and ethylene glycol molecules are much lower than that of agomelatine, the melting points dramatically decrease after formation of cocrystals. In addition, due to the hydrophilic nature of acetic acid and ethylene glycol, the agomelatine molecules become easier to dissolve in water after formation of cocrystals; thus the dissolution rates become faster, and the solubility

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becomes larger. The results presented here clearly demonstrate that the melting points and solubility can be tuned through cocrystals. Acknowledgment. This work was supported by NSFC (20625103, 20831005, 20821001) and the National Key Program of China (2009ZX09501-022). Supporting Information Available: The structure figures of Form I and the XRPD patterns of 1 and Form II; crystallographic information files. This material is available free of charge via the Internet at http://pubs.acs.org.

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