Sumatriptan Succinate Hemi(Ethanol Solvate)

Abstract

1-(3-(2-(Dimethylammonio)ethyl)-1H-indol-5-yl)-N-methylmethanesulfonamide succinate (sumatriptan succinate, HSum⁺·HSucc⁻) is a serotonin receptor agonist used to treat migraines. By the recrystallization of this substance from ethanol, its hemi(ethanol solvate), HSum⁺·HSucc⁻·0.5EtOH, was obtained. The solid was characterized by X-ray diffraction and FT-IR spectroscopy. In HSum⁺·HSucc⁻·0.5EtOH, solvent molecules link succinate anions into infinite O–H…O bonded chains, which are further connected by N–H…O interactions with cations into H-bonded layers.

1. Introduction

Sumatriptan succinate (HSum⁺·HSucc⁻) is the active pharmaceutical ingredient of commercially available drugs Imitrex, Treximet and others used to treat migraine headaches and cluster headaches. In addition, its anti-inflammatory properties were also reported [1]. The corresponding free base Sumatriptan (Sum) like all triptans acts as a serotonin 5-HT_1B/5-HT_1D receptor agonist [2,3]. During its metabolism, Sum transforms into a glucuronide of indol-3-yl-acetic acid derivative via several steps [4]. The crystal structures of both Sum and HSum⁺·Hsucc⁻ were published before [5,6].

Taking into account the strong effect of solvent molecules on the properties of solids, such as solubility, tabletability, stability and others, the pharmaceutical industry is highly interested in the crystal structures of all solid forms of active pharmaceutical ingredients which can occur during drug production. This information is required for phase identification and purity control. In our study of novel solid forms of known active pharmaceutical ingredients [7,8,9], the ability of sumatriptan succinate to form various solvates was examined. Recrystallization from ethanol afforded a hemisolvate, HSum⁺·HSucc⁻·0.5EtOH (1). Herein we report on the molecular and crystal structures of 1, Scheme 1.

2. Results and Discussion

Sumatriptan succinate was dissolved in ethanol without purification. After several days of standing in air at r.t., orange prismatic crystals precipitated. The precipitate was filtered off and studied using single-crystal X-ray diffraction, FT-IR and NMR spectroscopy, as well as powder X-ray diffraction. The powder XRD pattern indicates that 1 is unstable upon milling. Milling under hexane protection results in full ethanol loss and the formation of a solvent free HSum⁺·HSucc⁻ substance (Refcode ETITEG in the Cambridge Structural Database [10,11]). Rietveld refinement of the sample milled under ethanol protection revealed a mixture of 1 and HSum⁺·HSucc⁻ in the 0.2:0.8 ratio. At the same time all crystals of the precipitate that was formed had the crystal parameters of the target form 1 and were further used to collect the FT-IR spectrum.

The asymmetric unit of 1 is represented in Figure 1. It contains two cations, two anions, and one ethanol molecule. The positions of H(C), H(N) and H(O) can be easily revealed from difference Fourier maps. Thus, protonation of the dimethylamine moiety of Sum and deprotonation of only one of two carboxylic groups of Succ was observed for all symmetrically independent species. Our conclusion about the positions of hydrogen atoms is supported by interatomic and intermolecular distances. Particularly, C–O distances for deprotonated carboxylic groups vary from 1.238(4) to 1.274(4) Å. These values are intermediate between C=O and C–O(H) bond lengths for protonated groups in 1 equal to, respectively, 1.207(4)–1.210(4) and 1.313(4)–1.315(4) Å.

The molecular conformations of cations in 1 are nearly identical with the average R.M.S.D for non-hydrogen atoms equal to 0.069 Å. In Figure 2, Sum conformations in different solid forms are compared by superimposing the non-hydrogen atoms of the bicycle. It is clearly seen that rotation along single C–C, S–N and C–N groups is possible so that disposition of dimethylammonioethyl (dimethylaminoethyl) and N-methylmethanesulfonamide groups in all solids is different. The staggered conformation of succinate anions in two solvatomorphs is nearly equal: the maximal deviation of non-hydrogen atoms is 0.639 Å only; the C–C–C–C torsion angle is c.a. 60°.

Different cation conformations should be associated with different H-bonded motifs. Both in Sum and in HSum⁺·HSucc⁻ salts, the number of H-bond donors and acceptors is inequivalent, thus, different functional groups compete with each other to form the most stable H-bonding pattern. What is more, the presence of a solvent molecule in this case is expected only if the propensity of H-bond formation with this solvent is comparable or higher than the propensity of H-bond formation between the functional groups of the main components [12]. The propensities of H-bond formation for the functional groups present in HSum⁺·HSucc⁻ salts with and without ethanol were estimated using the H-bond Propensities tool of the Mercury package [13] as described in Refs. [14,15]. The data obtained are listed in

Table 1. Propensities of H-bonding in HSum⁺·HSucc⁻ salts.

HSum+·HSucc− (ETITEG [6])				1
Donor	Acceptor	Propensity	Observed	Donor	Acceptor	Propensity	Observed
R-COOH	CO2	0.85	Yes	R-COOH	CO2	0.84	Yes
	SO2	0.51			SO2	0.46
	COOH	0.33			COOH	0.26
					R-OH	0.34	Yes
Ammonium R3NH+	CO2	0.90	Yes	Ammonium R3NH+	CO2	0.81	Yes
	SO2	0.63			SO2	0.43
	COOH	0.43			COOH	0.23
					R-OH	0.31
Indole NH	CO2	0.97	Yes	Indole NH	CO2	0.87
	SO2	0.88			SO2	0.52
	COOH	0.79			COOH	0.31	Yes
					R-OH	0.40
Sulfonamide SO2NH	CO2	0.92	Yes	Sulfonamide SO2NH	CO2	0.91	Yes
	SO2	0.68			SO2	0.62
	COOH	0.50			COOH	0.40
				ROH	CO2	0.84	Yes
					SO2	0.47
					COOH	0.26
					R-OH	0.34

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The evaluated propensities indicate that in HSum⁺·HSucc⁻ (ETITEG; [6]), all donors take part in H-bonding with the most likely acceptors. The presence of ethanol molecules becomes possible because it is as likely an H-bond donor as COOH and R₃NH groups. In 1, two unlikely H-bonds are present, thus more stable polymorphs of this salt can exist. Fragments of experimentally obtained H-bonded networks in these two salts are compared in Figure 3. The parameters of H-bonds in solid HSum⁺·HSucc⁻·0.5EtOH are listed in

Table 2. Hydrogen bonding parameters for 1 (Å, °).

	D–H···A	D–H	H···A	D···A	D–H···A
1	N(1)–H(1)···O(1C)	0.90(3)	1.95(3)	2.844(4)	173(4)
2	N(2)–H(2)···O(3B i)	0.89(3)	2.07(3)	2.877(5)	151(3)
3	N(3)–H(3)···O(2C)	0.89(3)	1.81(3)	2.669(4)	162(3)
4	N(1A)–H(1AA)···O(2B ii)	0.87(3)	1.95(3)	2.794(4)	163(4)
5	N(2A)–H(2AA)···O(3C iii)	0.89(3)	2.06(3)	2.866(4)	161(1)
6	N(3A)–H(3A)···O(1B)	0.88(4)	1.80(4)	2.636(4)	158(5)
7	O(4C)–H(4C)···O(1S)	0.86(3)	1.68(3)	2.532(4)	170(4)
8	O(1S)–H(1S)···O(1B)	0.85(3)	1.78(3)	2.603(4)	162(5)
9	O(4B)–H(4B)···O(2C iii)	0.84(4)	1.70(4)	2.526(4)	165(4)

Symmetry codes: (i) 1 + x, y, z; (ii) x, −1 + y, z; (iii) −1 + x, y, z.

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HSucc⁻ anions form infinite chains in HSum⁺·HSucc⁻ (ETITEG; [6]) in accordance with the most likely H-bonds (red chains in Figure 3a). In HSum⁺·Hsucc⁻·0.5EtOH, ethanol molecules act as linkers within similar chains (red chains in Figure 3b). HSum⁺ cations connect these chains into infinite frameworks and layers, respectively. In both solids, the cation acts as a three-connected node of an H-bonded network, and the anion is a five-connected node. The resulting topologies of the underlying 3,5-c binodal H-bonded nets in these compounds evaluated with the ToposPro package [16] are, respectively, seh-3,5-P2₁/c and 3,5L24 (for notation of nets see Ref. [17]). Analysis of the H-bonding nets in the CSD using Topcryst service [18] indicates that these nets were previously met in, respectively, six and one hundred and seventy four organic solids.

To sum up, by recrystallization from ethanol, we obtained a novel solid form of sumatriptan succinate used to treat migraine and cluster headaches. Co-crystallization with ethanol is in accordance with the most likely H-bonds in a three-component mixture as estimated using the H-bond propensity tool, because the propensities of OH…O₂C and COOH…O₂C bonds were found to be similar. In both solids, the cations and anions act as three- and five-connected nodes, and ethanol molecules—as simple linkers between two anions. Nevertheless, the presence of solvent molecules strongly affects the overall H-bonding network. In HSum⁺·HSucc⁻, a 3D H-bonded framework is observed, while in HSum⁺·HSucc⁻·0.5EtOH, 2D layers are found.

3. Materials and Methods

Fine powder of sumatriptan succinate obtained from Sigma Aldrich (Moscow, Russia; 0.012 g, 0.0046 mmol) was dissolved in 3 mL of water-ethanol mixture. Single crystals were grown by slow evaporation. NMR spectra (Figures S1–S7, SI) were obtained for ¹H at 400 MHz, for ¹³C at 100 MHz and for ¹⁵N at 40 MHz, using Bruker AVANCE III WB 400 spectrometer (Bruker, Billerica, MA, USA). FTIR spectrum (Figure S8, SI) was recorded on an IR spectrometer with a Fourier transformer Shimadzu IRTracer100 (Kyoto, Japan) in the range of 4000–600 cm⁻¹ at a resolution of 1 cm⁻¹ (Nujol mull, KBr pellets). The powder XRD data were recorded at Bruker D8 Advance diffractometer (Bruker, Billerica, MA, USA) equipped a LynxEye detector and Ge(111) monochromator in a transmission mode. CuKα radiation with a wavelength of 1.544493 Å was used. The 2θ range was 4.0–60.0° with a step size of 0.2° (Figure S9, SI).

X-ray Diffraction

The intensities of reflections were collected at the Centre for Molecular Studies of INEOS RAS with Bruker D8 QUEST diffractometer at 100 K (MoKα = 0.71072 Å, φ and ω-scans). The structure was solved by the dual-space algorithm [19] and refined by full-matrix least squares against F² as two component inversion twin (SHELXL program [20]) using OLEX2 package [21], scale factors for two components are equal to 0.32(7) and 0.68(7), respectively. Non-hydrogen atoms were refined in an anisotropic approximation. Hydrogen atoms at carbon ones were calculated and included in the refinement with U_iso(H) = 1.2U_eq(C). Hydrogen atoms of N-H and O-H groups were located in difference Fourier maps and refined with unconstrained U_iso and fixed bond distances (0.88 and 0.85Å, respectively).

Crystal Data for C₁₉H₃₀N₃O_6.5S (M = 436.52 g/mol): monoclinic, space group Pc (no. 7), a = 9.834(9), b = 12.609(10), c = 16.946(16) Å, α = 90, β = 90.94(3), γ = 90°, V = 2101(3) ų, Z = 4, µ = 0.198 mm⁻¹, D_calc = 1.380 g cm⁻³, F(000) = 932, 22256 reflections measured (4.0° ≤ 2Θ ≤ 61.8°), 10388 unique (R_int = 0.0602, R_sigma = 0.0763) which were used in all calculations. The final R₁ was 0.0467 (I > 2σ(I)) and wR₂ was 0.1188 (all data).