(3,5-Dimethyladamantan-1-yl)ammonium methanesulfonate (memantinium mesylate): synthesis, structure and solid-state properties

The title salt crystallizes with three independent ionic pairs in the asymmetric unit. In the crystal, (3,5-dimethyladamantan-1-yl)ammonium cations and methanesulfonate anions associate via N—H⋯O hydrogen bonds into layers that extend parallel to (001) and comprise large supramolecular hydrogen-bonded rings.


Chemical context
Memantine or 3,5-dimethyladamantane-1-ylamine is an active pharmaceutical ingredient which acts as an uncompetitive NMDA receptor antagonist (Reisberg et al., 2003;Rammes et al., 2008;Parsons et al., 2013). The compound was approved for the treatment of moderate-to-severe Alzheimer's disease and is currently marketed as the chloride salt. The crystal structure of memantinium chloride 0.1-hydrate has previously been described (Lou et al., 2009). Herein we report the structure of an alternative salt, (3,5-dimethyladamantan-1yl)ammonium methanesulfonate (I) (memantinium mesylate), developed with the aim of producing a material with physicochemical properties superior to those of memantinium chloride.

Supramolecular features
The crystal packing of the title compound is characterized by hydrogen-bonding interactions between the protonated amino groups of cations and the oxygen atoms of the methanesulfonate anions (Table 1, Fig. 2). Each hydrogen atom of the protonated amino groups of the (3,5-dimethyladamantan-1yl)ammonium cations is engaged in hydrogen bonding with the neighbouring methanesulfonate anions. While each of the established N-HÁ Á ÁO hydrogen bonds has a characteristic D 1 1 (2) graph-set motif, they combine into larger R 4 4 (12) motifs (Fig. 2). Assemblies formed in such a way are supported by weaker C-HÁ Á ÁO contacts, as shown in Fig. 2. Such connec-tivity leads to the formation of supramolecular layers parallel to the (001) plane, which involve large hydrogen-bonded rings (Fig. 3).

Hirshfeld surface analysis
The Hirshfeld surfaces for the cations and anions constituting the asymmetric unit of (I) were calculated using Crystal-Explorer17 (Turner et al., 2017) and are shown in Fig. 4. Mapping the d norm values on the corresponding Hirshfeld surface allows a detailed analysis of hydrogen bonds and short intermolecular contacts (Spackman & Jayatilaka, 2009). In this case, red spots indicate N-HÁ Á ÁO hydrogen bonds, blue regions correspond to positive d norm values, and white areas indicate contacts of equal length to the sum of the van der Waals radii, i.e. d norm is 0. While the Hirshfeld surfaces for the three cations appear similar to each other, the two-dimensional fingerprint plots reveal distinctive differences between them. The full two-dimensional fingerprint plots along with the decomposed ones, displaying the contributions of the relevant contacts, are shown in Fig. 5. It can be seen that the N3-containing cation has the largest contribution of HÁ Á ÁO/ OÁ Á ÁH contacts (23.9%), while for the N1-and N2-containing cations this contribution amounts to 14.9 and 17.1%, respectively. Analysis of the fingerprint plots for the anions reveals that they have fairly similar environments within the crystal and consequently a comparable distribution of the intermolecular contacts (Fig. 5).

Synthesis and crystallization
To a solution of 10.0 g of (3,5-dimethyladamantan-1-yl)ammonium chloride (supplied by PLIVA Croatia Ltd.) in 300 ml   Views of the Hirshfeld surfaces mapped over d norm for: (a) the N1containing cation; (b) the S1-containing anion, (c) the N2-containing cation; (d) the S2-containing anion, (e) the N3-containing cation and (f) the S3-containing anion (range: À0.6178 to 1.7852 a.u.). of water, 140 ml of toluene was added and the pH adjusted to about 10.7 by using 40% NaOH (aq). The toluene and water layers were separated. To the toluene solution of 3,5-dimethyladamantane-1-ylamine, 3.3 ml of methanesulfonic acid at 293-298 K was added. The reaction mixture was stirred at 293-298 K for 1 h, cooled to 273-278 K and stirred at that temperature for 1 h. The resulting crystals were filtered off, washed with toluene and dried at 313 K/20 mbar for about 15 h. The obtained solid was slurried in 125 ml of acetone at 293-298 K for about 18 h, filtered off, washed with acetone and dried at 313 K/20 mbar for about 15 h. The product was recrystallized from i-propyl acetate, yielding crystals suitable for single-crystal X-ray diffraction, yield 11.7 g (92%).

Thermal analysis
The thermal stability of the title compound was investigated in the solid state by thermogravimetric analysis (TGA) and by differential scanning calorimetry (DSC). Thermogravimetric analysis was performed on TA Instruments TGA in closed aluminium pans with one hole on the crucible under a nitrogen flow (50 mL min À1 ) with a heating rate of 10 C min À1 in the temperature range 25-300 C.
Thermogravimetric analysis does not reveal any weight loss during heating up to about 200 C, whereupon a change in mass is observed that can be associated with the thermal decomposition of the sample (Fig. 6a). DSC analysis of (I) reveals two thermal events (Fig. 6b). The first endotherm at about 125 C suggests that the sample is experiencing a phase transition, as no weight loss can be observed on the corresponding TG curve in this temperature region. The second strong endotherm, observed on the DSC curve at about 210 C, can be ascribed to the melting point of the new phase. Existence of a new, stable phase was confirmed via a PXRD experiment, where comparison of the powder patterns of the starting sample (I) and the one obtained by heating (I) at about 130 C for 17 h revealed significant differences (Fig. 7). Additional confirmation for this conclusion is found in the DSC curve of the material obtained after heating (I), where only one endothermic event can be observed, the one appearing at 210 C and corresponding to its melting point.   The fingerprint plots for the ions constituting the asymmetric unit of (I): (a) the N1-containing cation; (b) the N2-containing cation, (c) the N3containing cation; (d) the S1-containing anion, (e) the S2-containing anion and (f) the S3-containing anion. Left side: full fingerprint plot, middle: contribution of the HÁ Á ÁO/OÁ Á ÁH contacts, and right side: contribution of the HÁ Á ÁH contacts to the intermolecular interactions.

IR spectroscopy
The infrared (IR) spectrum of title compound was recorded by using the ATR (attenuated total reflectance) technique on a PerkinElmer Spectrum Two instrument. The spectrum of (I) displays a broad band positioned at ca 2900 cm À1 , which corresponds to N-H stretching vibrations of the protonated amino group of the (3,5-dimethyladamantan-1-yl)ammonium cations superimposed with the C-H stretching vibrations of the adamantane skeleton and methyl groups of the methanesulfonate anion (Fig. 8). The bands corresponding to the S-O asymmetric and symmetric stretching modes appear at 1179 and 1042 cm À1 , respectively (Başkö se et al., 2012). The band at 780 cm À1 is associated with the C-S stretching vibration, whereas the one at 540 cm À1 corresponds to the bending mode of the SO 3 moiety (Başkö se et al., 2012).

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. Hydrogen atoms bonded to carbon atoms of the adamantane core were refined as riding with C-H = 0.98 Å for methine C atoms (C7-H7, C19-H19 and C31-H31) and C-H = 0.97 Å for the methylene H atoms, both with U iso (H) = 1.2U eq (C). Hydrogen atoms bonded to carbon atoms of the methyl groups of both the memantine cations and the methanesulfonate anions were refined as rotating rigid groups with C-H = 0.96 Å and U iso (H) = 1.5U eq (C). Hydrogen atoms bonded to nitrogen atoms were found in the difference-Fourier maps at final steps of the refinement and refined with U iso (H) = 1.2U eq (N). Their coordinates were refined independently, but N-H distances were restrained to 0.89 (2)

Special details
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.