Crystal structures of binary compounds of meldonium 3-(1,1,1-trimethylhydrazin-1-ium-2-yl)propanoate with sodium bromide and sodium iodide

3-(1,1,1-Trimethylhydrazin-1-ium-2-yl)propanoate (M, more commonly known under its commercial names Meldonium or Mildronate) co-crystalizes with sodium bromide and sodium iodide forming polymeric hydrates. Metal ions and M zwitterions are assembled into infinite layers via electrostatic interactions and hydrogen-bonded networks. These layers are connected via electrostatic attraction between halogenide ions and positive trimethylhydrazinium groups into a three-dimensional structure.


Chemical context
3-(1,1,1-Trimethylhydrazin-1-ium-2-yl)propanoate (M), more commonly known under its commercial names such as Meldonium or Mildronate, was introduced by Grindeks (Latvia) as an anti-ischemic medication (Liepinsh et al., 2017). The synthesis of M was originally described by Giller et al. (1975) and was improved in a number of patents and papers (Kalvins & Stonans, 2009;Kalvins et al., 2014;Silva, 2013). Recently M achieved controversial publicity as a doping agent. As a result of its inclusion in the World Anti-Doping Agency List of Prohibited Substances, it attracted the attention of pharmaceutical and forensic chemists (Gö rgens et al., 2015).
Binary compounds of M with various inorganic salts have been described in numerous M-related synthetic procedures (see above); their high stability was a challenge that was necessary to overcome for the preparation of pharmaceutically pure forms of M. The stability of a sodium iodide binary compound was given as an example in Silva (2013). The crystal structures of two such binary compounds, with sodium bromide (I) and with sodium iodide (II), are presented here.

Structural commentary
The labelling schemes for structures (I) and (II) are shown in Figs. 1 and 2. Molecules of (I), which crystallize in an acentric space group, have a non-crystallographic inversion centre at 0.6238 (6) 0.744 (5) 0.5001 (2). This symmetry is visible in Fig. 1; it is also demonstrated by overlay of the two chemically equivalent moieties, after inversion of one of them (Fig. 3). ISSN 2056-9890 Both Na ions have distorted octahedral environments (coordination number 6). The coordination sphere contains an anionic oxygen atom of a monodentate carboxylic group, two pairs of bridging O atoms of water molecules (O5, O8, O9 and O10), and a terminal water molecule (atoms O6 and O7 for Na1 and Na2 respectively). The shortest Na-O separations (Table 1) correspond to the anionic oxygens O1 and O3; the longest are opposite to the bridging atoms O5 and O8 (not shown in Fig. 1, but visible in Fig. 6).
The coordination polyhedra of the sodium ions in (II) are visibly different (Fig. 4, Table 2). Both have a distorted octahedral geometry and coordination number 6. The coordination polyhedron of Na1 contains an anionic oxygen atom O1 of a monodentate carboxylic group, atoms O3 and O4 of the bidentate carboxylic acid group, and three water molecules O5, O6, and O8. The O8 atom, which forms three bridging Labelling scheme of the asymmetric unit of compound (II) with 50% probability displacement ellipsoids.

Figure 1
Labelling scheme of the asymmetric unit of compound (I) with 50% probability displacement ellipsoids.
contacts to three different sodium ions, shows a much longer separation from Na1 than any of the other coordinated oxygen atoms ( Table 2). The octahedral environment around Na2 in (II) (Fig. 4, Table 2) is less distorted: it consists of two bridging oxygen atoms O3 and O4 of two distinct carboxylate groups and four water oxygen atoms. The shortest distance is Na2-O3 (involving carboxylate group oxygens); the two longest again belong to the bridging O8 atoms (Table 2).
All zwitterions of M have approximately the same geometry (the two pseudo-inversion-symmetric zwitterions in the structure of (I) are nearly superimposable, Fig. 3). Both monodentate carboxylates in (I) and that in (II) have slightly elongated C-O bonds for the oxygen atom bound to the corresponding Na ion (Tables 1 and 2). These bonds are slightly longer than the corresponding bonds in M monohydrate and dihydrate [1.258 (2) and 1.2618 (9) Å , respectively; CCDC entries CCDC 1822460 and 1822463; Nazarenko, 2018). This relatively small change could be interpreted as a shift of of the anionic charge towards the sodium-bound oxygen atom. The carbon-oxygen bond lengths within the bidenate carboxylate groups in (II) are essentially identical within two standard deviations.
The distribution of the Hirshfeld surface electrostatic potential of the zwitterion (Fig. 5) shows that only a small area around the carboxyl oxygen atoms is negatively charged: the remaining Hirshfeld surface has positive electrostatic potential. This makes this area attractive for anions, with the N-H group of the hydrazine fragment available as a donor of an electrostatically enhanced hydrogen bond. The lone-pair density of the same hydrazine nitrogen atom is not sufficient to overcome the total positive charge of the trimethylhydrazinium fragment and does not act as a hydrogen-bond acceptor.

Figure 6
The infinite chain of hydrated sodium ions along the [010] axis in (I).
Each bromide ion forms a hydrogen bond with a hydrazine N-H group. In addition, each of them forms two hydrogen bonds with neighboring water molecules (O12 and O14), thus forming two more infinite chains in the [010] direction. Water molecules O11 and O13 form bridges between the cation chain and the 'bromide' chains as hydrogen-bond donors; they are also acceptors of four hydrogen bonds from the water molecules O5 and O10, and O8 and O9 respectively. These hydrogen bonds connect chains into a two-dimensional network. Two more enhanced hydrogen bonds (Table 3), O7-H7AÁ Á ÁO2 and O6-H6AÁ Á ÁO4, also connect neighboring chains. The resulting network forms a layer in the (001) plane with the bromide ions and trimethylammonium groups forming each side (Fig. 7). These layers are bound together via electrostatic interaction of the corresponding positive and negative ions; no short intralayer contacts are visible.

Figure 7
Packing of (I). View along the [010] axis. Sodium ions are green.

Figure 9
Chains in the structure of (II) are connected via atom O8 (in green) and a network of hydrogen bonds (dashed lines).
with the help of weaker (and longer by almost 0.5 Å ) NaÁ Á ÁO8 contacts ( Fig. 9). An array of hydrogen bonds (Table 4, Fig. 9) additionally stabilizes the resulting layer. As in compound (I), both iodide ions are connected to zwitterions M via N-HÁ Á ÁI À hydrogen bonds. In addition, ion I1 is an acceptor of two hydrogen bonds with water molecules (O6-H6AÁ Á ÁI1 and O7-H7AÁ Á ÁI1, see Table 4). In absence of neighboring water molecules, two CH groups of the trimethylammonium fragment form close contacts with the ion I2. As in structure (I), the layers are tied together by the electrostatic interaction of the corresponding positive and negative ions; no short intralayer contacts are visible (Fig. 10).

Database survey
Prior to 2018, the only meldonium-related single-crystal structure in the Cambridge Structural Database (Groom et al., 2016, CSD Version 5.39) had been a crystal structure of the dihydrate form (refcode CABVOQ; Kemme et al., 1983)) measured at room temperature with no experimental positions for hydrogen atoms. Hydrates of M also were also studied using powder X-ray diffraction (Zvirgzdiņ š et al., 2011; Be "rziņ š & Actiņ š, 2014). Meldonium is closely related to betaines, a wide class of zwitterionic compounds with an onium atom that bears no hydrogen atoms and that is not adjacent to the anionic atom. The parent compound of the betaine class, N,N,N-trimethylglycine (TMG), has a very rich crystal chemistry: the CSD (Version 5.39) contains 217 different structures of its compounds. There are several known crystal structures of TMG binary compounds with potassium iodide (HIPQIG; Andrade et al., 1999), rubidium iodide (NEMKIZ; Andrade et al., 2001), potassium bromide (WIQPUH01; Andrade et al., 2000) and sodium bromide (JAZNEE; Rodrigues et al., 2005). These compounds show features similar to those of their meldonium analogs: infinite chains of hydrated alkali metal cations and layers of trimethylammonium groups. The obvious differences are the absence of N-HÁ Á ÁX À hydrogen bonds and the much smaller size of the organic domain. Packing of (II). View along the [001] axis. Sodium ions are green.

Synthesis and crystallization
Preparation and properties of binary compounds of M with sodium halogenides are described in detail in Giller et al. (1975) and Silva (2013
In the structure of (II), water molecules O6 and O7 were refined as rotating groups (AFIX 7). The positions and isotropic displacement parameters of the hydrazinium hydrogen atoms were refined.
In both structures, methylene hydrogen atoms were refined with riding coordinates and with U iso (H) = 1.2 U iso (C); methyl hydrogen atoms were refined as rotating idealized methyl groups and with U iso (H) = 1.5U iso (C). Hydrogen atoms of water molecules were refined in an isotropic approximation with U iso (H) = 1.5U iso (O).

Funding information
Financial support from the State University of New York for acquisition and maintenance of the X-ray diffractometer is gratefully acknowledged.  meldonium 3-(1,1,1-trimethyl-hydrazin-1-ium-2-yl)propanoate with sodium bromide and sodium iodide Alexander Y Nazarenko

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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )
x y z U iso */U eq