Hydrophobic vs. Hydrophilic:  Ionic Competition in Remacemide Salt Structures

Abstract

Remacemide [2-amino-N-(1-methyl-1,2-diphenylethyl)-acetamide] was developed as a potential antagonist for epilepsy, Parkinsonism, and Huntington's disease. This paper investigates hydrophilic and hydrophobic intermolecular interactions that occur within the series of crystal structures comprising remacemide 1 and six of its salts [2 ) chloride; 3 ) nitrate; 4 ) acetate (C 2 H 3 O 2 -); 5 ) hydrogenfumarate (C 4 H 3 O 4 -); 6 ) naphthalene-2-sulfonate (napsilate, C 10 H 7 O 3 S -); 7 ) 1-hydroxynaphthalene-2-carboxylate (xinafoate, C 11 H 7 O 3 -)]. The hydrophilic interactions are described through graph set analyses of the hydrogen bond motifs and networks. The lattice of 1 comprises unidirectional, one-dimensional chains of molecules parallel to the c-axis.In 2, the cation-anion hydrogen bonding imposes a well-defined hydrophilic stratum structure on the lattice. As the cation itself is amphiphilic, a natural consequence of this is the creation of two-dimensional stacked layers with alternating hydrophilic and hydrophobic character (lattice bilayers). This tendency to form bilayers within the lattice is also observed in structures 3-5 (polar anions) and structures 6-7 (amphiphilic anions). Relatively few well-directed intermolecular interactions are observed between aromatic rings, either in 1 or in the hydrophobic layers of 2-7. Therefore, it is concluded that it is the hydrophilic hydrogen bond interactions that dominate the crystal packing and drive the segregation into lattice bilayers in the salt crystal structures.

17 salts of ephedrine: crystal structures and packing analysis

“…Overall it is clear that the molecular packing in many of these solids reflects the amphiphilic nature of the molecular structure of ephedrine itself, with the almost ubiquitous existence of a molecular bilayer, in which the polar hydroxyl and (protonated) amino functionalities are sandwiched between the nonpolar aromatic moieties. This is as expected from the previously solved salt structures (Leusen et al, 1991(Leusen et al, , 1992Zingg et al, 1988) and is indeed seen in other systems which have similar amphiphilic molecular features such as remacemide (Lewis et al, 2005). In the case of the anhydrous solid, the polar functionalities are hydrogen-bonded directly through -OHÁ Á ÁNinteractions, while in the hemihydrate these interactions are modified by the inclusion of further extensive hydrogen bonding involving the water molecules.…”

“…It is also evident from the CSD records that there have been very few studies in which crystal structures of multiple salt forms of a single active drug have been reported. Recently (Lewis et al, 2005) the structures of six salts of remacemide have been determined, and the competition between hydrophilic and hydrophobic interactions as drivers for the crystal packings discussed. Our current work seeks to go further using the pharmaceutically active base (1R, 2S)-(À)-ephedrine (I) as a cation from which salts have been prepared from 17 anions, including carboxylates, sulfonates, phosphonates and inorganic species.…”

42 salt forms of tyramine: structural comparison and the occurrence of hydrate formation

“…A contributing factor is that understanding structure-property relationships requires the availability of relatively large and systematic series of structures of relevant salt forms, and such series are rare. Of such datasets that do exist (Black et al, 2007;Collier et al, 2006;Lewis et al, 2005) two are of phenylethylamine (PEA) based drugs. The PEA family includes pharmaceutically significant compounds such as the decongestant ephedrine, the anti-asthma drug salbutamol and the stimulant methamphetamine.…”