INTERRELATING MELTING POINT, DENSITY, HYDROGEN BONDING, MOLECULAR CONFORMATION AND SOLUBILITY IN A PAIR OF ORGANIC SALTS. Li, N.¹, Luft, J.¹, Pangborn, W.¹, Duax, W.L.¹, and Perlman, M.². ¹Hauptman-Woodward Medical Research Inst., Inc., Buffalo, N.Y. 14203 and ²Cambridge NeuroScience, Cambridge, MA 02139

Hydrochloride salts of N-(1-Naphthyl)-N'-(3-ethylphenyl) guanidine (CNS 1086A) and an N'-methyl analog aptiganel (CERESTAT^reg.1), which are N-methyl-D-aspartate ion channel blockers, have anomalous physical properties. The melting point of crystals of the salts differ by 70deg., their densities differ by 0.12g/cm³, and they exhibit significant differences in solubility. In general, high melting points suggest greater stability. Higher melting compounds of analogous composition might be expected to have higher density and lower solubility than the lower melting compounds. In this case the opposite relationships are observed. The higher melting salt is more soluble and less dense than the lower melting salt. Due to the addition of a methyl group in aptiganel there is a larger volume per molecule. However, the increased volume per molecule (66ų) is greater than might be expected. In the solid state CNS 1086A has an extended conformation with the planar groups well away from each other. The methyl substitution in aptiganel appears to induce or stabilize a conformation in which the rings are oriented toward one another. Due to its extended conformation planar rings of CNS 1086A are sufficiently exposed to permit stacking that contributes to closer packing of the molecules and higher density but not to a higher melting point. Although there were three NH...Cl hydrogen bonds in each structure, those in CNS 1086A are engaged in forming dimers whereas in aptiganel one of the hydrogen bonds links the molecules into infinite chains. This difference in hydrogen bonding provides the explanation for the anomalous relationship between melting points and density and solubility. Upon initial melting only van der Waals forces must be overcome to melt CNS 1086A crystals, while in aptiganel the crystals do not begin to melt until hydrogen bonds between adjacent molecules are broken. The broader melting point observed for CNS 1086A crystals is due to the fact that initial melting involves breaking van der Waals contacts followed by the disruption of hydrogen bonds as dimers disassociate to form monomers.

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