Cilengitide – Exceptional pseudopolymorphism of a cyclic pentapeptide

Abstract

Cilengitide (Cil) represents a cyclic pentapeptide, cyclo-(Arg-Gly-Asp-D-Phe-N-MeVal). Existence of an anhydrate form (A1) and a tetrahydrate form Cil1(H2O)4 has been observed. Surprisingly the anhydrate form proved to be more stable in aqueous environment compared to the tetrahydrate form. Assessment of thermodynamic stability has been carried out by competitive slurry experiments as well as by investigation of thermodynamic solubility. The lower solubility of the anhydrate form A1 can be explained by the hydrogen bonding motifs within the crystal structures. The tetrahydrate form Cil1(H2O)4 represents a special manifestation of a class of non-stoichiometric water–alcohol solvates Cil1(H2O)x(alcohol)y where methanol and ethanol can substitute water molecules in the crystal lattice of the tetrahydrate form leading to the hydrate-solvate systems Cil1(H2O)x(methanol)y named S1 and Cil1(H2O)x(ethanol)y named S2 with x⩽4, y⩽1 and y⩽2−0.5x. The non-stoichiometric water alcohol solvates exhibit a higher solubility compared to the anhydrate form but convert rapidly to the anhydrate form in aqueous environments. Accordingly, the better soluble non-stoichiometric water alcohol solvates cannot be obtained by crystallization from aqueous media. However slurries or crystallization from solvent mixtures containing methanol and ethanol represent a means to obtain the highly soluble pseudo-polymorphs S1 and S2 and to circumvent formation of the low soluble anhydrate form A1.