Amorphous Solid Forms of Ranolazine and Tryptophan and Their Relaxation to Metastable Polymorphs

Abstract

Different methods were explored for the amorphization of ranolazine, a sparingly soluble anti-anginal drug, such as mechanochemistry, quench-cooling, and solvent evaporation from solutions. Amorphous phases, with T_g values lower than room temperature, were obtained by cryo-milling and quench-cooling. New forms of ranolazine, named II and III, were identified from the relaxation of the ranolazine amorphous phase produced by cryo-milling, which takes place within several hours after grinding. At room temperature, these metastable polymorphs relax to the lower energy polymorph I, whose crystal structure was solved in this work for the first time. A binary co-amorphous mixture of ranolazine and tryptophan was produced, with three important advantages: higher glass transition temperature, increased kinetic stability preventing relaxation of the amorphous to crystalline phases for at least two months, and improved aqueous solubility. Concomitantly, the thermal behavior of amorphous tryptophan obtained by cryo-milling was studied by DSC. Depending on experimental conditions, it was possible to observe relaxation directly to the lower energy form or by an intermediate metastable crystalline phase and the serendipitous production of the neutral form of this amino acid in the pure solid phase.

Amorphous phases of ranolazine, tryptophan, and co-amorphous mixtures were produced and their stepwise relaxations toward low-energy crystals were investigated. Unprecedently, three polymorphs of ranolazine were discovered and the crystal structure of the most stable solved. Amorphous tryptophan relaxation led to the serendipitous appearance of its neutral form. A co-amorphous mixture showed enhanced thermal and kinetical stability and improved ranolazine aqueous solubility.