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

Authors: Silva, JFC; Silva, PSP; Silva, MR; Fantechi, E; Chelazzi, L; Ciattini, S; Eusebio, MES; Rosado, MTS

Ref.: Cryst. Growth Des. 23(9), 6679-6691 (2023)

Abstract: Different methods were explored for the amorphizationof 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 obtainedby cryo-milling and quench-cooling. New forms of ranolazine, namedII and III, were identified from the relaxation of the ranolazineamorphous phase produced by cryo-milling, which takes place withinseveral hours after grinding. At room temperature, these metastablepolymorphs relax to the lower energy polymorph I, whose crystal structurewas solved in this work for the first time. A binary co-amorphousmixture of ranolazine and tryptophan was produced, with three importantadvantages: higher glass transition temperature, increased kineticstability preventing relaxation of the amorphous to crystalline phasesfor at least two months, and improved aqueous solubility. Concomitantly,the thermal behavior of amorphous tryptophan obtained by cryo-millingwas studied by DSC. Depending on experimental conditions, it was possibleto observe relaxation directly to the lower energy form or by an intermediatemetastable crystalline phase and the serendipitous production of theneutral form of this amino acid in the pure solid phase. Amorphous phases of ranolazine, tryptophan,and co-amorphousmixtures were produced and their stepwise relaxations toward low-energycrystals were investigated. Unprecedently, three polymorphs of ranolazinewere discovered and the crystal structure of the most stable solved.Amorphous tryptophan relaxation led to the serendipitous appearanceof its neutral form. A co-amorphous mixture showed enhanced thermaland kinetical stability and improved ranolazine aqueous solubility.

DOI: 10.1021/acs.cgd.3c00565