Composition-dependent changes in the crystallization mechanism in drug-drug coamorphous systems of related neuropeptide Y Y5 receptor antagonists.

This study investigated the stabilization mechanisms of coamorphous systems using the related neuropeptide Y Y5 receptor antagonists NPY(A) and NPY(B). Physical mixtures (PMs) formed a eutectic mixture at an equimolar ratio. Thermal analysis during melting-cooling showed a single glass transition temperature (Tg) for each drug and the PMs, indicating amorphization of the individual drugs and coamorphization of NPY(A)-NPY(B). The Tg of NPY(A) was higher than that of NPY(B). Annealing at 15-17°C below Tg increased the Tg of all samples through structural relaxation. However, the τβ values obtained from both the Kohlrausch-Williams-Watts equation and ΔTg did not increase after coamorphization. Annealing promoted nucleation and accelerated crystallization of NPY(A), but not NPY(B). These phenomena were also observed in the coamorphous systems, suggesting composition-dependent crystallization mechanisms. Infrared spectroscopy revealed weak intermolecular interactions in the coamorphous systems. Isothermal crystallization tests showed that NPY(A)-rich and NPY(B)-rich coamorphous systems were stabilized by Tg elevation and nucleation inhibition, respectively. Spray-dried coamorphous systems exhibited improved stability and enhanced dissolution of both drugs in pH 6.8 phosphate buffer.