A design of experiment approach to identify the most stable composition of a ternary co-amorphous system

Ternary co-amorphous systems, comprising a drug, a low molecular weight co-former, and a polymer, are a promising approach to address the solubility and stability challenges of poorly water-soluble drugs. However, it is unclear how the addition of a third component influences the stability of the binary system and how to identify the optimal composition of a ternary system. In previous studies we calculated weight percentages of the components via a modified Gordon-Taylor equation assuming the measured glass transition temperature reflected the composition of the ternary system. In this study, the underlying assumptions for these calculations are experimentally verified using a range of ternary mixtures of the system carvedilol-tryptophan- hydroxypropyl methylcellulose. Samples were prepared either by ball-milling all three components simultaneously or by establishing different binary systems and subsequently adding the third component. Design of experiments combined with multivariate analysis of differential scanning calorimetry and X-ray powder diffraction results was used to investigate the influence of preparation time and pathway on thermal and diffractometric properties of the systems, as well as their physical stability. It was hypothesized that the composition with least dependence on the input variables (i.e. the most robust composition) would be the most stable one. The study confirmed this hypothesis. The calculation method proposed in previous studies was verified and the most stable composition found in this study matched the calculated composition. • A DoE approach identified the most stable ternary co-amorphous system of carvedilol, tryptophan and HPMC. • The optimal composition is independent of the preparation pathway. • Relevant descriptors were identified via a principal component analysis.