Influence of variation in molar ratio on co-amorphous drug-amino acid systems

Molecular interactions were investigated within four different co-amorphous drug-amino acid systems, namely indomethacin-tryptophan (Ind-Trp), furosemide-tryptophan (Fur-Trp), indomethacin-arginine (Ind-Arg) and furosemide-arginine (Fur-Arg). The co-amorphous systems were prepared by ball milling for 90 min at different molar ratios and analyzed by XRPD and DSC. Interactions within the co-amorphous samples were evaluated based on the deviation between the actual glass transition temperature (T-g) and the theoretical T-g calculated by the Gordon-Taylor equation. The strongest interactions were observed in the 50 mol% drug (1:1 M ratio) mixtures, with the exception of co-amorphous Ind-Arg where the interactions within the 40 mol% drug samples appear equally strong. A particularly large deviation between the theoretical and actual T(g)s was observed within co-amorphous Ind-Arg and Fur-Arg systems. Further analysis of these co-amorphous systems by C-13 solid-state NMR (ssNMR) and FTIR confirmed that Ind and Fur formed a co-amorphous salt together with Arg. A modified approach of using the Gordon-Taylor equation was applied, using the equimolar co-amorphous mixture as one component, to describe the evolution of the T(g)s with varying molar ratio between the drug and the amino acid. The actual T(g)s for co-amorphous Ind-Trp, Fur-Trp and Fur-Arg were correctly described by this equation, confirming the assumption that the excess component was amorphous forming a homogeneous single component within the co-amorphous mixture without additional interactions. The modified equation described the T(g)s of the co-amorphous Ind-Arg with excess Arg less well indicating possible further interactions; however, the FTIR and ssNMR data did not support the presence of additional intermolecular drug-amino acid interactions. (C) 2016 Elsevier B.V. All rights reserved.