Co-amorphous drug amino acid mixtures were previously shown to be a promising approach to create physically stable amorphous systems with the improved dissolution properties of poorly water-soluble drugs. The aim of this work was to expand the co-amorphous drug amino acid mixture approach by combining the model drug, naproxen (NAP), with an amino acid to physically stabilize the co-amorphous system (tryptophan, TRP, or arginine, ARG) and a second highly soluble amino acid (proline, PRO) for an additional improvement of the dissolution rate. Co-amorphous drug-amino acid blends were prepared by ball milling and investigated for solid state characteristics, stability and the dissolution rate enhancement of NAP. All co-amorphous mixtures were stable at room temperature and 40 °C for a minimum of 84 days. PRO acted as a stabilizer for the co-amorphous system, including NAP–TRP, through enhancing the molecular interactions in the form of hydrogen bonds between all three components in the mixture. A salt formation between the acidic drug, NAP, and the basic amino acid, ARG, was found in co-amorphous NAP–ARG. In comparison to crystalline NAP, binary NAP–TRP and NAP–ARG, it could be shown that the highly soluble amino acid, PRO, improved the dissolution rate of NAP from the ternary co-amorphous systems in combination with either TRP or ARG. In conclusion, both the solubility of the amino acid and potential interactions between the molecules are critical parameters to consider in the development of co-amorphous formulations.

It could be shown that strong intermolecular interactions between drug and co-amorphous coformer that persist during the dissolution are crucial to prevent recrystallization and to enhance dissolution of a co-amorphous formulation.

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Two coamorphous drug-amino acid systems, indomethacin-tryptophan (Ind-Trp) and furosemide-tryptophan (Fur-Trp), were analyzed toward their ease of amorphization and mechanism of coamorphization during ball milling. The two mixtures were compared to the corresponding amorphization of the pure drug without amino acid. Powder blends at a 1:1 molar ratio were milled for varying times, and their physicochemical properties were investigated using XRPD, (13)C solid state NMR (ssNMR), and DSC. Comilling the drug with the amino acid reduced the milling time required to obtain an amorphous powder from more than 90 min in the case of the pure drugs to 30 min for the coamorphous powders. Amorphization was observed as reductions in XRPD reflections and was additionally quantified based on normalized principal component analysis (PCA) scores of the ssNMR spectra. Furthermore, the evolution in the glass temperature (Tg) of the coamorphous systems over time indicated complete coamorphization after 30 min of milling. Based on the DSC data it was possible to identify the formation mechanism of the two coamorphous systems. The Tg position of the samples suggested that coamorphous Ind-Trp was formed by the amino acid being dissolved in the amorphous drug, whereas coamorphous Fur-Trp was formed by the drug being dissolved in the amorphous amino acid.