Formation Mechanism of Coamorphous Drug–Amino Acid Mixtures

Abstract

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.

Dissolution behavior of co-amorphous amino acid-indomethacin mixtures: The ability of amino acids to stabilize the supersaturated state of indomethacin

“…spectrum of the precipitate, except that the peaks in the ARG-IND CA spectrum were broader, which is typical of an amorphous material [33,34]. The narrower peaks in the current spectrum were indicative of the more crystalline nature of the precipitate.…”

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

“…FTIR spectra revealed that Nap and Ind formed heterodimers interacting via intermolecular hydrogen bonds in the co-amorphous mixture, which explains the high stability for the sample with equal molar ratio drug (11,12). Although it has not been possible to detect specific interactions within co-amorphous Ind-Trp by FTIR (14) and co-amorphous IndTrp and Fur-Trp by ssNMR (16), the deviation from the Gordon-Taylor equation indicates that the largest increase in physical stability can be expected at around 50 mol% drug. The modified…”

“…Co-amorphous Ind-Trp and Fur-Trp mixtures containing 50 mol% drug have previously been prepared by ball milling for 90 minutes and investigated by FTIR and ssNMR in order to characterize molecular interactions within each of the co-amorphous systems (14,16). In neither of the two systems, it was possible to identify specific interaction sites (besides possible π-π interactions) although the actual T g s for the co-amorphous systems are higher than the T g s calculated by the Gordon-Taylor equation, suggesting interactions between the drug and the amino acid.…”

“…In contrast to polymer-based glass solutions, co-amorphous formulations are based on the combination of at least two species of low molecular weight components that all are crystalline before being processed. The preparation of co-amorphous systems is mostly done by ball milling, and the fact that single Tgs are found by DSC indicates that the obtained systems were homogeneous mixtures (8)(9)(10)(11)(12)(13)(14)(15)(16). One advantage of ball milling is that it is inflicting only very limited chemical degradation (17), specifically for some indomethacin systems degradation levels of less than 1.5% were found (13).…”

“…Furthermore, during formation of co-amorphous Fur-Trp by ball milling, the drug is dissolved in the amorphous amino acid whilst during formation of co-amorphous Ind-Trp the amino acid is dissolved in the amorphous drug (16).…”