Phase behavior of binary and ternary amorphous mixtures containing indomethacin, citric acid, and PVP.

PURPOSE

To better understand the nature of drug-excipient interactions we have studied the phase behavior of amorphous binary and ternary mixtures of citric acid, indomethacin and PVP, as model systems.

METHODS

We have prepared amorphous mixtures by co-melting or coprecipitation from solvents, and have measured glass transition temperatures with differential scanning calorimetry.

RESULTS

Citric acid and indomethacin in the amorphous state are miscible up to 0.25 weight fraction of citric acid, equivalent to about 2 moles of citric acid and 3 moles of indomethacin. Phase separation, as reflected by two Tg values, occurs without crystallization leading to a saturated citric acid-indomethacin amorphous phase and one essentially containing only citric acid. PVP-citric acid and PVP-indomethacin form non-ideal miscible systems at all compositions. A ternary system containing 0.3 weight fraction of PVP produces a completely miscible system at all citric acid-indomethacin compositions. The use of 0.2 weight fraction of PVP, however, only produces miscibility up to a weight fraction of 0.4 citric acid relative to indomethacin. The two phases above this point appear to contain citric acid in PVP and citric acid in indomethacin, respectively.

CONCLUSIONS

Two components of an amorphous solid mixture containing citric acid and indomethacin with limited solid state miscibility can be solubilized as an amorphous solid phase by the addition of moderate levels of PVP.