Development of indomethacin amorphous solid dispersion by applying acid-base supersolubilization (ABS) principle to enhance solubility and enable low-temperature hot melt extrusion.

This study explores a novel acid-base supersolubilization (ABS) principle for enhancing the solubility and dissolution rate of indomethacin, a poorly water-soluble and weakly acidic drug, by interaction with the weak base tromethamine. The reported aqueous solubilities of indomethacin are 1.5 and 105.2 µg/mL at pH 1.2 and 7.4, respectively. However, in the present investigation, they were increased to 2.5 mg/mL at pH 7.3 and greater than 240 mg/mL at pH ∼ 8.0 by interaction with tromethamine. Such an acid-base interaction also occurred in the solid state, which reduced the melting temperature of indomethacin. An amorphous solid dispersion (ASD) could be prepared using the indomethacin-tromethamine mixture at a 1:2 M ratio, along with poloxamer 407 as surfactant and Kollidon® VA64 as polymeric matrix, by hot melt extrusion (HME) at 80 °C. The lowering of processing temperature prevented any degradation of indomethacin during HME. The amorphous nature of indomethacin in ASDs was confirmed by DSC and PXRD analysis. In vitro dissolution studies at pH ∼ 1, pH 6.8, and when pH was changed stepwise from 1 to 6.8, demonstrated that the ASD with tromethamine achieved and maintained rapid and high (>80 %) indomethacin release at pH ∼ 1 and complete release (100 %) at pH 6.8. This improvement in dissolution performance, along with the ability to perform HME at lower temperatures, demonstrates the potential of the ABS principle to overcome longstanding challenges in developing ASDs for poorly water-soluble drugs.