In situ co-amorphisation of arginine with indomethacin or furosemide during immersion in an acidic medium – A proof of concept study

Abstract

The concept of controlled in situ amorphisation of drug/polymer mixtures has been introduced previously with indomethacin-Eudragit® E and naproxen-Eudragit® E compacts. In the present study, the feasibility of in situ amorphisation of a crystalline API with the low molecular weight coformer arginine was investigated. This research was based on a previous study, which showed that a high relative humidity (75% RH) may induce co-amorphisation of indomethacin with arginine. It was assumed that an in situ co-amorphisation may be achieved, if a tablet containing a crystalline acidic API and the basic amino acid arginine, coated with a gastro-resistant but water-permeable coating, is exposed to an acidic medium. To investigate this hypothesis, tablets containing arginine and either indomethacin or furosemide were coated with Eudragit®L. After different time periods of immersion (10, 20, 30, 60, 120 min) in 0.1 MHCl, samples were analysed with respect to their solid state properties by XRPD, FTIR spectroscopy and modulated temperature DSC. In both formulations co-amorphous API-arginine was already detected after 10 min of immersion. The maximum of co-amorphous content was reached after 20 min with both formulations, while longer immersion time periods than 60 min revealed a partial API recrystallisation. In addition, during immersion of the indomethacin-arginine formulation, basic hydrolysis of indomethacin was observed, which could be prevented by addition of citric acid to the tablet formulation. However, this addition also inhibited the co-amorphisation of indomethacin. In this proof-of-principle study it was shown that the concept of in situ co-amorphisation of APIs with arginine might be a feasible formulation approach for those poorly water-soluble drugs, which are not susceptible to basic hydrolysis.