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 M HCl, 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.