The effects of drug/silicate ratio and moisture content on chemical stability of amorphous quinapril hydrochloride (QHCl) coground with magnesium aluminometasilicates (Neusilin US2 and Neusilin FL2) were investigated. Amorphous QHCl/Neusilin samples containing 0-95% (w/w) Neusilin were prepared by cryogrinding. All samples were found to be amorphous and remained so for the duration of the study. The chemical stability of neat amorphous QHCl and QHCl coground with various percentages of Neusilin was studied at 40ยฐC and at various moisture contents, as dictated by varying storage relative humidity (%RH). QHCl hydrolysis, forming a dicarboxylic acid (DCA) product, slightly increased with increasing percentages of Neusilin in the coground amorphous samples. On the contrary, QHCl cyclization, forming a diketopiperazine (DKP) product, was slow at both lower (e.g., 5%) and higher (e.g., 95%) percentages of Neusilin and markedly faster at intermediate percentages (e.g., 50%) of Neusilin. This complex effect of drug/silicate ratio on cyclization of quinapril was correlated with the surface acidity of the coground amorphous systems. For neat amorphous QHCl, increasing moisture resulted in increased DKP and DCA formation, as expected. Similarly, higher DCA formation was observed in QHCl/Neusilin coground amorphous samples with increasing moisture. However, DKP formation in coground amorphous samples was high both at lower (e.g., 0% RH) and higher (e.g., 75% RH) humidity, and low at intermediate (e.g., 48% RH) humidity. This complex relationship between DKP formation and moisture content for coground amorphous samples can be explained by the competitive adsorption of drug and water molecules on Neusilin surfaces, which was confirmed by Fourier transform infrared (FTIR) spectroscopy. Therefore, drug/silicate ratio, solid-state equivalent pH (surface acidity), and moisture have significant effects on chemical stability and should be considered in formulation and packaging optimization to develop both chemically and physically stable amorphous drug formulations using silicates.