Chemical stability of amorphous pharmaceuticals prepared with silicates.

摘要

Poor solubility of new drug candidates resulting in low bioavailability is becoming a major problem in drug formulation development. Amorphous pharmaceuticals are being increasingly investigated to improve dissolution rate and bioavailability of poorly soluble drugs. However, physical and chemical stability issues often limit the application of amorphous systems in drug product development. Preparation of amorphous drugs using silicates, in particular, has been shown to vastly improve physical stability. However, the catalytic activity of silicates to facilitate chemical reactions may accelerate drug degradation. In this study, several factors and mechanisms affecting the chemical stability of amorphous drugs prepared with silicates (Neusilin and Aerosil) were investigated using quinapril hydrochloride (QHCl) as a model drug. Amorphous samples were prepared by cryo-grinding. The effects of pH grade of silicates, drug:silicate ratio and relative humidity (%RH) on chemical stability of the co-ground amorphous drug were determined.In conclusion, the effects of pH grade of silicates, drug:silicate ratio and %RH all contribute to the chemical stability of the amorphous drug prepared with silicates. Solid-state surface acidity measurement is the best predictor of pH-stability profiles of amorphous formulations. pH-modifiers were shown to improve chemical stability without compromising the physical stability of the amorphous formulation.The pH grade of silicates significantly affects the chemical stability of co-ground amorphous QHCl with greater degradation observed in lower pH grades of Neusilin. The addition of acidic or basic pH-modifiers influences QHCl degradation in accordance with the pH-stability profile of the drug in the amorphous state. However, the pH-stability profile of amorphous QHCl prepared with different pH grades of silicates was not consistent with the pH-stability profile of the drug in solution. A solid-state equivalent pH (pHeq) of amorphous samples was measured using diffuse reflectance spectroscopy and the results indicate that pHeq provides a more accurate prediction of the effective surface acidity and degradation of QHCl in amorphous formulations than the suspension pH. The chemical stability of co-ground amorphous QHCl was also influenced by drug:silicate ratio and %RH. The degradation of amorphous QHCl co-ground with Neusilin was low at both lower and higher percentages of Neusilin with maximum degradation observed at intermediate percentages. This effect of drug:Neusilin ratio was correlated with the pHeq of the amorphous formulation, which changes with percentages of Neusilin. Amorphous QHCl co-ground with Neusilin showed greater degradation at both lower and higher %RH with maximum stability observed at intermediate %RH. This complex relationship between degradation rate and %RH is consistent with the competitive adsorption of drug and water molecules on silicate surfaces.