How Does Residual Water Affect the Solid-state Degradation of Drugs in the Amorphous State?

Abstract

It is widely recognized in the pharmaceutical field that exposure of solid drugs (small molecules or proteins) to high relative humidity and the resulting association of water vapor with the solid generally accelerate the rate of chemical degradation.1 Although there are true solid-state reactions that take place only in the crystalline state or to a much lesser extent in the liquid or solution state than in the crystal,2,3 most instabilities observed for drugs occur in solution much more readily than in the solid state; when they do occur over practical time scales in the solid state, it is very likely that the reaction is taking place in the more disordered amorphous regions of the solid.4 Indeed, it has been shown in a number of cases that under otherwise identical conditions reactivity of a particular substance in the amorphous state is greater than that in the crystalline state.5-8 Generally, for reactions occurring in the amorphous solid state, the rate of reactivity increases with increasing water content, and this can be attributed to the ability of the amorphous solid to absorb water vapor into its bulk structure, forming an amorphous solution.9,10 In a few cases it has been reported that a certain amount of water must be present to ensure chemical stability, e.g., lipid peroxidation rates decrease with the addition of small amounts of water;11,12 however, a destabilizing effect of absorbed water is more generally the case for the major types of drug degradations, e.g., hydrolysis, oxidation, or deamidation. An examination of the literature indicates that discussions concerning solid-state reactivity in the amorphous state have followed along two lines. In some work correlations appear to exist between the rate of reactivity and the glass transition temperature, Tg, strongly supporting the role of water as a plasticizer in facilitating chemical reactivity by increasing molecular mobility.13,14 In other studies, a lack of correlation with Tg and reactivity well below Tg has been shown to occur, and there also appears to be a better correlation of reactivity with water activity, aw, defined as: aw ) p/po (1)