Chemical Stability of Indomethacin in the Solid Amorphous and Molten States

Characteristics and Significance of the Amorphous State in Pharmaceutical Systems

“…As an example of the first case we can consider a recent study of degradation of indomethacin in the liquid state (above T m ) and just below T m in the amorphous state (about 100°C above T g ), where it was shown that the rate constants fit the Arrhenius equation with no discontinuity as the sample changed from the amorphous solid to the melt. 113 If free volume factors are important, we would expect the non-Arrhenius behavior to parallel the effects of temperature on relaxation rates, as reflected in the VTF or WLF equations described earlier (eqs 1 and 2). Depending on the fragility of the amorphous state we might expect greater or lesser deviations from Arrhenius behavior.…”

“…We would expect a comparison of reaction rates of crystalline and amorphous forms of a drug under otherwise identical conditions to reveal greater rates with the amorphous forms than with the crystalline forms, and this has been shown to be the case for a number of systems. 113,114 It is possible that a particularly solid state reaction would require a high level of positional specificity between reacting species and that this would occur most readily in a highly ordered crystalline state. In such cases reactivity in the amorphous or liquid states would be reduced relative to that in the crystalline state.…”

Solid‐state chemical stability of proteins and peptides

“…For small molecule drugs in the solid-state, the crystalline drug is generally less prone to chemical decomposition than the amorphous form. 14,70 However, the crystalline state may not be more stable for protein and peptide formulations. Oliyai et al found that the Asp-hexapeptide was more stable in a lactose matrix (amorphous) than in mannitol (crystalline).…”

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

“…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][6][7][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.…”