Effects of Water Vapor Absorption on the Physical and Chemical Stability of Amorphous Sodium Indomethacin - Market Research

Effects of Water Vapor Absorption on the Physical and Chemical Stability of Amorphous Sodium Indomethacin
March 12,2004
Ping Tong, and George Zografi
AAPS PharmSciTech
Abstract
This study reports on the effects that water absorbed into amorphous sodium indomethacin (NaIMC) can have on simultaneous tendencies to crystallize to its trihydrate form and to undergo base-catalyzed hydrolysis because of the plasticizing effects of water on molecular mobility. Measurement of water vapor absorption at 30?C and powder x-ray diffraction patterns as a function of relative humidity (RH) reveal that upon exposure to 21% RH, NaIMC does not crystallize over a 2-month period. Measurements of the glass transition temperature as a function of such exposure reveals a change in Tg from 121?C, dry, to 53?C at 21% RH, such that Tg at 21% RH is ~13?C above the highest storage temperature of 40?C used in the study. At 56% RH and higher, however, crystallization to the trihydrate occurs rapidly; although over the 2-month period, crystallization was never complete. Assessment of chemical degradation by high-performance liquid chromatography analysis revealed significant instability at 21% RH; whereas at higher RH, the extent of chemical degradation was reduced, reflecting the greater crystallization to the more chemically stable crystalline form. It is concluded that when amorphous forms of salts occur in solid dosage forms, the simultaneous effects of enhanced water vapor sorption on crystallization and chemical degradation must be considered, particularly when assessing solid-state chemical degradation at higher temperatures and RH (eg, 40?C 75% RH).

Introduction
An important aspect of early drug product development is the choice of the solid form of a drug that can provide optimal stability and bioavailability when formulated as a solid dosage form. A particularly challenging problem is the development of relatively hydrophobic drugs that often will not dissolve rapidly enough to be sufficiently absorbed upon administration. When the drug exhibits appropriate acid-base properties, the formation of crystalline salt forms, with enhanced water solubility, is a desirable strategy to accomplish this objective.
In some cases, however, the processing of crystalline salts (eg, lyophilization, milling, wet granulation, polymer film coating) can lead to partially or fully amorphous material.1,2 This result may be achieved purposefully, as in the lyophilization as a reconstitutable product of chemically unstable drugs intended for injection,3,4 or inadvertently, as when crystalline materials are milled, producing unexpected and often undetectable amorphous regions on the solid surface.5,6 Since amorphous forms of a drug are most often more chemically unstable than their corresponding crystalline forms,3,4 and since the amorphous form is thermodynamically metastable relative to the crystal,2 the chances for physical (crystallization) and chemical instability are greatly enhanced under such circumstances. Furthermore, the exposure of such materials to elevated RH and temperatures would be expected to enhance crystallization and/or chemical degradation because of the well-recognized ability of water to act as a plasticizer in lowering the glass transition temperature, Tg, and increasing the molecular mobility that controls the rate of such diffusion-limited processes.7,8
In this study, sodium indomethacin (NaIMC) has been used as a model of a hydrophobic molecule (indomethacin, IMC) with greatly increased solubility in water as the salt. Previous studies from this laboratory with amorphous NaIMC have characterized such parameters as Tg, molecular mobility, fragility, and molecular dispersions of the sodium salt, with its free acid form.9,10 In this study, the water vapor sorption by amorphous NaIMC is examined, with particular attention to the simultaneous effects of water on crystallization and chemical degradation, 2 forms of instability that would be expected to offset any advantages of using salts, such as enhanced aqueous solubility and improved oral bioavailability.

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