Solubility of the Amorphous Form

As described above, amorphous solids are disordered in nature, and contain only short range order between the constituent molecules. Amorphous solids lack the stabilizing influence of lattice energy, and therefore are thermodynamically less stable than any of the corresponding crystalline forms of the substance. Since the amorphous form represents the most highly energetic solid state form of a material (Hancock and Zografi, 1996), it follows that amorphous materials exhibit the highest degree of solubility for a given substance.

In some instances, the relative solubilities of the amorphous and crystalline forms of a substance can be estimated using the same methodologies as would be used in the measurement of the solubility of polymorphic materials. Using a theoretical approach, Hancock and Parks (2000) proposed that the solubility advantage of the amorphous drug to its most stable crystalline form was about 16-fold to 1600-fold. The maximum concentration measured during the course of dissolution of the amorphous form was taken to represent the solubility of the amorphous form. However, the empirical data were less than that predicted, suggesting that the amorphous substances partially converted to a crystalline form during the lifetime of the solubility measurement. It is probably true that amorphous materials cannot achieve their maximum theoretical solubility under practical experimental conditions owing to phase transformations.

Sato et al. (1981) measured the solubility of amorphous substance by adding a nucleation inhibitor, but the measured solubility could have been affected by the presence of the nucleation inhibitor.

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