Solubility of Solvatomorphic Substances

Solvatomorphs are formed when solvent molecules become incorporated into a crystalline solid, and occupy regular positions in the crystal lattice. In other cases, the crystal structure may contain channels having repetitive sites of hy-drophilicity or hydrophobicity, and solvent molecules can become attached to those sites. Hydrates are those solvatomorphs where water molecules constitute an integral part of the crystal structure, and are typically contained in a defined ratio. Hydrates will be specifically discussed since those solvatomorphs are often of highest interest for pharmaceutical applications, but the results of the discussion apply equally well to solvatomorphs containing solvent molecules other than water.

In the presence of water, hydrated and anhydrous crystals can be considered as being in equilibrium:

where A(solid) and A ■ mH2O(solid) refer to the anhydrous and hydrated phase, respectively, m is the stoichiometry of the hydrate, and Kh is the equilibrium constant of hydration:

Equation (47) indicates that the activity ratio of the hydrated and anhydrous crystals depend on the activity of water. When a[H2O]m is greater than {a[A ■ mH2O(solid)]/Kh ■ a[A(solid)]}1/m, the hydrated form is more stable than the anhydrous form (Zhu and Grant, 1996). Obviously when the value of

{a[A ■ mH2O(solid)]/Kh ■ a[A(solid)]}1/m, exceeds that of a[H2O]m, the anhydrate form would be more stable. The addition of a miscible cosolvent would reduce the water activity, and would move the position of equilibrium toward that of the anhydrous form.

As a rule of thumb, hydrated crystalline forms are usually less soluble in water than are the corresponding anhydrate crystalline forms (Grant, 1990), and thus solid solvates are usually less soluble in the solvating solvent than the original solid. However, the solubility of a solvate in a solvent that is miscible with the solvating solvent is higher than the corresponding non-solvated form. This phenomenon arises because the negative energy change of mixing associated with the solvents provides an additional contribution to the negative free energy of solution.

When a[H2O] equals zero, then a [A ■ mH2O(solid)]/ a[A(solid)] also equals zero. The consequence of this is that, thermodynamically speaking, the hydrated form is only stable in the presence of water. For this reason, the solubility of a hydrate crystal form can only be measured in water, as the solubility of a solvate can only be measured in the solvating liquid corresponding to the included solvate molecule. Similar to the metastable polymorphs, however, a solvate may be temporarily stable in absence of the solvating liquid due to a high energy barrier of desolvation.

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