Hydrate non-stoichiometric

Evaluation of the interaction of the API with water is an important and essential pre-formulation activity. For the purposes of our discussion, we will assume (/) the API of interest is a non-porous solid, (//) the API does not form a non-stoichiometric hydrate, and ( 7/) non-aqueous solvates of the API will not be considered for development. If these issues are of interest, they are addressed in the literature (35). 

Clathrate hydrates form when small (<0.9 nm) non-polar molecules contact water at ambient temperatures (typically <3(X) K) and moderate pressures (typically >0.6 MPa). On a molecular scale, single small guest molecules are encaged (enclathrated) by hydrogen-bonded water cavities in these non-stoichiometric hydrates. Guest repulsions prop open different sizes of water cages, which combine to form three well-defined unit crystals shown in Figure 1. 

Figure 2 The phase diagram of CH +H2O. Note that the non-stoichiometric hydrate region replaces the previously proposed vertical line for stoichiometric hydrate concentration...

Note. The secondary pharmaceutical products (JLe., dosage forms) contain usually a non-stoichiometric hydrate essentially containing upto 16% water and, therefore, all such products must indicate explicitely by the labeling on the package itself. 

Hydrates are of large practical importance because water is ubiquitous in the atmosphere and, as mentioned in Section 5.2, the probability that a certain compound can crystallize as a hydrate is large. Both stoichiometric and non-stoichiometric hydrates are known. In the first case, the ratio between the number of water molecules and the number of compound molecules in the crystal is well... 

Kinetically driven crystallization often involves an initial amorphous phase that may be non-stoichiometric, hydrated, and susceptible to rapid phase transformation. Amorphous calcium carbonate (ACC) for instance is highly soluble, has a low density of almost half of the crystalline mineral indicating a high hydration [62], and rapidly transforms to calcite, vaterite, or aragonite unless kinetically stabilized. In aqueous solution, this transformation into vaterite or calcite takes place within seconds or less even if additives are present, as shown by recent SAXS/WAXS measurements of ACC transformation in the presence of a DHBC [63]. 

Thermodynamics of equilibria between water vapor and saline hydrates non-stoichiometric hydrates... 

Figure 4.5. Equilibrium isotherm between water vapor and a) a stoichimetric hydrate and b) a non-stoichiometric hydrate...

If the variance is 2, we say that we have a divariant hydrate the two hydrate forms with n and n+p water molecules are merely two extreme forms of the single hydrate phase, whose composition varies continuously with the pressure and temperature. Thus, it is a solid solution or, which is equivalent, a non-stoichiometric hydrate. The water contained in the solid is sometimes referred to as zeolitic because zeolites constitute a family of solids which have that property shared by other hydrates noted in the existing literature. 

Non-stoichiometric hydrates with mobile water molecules... 

Figure 4.7. Equilibrium isotherms between water vapor and a non-stoichiometric hydrate with non-localized water molecules...

Non-stoichiometric hydrates with iocaiized water moiecuies... 

Non-stoichiometric hydrates with water vacancies The equilibrium is now written as ... 

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