Stoichiometric hydrates

As follows from his laboratory notes, the first discovered clathrate hydrate (of chlorine) was observed, but not recognized, by Davy in 1810. Then Cl2, Br2, so2) co2, ch3ci, ch4, c2h, and numerous other gases were shown to form clathrate hydrates [22, 23]. Contrary to inorganic stoichiometric hydrates, those involving hydrocarbons are both non-stoichiometric and crystalline. In addition, gas hydrate composition was found to depend on temperature, pressure, and some... 

Forms stoichiometric hydrates with a Dissolves a molecule within an... 

Falk, M., Knop, O. Water in Stoichiometric Hydrates, in Water a Comprehensive Treatise (ed. F. Franks) Vol. II, p. 55 New York Plenum Press 1973. 

Stoichiometric hydrates are the most important solvates affecting the solubility of marketed pharmaceuticals. Hemihydrates, monohydrates, and dihydrates are the most common stoichiometric ratios of water incorporated into the crystalline lattice of drugs. Pfeiffer et al. (1970) have shown how different hydrates of cephalosporins could be isolated from solvent systems of varying water activity. Cephalexin has a monohydrate and a dihydrate form, which are stable under different relative humidity conditions. Cefazolin has a monohydrate, a sesquihydrate (1.5 moles water), and a pentahydrate form (Byrn and Pfeiffer, 1992). Jozwiakowski et al. (1996) have found that lamivudine can form a 0.2 hydrate, where only one of L ve lamivudine molecules in the crystal lattice is associated with a water molecule. Multiple solvates can be formed for the same drug Stephenson et al. (1994) have shown that dithromycin can crystallize in at least nine solvate forms, including a cyclohexane trisolvate and an acetonitrile trihydrate. In addition, Byrn et al. (1995) have noted that desolvated forms of some drugs have unique properties that differ from their nonsolvated counterparts. 

Falk M, Knop O (1973) Water in stoichiometric hydrates. Chap 2. In Franks F (ed) Water. A comprehensive treatise. Vol. 2. Plenum Press, NY, London, pp 55-113... 

These differences may result, in part, from the higher coordination number of aluminum in AIF3. In it, each aluminum atom is surrounded by a distorted octahedron of six fluorine atoms. Each fluorine is two-coordinate, being comer-shared by pairs of octahedra. Thus, the stmcture is similar to ReOs and has a relatively open lattice. As a result, numerous sites exist for water molecules, leading to the occurrence of a wide range of nonstoichiometric and stoichiometric hydrates (AIF3 (H20) n = 1, 3, 9). Quite curiously, no hexahydrate corresponding to [Al(H20)6]Cl3 is known. 

Solid hydrate research covers various classes of chemical compounds, which possess different importance and practical use. There are stoichiometric hydrates and those with varying water content as zeolitic hydrates. There are true hydrates and pseudohy-drates The latter contain water as hydroxide or hydroxonium ions or as -OH and -H groups ( water of constitution ). The true hydrates with separable H2O molecules ( water of crystallization ) include inorganic salts, i.e., the so-called salt hydrates, hydrates of organic compounds, and the clathrates, as, e.g., the novel gas clathrates. This article is mainly concerned with the salt hydrates. 

We will restrict our discussion to stoichiometric hydrate. The thermodynamics of hydrate formation has been discussed by Lohani and Grant (45). Assuming that a drug D, forms a hydrate with m moles of water of crystallization, the equilibrium can be... 

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...

When the compound is isolated from certain organic solvents, particularly ordinary alcohols, the corresponding solvate is obtained. When the solvent is removed by drying, the resulting solid is hygroscopic and adsorbs water from the atmosphere to give stoichiometric hydrates. With other organic... 

Falk, M. and Knop, O. Water in stoichiometric hydrates. Water, A Comprehensive Treatise, F. Franks, ed.. Plenum Press, New York, pp. 55-113,1973. 

When all hydrate cages are filled, the three crystal types have similar concentrations of 85 mol% water arrd 15 mol% guest molecirles. Stmcture I hydrate with CH and has minimiun (stoichiometric) hydration mtmbers of 5.75 and 7.67, respectively. Only large cavities in the Stmcture II hydrate are occupied with C3HJJ (and i-C Hj ), and such hydrates have a hydration mtmber of 17 (e.g. Sloan 1998). However, hydration... 

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. 

The equilibrium thermodynamics of stoichiometric hydrates has been described by several authors. The overview presented here is intended both to review the basic thermodynamics of crystalline hydrate formation/stability and to highlight the intrinsic differences between polymorphic systems and hydrate systems (a discussion of the kinetics of dehydration/hydration will be given in Section IV). The following description is a hybrid based on the work of Grant and Higuchi [7] and that of Carstensen [8]. 

Born was, however, taken with the fundamental idea Fajans had about the process of hydration. Fajans recognized that the polarization of water in the presence of an ion and not the formation of stoichiometric hydrates was the dominating characteristic of ionic hydration. The idea that the dipole moment of water in proximity to the ions would be partially aligned was noted in the writings of Fajans [8] and Born [Ij. Born utilized the concept of Nernst, by then familiar, that the dissolution of salts is correlated with solvent dielectric or solvent polarity. Born sought to quantify the idea. 

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... 

While the thermodynamic properties of nonsolvated forms depend only on temperature and pressure, the free energy of hydrates (and solvates) is influenced by the activity of the water (or solvent) in the environment Formation ofa stoichiometric hydrate with n molecules of water per compound molecule can be described by Equation 5.7 ... 

DVS instrument, the mass of the sample is measured as a function of relative humidity (r.h.). Humidity is either changed continuously or stepwise and the mass of the sample is plotted as a function of humidity (or time). Figure 8.11 shows a typical DVS diagram of a substance that forms one hydrate. When humidity is increased from 0% to 95%, a sharp mass increase is observed at 80% th. From the magnitude of the mass increase, it can be calculated if a hemi, mono, sesqui, and so on hydrate is formed. When the humidity is decreased from 95% to 0%, a loss in mass is observed at w50% r.h. Such a hysteresis is typical for a substance that forms a stoichiometric hydrate and it is due to kinetic hindrance of hydration and dehydration. Some hydrates show extreme hystereses, such that hydration or dehydration may not be observed at all in a standard DVS experiment. Substances that form nonstoichiometric hydrates or that just adsorb surface water normally show a more continuous mass increase and decrease and almost no hysteresis. Substances that can form several hydrates may lead to complicated DVS traces (Figure 8.12). 

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. 

Figure 4.6. Pressure-temperature diagram for a stoichiometric hydrate...

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... 

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