Solvated species

Beryllium(II) is the smallest metal ion, r = 27 pm (2), and as a consequence forms predominantly tetrahedral complexes. Solution NMR (nuclear magnetic resonance) (59-61) and x-ray diffraction studies (62) show [Be(H20)4]2+ to be the solvated species in water. In the solid state, x-ray diffraction studies show [Be(H20)4]2+ to be tetrahedral (63), as do neutron diffraction (64), infrared, and Raman scattering spectroscopic studies (65). Beryllium(II) is the only tetrahedral metal ion for which a significant quantity of both solvent-exchange and ligand-substitution data are available, and accordingly it occupies a... 

These data are interpretable in terms of a reaction scheme where the primary photoreaction is the dissociation of CO to give, first a Ru3(C0)11 intermediate (XI), then the solvated species Ru3(C0) qS... 

Typical decomposition reactions listed by Gerischer [8] are shown in the following where (aq) means a solvated species ... 

Because ammonia is the solvent, the solvated species is known as an ammoniate. The solvent molecules are not always bound in the solid in the same way. For example, some solids may contain water of hydration, but in other cases the water may be coordinated to the metal ion. In classifying materials as hydrates or ammoniates, the mode of attachment of the solvent is not always specified. 

Although in this scheme the basic species is written as F for simplicity, the solvated species is actually HF2 in liquid HF. 

When the crystallography of compounds related by polymorphism is such that nuclei in the two structures are magnetically nonequivalent, it will follow that the resonances of these nuclei will not be equivalent. Since it is normally not difficult to assign organic functional groups to observed resonances, solid state NMR spectra can be used to deduce the nature of polymorphic variations, especially when the polymorphism is conformational in nature. Such information is extremely valuable at the early states of drug development when solved single crystal structures for each polymorph or solvate species may not yet be available. 

The primary method for demonstration of the existence of drug polymorphs, or solvate species, is that of powder x-ray diffraction (XRD). Such measurements represent a specification of the internal structure within a crystal, and an evaluation of its lattice type. Since dissolution and subsequent drying can sometimes yield an undesired structure, it is also important to confirm crystal structures at each formulation stage during the beginning of the development process. 

Differential thermal analysis proved to be a powerful tool in the study of compound polymorphism, and in the characterization of solvate species of drug compounds. In addition, it can be used to deduce the ability of polymorphs to thermally interconvert, thus establishing the system to be monotropic or enantiotropic in nature. For instance, form I of chloroquine diphosphate melts at 216°C, while form II melts at 196°C [18]. The DTA thermogram of form I consists of a simple endotherm, while the thermogram of form II is complicated (see Fig. 4). The first endotherm at 196°C is associated with the melting of form II, but this is immediately followed by an exotherm corresponding to the crystallization of form I. This species is then observed to melt at 216°C, establishing it as the thermodynamically more stable form at the elevated temperature. 

Differential thermal analysis proved to be a powerful aid in a detailed study that fully explained the polymorphism and solvates associated with several sulfonamides [19]. For instance, three solvate species and four true polymorphs were identified in the specific instance of sulfabenzamide. Quantitative analysis... 

In a manner similar to that just described for differential thermal analysis, DSC can be used to obtain useful and characteristic thermal and melting point data for crystal polymorphs or solvate species. This information is of great importance to the pharmaceutical industry since many compounds can crystallize in more than one structural modification, and the FDA is vitally concerned with this possibility. Although the primary means of polymorph or solvate characterization s centered around x-ray diffraction methodology, in suitable situations thermal analysis can be used to advantage. 

Differential scanning calorimetry can also supply valuable information regarding solvate species, and it is particularly useful with respect to temperature and energetics of the desolvation process Two samples of the developmental compound L-706000-001T were shown to be chemically identical, and each contained two moles of water. The XRD powder patterns for the two samples were found to be quite different, demonstrating the existence of polymorphism... 

One of the most powerful techniques available for the evaluation of the solubility attributes of polymorphic or solvate species is solution calorimetry. Each distinct crystal phase is characterized by a well-defined heat of solution as it dissolves into a given solvent system, and the difference between the heats of solution of each phase in the same defined solvent system equals the heat of transition between them at the temperature of measurement. Solution calorimetry has been used to complement or to investigate a wide variety of crystal properties,... 

The chemical nature of the solvent. This may lead to the formation of stable solvated species and a modification of flame conditions depending on the degree of inflammability. 

Reports on studies of solvent exchange reactions on actinide compounds are very scarce. The most studied cation is U02+. The commonly observed solvated species have five (H20, DMSO, DMF, TMP) (262,263)... 

A Rayleigh-Schrodinger-type perturbation theory has recently been developed by Angyan [107], The consideration of external perturbations, like electric fields, permits the calculation of response functions for solvated species. 

Because more than one solvated species may be extracted, the distribution ratio becomes... 

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