Nonaqueous solvates

The physical properties of the anhydrate form and two polymorphic monohydrates of niclosamide have been reported [61], The anhydrate form exhibited the highest solubility in water and the fastest intrinsic dissolution rate, while the two monohydrates exhibited significantly lower aqueous solubilities. In a subsequent study, the 1 1 solvates of niclosamide with methanol, diethyl ether, dimethyl sulfoxide, N,/V -dimethyl formamide, and tetrahydrofuran, and the 2 1 solvate with tetraethylene glycol, were studied [62], The relative stability of the different solvatomorphs was established using desolvation activation energies, solution calorimetry, and aqueous solubilities. It was found that although the nonaqueous solvates exhibited higher solubilities and dissolution rates, they were unstable in aqueous media and rapidly transformed to one of the monohydrates. 

One can assume that as the hydrate has already interacted intimately with water (the solvent), then the energy released for crystal break-up, on interaction of the hydrate with solvent, is less than for the anhydrous material. The nonaqueous solvates, on the other hand, tend to be more soluble in water than the nonsolvates. The n-amyl alcohol solvate of fludrocortisone acetate is at least five times as soluble as the parent compound, while the ethyl acetate solvate is twice as soluble. 

The different forms of a material have varying solubilities. The amorphous substance is more soluble than the crystalline counterpart. Among the crystalline forms, the metastable polymorphs are generally more soluble than the stable polymorphs. Hydrated crystals tend to exhibit a lower solubility in water compared with their anhydrous form. On the contrary, the aqueous solubilities of the nonaqueous solvates are often greater than those of the unsolvated forms. 

Similarly, Angell and coworkers [43] reported that the studied acid-base pairs with the high ionicity are those with a proton transfer gap of about 0.7 eV, corresponding to Ap a values of ca. 12. The very high Ap/sTa values required to achieve complete proton transfer in protic ionic liquids should be compared with those in aqueous solutions, as discussed above. It seems that the nonaqueous solvation environment of ionic liquids has a very strong effect on the energetics of proton transfer. 

Solubility can often be decreased by using a nonaqueous solvent. A precipitate s solubility is generally greater in aqueous solutions because of the ability of water molecules to stabilize ions through solvation. The poorer solvating ability of nonaqueous solvents, even those that are polar, leads to a smaller solubility product. For example, PbS04 has a Ks of 1.6 X 10 in H2O, whereas in a 50 50 mixture of H20/ethanol the Ks at 2.6 X 10 is four orders of magnitude smaller. 

The crown ethers and cryptates are able to complex the alkaU metals very strongly (38). AppHcations of these agents depend on the appreciable solubihty of the chelates in a wide range of solvents and the increase in activity of the co-anion in nonaqueous systems. For example, potassium hydroxide or permanganate can be solubiHzed in benzene [71 -43-2] hy dicyclohexano-[18]-crown-6 [16069-36-6]. In nonpolar solvents the anions are neither extensively solvated nor strongly paired with the complexed cation, and they behave as naked or bare anions with enhanced activity. Small amounts of the macrocycHc compounds can serve as phase-transfer agents, and they may be more effective than tetrabutylammonium ion for the purpose. The cost of these macrocycHc agents limits industrial use. 

However, solubility, depending as it does on the rather small difference between solvation energy and lattice energy (both large quantities which themselves increase as cation size decreases) and on entropy effects, cannot be simply related to cation radius. No consistent trends are apparent in aqueous, or for that matter nonaqueous, solutions but an empirical distinction can often be made between the lighter cerium lanthanides and the heavier yttrium lanthanides. Thus oxalates, double sulfates and double nitrates of the former are rather less soluble and basic nitrates more soluble than those of the latter. The differences are by no means sharp, but classical separation procedures depended on them. 

Padova, J. I. Ionic Solvation in Nonaqueous and Mixed Solvents 7... 

The determination of the real energies of solvation from measurements of the voltaic cells (Section VI) makes it possible to find the absolute electrode potentials in nonaqueous solvents owing to the relation... 

Nonaqueous electrolyte solutions are analogous to aqueous solutions they, too, are systems with a liquid solvent and a solute or solutes dissociating and forming solvated ions. The special features of water as a solvent are its high polarity, e = 78.5, which promotes dissocation of dissolved electrolytes and hydration of the ions, and its protolytic reactivity. When considering these features, we can group the nonaqueous solvents as follows ... 

Events of electron photoemission from a metal into an aqueous solution had first been documented in 1966 by Geoffrey C. Barker and Arthur W. Gardner on the basis of indirect experimental evidence. The formation of solvated electrons in nonaque-ous solutions (e.g., following the dissolution of metallic sodium in liquid ammonia) had long been known, but it was only in the beginning of the 1950s that their existence in aqueous solutions was first thought possible. It is probably for this reason that even nowadays in aqueous solutions we more often find the term solvated than hydrated electrons. 

This dependence is fundamental for electrochemistry, but its key role for liquid-liquid interfaces was first recognized by Koryta [1-5,35]. The standard transfer energy of an ion from the aqueous phase to the nonaqueous phase, AGf J, denoted in abbreviated form by the symbol A"G is the difference of standard chemical potential of standard chemical potentials of the ions, i.e., of the standard Gibbs energies of solvation in both phases. 

The extent of hydration or solvation of a molecule also has a profound effect on the transport of the substance. The apparent solubility of the drug in both aqueous and nonaqueous media may be influenced by the absence or presence of moisture. Diffusion of drugs in polymeric systems may also be influenced by the hydration of the polymers and hydration of the membrane through which transport is occurring for example, skin hydration may enhance the diffusion of drug molecules significantly. 

The preparation of four niclosamide solvates and the study of their physical transformation and stability of the crystal forms in different suspension vehicles by DSC and thermal gravimetry (TG) were reported [18]. Thermal analysis showed that the niclosamide solvates were extremely unstable in a propylvinylpropyline (PVP)-vehicle and rapidly changed to monohydrated crystals. A suspension in propylene glycol was more stable and TG analysis showed that crystal transformation was less rapid. In this vehicle, the crystals transformed to the anhydrate, rather than the monohydrate, since the vehicle was nonaqueous. The TEG-hemisolvate was the most stable in suspension and offered the possibility of complex exploitation [18]. 

The chemical and physical stability of aqueous and nonaqueous suspensions of a number of solvatomorphs of niclosamide has been evaluated in an effort to develop pharmaceutically acceptable suspension formulations [90]. Studied in this work was the anhydrate, two polymorphic monohydrates, the 1 1, Y, A"-dimethyI I ormam ide solvatomorph, the 1 1 dimethyl sulfoxide solvatomorph, the 1 1 methanol solvato-morph, and the 2 1 tetraethylene glycol hemisolvate. All of the solvatomorphs were found to convert initially to one of the polymorphic monohydrates, and over time converted to the more stable monohydrate phase. The various solvatomorphs could be readily desolvated into isomorphic desolvates, but these were unstable and became re-hydrated or re-solvated upon exposure to the appropriate solvent. 

Besides temperature and addition of non-solvent, pressure can also be expected to affect the solvency of the dispersion medium for the solvated steric stabilizer. A previous analysis (3) of the effect of an applied pressure indicated that the UCFT should increase as the applied pressure increases, while the LCFT should be relatively insensitive to applied pressure. The purpose of this communication is to examine the UCFT of a nonaqueous dispersion as a function of applied pressure. For dispersions of polymer particles stabilized by polyisobutylene (PIB) and dispersed in 2-methylbutane, it was observed that the UCFT moves to higher temperatures with increasing applied pressure. These results can qualitatively be rationalized by considering the effect of pressure on the free volume dissimilarity contribution to the free energy of close approach of the interacting particles. 

The chaotropic properties of many chemical compounds prevent the H2O cage structures necessary for the formation of solvates and thus facilitate the transfer of nonpolar molecules between nonaqueous and aqueous phases. Water is incombustible and nonflammable, odorless and colorless, and is universally available in any quality important prerequisites for the solvent of choice in catalytic processes. The DK and d can be important in particular reactions and are advantageously used for the analysis and control of substrates and products. The favorable thermal properties of water make it highly suitable for its simultaneous dual function as a mobile support and heat transfer fluid, a feature that is utilized in the RCH/RP process (see below). 

A fair number of mixed solvates, compounds containing molecules of crystallization of two different solvents, are also known. Generally, these are obtained either by recrystallizing halide hydrates from a nonaqueous solvent, or by crystallizing a halide from an appropriate solvent mixture, such as an alcohol intentionally or unintentionally containing significant amounts of water. Examples include... 

There seem to be no direct calorimetric determinations of enthalpies of solution of rare-earth tribromides in nonaqueous solvents,3 and very few reports on the temperature variation of solubilities whence solution enthalpies might be roughly estimated. The most detailed set of data concerns cerium tribromide in pyridine (257). In this system there exists a series of solvates (cf. Section IH,C,2), but sufficient solubilities were determined for the estimation of enthalpies of solution of each solvate. These enthalpies are included in Fig. 3, which shows an extraordinary zig-zag variation of solubility with temperature. The actual values of enthalpies of solution cannot be accurate, but at least it is clear that they change sign and magnitude in an eccentric manner. 

In principle, Gibbs free energies of transfer for trihalides can be obtained from solubilities in water and in nonaqueous or mixed aqueous solutions. However, there are two major obstacles here. The first is the prevalence of hydrates and solvates. This may complicate the calculation of AGtr(LnX3) values, for application of the standard formula connecting AGt, with solubilities requires that the composition of the solid phase be the same in equilibrium with the two solvent media in question. The other major hurdle is that solubilities of the trichlorides, tribromides, and triiodides in water are so high that knowledge of activity coefficients, which indeed are known to be far from unity 4b), is essential (201). These can, indeed, be measured, but such measurements require much time, care, and patience. 

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