Solubility estimation

The solubilities in water and octanol of the pyrazino[l,2-A]quinazolones 23 (R1 =Me, R4 = H R1 = R4 = Me) with various N-2 substituents were determined. Solubility ratios and partition coefficient values were fitted to a predictive equation to evaluate the possibility of aqueous solubility estimates <1997IJP233>. 

However, from our point of view, there remains a lack of sufficiently precise and reliable methods to compute thermodynamic water solubility. The majority of methods work only for congeneric series of compounds, and many have not been developed to function in areas of pharmaceutical research using drug-like molecules. Most of the methods do not use the three-dimensional structure of the compounds, while some depend on previous knowledge of certain experimental properties of the compounds of interest. Moreover, all of the methods are dependent upon the quality of solubility values in the training set used to develop the model indeed, this latter point is a critical limitation that has a major influence on solubility estimations. 

The already mentioned data set used by us for solubility estimation showed that both (24.8) and (24.9), combined with ClogP for Kov, prediction, were suited for classic aroma compounds. 

This discussion has been largely limited to solubility parameter approaches that some considerto be of limited application since they have quantitative limits. It should be appreciated that these theoretical approaches and their applications have led to a deeper understanding of solubility behavior and of predictive approaches to solubility estimations. More to the point, extrapolations and interpolations dramatically extend the applicability of these approaches to the estimation, albeit a crude estimation, of the solubility of a new compound in a well-studied solvent, or of a well-characterized compound in a new solvent. In 1949, Hildebrand stated ... 

There are also empirical equations available that can be used for solubility estimation. Yalkowsky and Valvani (1980) developed the following equation by considering the transfer of a solute from the solid state to octanol followed by its transfer to the aqueous phase ... 

Behme and Brooke (1991) have derived an equation for estimating the solubility ratio of two polymorphs at a given temperature using DSC data on the enthalpy of fiMty) nd the melting temperature of each form. The free energy of the transition orthe natural logarithm of the solubility ratio multiplied byRT (Equation 19.6) was estimated by the difference between the solubility estimates for each form calculated by Equation 19.10 ... 

Few direct, experimental determinations of radionuclide solubilities applicable to this study are available in the literature. However, solubility estimates for some radionuclides can be extracted from the results of conventional sorption experiments (26). In addition, natural levels of some elements listed in Table II that are observed in Hanford groundwaters provide crude estimates of minimum solubility limits for them. Finally, measured solubility results for americium in aqueous solutions have been reported (27). 

Solubility estimates made by the techniques discussed above are reported in the last column of Table H. In addition to the limited number of such measurements, the results do not compare favorably in all cases with the theoretical values listed. This fact is hardly surprising considering the recognized limitations in the thermodynamic data base and difficulties encountered in interpreting results of solubility experiments. Furthermore, the theoretical estimates are based on the assumption that the thermodynamically most stable solid for a radionuclide controls its solubility. The effects of metastability are not included and, in this sense, theoretical solubility estimates are not conservative. A series of sorption-type experiments designed to yield solubility estimates for a number of the radionuclides included in this paper is in progress, and the results will be reported at a later date. 

The particle-size counting procedure overestimated the true solubility since there is a limit below which particle size cannot be counted. The mean solubility estimate was 1.05 mg/liter by this method in 0.9% NaCl (0.154 M), in good agreement with the spectrophoto-metric method. 

Patterson et al. (2001) examined the uptake of F by Wyoming big sagebrush and western wheatgrass in the area where the PL and TP transects were made, and reported very little or no translocation of F from roots to plant leaves. The solubility estimates, combined with the observations of plant uptake, indicate that precipitation of CaF2 in these soils may limit root uptake of F. Therefore, the soil geochemistry supports the Patterson (2002) findings of F plant uptake via stomatal entry. 

In their original discovery of miniemulsion polymerization, Ugelstad and co-workers [5] used either cetyl alcohol (CA water solubility estimated at 6x10 [43]) or hexadecane (HD water solubihty estimated at 1x10 [43]) to retard monomer diffusion from submicron monomer droplets. Both CA and HD, referred to here as costabilizers, are volatile organic components and are therefore not entirely desirable in the final product. Other researchers have used polymers, chain transfer agents, and comonomers as stabiUzers, as will be discussed later. 

Methods of Estimating Solubilities. Estimating the solubility of a given mineral in seawater appears to us to be a difficult task. A number of investigations have used varying approaches for a limited number of minerals (10, 11, 12, 13, 26). Problems arise when... 

Layers Lost Vs. Apparent Solubility Estimates. Figure 5 shows a summary data plot wherein the vertical axis gives the apparent number of layers removed or extracted of silica (0-6 week data set, dissolved silica concentration 1-5 yiM, pH range 7.5-8.5) and the horizontal axis gives our estimated "apparent" solubility values in dissolved silica. Each mineral is represented by a box because of the effect of pH on both the actual dissolution rate or surface flux and on our "cross-over" or "apparent" solubilities. This can also be seen in Figures 4a-z, wherein higher pH values usually result in higher dissolution rates and lower solubilities. 

Dickhut, R. M. Armstrong, D. E. Andren, A. W. The solubility of hydrophobic aromatic chemicals in organic solvent water mixtures - evaluation of 4 mixed solvent solubility estimation methods./. Environ. Toxicol Chem. 1991, 10, 881—889. 

The P values in Table 26 cover 10 orders of magnitude. Some of the values may be subject to error and will have to be modified, because of ion association effects and difficulties associated with solubility estimations. Not all values are at the same temperature, which is a serious failing for a free energy term. Despite these shortcomings, they are in good agreement with the qualitative reasoning summarized by Fig. 1 and they do allow predictions to be made about the chemistry of anions on transfer from DMF to methanol. More accurate values at 25°C should soon be available. 

Chickos, J.S., Nichols, G. and Ruelle, P. (2002) The estimation of melting points and fusion enthalpies using experimental solubilities, estimated total phase change entropies, and mobile order and disorder theory. /. Chem. Irf. Comput. Sci, 42, 368-374. 

In fact, several well known models in the literature allow solubilities in water to be estimated reasonably well from a knowledge of log P (and according to the functional groups present). For example, Hansch et al. (1968) has published several linear free energy relationships (LFERs) between molal solubility and log P for various classes of monofunctional molecules. The correlation coefficients for the LFERs (a measure of goodness of fit ) were in the range 0.93-0.99, indicating that solubility estimations, at least for some classes of material, are likely to be relatively accurate. 

METHODS USED FOR SOLUBILITY ESTIMATIONS IN IONIC MELTS... 

At about atmospheric pressure, for most gases, equating fg with Pg involves negligible errors in gas solubility estimations. For dilute solutions, up to mole fraction solubility limit of 2 (Pg atm) < O.Ol, Henry s law is applicable, and one can write... 

Methods used for solubility estimations in ionic melts. 

---