Solubility methods

Glomme, A., Marz, J., Dressman, J. B. Comparison of a miniaturized shake-flask solubility method with automated potentiometric acid/base titrations and calculated solubilities. /. Pharm. Set. 2005, 94, 1-15. 

The graphically deduced constants are subsequently refined by a weighted nonlinear least squares procedure [472]. Although the potentiometric method can be used in discovery settings to calibrate high-throughput solubility methods and computational procedures, it is too slow for HTS applications. It is more at home in a preformulation lab. 

Table 6.3 lists a set of reliably determined log So solubility constants for a series of ionizable drugs determined by the pH-metric DTT solubility method. 

Yalkowsky, S. H. Baneijee, S., Aqueous Solubility Methods of Estimation for Organic Compounds, Marcel Dekker, New York, 1992. 

Arakawa, T. and Timasheff, S.N. (1985) Theory of protein solubility. Methods in Enzymology 114, 49-77. 

All the methodology just described requires that the solubilities of the analyte and its impurities be totally additive, which implies that the solubility of any given species cannot be affected by the presence of any other dissolved substance. Such a lack of independence is most commonly indicated by the existence of curved lines when the data are plotted in the conventional manner, and it has been discussed in great detail [38]. In the presence of specific molecular interactions, the phase solubility method cannot be used without the benefit of detailed knowledge of the nature and magnitude of the interactions. Such interactions can either increase or decrease the overall solubility, and the outcome is difficult to predict a priori. A thorough investigation is required to deduce the nature of the interactions if the phase solubility method is to be used. 

It is estimated that half of all pharmaceuticals are formulated as salts, to achieve increased stability and bioavailability [13]. Predictive solubility methods are very limited for this area, and the development of new models to address this category is very important. The NRTL-SAC model has recently been extended by C.-C. Chen, and Y. Song to represent such electrolytic solutes, that partly dissociate to ions in solution. This extension has been achieved by the addition of one new segment type into the preceding NRTL-SAC model. NRTL-SAC thus becomes a limiting case of the eNRTL-SAC formulation [27]. 

A drug s solubility is usually determined by the equilibrium solubility method, by which an excess of fhe drug is placed in a solvent and shaken at a constant temperature over a prolonged period of time until equilibrium is obtained. Chemical analysis of the drug content in solution is performed to determine degree of solubility. 

Kortiim and Vogel (1955) drew attention to the fact that the spectroscopic determination of the K-values suffered from a degree of uncertainty because of the unknown extinction coefficients of the complexes. For this reason, the authors preferred to determine the constant by means of a solubility method which had already proved of value in analogous investigations of the systems dioxan-iodine and methyl butyl ether-iodine (Kortiim and Kortiim-Seiler, 1950). In this method the solubility of iodine is determined as a function of the composition of solvent mixtures. values obtained by this method are summarized in Table 13. 

Aqueous Solubility, Methods of Estimation for Organic Compounds,... 

There are no US specifications covering the analysis of HNDPhA or its detn in expl mixts. Thomas (Ref 1) used the solubility method in detg the qualitative quantitative analyses of binary mixts of HNDPhA TNT and of other mixts of nitrated derivs or of nitrates. 

Differential Solubility Methods. Numerous methods have been developed to obtain one or more of the various caseins from whole casein or directly from skim milk based on their differential solubility (Thompson 1971 Mackinlay and Wake 1971 Whitney 1977). While some early procedures indicated the possibility of fractionating whole casein into different components, it was not until the 1950s that systematic procedures were proposed for the fractionation of casein into Warner s a-, 0-, and y-caseins. Hipp et al. (1952) developed two procedures which have been used extensively or partially incorporated into other methods. The first is based upon the differential solubilities of the caseins in 50% alcohol in the presence of ammonium acetate by varying the pH, temperature, and ionic strength. The second procedure involves the dispersion of whole casein in 6.6 M urea and the separa-... 

Differential Solubility Methods. Many methods have been developed for isolating the major whey proteins based on their solubilities in different systems. Some of the methods have been employed to obtain only one protein others can be used to secure all of the major... 

Equations similar to those for mutarotation have been derived, expressing the relationship between the solubility behavior of the two forms of lactose and the equilibrium or rate constants (Hudson 1904). The constants derived by both mutarotation and solubility methods are in agreement. The solubility equations have been used to develop procedures for measuring a- and /3-lactose in dry milk (Roetman 1981). 

When acid DNase activity is assayed by the acid-solubility method the optimal DNA concentration is 0.4 mg/ml (9) and higher substrate concentrations appear to be inhibitory (16, 21, 34)- It has been shown, however, that this inhibition is because increasing substrate concentration decreases the efficiency of acid-soluble oligonucleotide release since the number of breaks per unit length of DNA is lower. If a direct method of estimating enzymic activity is used, such as the determination of phosphatase-sensitive phosphate, it can be shown that the inhibition by high substrate seen by the acid solubility method is only apparent (34)-... 

Negative values ofN —N0, the electrolyte effect on the association numbers of water, are called the structure-breaker effect. One can speak of negative hydration31. The estimation of the hydration numbers by spectroscopic or solubility methods gives only an approximation of the sum effect. The spectra of the H-bond bands show in second approximation distinct differences between the ion effects on the H-bonds7 ). — The partial molar volume Vx of water in electrolyte solutions is negative in all solutions but the series of -values corresponds to the Hofmeister ion series too. The negative V1 volume indicates an electrostriction effect around the ions. 

Preformulation should include rigorous studies to determine the number of polymorphs that exist, relative degree of stability of the various polymorphs, solubilities, method of preparation of each form, effect of micronization and tableting, and interaction with formulation ingredients. 

A phase solubility method was described by Dittert et al. (1964) to generate data that demonstrate the sensitivity of solubility to pH that is exhibited by weak acid and weak base drugs. Kramer and Flynn (1972) presented equations that deLne the aqueous solubilities of organic hydrochlorides. At low pH, the solubility, S, is the sum of the concentration of the organic base, [B], and the intrinsic solubility of its protonated form, [BH]0, as described in the following equation ... 

Owing to the individual fragmentation based on the described concept of maximum similar substructure the accuracy loss of COSMO/rag is only about 0.05-0.1 log-units compared to direct DFT/COSMO calculations (Fig. 11.9) for typical life science data sets. Water solubility appears to be especially insensitive to the approximations of COSMO/rag. As shown in Fig. 11.10, the rms error only increased from 0.66 to 0.71 log-units for the dataset used in the development of the drug solubility method. 

Yalkowsky, S.H. and Banerjee, S. 1992. Aqueous solubility Methods of estimation for organic compounds. Marcel Dekker Inc., NY. 

Yalkowsky, S.H., Banerjee, S. (1992) Aqueous Solubility. Methods of Estimation for Organic Compounds. Marcel Dekker, New York. Yao, C.C.D., Haag, W.R. (1991) Rate constants for direct reactions of ozone with several drinking water contaminants. Water Res. 25, 761-773. 

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