Cosolvent solubility method

Furthermore, pH electrode calibration can be performed in situ by the new method [48], concurrently with the pKj determination. This is a substantial improvement in comparison to the traditional procedure of first doing a blank titration to determine the four Avdeef-Bucher parameters [24]. The traditional cosolvent methods used with sparingly soluble molecules can be considerably limited in the pH<4 region when DMSO-water solutions are used. This is no longer a serious problem, and routine blank titrations are now rarely needed in the new in situ procedure. 

Oumada et al. [148] described a new chromatographic method for determining the aqueous pKa of dmg compounds that are sparingly soluble in water. The method uses a rigorous intersolvent pH scale in a mobile phase consisting of a mixture of aqueous buffer and methanol. A glass electrode, previously standardized with common aqueous buffers, was used to measure pH online. The apparent ionization constants were corrected to a zero-cosolvent pH scale. Six sparingly soluble nonsteroidal antiinflammatory weak acids (diclofenac, flurbiprofen, naproxen, ibu-profen, butibufen, fenbufen) were used successfully to illustrate the new technique. 

Much effort has been expended on models that can be used to predict the solubility behavior of solutes, with good success being attained using a semi-empirical, group contribution approach [75]. In this system, the contributions made by individual functional groups are summed to yield a composite for the molecule, which implies a summation of free energy contributions from constituents. This method has proven to be useful in the prediction of solubility in water and in water-cosolvent mixtures. In addition to the simplest methodology, a variety of more sophisticated approaches to the prediction of compound solubility have been advanced [68]. 

Cosolvent flooding is an experimental method for removing DNAPLs trapped below the water table. It involves injecting a highly concentrated aqueous mixture of solvents, such as alcohols, a chemical that is miscible with either phase in the aquifer. This process has the tendency to increase or enhance DNAPL (or LNAPL) solubility greatly, and to reduce the NAPL-water interfacial tension. Depending upon the phase behavior between the cosolvent and NAPL, a cosolvent flood can be developed to emphasize either enhanced dissolution (i.e., use of methane flooding for the dissolution of TCE) or NAPL mobilization. 

Fig. 3 Concept of the ion-association method for fabricating ion-based organic dye nanoparticles in pure aqueous media. The approach is based on ion-pair formation between the ionic dye (for example, cationic dye) and the hydrophobic counterion that is soluble in water [for example, tetraphenylborate (TPB) or its derivative anion], which gives rise to a hydrophobic phase in water. For preparation, organic cosolvent is unnecessary. The size of the dye nanoparticles can be controlled by adjusting the interionic interaction between the dye cation and the associative hydrophobic counteranion...

Drug dissociation constants are experimentally determined by manual or automated potentiometric titration or by spectrophotometric methods.40 Current methods allow determination of pXa values with drug concentrations as low as 10 to 100 pM. For highly insoluble compounds (concentration <1 to 10 pM), the Yesuda-Shedlovsky method41 is commonly used where organic cosolvents (i.e., methanol) are employed to improve solubility. The method takes three or more titrations at different cosolvent concentrations, and the result is then extrapolated to pure aqueous system. The dissociation constant can also be determined with less accuracy from the pH-solubility profile using the following modification of Henderson-Hasselbach equation ... 

Crystallization is often used as a method of product isolation. Crystallization of the reaction product may be induced if, to the reaction medium, in which it is well soluble, a cosolvent is added in which the product is insoluble. Because for the latter purification method the solubility should be high at high temperatures but much lower at low temperatures, the temperature coefficient of the solubility becomes an important criterion for the employment of a solvent. A further guide is the fact that substances tend to dissolve in solvents with similar polarities, so that a solvent and cosolvent for the recrystallization of a given product can be selected according to the polarities. 

Current work with supercritical fluids can also illustrate the importance of cosolvents. Cosolvent effects in supercritical fluids can be considerable for systems where the cosolvent interacts strongly with the solute. A correlation suggests that both physical and chemical forces are important in the solvation process in polar cosolvent supercritical CO2 mixtures. The model coupled with the correlation represents a step toward predicting solubilities in cosolvent-modified supercritical fluids using nonthermody-namic data. This method of modeling cosolvent effects allows a more intuitive interpretation of the data than either a purely physical equation of state or ideal chemical theory can provide (Ting et al., 1993). 

Sodium and lithium are the most common metals, and diethyl ether, tetrahydro-furan, and HMPA are often used as cosolvents to overcome solubility problems. The Benkeser method,37 204 employing lithium in low-molecular-weight amines (methylamine, ethylamine, ethylenediamine), is a more powerful reducing agent... 

The simplest and most generally useful synthetic method for metal diketonates is from the diketone and a metal such as a halide, hydroxide, oxide, sulfate, carbonate, carboxylate, etc. in a variety of solvents such as water, alcohol, carbon tetrachloride or neat diketone. Since many / -diketones are poorly soluble in water, use of an organic solvent or cosolvent may be helpful. Optionally, a base such as sodium carbonate, triethylamine or urea may be added. Addition of a base early in the reaction converts the diketone to its conjugate base, which usually has greater solubility in aqueous media.159 In some cases, metal halide complexes of the diketone form as intermediates, e.g. SnCl4(MeCOCH2COMe), which has been formulated as... 

The potential of the compound precipitating upon injection needs to be evaluated. This is particularly important for formulations containing cosolvent systems or formulations where the compound is solubilized via pH adjustment. In these cases, the solubility of the compound changes nonlinearly upon dilution and the compound may precipitate at the injection site (Yalkowsky and Rose man, 1981). Severalin vitro methods including static serial dilution, dynamic injection, and dropwise dilution have been successfully applied as a screening tool to detect the precipitation problem (Yalkowsky etal., 1983 V ferd and Yalkowsky, 1993 Ping etal., 1998). Details ofthese methods will be discussed in subsequent chapters. 

In Rubino s [9] review of approaches to predicting solubility in cosolvent systems, Yalkowsky and Roseman [60] proposed one of the simplest and most useful methods. Their equation,... 

Amongst the lipases, the pig pancreatic lipase (PPL), the yeast lipase from Candida cylindracea (rugosa) (CCL), and the bacteria lipases from Pseudomonas fluorescens (cepecia) (PEL) and other unclassified Pseudomonas species (PSL) have been most widely used. The experimental methods are very straightforward and little different in their execution from conventional chemical reactions. Hydrolysis reactions are conducted on the soluble lipase in buffered aqueous solutions, commonly in the presence of an organic cosolvent. In organic media the enzyme is added as a powder or in an immobilized form and the resulting suspension stirred or (better) shaken at approximately 40 °C. The enzyme is removed by filtration. 

Solubility can also be enhanced by the presence of other compounds. This phenomenon is caused by one or more compounds acting as solubility enhancers for other compounds present on a surface. This phenomenon is sometimes called the local cosolvent effect. A typical method of enhancing contaminant solubility is through the addition of a small amount of secondary solvent to the SCF cleaning system. Alcohols are commonly used in this manner to increase solubilities of more polar contaminants. However, more subtle local cosolvent effects have been observed. Perhaps a classic example was first reported by Kumik and Reid. In their study, they observed that the solubilities of both naphthalene and benzoic acid in supercritical CO2 were enhanced by 107% and 280%, respectively, when both species were present. It has also been shown that there needs to be enough of a secondary component present in solution about the local contaminant environment to enhance the solubility of another compound, This example demonstrated that an excess of phenanthrene promoted the solubility of anthracene in supercritical COj, but since anthracene was only present in very small quantities, it did not help to enhance the overall solubility of phenanthrene. A... 

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