Cosolvent systems

Pesticide Solvent. The majority of organic fungicides, insecticides, and herbicides (qv) are soluble in DMSO, including such difficult-to-solvate materials as the substituted ureas and carbamates (see Fungicides, agricultural Insect control technology Pesticides). Dimethyl sulfoxide forms cosolvent systems of enhanced solubiUty properties with many solvents (109). 

Timasheff, S.N. (1982). Preferential interactions in protein-water-cosolvent systems. In Biophysics of Water, ed. F. Franks, pp. 70-2. London John Wiley. 

Whereas stoichiometric versions of this strategy were initially reported [43, 44], a catalytic process involving a Ni(COD)2/PBu3 catalyst system, Et3B as reducing agent, and a methanol/THF cosolvent system was recently developed. The process proceeds both inter- and intramolecularly to provide access to a variety of cyclopentenol derivatives (Scheme 22). 

Suspensions are two-phase systems consisting of a finely divided solid dispersed in a liquid, solid, or a gas (Table 6). They are appropriate when the drug to be incorporated is not sufficiently soluble in an ordinary solvent or cosolvent system. They are used orally and topically. Examples of compounded suspensions include pediatric oral liquids where a commercial pediatric dosage form is not available. Commercial tablets and capsules are formulated into a vehicle and can be individually flavored to the patient s preference. 

The experiments for establishing the envelopes in Figures 3 and A indicated that it is possible to mix two liquids, which Individually are not solvents, in the appropriate volumetric proportions such that together they form a "cosolvent system."... 

The first novel casting solution to be investigated consisted of THF and formamlde, a pair of non-solvents combined to serve as a cosolvent system. This system was selected because by simply varying the proportions of the two liquids it has the ability to dissolve SPSF-Na of all degrees of sulfonatlon under the desired conditions (15 wt-% polymer, 25°C) In a similar manner, dioxane-formamide mixtures may be employed. 

Optimizing solvents and solvent mixtures can be done empirically or through modeling. An example of the latter involves a single Sanchez-Lacombe lattice fluid equation of state, used to model both phases for a polymer-supercritical fluid-cosolvent system. This method works well over a wide pressure range both volumetric and phase equilibrium properties for a cross-linked poly(dimethyl siloxane) phase in contact with CO2 modified by a number of cosolvents (West et al., 1998). 

For cosolvent systems, because the heat of solution in different solvent systems is generally different, the temperature effect on solubility in these systems is also different. Detailed solubility mapping in the solvents of interest, including the effect of pH (forionizable compounds), temperature,... 

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. 

Because of the need for better predictability in more aqueous cosolvent systems, the Scatchard-Hildebrand equation was modiLed into the Extended Hildebrand equation [40,41] ... 

The solubility parameter approach was subsequently expanded from three to four terms with the division of the hydrogen-bonding parameter into acidic and basic solubility parameters to quantify electron-donor and electron-acceptor properties [48,49], However, the expansion of these solubility parameter terms did not make the equation any easier to use foptfiBi prediction of solubility in cosolvent systems. 

On the basis of excess Gibb s energy approach of VNfohl [56], Williams and Amidon [57-59] predicted solubilities in aqueous cosolvent systems. This approach is based on expressing the solubility of a compound in a binary solvent system as the sum of the solubilities of the compound in each pure solvent plus any interaction terms resulting from solvent-solvent to solvent-solute interactions. This approach predicted solubilities fairly well, but included some simplifying assumptions about solute-solvent interactions that may not be applicable to all systems. 

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,... 

Gould et al. [75] studied the solubility relationships of polar, semipolar, and nonpolar drugs in mixed cosolvent systems. As expected, the nonpolar compound showed a log-linear increase in solubility with increasing cosolvent content. The semipolar compound showed parabolic log solubility curves. The polar compound showed a log-linear decrease in solubility with addition of cosolvent. 

Wittaya-areekul, S., Nail, S.L. Freezedrying of tert-butyl alcohol/water cosolvent systems effeects of formulation and process variables on residual solvents. J. Pharm. Sci. 87,491-495,1998... 

Figure 1.13 shows [r ] values in m- cresol/cyclohexane mixtures for POTC1. When [r ] is plotted against solvent composition for POT polyamide, (Fig. 1.12). This plot shows a maximum at 40 vol% cyclohexane. This feature of attaining a maximum has also been observed in the cosolvent system POTC1 in m - cresol/ cyclohexane at the same solvent composition. (Fig. 1.13).

Solubilization of Weak Acids or Weak Bases in Cosolvent Systems... 

When the solubility of a mixed solvent is logarithmically additive, the solubility of the solute in a mixed cosolvent system, xr2m, is given by ... 

If a drug is a weak acid, the concentrations of the un-ionized species, [HA]C, and the ionized species, [A ]c, in a water/cosolvent system are in equilibrium and the total solubility, [HA])ot, in the water/cosolvent system is given by ... 

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