Aqueous solubilities with cosolvents

As mentioned previously, the physical state of a solute is susceptible to modifications by interaction with cosolvents. In principle, a cosolvent can enhance solute solubility by changing the solvency of the medium, by direct solute interaction, by adsorption, or by partitioning (Chiou et al. 1986). In a batch experiment testing the effect of humic acid on kerosene dissolution in an aqueous solution, Dror et al. (2000a) found a linear correlation between the amount of humic acid and the amount of kerosene that dissolved (Fig. 6.5). 

In another example of a polyethylene glycol/surfactant, solid dispersion is presented by Dannenfelser et al. (2004) with a poor water-insoluble drug exhibiting only a g1i7iL aqueous solubility. At 40 mg/mL, the PEG 3350/polysorbate 80 solid dispersion exhibited similar exposure as that of a cosolvent-surfactant solution and a ten-time increase over a dry blend formulation, thus enabling a solid oral dosage form for clinical trials. 

Differences in solubility between different crystal forms alter the driving force for dissolution, controlled by the difference between the solution concentration and the saturation concentration (Cs - C). Hamlin et al. (1965) have shown that dissolution rate correlates well with solubility for a large number of pharmaceutical compounds varying in solubility from 0.01 to 10 mg/mD t 37 Nicklasson and Brodin (1984) have shown that using cosolvent mixtures fordrugs with poor aqueous solubility produces a good correlation between dissolution rate and solubility. 

Identification of pharmaceutically acceptable vehicles that afford sufficient solubilization while maximizing physiological compatibility for preclinical pharmacokinetic evaluation is critical. The most frequently used solubilization techniques include pH manipulation for ionizable compounds use of cosolvents such as PEG 400, ethanol, DMSO, and propylene glycol micellar solubilization with surfactants such as Tween 80 or SLS complexation with cylodextrins [40]. By using the solubilization techniques, the enhancement in solubility of poor water-soluble compounds can be significant compared to aqueous solubility and can facilitate the absorption of drug molecules in the gastrointestinal tract when delivered in solution form. 

Solution formulations, however, do not typically have these same constraints, and complexation provides an alternative to the use of non-aqueous solvents or large volumes. A few derivatized CDs (e.g., hydro-xypropyl and sulfobutyl ether) can be safely administered by parenteral routes. This is often where complexation and its improvements in aqueous solubility can be most readily utilized. The derivatized CDs often can be used to replace cosolvents such as ethanol, polyethylene glycol, and lipids, as well as provide an alternative to the use of emulsions and liposomes. The hydroxypropyl and sulfobutyl ether derivatives are stable in solution and can be readily autoclaved, often improving the heat stability of drugs. There are however, reports of complexation of CDs with anti-oxidants and preservatives " with both decreased and increased efficacy. ... 

The aqueous solubility of a drug in the 2-8 pH range has a direct influence on its oral and parenteral formulations. A drug with poor solubility (i.e., less than O.lmg/ml) in acidic media may show poor and erratic oral bioavailability due to the dependency of absorption processes in GI fluids. Intravenous dosing requires that the drug be administered in a soluble form. The adjustment of pH, the addition of a cosolvent or a ligand for complexation, or the formation of an emulsion may permit solubilization, but each of these techniques has limitations. Rapid intravenous... 

Other vehicles may be added to parenteral products if the aqueous solubility is limited. However, these vehicles must be non-toxic, non-sensitizing, and non-irritating.In addition, these solvents must be compatible with the drug and other components in the formulation. Cosolvents often used in parenteral formulations include propylene glycol, ethanol, polyethylene glycols, glycerin, and dimethylacetamide. In addition, fixed vegetable oils, such as peanut, cottonseed, sesame and castor oil, can be used however the USP provides clear restrictions on their use in parenteral products. 

One of the main problems associated with developing a parenteral or any other solution formulation of a compound is its aqueous solubility. For poorly soluble drug candidates, there are several strategies for enhancing their solubility. These include pH manipulation, cosolvents, surfactants, emulsion formation and complexing agents. More sophisticated delivery systems, e.g., liposomes, can also be used in this way. 

The toxicity and side effects of cosolvents or surfactants are also problems in formulations [57]. Drug carriers, such as nanoparticles [58], conjugates [3], and micelles [6], have shown promising results with significantly improved solubility. Their capacity to solubilize varies, depending on the incorporated drugs. For example, PTX can be incorporated into PEO-PLA micelles. The solubility of PTX can be up to 50 mg/mL [59], while the solubility of PTX in water has been shown to be as low as 0.5 pg/mL [60]. In addition, the aqueous solubility of PTX that was conjugated to PEG and a polyamidoamine (PAMAM) dendri-mer increased dramatically to 2.5 mg/mL and 3.2 mg/mL, respectively [61]. 

It is more difficult to evaluate the effects of cosolvents which have limited miscibility with water. In the literature, such organic solvents have been termed as both cosolvents and eosolutes, and there is no clear criteria for the distinction. Cosolvent is usually miscible with water, or to be used in an attempt to increase the aqueous solubility of the solute. Cosolute, on the oflier hand, may be organic chemicals which have a similar chemical structure or behave similarly with the solute when they exist in water alone. The effects of cosolutes have been examined in a limited number of published papers. ... 

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