Solubilization cosolvent-water mixtures

Yalkowsky, Rubino, and others [63-67] have further studied log-linear cosolvent solubilization. For organic solutes in propylene glycol-water mixtures, Yalkowsky and Rubino found that the following equation... 

Yalkowsky, S.H. Rubino, J.T. Solubilization by cosolvents I organic solutes in propylene glycol-water mixtures. J. Pharm. Sci. 1985, 74 (4), 416-421. 

Yalkowsky SH, Rubrno JT. Solubilization by cosolvents. Part 2. Organic solvents in propylene glycol-water mixtures. J Pharm Sci 1985 74 416-421. 

S/v is the solubility in water, and f is the fraction of organic solvent in the cosolvent mixture. If the cosolvent mixture contains more than two organic solvents (i.e., a ternary or higher cosolvent mixture), the total drug solubility can be approximated by a summation of solubilization potentials as... 

To evaluate the effects of cosolvent on surfactant delivery and PCE recovery, Box B was flushed with 4% Tween 80 + 5% EtOH at a Darcy velocity of 4.8 cm/hr. The surfactant/cosolvent mixture, which had a density of 0.994 g/cm3, was also representative of a neutral buoyancy flood solution (Shook et al, 1998). It is important to recognize that "neutral buoyancy" refers to density of flushing fluid after solubilization of the DNAPL. Thus, the initial density of the surfactant formulation must be less than that of the resident aqueous phase. Figure 5b shows the location and shape of the 4% Tween 80 + 5% EtOH front after flushing Box B with 0.5 pore volumes of solution. The lower density of the 4% Tween 80 + 5% EtOH solution (0.994 g/cm3) relative to the density of resident pore water (0.998 g/cm3) caused the injected solution to flow preferentially along the top of Box B (Figure 5b). This effect can become severe at low flow rates (Taylor, 1999). The... 

Ritonavir is solubilized in a cosolvent mixture of propylene glycol, ethanol, water, the surfactant Cremophor EL, and peppermint oil to 80 mg/ml in the Norvir oral solution. A similar cosolvent mixture of propylene glycol, 42% ethanol, water, glycerin, the surfactant Cremophor RH 40, and peppermint oil is used to cosolubilize ritonavir to 20 mg/ml and lopinavir, a non-ionizable water-insoluble HIV protease inhibitor, to 80 mg/ml in the Kaletra oral solution. The dose of Kaletra Oral Solution is up to 5 ml twice daily, which is 2.1 ml of ethanol per dose representing the estimated maximum amount of ethanol administered orally per dose. 

The solubilization techniques for injectable formulations are similar to those in oral formulations and include pH adjustment, mixed aqueous/organic cosolvents, organic solvent mixtures, cyclodextrin com-plexation, emulsions, liposomes, polymeric gels, and combinations of techniques. " Molecules that are non-ionizable, lipophilic, and non-polar are challenging to formulate owing to their low water solubility and no effect of pH on solubility. Examples include paclitaxel, docetaxel, cyclosporin A, etoposide, loraze-pam, tacrolimus, testosterone enanthate, and halo-peridol decanoate, and they are all solubilized in non-aqueous solutions composed entirely of organic solvent(s), which are usually but not always diluted prior to administration. 

As exemplified by the case of oxfenicine, the solubilization approach by cosolvent mixtures appears not to be usefnl for polar drug substances simply becanse they are less soluble in non-polar solvents than they are in water. Electrolytes are at least partly ionized, and therefore they exhibit pH-dependent solubility in aqueous media, while the fraction of the less water-soluble, non-ionized species may benefit from cosolvent solubilization as shown in the... 

Homogeneous solutions are the preferred formulation systems for parenteral administration because they can be easily visually inspected for the absence of particulate matter. For this reason, cosolvent solubilization is the first choice for parenteral products once purely aqueous systems provide insufficient solvency. The compositions of three commercial, injectable products are given in Table 39.5. The first product (1) has a low percentage of cosolvent in the separate solvent ampoule. The drug substance is provided as a dry powder because of its limited stability in solution. The second one (2) is solubiUzed with two cosolvents amounting to 50% of the total volume, whereas in the third product the drug dose is dissolved in a water-free mixture of cosolvents. This draws the attention to a further point to consider when cosolvents are employed in formulations. The formulation has to be devised such that the effect of dilution of... 

Numerous experimental data exist in the literature on flic solubility of organic solutes, including both drugs and environmental pollutants, in various mixtures of water and cosolvents. Experimental observations are often illustrated by plotting the logarithm of solubility of the solute versus the volume fraction of cosolvent in the solvent mixture. A few examples of solubilization curves are shown in Figure 14.21.2.1, which shows three typical situations for solutes of different hydrophobicity in the mixture of water and ethanol. 

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