Cosolvency lipophilicity

Many research compounds are poorly soluble in water. When very lipophilic molecules precipitate in the donor wells, it is possible to filter the donor solution before the PAMPA sandwich is prepared. On occasion, the filtered donor solution contains such small amounts of the compound that determination of concentrations by UV spectrophotometry becomes impractical. One strategy to overcome the precipitation of the sample molecules in the donor wells is to add a cosolvent to the solutions (Section 7.4.4). It is a strategy of compromise and practicality. Although the cosolvent may solubilize the lipophilic solute molecule, the effect on transport may be subtle and not easy to predict. At least three mechanisms may cause Pe and membrane retention (%R) values to alter as a result of the cosolvent addition. To a varying extent, all three mechanisms may simultaneously contribute to the observed transport ... 

The cosolvent may increase the aqueous solubility of the sparingly soluble molecules, which would lower the membrane-donor solution partition coefficient. According to Eq. (2.3), Pe will decrease. Since %R is related to lipophilicity (Section 7.7.2), the retention is also expected to decrease. 

The most dramatic effects are with the bases. The first seven bases in Table 7.19 are the most lipophilic. Cosolvent causes their %R to decrease, consistent with effect (2) listed above. For the three least-lipophilic bases, %R increases with cosolvent, consistent with effect (1). Chlorpromazine and verapamil experience... 

The catalysts were conditioned in a 1-cyanooctane/aqueous NaCN mixture for 24 h at room temperature to avoid the induction period of the reaction. Rates (converted from a weight basis to a molar basis) with catalysts 47-49 significantly decreased as the % RS increased over the range 5 % to 50 %. With equal loadings activities of the polymer-supported amine oxides decreased with decreased lipophilicity of the catalysts (49 > 48 > 47). Lipophilic character appears to be an important factor for activity of polymer-supported cosolvents. 

For the preparation of a micellar solution, the water-insoluble drug and lipophilic excipients can be dissolved in a liquid surfactant by mixing at a relatively high temperature (43S 6flntil a clear solution is obtained. If necessary, a cosolvent can be added to aid solubility in the surfactant. Then a water or buffer solution containing hydrophilic excipients is added to the desired volume while mixing. In some cases, the aqueous solution needs to be heated to the same temperature as that > the surfactant to obtain desirable results. 

The new cyclosporine formulation (Sandimmun Neoral, Novartis Pharmaceuticals Corporation, East Hanover, NJ) is a self-microemulsifying drug delivery system, which consists of the drug in a lipophilic solvent (corn oil), hydrophilic cosolvent (propylene glycol) surfactant and an antioxidant [37]. Upon contact with GI fluids, Sandimmun Neoral readily forms a homogenous, monophasic microemulsion, which allows the absorption of the drug molecules. Unlike Sandimmun, the formation of this microemulsion is independent of bile salt activity, and indeed, studies have shown that the absorption of cyclosporine from the new formulation is much less dependent on bile flow [38] and is unaffected by food intake [39],... 

These equations illustrate the concept that the slope in Eq. (4) will be greater for a given cosolvent-water mixture the more lipophilic the solute. That is, the increase in solubility relative to water will be greater the larger the value of log P for the solute. In general, solutes with a log P > 2 will behave as non-polar solutes in most pharmaceutical solvents and will demonstrate a continual increase in with increasing /. 

Alternatively, Rubino and Yalkowsky found that a was a linear function of cosolvent polarity for a given solute. This is illustrated in Fig. 3 for the three lipophilic compounds phenytoin, diazepam, and benzocaine. Thus, knowledge of the solubility of a given drug in water and at least two cosolvents would permit cr to be estimated for other cosolvents by interpolation using an index of the desired cosolvent polarity. These studies permit the use of Eq. (4) as a means to rationally choose or eliminate solvents for formulation studies based on limited experimental solubility data and commonly obtained indexes of solute and solvent polarity. 

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. 

SCF carbon dioxide is a lipophilic solvent since the solubility parameter and the dielectric constant are small compared with a number of polar hydrocarbon solvents. Co-solvents(also called entrainers, moditiers, moderators) such as ethanol have been added to fluids such as carbon dioxide to raise the solvent strength while maintaining it s adjustability. Most liquid cosolvents have solubility parameters which are larger than that of carbon dioxide, so that they may be used to increase yields, or to decrease pressure and solvent requirements. A summary of the large increases in solubility that may be obtained with a simple cosolvent is given at the top of Table I. Cosolvents, unlike carbon dioxide, can form electron donor-acceptor complexes (for example hydrogen bonds) with certain polar solutes to influence solubilities and selectivities beyond what would be expected based on volatilities alone. Several thermodynamic models have been developed to correlate and in some cases predict effects of cosolvent on solubilities( ,2). They are used extensively in SCF research and development... 

SCFs offer a nonaqueous environment which can be desirable for enzymatic catalysis of lipophilic substrates. The lipophilic substance cholesterol is 2 to 3 orders of magnitude more soluble in CX>2-cosolvent blends than in waterQ). In CO2 based blends, it may be oxidized to cholest-4en-3one, a precursor for pharmaceutical production using an immobilized enzyim(22). The enzyme polyphenol oxidase has been found to be catalytically active in supercritical CO2 and fluoroform (22). The purpose of using a SCF is that it is miscible with one of the reactants-oxygen. Lipase may be used to catalyze the hydrolysis and interesterification of triglycerides in supercritical OO2 without severe loss of activity(24). These reactions could be integrated with SCF separations for product recovery. 

Supercritical fluids (SCFs) such as carbon dioxide have a "hydrocarbon-like solvent strength at typical conditions, so that they are appropriate solvents for lipophilic substances. The solvent strength may be raised significantly by the addition of small amounts of cosolvents such as ethanol to increase solubilities of moderately polar substances selectivelyQ), sometimes by several hundred percent(2,2 4). The solvent and cosolvent form clusters about solutes, in which the cosolvent concentrations are enhanced significantly( ,fi). The present objective is to explore the effects of considerably more powerful solvent additives, that is surfactants. Since very little is known about surfactants in SCFs, spectroscopic probes were used to measure polarities inside the reverse micelles. Polarity is a key indicator of the ability of a reverse micelle to solvate a hydrophile. Using the... 

The polar character of this molecule often requires the use of polar cosolvents to ensure its complete solubilization. This aspect not only affects the productivity and consequently, once again, the economy of the process but also raises important environmental issues. New smart-designed lipophilic derivatives analogous to NHPI need to be developed to solve this problem. 

During the discovery phase, when availability of compound is at a preminm, the formulation of a simple injectable product for use in animal stndies can be problematical. If a drug candidate reqnired for formulation as a parenteral product is non-ionizable, lipophilic or does not form a water-soluble salt with acceptable properties, solubilization by use of cosolvents shonld be considered as the next option. In cases... 

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