Cosolvents, pharmaceutical

An intriguing influence of a cosolvent immiscible with water on the enantioselec-tivity of the enzyme-catalyzed hydrolysis was observed. It was proven that enzyme enantioselectivity is directly correlated with the cosolvent hydrophobicity. In the best example, for ethyl ether as cosolvent, the reaction proceeded with E = 55, and the target compound was obtained in 33% yield with 92.7% ee. This finding may be of great practical importance, particularly in industrial processes [24], since it will enable better optimization of enzyme-catalyzed processes. It is clear that, in future, immobilized enzymes, as heterogeneous catalysts, wiU be widely used in most industrial transformations, especially in the preparation of pharmaceuticals [25]. 

In this type of reaction the active drug undergoes decomposition following reaction with the solvent present. Usually the solvent is water, but sometimes the reaction may involve pharmaceutical cosolvents such as ethyl alcohol or polyethylene glycol. These solvents can act as nucleophiles, attacking the electropositive centers in drug molecules. The most common solvolysis reactions encountered in pharmaceuticals are those involving labile carbonyl compounds such as esters, lactones, and lactams (Table 1). 

Bonacucina, G., Martelli, S., Palmieri, G.F. (2004). Rheological, mucoadhesive and release properties of Carbopol gels in hydrophilic cosolvents. International Journal of Pharmaceutics, 282, 115-130. 

Li, P, L. Zhao, and S. H. Yalkowsky (1999). Combined effect of cosolvent and cyclodextrin on solubilization of nonpolar drugs journal of pharmaceutical sciende harm. Sci., 88 1107-1111. 

A better estimate of all attractive forces surrounding a molecule was found in the use of the solubility parameter [32,33], Hancock et al. [34] has reviewed the use of solubility parameters in pharmaceutical dosage form design. The solubility parameter is used as a measure ofthe internal pressures ofthe solvent and solute in nonideal solutions. Cosolvents that are more polar have larger solubility parameters. The square root ofthe cohesive energy density, that is, the square root of the energy of vaporization per unit volume of substance, is known as the solubility parameter and was developed from Hildebrand s Regular Solution Theory in the Scatchard-Hildebrand... 

Rubino, J.T. The effects of cosolvents on the action of pharmaceutical bilffgespnt. Sci. Technol.,... 

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. 

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],... 

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. 

Due to the complexity of intermolecular interactions in hydrogen-bonded solutions, such as those used in pharmaceutical applications, no single parameter is capable of quantifying all interactions. Several theories have been developed to estimate drug solubility in cosolvent-water mixtures. The relationships that have resulted from these theories range from relatively simple to complex, depending on the desired accuracy of solubility prediction. Some theories and guidelines... 

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 /. 

When water is a reactant in the degradation process, that is, when the reaction is hydrolytic, replacement of all or part of the water with a cosolvent may enhance the stabilityof the drug. This does not imply that solvolysis will not occur with solvents other than water. Indeed, many pharmaceutical solvents or solvent blends are sufficiently nucleophilic to participate in substitution reactions however, they are often less reactive than pure water. ... 

---