Stabilizers water-miscible solvent

Water and water-miscible solvent biphasic systems Enhanced enzyme activity and stability at low concentration Inhibitory effect on the biocatalyst at high concentration... 

Some pesticides are sufficiently soluble in water to permit their formulation in water. However, this may not be done unless hydrolytic stability and toxicity hazard are favorable. Instead, such compounds are dissolved in a water-miscible solvent to avoid hydrolysis and then mixed with water before application. Examples of such formulations are Azodrin WMC (formulated in hexylene glycol) and Lannate WMC (formulated in dimethyl formamide and methyl alcohol). 

The device of using mixed solvents is resorted to when drug solubility in one solvent is limited or perhaps when the stability characteristics of soluble salts forbid the use of single solvents. Many pharmaceutical preparations are complex systems. Common water-miscible solvents used in pharmaceutical formulations include glycerol, propylene glycol, ethyl alcohol and polyoxyethylene glycols. As can be imagined, the addition of another component complicates any system and explanations of the often complex solubility patterns... 

Organic solvents are often used in the manufacture, purification, precipitation and crystallization of protein pharmaceuticals (Sukumar et al., 2005). Water miscible solvents such as ethanol, acetonitrile and propanol have been utilized to promote the stabilization of reversible denaturation and aggregation, with recovery of the native conformation. For example, insulin has been precipitated and/or crystallized in a wide variety of solvents (Brange and Lanlqaer, 1993). 

The use of a partly water-miscible solvent in which the drug and polymer is dissolved is shown in Scheme 5. An emulsion is formed on addition of the polymer-drug solution to an aqueous phase containing a stabilizer. Because of the partial miscibility of the first solvent, solvent diffuses from the dispersed droplets into the bulk to provide after some time polymer nanoparticles containing drug. 

Both stabilizing and destabilizing effects of solvents on enzymes have been reported. A reasonably reliable measure of the compatibility of solvents with enzymes is the log P value, where P is defined as the distribution coefficient of a solvent between water and 1-octanol in a two-phase system[64> 791. Solvents with a log P value above 4 are suitable (e. g. aromatics, aliphatics) whereas water-miscible solvents with a log P value below 2 (short chain esters, DMF, short-chain alcohols) are not suitable for employment with biocatalysts. The latter solvents interfere with the water at the boundary of the protein itself and so disrupt the binding forces necessary to maintain an active form of the enzyme. Surprisingly, tert-butanol has a stabilizing effect on some oxidative enzymes(801, despite its low log P value (0.35). 

When the diacid chloride component has relatively high hydrolytic stability, completely or partially water-miscible solvents are particularly useful in the preparation of those aromatic polyamides which are frequently obtaii only in low molecular weight when water-immiscible solvents are used. Water miscible solvents accelerate the reaction rate, enhance polymer swelling and cilitate product recovery. Typical examples are cyclohexanone, 2,4-dimethyltetra-methylenesulphone, methylethylketone, tetramethylenesulphone, acetone, THF and isopropanol [20]. 

Solutions show very good viscosity stability over the pH range of 2-12 and good tolerance of water-miscible solvents... 

For water-miscible solvents, the correlation of the stability of immobilized enzyme with physicochemical parameters of organic solvent was investigated. Two parameters, log P (the partition coefficient between the n-octanol-water phases, i.e., reflecting the hydrophobicity of organic solvents) and Et (30) (the polarity of organic solvents), were chosen. As shown in Fig. 13 [59], either the log P or Et (30) value was found to be applicable to correlate the stability of the immobilized enzyme in the water-miscible organic solvents. Therefore, the inactivation of the immobilized enzyme in water-miscible organic solvents was affected by the extent to which they remove water from the surface of the enzyme molecule. 

In this case the polymer is dissolved in a water miscible solvent such as acetone. The acetone solution is carefully added to water while stirring. The polymer precipitates out as nanoparticles which are stabilized against flocculation by electrostatic repulsion (resulting from the presence of COOH groups on the particle surface). Using this procedure surfactant-free nanoparticles with diameter < 150 nm could be prepared. Later the procedure was modified by incorporation of poloxamers or poloxam-ines in the aqueous phase. These block copolymers are essential for surface modification of the nanoparticle as is discussed below. 

Another method for the synthesis of stable metal nanoparticles involves first mixing the metal hydrosols and an ethanol solution of dodecylamine and then extracting the dodecylamine-stabilized metal nanoparticles into toluene. The ethanol, a water miscible and good solvent for dodecylamine, was used as an intermediate solvent to improve the interfacial contact between citrate-stabilized metal nanoparticles and alkylamine. The extraction of dodecylamine-stabilized metal... 

The procedure chosen for the preparation of lipid complexes of AmB was nanoprecipitation. This procedure has been developed in our laboratory for a number of years and can be applied to the formulation of a number of different colloidal systems liposomes, microemulsions, polymeric nanoparticles (nanospheres and nanocapsules), complexes, and pure drug particles (14-16). Briefly, the substances of interest are dissolved in a solvent A and this solution is poured into a nonsolvent B of the substance that is miscible with the solvent A. As the solvent diffuses, the dissolved material is stranded as small particles, typically 100 to 400 nm in diameter. The solvent is usually an alcohol, acetone, or tetrahydrofuran and the nonsolvent A is usually water or aqueous buffer, with or without a hydrophilic surfactant to improve colloid stability after formation. Solvent A can be removed by evaporation under vacuum, which can also be used to concentrate the suspension. The concentration of the substance of interest in the organic solvent and the proportions of the two solvents are the main parameters influencing the final size of the particles. For liposomes, this method is similar to the ethanol injection technique proposed by Batzii and Korn in 1973 (17), which is however limited to 40 mM of lipids in ethanol and 10% of ethanol in final aqueous suspension. 

Often the enzyme stability can be improved by using a suitable water-immiscible solvent instead of a water-miscible one. Two-phase systems are obtained with the enzyme and other hydrophilic substances present in the aqueous phase while hydrophobic substrates and products mainly partition to the organic phase (Figure 9.1). Water immiscible solvents often used for enzymatic reactions are hydrocarbons, ethers and esters further details on solvents are found in the section 9.5 Selection of solvents , below. In order for the bioconversion to occur, the substrates must be transferred to the enzyme in the aqueous phase after the reaction hydrophobic... 

Ionic liquids are a class of solvents and they are the subject of keen research interest in chemistry (Freemantle, 1998). Hydrophobic ionic liquids with low melting points (from -30°C to ambient temperature) have been synthesized and investigated, based on 1,3-dialkyl imidazolium cations and hydrophobic anions. Other imidazolium molten salts with hydrophilic anions and thus water-soluble are also of interest. NMR and elemental analysis have characterized the molten salts. Their density, melting point, viscosity, conductivity, refractive index, electrochemical window, thermal stability, and miscibility with water and organic solvents were determined. The influence of the alkyl substituents in 1,2, 3, and 4(5)-positions on the imidazolium cation on these properties has been scrutinized. Viscosities as low as 35 cP (for l-ethyl-3-methylimi-dazolium bis((trifluoromethyl)sulfonyl)amide (bis(triflyl)amide) and trifluoroacetate) and conductivities as high as 9.6 mS/cm were obtained. Photophysical probe studies were carried out to establish more precisely the solvent properties of l-ethyl-3-methyl-imidazolium bis((trifluoromethyl)sulfonyl)amide. The hydrophobic molten salts are promising solvents for electrochemical, photovoltaic, and synthetic applications (Bon-hote et al., 1996). 

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