Water-organic solvent mixtures, ionization

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. 

Peters JJ, Determination of ionization constants in mixed aqueous solvents of varying composition by a single titration, /. Pharm. Sci., 67,127-129 (1978). NB The paper recognizes riie problem of long extrapolations from aqueous-organic solvent mixtures to estimate pXa values of poorly water-soluble substances. No activity corrections were applied. See Cinnarizine for further details. 

Sample preparation requires only dissolution of the sample to a suitable concentration in a mixture of water and organic solvent, commonly methanol, isopropanol, or acetonitrile. A trace of formic acid or acetic acid is often added to aid protonation of the analyte molecules in the positive ionization mode. In negative ionization mode ammonia solution or a volatile amine is added to aid deprotonation of the analyte molecules. 

Reversed-phase separations currently dominate in CEC. As a result, the vast majority of the mobile phases are mixtures of water and an organic solvent, typically acetonitrile or methanol. In addition to the modulation of the retention, the mobile phase in CEC also conducts electricity and must contain mobile ions. This is achieved by using aqueous mixtures of salts instead of pure water. The discussion in Sect. 2 of this chapter indicated that the electro osmotic flow is created by ionized functionalities. The extent of ionization of these functionalities that directly affects the flow rate depends on the pH value of the mobile phase. Therefore, the mobile phase must be buffered to a pH that is desired to achieve the optimal flow velocity. Obviously there are at least three parameters of the mobile phase that have to be controlled (i) percentage of the organic solvent, (ii) the ionic strength of the aqueous component, and (iii) its pH value. 

The ionization constants of 2,2 -bipyridine in various organic solvent and water mixtures, - " at different ionic strengths " " and at... 

The ionization potentials of some of the bipyridines have been investigated. Solubility data for 2,2 -bipyridine in aqueous solution, in aqueous solvent mixtures, and in various aqueous salt solutions have been obtained, whereas the heat of solution, heat capacities, and related data for 2,2 - and 4,4 -bipyridines in water have been measured. The enthalpies of solution of 2,2 -bipyridine in water and aqueous solvent mixtures have also been obtained. Dielectric relaxation studies of 2,2 -bipyri-dine in carbon tetrachloride have been reported in connection with hindered internal rotation. Partition coefficients for 2,2 -bipyridine between water and various organic solvents have been measured. ... 

Electrospray ionization (ESI) was first employed more than 20 years ago, but it is fairly recently that it became a routine technique for the soft ionization of a wide range of polar analytes, including biomolecules. For this technique, the analyte is usually dissolved in a mixture of an organic solvent (most commonly acetonitrile or methanol) and water with a pH modifier [e.g. formic (methanoic) or acetic (ethanoic) acid for positive ion mode]. The presence of the pH modifier ensures that ionization takes place in the solution state. This is the only common case where ionization occurs before ion vaporization the exact mechanism of the vaporization (Figure 5.6) is still not clearly understood in ESI. 

In Eq. (7-14), k and ko are the specific rate constants for the SnI solvolysis of RX (in this case t-BuCl) in a given solvent and in the standard solvent, respectively, m is the sensitivity of the specific rate of solvolysis of RX to changes in the solvent ionizing power (T), T is a parameter characteristic of the given solvent, and c is the intercept (zero for an ideally behaved solvolysis). Eq. (7-14) is expected to be applicable to reactions very similar to the standard reaction, that is, SnI substitutions. The similarity between Y and m of Eq. (7-14), and a and g of the Hammett equation (7-6) is obvious. Y values are known for some pure, mainly protic solvents and for various binary mixtures of organic solvents with water or a second organic solvent [35, 36]. Typical Y values are... 

The choice of an appropriate sheath liquid and its flow rate is essential to achieve good performance. This choice is a compromise between separation (to maintain an efficient electrophoretic separation) and ionization performances (to assist droplet formation and spray stability). Most CE-ESI-MS applications described in the literature for the analysis of protonated compounds use a sheath liquid containing a mixture of organic solvent, water and formic or acetic acid. In method development, the impact of the nature of the sheath liquid on the expected chiral separation can be evaluated by placing it in the outlet vial. The solubility of the chiral resolving agent in the sheath liquid has to be carefully investigated to avoid its precipitation at the spray needle. 

The reaction medium, especially the pH, determines the constants for a given pair of reactants. To obtain an equilibrium that is shifted in favor of peptide product formation the ionization equilibrium must be manipulated. One efficient method is the addition of water-miscible organic solvents to the aqueous reaction mixture thereby lowering the dielectric constant of the medium, reducing the acidity of the carboxyl group, and to a lesser extent the basicity of the amino group of the nucleophilic amine component[100 1011 The use of biphasic systems (for a review... 

The composition of the solvent strongly influences the HX rate, mainly by modifying the water ionization constant, K, and therefore the concentrations of OH" and HjO ions. Englander and Kallenhach [24] showed that the measured base-catalyzed chemical exchange rates of unstructured poly-DL-alanine in mixtures of aqueous-organic solvents (50% methanol and 50% dioxane) are reduced in... 

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