Cosolvent titrations

Furthermore, pH electrode calibration can be performed in situ by the new method [48], concurrently with the pKj determination. This is a substantial improvement in comparison to the traditional procedure of first doing a blank titration to determine the four Avdeef-Bucher parameters [24]. The traditional cosolvent methods used with sparingly soluble molecules can be considerably limited in the pH<4 region when DMSO-water solutions are used. This is no longer a serious problem, and routine blank titrations are now rarely needed in the new in situ procedure. 

Mixed-solvent solutions of various cosolvent-water proportions are titrated and psKa (the apparent pKa) is measured in each mixture. The aqueous pKa is deduced by extrapolation of the psKa values to zero cosolvent. This technique was first used by Mizutani in 1925 [181-183]. Many examples may be cited of pKa estimated by extrapolation in mixtures of methanol [119,161,162,191,192,196,200], ethanol [184,188-190,193], propanol [209], DMSO [212,215], dimethylformamide [222], acetone [221], and dioxane [216]. Plots of psKa versus weight percent organic solvent, Rw = 0 — 60 wt%, at times show either a hockey-stick or a bow shape [119]. For Rw > 60 wt%, S-shaped curves are sometimes observed. (Generally, psKa values from titrations with Rw > 60 wt% are not suitable for extrapolation to zero cosolvent because KC1 and other ion pairing interferes significantly in the reduced dielectric medium [223].)... 

Usually, the solubility of the salt is determined from separate, more concentrated solutions. To conserve on sample, the titration of the salt may be performed with an excess of the counterion concentration [479]. Also, some amount of sample salt may be conserved by titrating in cosolvent mixtures, where salts are often less soluble. 

Drug dissociation constants are experimentally determined by manual or automated potentiometric titration or by spectrophotometric methods.40 Current methods allow determination of pXa values with drug concentrations as low as 10 to 100 pM. For highly insoluble compounds (concentration <1 to 10 pM), the Yesuda-Shedlovsky method41 is commonly used where organic cosolvents (i.e., methanol) are employed to improve solubility. The method takes three or more titrations at different cosolvent concentrations, and the result is then extrapolated to pure aqueous system. The dissociation constant can also be determined with less accuracy from the pH-solubility profile using the following modification of Henderson-Hasselbach equation ... 

As with buffers, ionizing groups on a protein surface are expected to be affected by cosolvents and temperature variations. Examples of potentiometric titration will be shown and discussed in Section IV. They were obtained with the following techniques adapted to mixed solvents and to subzero temperatures. 

Titration curves of cytochrome c (Fig. 30) indicate that the cosolvent induces a significant change in the acidic paH range with a variation in the net proton charge, ZH, of 0.6 unit at paH 6.0. 

Reliability assessment (data quality) is based on information in the original source describing the method used (including evidence for calibration of pH meters exclusion of CO2 in determining pKg values above 6.5), whether pKa values for standard compounds were measured, presence of organic cosolvents, the presence or absence of corrections for [H" "], [OH ] in potentiometric titrations, and use of mean ionic activity coefficients in the calculations. Considerable effort has been made to locate the original source for each measured value. Where only secondary sources have been located, data reliability cannot be assessed with confidence. 

Avdeef A, Box KJ, Comer JEA, Gilges M, Hadley M, Hibbert C, Patterson W and Tam KY, PH-metric log P11. pK determination of water-insoluble drugs in organic solvent-water mixtures,/. Pharm. Biomed. Anal, 20, 631-641 (1999). NB Used a Sirius PCAlOl autotitrator. Titrations were performed in a range of aqueous organic cosolvent mixtures, as follows ... 

Newton DW, Murray W] and Lovell MW, pKg determination of benzhydrylpiperazine antihistamines in aqueous and aqueous methanol solutions, /. Pharm. Set, 71(12), 1363-1366 (1982). NB Attempted to measure pKa for meclizine by extrapolation of apparent pKa values in cosolvent-water mixtures to 0% cosolvent, but found diat meclizine could only be titrated in >47.8% methanol solutions, which was too hi. ... 

Cosolvent Processing. There are few examples of the use of cosolvents in the preparation of Q[ ] association complexes, but the principle is sound. The problem exists for the unsubstituted Q[ ] that there are few organic solvents that can dissolve both the Q[n] and an organic drug. While trifluoroacetic acid (TFA) has been used to encapsulate a-carborane in Q[7] with water titrated into the mixture and eventual evaporation of TFA, it would not be broadly applicable. With the development of substituted Q[n] that have a broader solvent range, this approach becomes more appropriate. 

A well-known use of pyridine as a cosolvent is in the Karl Fischer titration of water in organic solvents, described in Bassett et al. (1978). A solution of iodine and sulfur dioxide in pyridine/methanol or pyridine/cellosolve is fairly stable in the absence of water, but when it is added to a sample of a solvent containing water, reaction 7.7 occurs quantitatively. 

It turns out that amitriptyline and propranolol hydrochlorides can be titrated in a water/ethanol mixture with a 0.1 mol/L sodium hydroxide solution with a pH-metric equivalence point detection. Levomepromazine hydrochloride can be titrated in the same conditions but with propanol instead of ethanol as cosolvent. Propanol is preferred to ethanol because of the very high lipophilicity of the levomepromazine base. 

Aelion et at. [51,52] investigated the hydrolysis of TEOS under acidic and basic conditions using several cosolvents ethanol, methanol, and dioxane. The extent of hydrolysis (Eq. 8) was determined by distillation of the ethanol by-product. Karl Fischer titration was used to follow the consumption of water by hydrolysis (Eq. 8) and its production by condensation (Eq. 10). Quantitative information (for example, specific rate constants) derived from these investigations is unreliable due to the inadvertent consumption of silanol groups by the Karl Fischer reagent, but it is worthwhile to present here and in the following sections some of the qualitative features of their... 

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