pH-Metric log P. 3. Glass electrode calibration in methanol-water, applied to pKa determination of water-insoluble substances

Abstract

A serle• of semlaqueous HCI solutions of known concentration, containing 0.1 M KN03 (as Ionic strength adjuster) and 0-70 wt % methanol, was titrated at 21, 25, and 37 °C with standardized KOH, pH 2-12. The pH measuring circuit (Rosstype electrode) was calibrated with an aqueous pH buffer (Nernet slope assumed). The operational pH readings were related to peH (=log [H+]) by the four-parameter equation:The parameters were determined by a weighted nonlinear least squares procedure, which allows for C02 corrections. This calibration procedure was applied at 25 °C In titrations to determine the pK, values of acetic add, benzoic add, 4-n-butoxyphend, 4-ethoxyphend, 1-benzyWmkfazde, (± )-proprandd, and Af-methyl-o-gluc amine and of two water-insoluble highly lipophilic benzdc acid derivatives of pharmaceutical Interest, with the aim of determining their odanol-water partition coefficients. Ya-•uda-Shedlovsky plots were used to extrapolate semlaqueous apparent p/f,'s to zero methanol.

Molecular Properties and CYP2D6 Substrates: Central Nervous System Therapeutics Case Study and Pattern Analysis of a Substrate Database

“…The percentage of compound remaining versus time for each substrate concentration was fitted to a first-order decay function to determine the initial substrate depletion rate constant (k dep ). K M was determined by plotting the k dep versus substrate concentration on a linear-log plot using the following equation: (Avdeef et al, 1993). In brief, stock solutions of test compounds were prepared at a concentration of 20 mg/ml in dimethylsulfoxide.…”

“…The pK a was determined in a mixture of water and cosolvent with a minimum of three ratios of water/ cosolvent titrated to obtain an apparent pK a in the presence of cosolvent (p s K a ). The potentiometric pK a was determined by extrapolation of the p s K a values measured in the cosolvent titrations using the Yasuda-Shedlovsky technique (Avdeef et al, 1993). CYP2D6 Kinetics Database.…”

Equilibrium solubility measurement of ionizable drugs – consensus recommendations for improving data quality

“…electrode used is largely unidentified. In contrast, attention to such detail is the norm in pK a determination practice, where specialized calibration methods are well developed [22,27,44,45,[111][112][113]. Researchers who determine pK a values using commercial analyzers are well acquainted with the four-parameter electrode standardization procedure, described in Appendix C. Those using the Sirius Analytical titrators will recognize the procedure as the "Four-Plus" method, and those using the Pion titrators will recognize it as the "ABC" method.…”

Physico-chemical Profiling of ACE-inhibitor Lisinopril: Acid-base Properties

“…The effect of methanol on the protonation constant is known to depend on the charge of the basic site. For acids, the apparent log s K value increases with the increasing weight percent of methanol, while a decrease is usually observed for bases [25]. Using this co-solvent method, we obtained a more reliable value for logK 4 since the log s K 4 values in methanol-water mixtures shifted up to the measurable pH range.…”