Solubility automated potentiometric method

We report here studies conducted with 58 crystalline drug-like compounds. The solubilities are of high quality, having been determined in only three laboratories using the same automated potentiometric method. However, the set is too small to... 

Glomme, A., Marz, J., Dressman, J. B. Comparison of a miniaturized shake-flask solubility method with automated potentiometric acid/base titrations and calculated solubilities. /. Pharm. Set. 2005, 94, 1-15. 

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 ... 

Avdeef (1998) has reported an automated potentiometric titration method for the determination of solubilities of drug substances containing ionizable groups, where a graphical procedure is used for the estimation of solubility constants based on Bjerrum difference plots. One useful relation derived in this work was ... 

Glomme A, Marz J, and Dressman JB. Comparison of a Miniaturized Shake-Flask Solubility Method with Automated Potentiometric Acid/Base Titrations and Calculated Solubilities. yPAarro Sci 2005 94 1-16. 

The acid-base equilibrium constants of the beta-blockers atenolol, oxprenolol, timolol, and labetalol were determined by automated potentiometric titrations. The pKg values were obtained in water-rich or water methanol medium (20% MeOH) to obviate the solubility problems associated with the compounds. The initial estimates of pKa values were obtained from Gran s method and then, were refined by the NYTIT and ZETA versions of the LETAGROP computer program. The resultant values were 9.4 (/ = 0.1 M KCI, 20% methanol) for atenolol, 9.6 (/ = 0.1 M KCI) for oxprenolol, 9.4 (/ = 0.1 M KCI, 20% methanol) for timolol and 7.4 and 9.4 (/ = 0.1 M KCI) for labetalol. The potentiometric method was found to be accurate and easily applicable. The operational criteria for applying the methodology are indicated. 

Water-soluble potassium (expressed as K2O) can be determined by manual or automated flame photometric and tetraphenylboron titration methods for all types of fertilizer samples. Atomic absorption can be used for samples below 5% K2O to maintain the highest degree of precision and accuracy. (Note Tetraphenylboron method for potassium is being used less often because of safety issues associated with formaldehyde.) Methods using ICP-OES for high concentration of potassium are currently being developed. Note Potentiometric measurements can be used to determine potassium in fertilizers but are not official approved methods and do not meet the accuracy and precision requirements as current methods. 

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