Potentiometric method, solubility

Recent Improvements in the Potentiometric Method Applied to Sparingly Soluble Drugs... 

Since most drug discovery projects deal with very sparingly soluble compounds, the usual CE sample concentration would lead to precipitation. The handling of real dmg candidate molecules is poorly developed in CE applications, in comparison to the most robust potentiometric method. 

Potentiometric methods for solubility measurement have been reported in the literature [467-471]. A novel approach, called dissolution template titration (DTT), has been introduced [472-474], One publication called it the gold standard [509]. 

The graphically deduced constants are subsequently refined by a weighted nonlinear least squares procedure [472]. Although the potentiometric method can be used in discovery settings to calibrate high-throughput solubility methods and computational procedures, it is too slow for HTS applications. It is more at home in a preformulation lab. 

Potentiometry is used in the determination of various physicochemical quantities and for quantitative analysis based on measurements of the EMF of galvanic cells. By means of the potentiometric method it is possible to determine activity coefficients, pH values, dissociation constants and solubility products, the standard affinities of chemical reactions, in simple cases transport numbers, etc. In analytical chemistry, potentiometry is used for titrations or for direct determination of ion activities. 

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... 

The titrations can be carried out both satisfactorily and effectively in such situations where the solubility relations offer erroneous and unsatisfactory results given by visual indicator and potentiometric methods. For instance ... 

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 ... 

Worked Example 3.5. A new means of extracting nickel from its ore is being investigated. The first step is to crush the rock to powder, roast it, and then extract soluble nickel species (as Ni " ") into an aqueous solution. The activity, a(Ni +), is monitored by a potentiometric method, where a wire of pure nickel metal functions as an electrode and is immersed in aliquot samples taken from the plant. This wire monitors the electrode potential NP+,Ni.If 2+,Ni =-0-230 V, what is if afNi " ) = 10... 

An additional point worth mentioning is that the potentiometric method can monitor several partially soluble salts at once. For example, if a solution contains chloride, bromide and iodide ions, then a plot of emf against the volume of cation (e.g. Ag ) will contain three inflection points (see Figure 4.8), one for each of the three silver halides. for Agl is smaller than that for AgCl, while (AgBr) has an intermediate value, so the first inflection point represents the precipitation of Agl, the second represents formation of AgBr and the third represents the formation of insoluble AgCl. ... 

A potentiometric method for determination of ionization constants for weak acids and bases in mixed solvents and for determination of solubility product constants in mixed solvents is described. The method utilizes glass electrodes, is rapid and convenient, and gives results in agreement with corresponding values from the literature. After describing the experimental details of the method, we present results of its application to three types of ionization equilibria. These results include a study of the thermodynamics of ionization of acetic acid, benzoic acid, phenol, water, and silver chloride in aqueous mixtures of acetone, tetrahydrofuran, and ethanol. The solvent compositions in these studies were varied from 0 to ca. 70 mass % nonaqueous component, and measurements were made at several temperatures between 10° and 40°C. 

Dissociation constants of ionizable components can be determined using various methods such as potentiometric titrations [85] CE, NMR, [86] and UV spectrophotometric methods [87]. Potentiometric methods have been used in aqueous and hydro-organic systems however, these methods usually require a large quantity of pure compound and solubility could be a problem. Potentiometric methods are not selective because if the ionizable impurities in an impure sample of the analyte have a pK similar to that of the analyte, this could interfere with determining the titration endpoint. If the titration endpoint is confounded, then these may lead to erroneous values for the target analyte pKa. 

The solubility of many silver salts, AgB, can be easily measured by potentiometric methods, based on the Nemst equation. Such solubilities give y g+. VI- If VI- for one anion, B-, is calculated on the basis of assumptions (i), (ii) and (iii), Vlg+ estimated and thus VI-) for all... 

With the potentiometric approach, determination of intrinsic solubility is based upon the measurement of the pH shift caused by compound precipitation during acid-base titration of ionizable compounds. Two commercial potentiometric methods currently available are pSol [30, 39] and Cheqsol [40-42], In the pSol method developed by Avdeef, a minimum of three titrations in the direction of dissolution are performed. Normal pH versus volume titration plots are reexpressed as Bjerrum plots, that is, average number of bound protons versus pH. The Bjermm plots enable the shift in compound pKa to be more readily observed and are used to determine intrinsic solubility (S0) via Equation 2.5 ... 

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. 

With the preliminary estimate of c just given, A is found to be 137.93, yielding with equation. (1) the slightly higher value, 1.306 X 10Bf for the solubility of silver chloride at 25°. This agrees, within experimental error, with the determination, described in Chapter 17, of the same quantity by Brown and Maclnnes using a potentiometric method. 

Papers devoted to the studies of metal-oxide solubilities in molten potassium halides are few. In particular, Guyseva and Khokhlov reported the determination of the solubility product of MgO in molten KC1 in the 1067-1195 K temperature range [374], The study was performed by the potentiometric method using the Pt(02) gas-oxygen electrode. The experimental method consisted of the addition of a known quantity of MgCl2 to the pure melt, and measurements of e.m.f. for the following cell ... 

V.L. Cherginets and E.G. Khailova, Determination of Solubility Products of Oxides in Molten by Potentiometric Method with the Use of Metallic and Oxygen Electrodes, Zh. Neorg. Khim. 36 (1991) 1277-1280. 

V.M. Ivenko, Determination of Solubility of Barium Oxide in BaC12-KCl-NaCl Eutectic by Potentiometric Method (Abstract of 10th All-Union Conference on Physics, Chemistry and Electrochemistry of Ionic Melts and Solid Electrolytes, Ekaterinbourg, Vol. 1. 1992) p. 74. 

Singer JM, O Hare MJ, Rehm CR and Zarembo JE, Chlorthalidone, APDS, 14, 1-34 (1985) Fleurren ALJ, van Ginneken CAM and van Rossum JM, Differential potentiometric method for determining dissociation constants of very sli tly water soluble drugs applied to die sulfonamide diuretic chlorthalidone, /. Pharm. Sci., 68(8), 1056-1058 (1979). NB The sulfonamide function present in chlordialidone, is considered to be responsible for the acid dissociation. The ionization constant of chlorthalidone was determined based on spectrophotometric measurements of the concentration [chlor] at various pH values ... 

When no linear region prior to the endpoint can be easily obtained, one can add alcohol or some other water-soluble organic compound to reduce the dissociation of the acid so that it behaves more like a very weak acid. This often may be the easiest approach for titrating weak and moderately weak acids. If these techniques fail, then potentiometric methods should be tried. 

In aqueous solution pristinamycin 1 shows two acid-base equilibria (determined by potentiometric methods [41]) associated with (i) protonation of the dimethylamino function of the iV-methyl 4-dimethylaminophenylalanine residue - pKji =4.1 and (ii) deprotonation of the hydroxy group of the hydroxy-picolinic acid residue - pK,2 = 7.3. The molecule is neutral between pH = 4 and pH = 7 and is water soluble at pH less than 3 as the corresponding acid-salt. 

NiO solubility in molten KF-LiF at 550 C determined by potentiometric method is 1.3x10 This value considerably exceeds values obtained for the above chloride melts. The increase of NiO solubility occurred due to formation of fluoride complexes which are more stable than chloride ones. 

The bismuth forms a sparingly soluble metal complex with the pyrrolidine dithiocarbamate. The potentiometric method of titration is highly sensitive for small quantities of bismuth. An evaluable jump is still obtained with the standard solution. However, no explanation has yet been given as to why there is a potential jump at all. During potentiometric titration there is presumably a small quantity of a reversible oxidation product present, with the result that a measurable redox potential may be formed between the... 

As well as these titrimetric methods, the AOAC details a potentiometric method that is also recommended in Codex Alimentarius standards. The vegetables or legumes are dispersed in water and acidified, with the soluble chlorides titrated potentiometrically with silver nitrate. Many instruments are also now available with ion-selective electrodes that can be applied to the determination of salt in foods. They offer reasonable accuracy with ease of use and are particularly suitable for quality assurance purposes. 

The gravimetric determination of potassium as its barely soluble tetraphenylborate is recommended and described here. This method has also been applied to seawater for an ocean-wide survey of the element (see Table 11-1). The procedure is preferred because of its high accuracy and precision and the minimum amount of equipment required to perform the analysis. Basically, the method outlined here is that developed by Wittig (1950) and Raff and Brotz (1951). A brief description of a potentiometric method is presented in Section 11.2.3.6. 

Therefore the setup where the dissolution reaction is followed by potentiometric measurements of the pertinent H -concentration within the galvanic cell (glass electrode solution salt bridge reference electrode) is an optimal system for solubility measurements. This method is called potentiometric method of solubility measiuements ( Potentio in Table 1.1). An example of such measurements could be tiiat of solubility of metal oxides at temperatures up to 300°C performed in ORNL using simultaneously sampling method and the hydrogen-electrode concentration cell (HECC). The details of such measurements and experimental setup can be found in Chapter 3 in this Book. 

METHOD DEVELOPMENT FOR THE POTENTIOMETRIC STRIPPING ANALYSIS OF SOLUBLE COPPER IN DENTAL MATERIALS... 

All stated pK values in this book are for data in dilute aqueous solutions unless otherwise stated, although the dielectric constants, ionic strengths of the solutions and the method of measurement, e.g. potentiometric, spectrophotometric etc, are not given. Estimated values are also for dilute aqueous solutions whether or not the material is soluble enough in water. Generally the more dilute the solution the closer is the pK to the real thermodynamic value. The pK in mixed aqueous solvents can vary considerably with the relative concentrations and with the nature of the solvents. For example the pK values for V-benzylpenicillin are 2.76 and 4.84 in H2O and H20/EtOH (20 80) respectively the pK values for (-)-ephedrine are 9.58 and 8.84 in H2O and H20/Me0CH2CH20H (20 80) respectively and for cyclopentylamine the pK values are 10.65 and 4.05 in H2O and H20/EtOH (50 50) respectively. pK values in acetic acid or aqueous acetic acid are generally lower than in H2O. 

Titrations can be carried out in cases in which the solubility relations are such that potentiometric or visual indicator methods are unsatisfactory for example, when the reaction product is markedly soluble (precipitation titration) or appreciably hydrolysed (acid-base titration). This is because the readings near the equivalence point have no special significance in amperometric titrations. Readings are recorded in regions where there is excess of titrant, or of reagent, at which points the solubility or hydrolysis is suppressed by the Mass Action effect the point of intersection of these lines gives the equivalence point. 

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