Ion pair titrations

Ion pair titration using a coloured indicator complex is used in pharmacopoeial assays of dicyclamine elixir, procyclidine tablets, sodium dodecyl sulphate and cetrimide emulsifying ointment. 

These compounds can be determined by either acid-base titration as carboxylic acids or by ion-pair titration. In the case of ion-pair titration, sarcosinates, like other carboxylic acids, can be titrated by two-phase titration at high pH with a cationic titrant (137). In addition, their titration has been demonstrated at low pH either by two-phase titration with an anionic surfactant (138) or one-phase titration with tetraphenylborate using a surfactant-selective electrode (139). These procedures are described in Chapter 16. Both acid-base titration and titration with a cationic surfactant will measure free fatty acid along with the acylsarcosine content. While titration at low pH with anionic titrants is presumably not subject to interference by free fatty acid, this has not been confirmed in the literature. 

Acid-base potentiometric titration is applicable to amphoterics. Typically, either an excess of acid or of base is added, and the titration is conducted with base or acid, respectively. The first inflection is due to the excess acid or base and subsequent inflections are due to end points associated with the surfactant. Hydrolysis and consequent blurring of the end point can be minimized by using a highly alcoholic solvent (114). Since other acidic or basic components will interfere, this approach is only applicable to concentrated surfactant solutions, not to formulations. In fact, impurities in the concentrated surfactant will interfere, which sometimes limits the usefulness of titration for assay. For determination of amphoterics in formulations, ion-pair titration is often used. 

Mohammed, H. Y., F. F. Cantwell, Photometric ion-pair titrations in the presence of an immiscible solvent and their application to drug analysis. Anal. Chem., 1979,5/, 1006-1012. 

One can write acid-base equilibrium constants for the species in the inner compact layer and ion pair association constants for the outer compact layer. In these constants, the concentration or activity of an ion is related to that in the bulk by a term e p(-erp/kT), where yp is the potential appropriate to the layer [25]. The charge density in both layers is given by the algebraic sum of the ions present per unit area, which is related to the number of ions removed from solution by, for example, a pH titration. If the capacity of the layers can be estimated, one has a relationship between the charge density and potential and thence to the experimentally measurable zeta potential [26]. 

In the discussion of the relative acidity of carboxylic acids in Chapter 1, the thermodynamic acidity, expressed as the acid dissociation constant, was taken as the measure of acidity. It is straightforward to determine dissociation constants of such adds in aqueous solution by measurement of the titration curve with a pH-sensitive electrode (pH meter). Determination of the acidity of carbon acids is more difficult. Because most are very weak acids, very strong bases are required to cause deprotonation. Water and alcohols are far more acidic than most hydrocarbons and are unsuitable solvents for generation of hydrocarbon anions. Any strong base will deprotonate the solvent rather than the hydrocarbon. For synthetic purposes, aprotic solvents such as ether, tetrahydrofuran (THF), and dimethoxyethane (DME) are used, but for equilibrium measurements solvents that promote dissociation of ion pairs and ion clusters are preferred. Weakly acidic solvents such as DMSO and cyclohexylamine are used in the preparation of strongly basic carbanions. The high polarity and cation-solvating ability of DMSO facilitate dissociation... 

Poloxamers are used primarily in aqueous solution and may be quantified in the aqueous phase by the use of compleximetric methods. However, a major limitation is that these techniques are essentially only capable of quantifying alkylene oxide groups and are by no means selective for poloxamers. The basis of these methods is the formation of a complex between a metal ion and the oxygen atoms that form the ether linkages. Reaction of this complex with an anion leads to the formation of a salt that, after precipitation or extraction, may be used for quantitation. A method reported to be rapid, simple, and consistently reproducible [18] involves a two-phase titration, which eliminates interferences from anionic surfactants. The poloxamer is complexed with potassium ions in an alkaline aqueous solution and extracted into dichloromethane as an ion pair with the titrant, tet-rakis (4-fluorophenyl) borate. The end point is defined by a color change resulting from the complexation of the indicator, Victoria Blue B, with excess titrant. The Wickbold [19] method, widely used to determine nonionic surfactants, has been applied to poloxamer type surfactants 120]. Essentially the method involves the formation in the presence of barium ions of a complex be-... 

The two-phase titration is based on the reaction of anionic surfactants with cations—normally large cationic surfactants—to form an ion pair. The preferred cationic is benzethonium chloride (Hyamine 1622, 1) because of the purity of the commercially available product. On neutralization of the ionic charges, the ion pair has nonpolar character and can be extracted continuously into the organic phase, e.g., chloroform, as it is formed. The reaction is monitored by addition of a water-soluble cationic dye, dimidium bromide (2), and a water-soluble anionic dye, disulfine blue (3). The cationic dye forms an extractable... 

The experimental approaches used to characterize ion-pair partitioning are cyclic voltammetry and potentiometric titration. Cyclic voltammetry is overall more powerful, but requires special instrumentation which is not commercially available as a ready-to-use set-up. For this reason the potentiometric titration technique has been more widely used. 

The measurement of log and log Pi by dual-phase potentiometric titration has been described by Avdeef [33], Briefly, the method is based on the shift in the apparent pK upon addition of the partition solvent In absence of ion-pair extraction, the apparent pK (PoK) is related to the aqueous pK by the equation below ... 

However, as stated above, the partition coefficients measured by the shake-flask method or by potenhometric titration can be influenced by the potenhal difference between the two phases, and are therefore apparent values which depend on the experimental condihons (phase volume ratio, nature and concentrahons of all ions in the solutions). In particular, it has been shown that the difference between the apparent and the standard log Pi depends on the phase volume raho and that this relationship itself depends on the lipophilicity of the ion [80]. In theory, the most relevant case for in vivo extrapolation is when V /V 1 as it corresponds to the phase ratio encountered by a drug as it distributes within the body. The measurement of apparent log Pi values does not allow to differentiate between ion-pairing effect and partihoning of the ions due to the Galvani potential difference, and it has been shown that the apparent lipophilicity of a number of quaternary ion drugs is not due to ion-pair partitioning as inihally thought [80]. 

Whereas in many instances potentiometric non-aqueous titrations of acids can show anomalies24 depending on the type of solvents and/or electrodes (owing to preferential adsorption of ions, ion pairs or complexes on the highly polar surface of the indicator electrode, or even adherence of precipitates on the latter), conductometric non-aqueous titrations, in contrast, although often accompanied by precipitate formation30, are not hindered by such phenomena sometimes, just as in aqueous titrations, the conductometric end-point can even be based on precipitate formation34. 

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].)... 

Scherrer, R. A. Crooks, S. L., Titrations in water-saturated octanol A guide to partition coefficients of ion pairs and receptor-site interactions, Quant. Struct.-Act. Relat. 8,59-62 (1989). 

Isaeva [181] described a phosphomolybdate method for the determination of phosphate in turbid seawater. Molybdenum titration methods are subject to extensive interferences and are not considered to be reliable when compared with more recently developed methods based on solvent extraction [182-187], such as solvent-extraction spectrophotometric determination of phosphate using molybdate and malachite green [188]. In this method the ion pair formed between malachite green and phosphomolybdate is extracted from the seawater sample with an organic solvent. This extraction achieves a useful 20-fold increase in the concentration of the phosphate in the extract. The detection limit is about 0.1 ig/l, standard deviation 0.05 ng-1 (4.3 xg/l in tap water), and relative standard deviation 1.1%. Most cations and anions found in non-saline waters do not interfere, but arsenic (V) causes large positive errors. 

The titration of metal ions in alcohol solvents28 follows the same sort of rules as titrations of metal ions in water29 but poses additional problems due to the lower polarity that increases ion pairing and oligomerization of the metal ions. We have performed several such titrations with the analysis of the potentiometric data depending on the level of information one requires. More complete and time-consuming analyses are reserved for the most effective catalytic metals, namely La3 +, and for the transition metal ion Zn2+ and Cu2+ along with some simple complexes of the latter two which we describe a little later. For the other metal ions described in our titration papers,7,8 we only present the data in terms of the... 

Figure 3 Titration of Et30+PF6" in CH2C12 at 0 °C with EtzO. The equivalent conductance at zero concentration, A0/mho cm2 mol 1, and the dissociation constant FCp/mol l 1 of the ion-pairs, as functions of the ratio [Et20]/[Et30+PF6 ]...

Although the ester mechanism is not yet generally accepted, the evidence accumulating since it was first put forward is in its favour, and the evidence which is alleged to be against it, or which has been interpreted in terms of ion-pairs in place of the ester, is certainly compatible with the ester theory [13, 14,15]. We note in passing an interesting application of the polymerisation of styrene by perchloric acid it was used as an indicator-reaction in the enthalpy titration of weak bases [16]. 

Solvation of the lithio cation of the silylated reagents by HMPA leads to solvent-separated ion pairs (Eq. 9.5). Titration experiments indicate coordination by four HMPA molecules. These solvated complexes, including the TBS derivative, exist entirely as the propargyl structures, emphasizing the importance of the silyl group to charge stabilization. 

The relative order of the catalytic activities of the crown ethers ([20] + [21]) > [9] > [ 11 ] > [ 13] > [8]) is the same as the relative order of their capacities to bind K+ (Table 4). However, the intrinsic reactivities of the ion pairs were also dependent on crown-ether structure, as was shown by experiments in which the alkylation rates were determined at various crown/phenoxide molar ratios. The curve obtained (Fig. 2) is similar to the curves found in titration experiments (Live and Chan, 1976 De Jong et al., 1976b), and shows that the rate constant reaches a maximum (called plateau kinetics in the literature) when all of the salt is complexed. 

The fact that the EP wants to replace old TEC methods with more selective, efficient, and sensitive separation methods provides the chance for the introduction of more CE methods. The continuous development of analytical methods is reflected in the national and international pharmacopoeias. This might be demonstrated for atropine sulfate. Whereas the Deutsches Arzneibuch, 7th Edition (DAB 7) only limits the tropic acid by extraction and titration with NaOH and phenolphthalein indication, the 4th edition of the EP looked for foreign alkaloids and decomposition products by means of TEC with a potassium iodobismuthate for detection. By intensity comparison of the obtained spots, it was possible to limit these impurities to 0.5%. The EP 5 utilizes an ion-pair HPLC method that is able to limit most of the impurities to less than 0.2%. To make the method more robust, an HPLC method using a polar embedded was applied, which might be the next step for the EP. However, recently the same authors have reported on a MEEKC method being as robust and precise as the latter HPLC method (see Eigure 6) but far more sensitive and, therefore, a future perspective for the EP. 

The use of distribution coefficients for the QSAR treatment of ionizable compounds has been extended to consideration of ion-pair partitioning into biolipid phases. Two experimental methods for determining ion-pair partition coefficients are described. One is a single-phase titration in water-saturated octanol, in which case (for acids) log Pj = log P + pKa - pKa. The other is a two-phase titration (octanol/water) from which the ratio (P + 1)/(Pj + 1) can be calculated. An example outcome is that the uncoupling activity of phenols can be represented by an equation in log instead of log D and pKa. 

We decided to try a direct titration in water-saturated octanol. What we hoped to achieve, if not duplicating literature values, was to obtain partition coefficients proportional to "true" values so that regression analyses could be run and would be meaningful. Secondly, this should be a rapid method to assess structural features in a series for their effect on ion-pair partitioning. 

---