PH-dependent solubility

Fig. 17 shows the pH-solubility profile for cocrystal plotted according to Eq. (34) with cocrystal K p values of 1 X 10 and 1 x 10 and acidic ligand pKa = 5. The pH-solubility profile of a cocrystal with one component that is a weak acid is similar to that of a weak acid. At pH < pKa, the cocrystal solubility is at its lowest intrinsic solubility value, given by K pf-. At pH = pKa, the cocrystal solubility is 1.4 times higher, and at pH > pKa, the solubility increases exponentially. Also, increasing the K p value increases the intrinsic solubility of cocrystal as observed in Fig. 17. The K p value is characteristic of the cocrystal of an API with a specific ligand. Therefore, if multiple cocrystals exist for the same API, determination and comparison of the K p and values enables one to select the cocrystal with the desired solubility pH dependence.

Equations (3-6) for the potentiometric and spectrophotometric methods will provide thermodynamic pKa values. For the solubility-pH dependence method [Eqs. (7-8)], the values obtained are apparent values (pKg )/ which are relevant to the ionic strength (7) of the aqueous buffers used to fix the pH value for each solution. If the ionic strength of each buffer solution is controlled or assessed, then the apparent value can be corrected to a thermod)mamic value, using an activity coefficient from one of the Debye-Hiickel equations (Section 2.2.5). If the solubility-pH dependence is measured in several buffer systems, each with a different ionic strength, then the Guggenheim approach can be used to correct the result to zero ionic strength [Eq. (17)]. 

The most common methods used for pharmaceutical pK values are based on pH measurements, Eqs. (3-8). Thus, they cannot be interpreted with greater accuracy than 0.02 pKa unit [see the definition in Section 2.1, Eq. (1)]. This level of precision and accmacy should always be the aim in determining pK values for inclusion in the drug sciences literature. Potentiometric titrations [Eqs. (3-4)] are often performed with this level of accmacy, primarily for compounds with either a single ionization step or for multiple ionizations with >4 log units between the pKa values. The careful use of precise pH meters (e.g., the series of Beckman Research models, or the corresponding Radiometer, Orion, or Metrohm instruments) for the determination of pH data means that reproducibility for replicate measurements may be rather better than 0.02. In the author s experience, these instruments may be calibrated with a reproducibility of 0.002 pH imit, which can be maintained (with proper temperature control and exclusion of CO2) for at least 8 h. This does not imply accuracy of 0.002 pH unit, which is not possible according to the current definition of pH. Spectrophotometric [Eq. (5)] and solubility-pH dependence [Eqs. (7-8)] methods are potentially capable of similar accuracy, but often do not give results better than 0.05 pKa unit, due to the inevitable inclusion of additional sources of error from the absorbance or concentration measurements. 

For the solubility-pH dependence method [Eqs. (7-8)], other factors controlling accuracy (apart from the pH measurement) include (a) the completeness... 

NB Solubility-pH dependence in Britton-Robinson buffer solutions was used to estimate the pK value, after equilibration, filtration and appropriate dilution with O.OIN NaOH, followed by UV absorption measurements ( wnax not specified). Partition-pH dependence measurements were between ether and Britton-Robinson buffers in the pH range 2.4 10.4. The substantially different values from each type of measurement (see also no. 592) deserves further investigation. 

NB This paper gave a detailed discussion of the solubility-pH dependence equation. Values for the correlation coefficient (r = 0.99 to 1.00) indicated very good fit of ttie experimental data to ttie solubility-pH equation for a single ionizing group. 

Chang ZL, Verapamil, APDS, 17, 643-674 (1988). NB No reference given. Extrapolated from MeOH-water mixtures. Solubility-pH data (Yunker M and Woodward S, Abbott Labs, personal communication) with the standard solubility-pH dependence equation gave a pJC value of 9.06 0.27. 

Sirius , autotitration equipment, 11,18 Sodium tetraborate (borax) solutions, 16 Solubility-pH dependence method, 10-15, 18-19,22... 

In addition to sulfonic acid groups, carboxylic acid groups as ring substituents results in self-doping of polyaniline and influence properties such as solubility, pH dependent redox activity, conductivity, thermal stability, etc. Sulfonated polyanilines are typically obtained by postpolymerization modifications such as electrophilic and nucleophilic substitution reactions. However, carboxylic-acid-functionalized polyanilines are typically synthesized directly by chemical and electrochemical polymerization of monomer in the form of homopolymer or copolymer with aniline. In contrast to sulfonated polyaniline, very few monomers are available for the synthesis of carboxyl acid functionalized polyaniline. Anthranilic acid (2-aminobenzoic acid) is an important monomer and is often used for the synthesis of carboxyl acid functionalized polyanilines. 

Table 11.1 shows that co-crystal solubility is governed by at least two parameters, Kgp and and one variable, solution pH. In most cases values are known and Kgp can be calculated from experimentally measured co-crystal solubility at one pH. Alternatively, one can target solubility and pH values and calculate the required and K p. Most frequently, several co-crystals of a given drug are discovered for which the solubility is not known. One can calculate the solubility-pH dependence from the and Ksp values and streamhne the co-crystal selection process. 

Another important parameter that may affect a precipitate s solubility is the pH of the solution in which the precipitate forms. For example, hydroxide precipitates, such as Fe(OH)3, are more soluble at lower pH levels at which the concentration of OH is small. The effect of pH on solubility is not limited to hydroxide precipitates, but also affects precipitates containing basic or acidic ions. The solubility of Ca3(P04)2 is pH-dependent because phosphate is a weak base. The following four reactions, therefore, govern the solubility of Ca3(P04)2. 

Two general methods are used for homogeneous precipitation. If the precipitate s solubility is pH-dependent, then the analyte and precipitant can be mixed under conditions in which precipitation does not occur. The pH is then raised or lowered as needed by chemically generating OH or H3O+. For example, the hydrolysis of urea can be used as a source of OH . 

The lanthanides form many compounds with organic ligands. Some of these compounds ate water-soluble, others oil-soluble. Water-soluble compounds have been used extensively for rare-earth separation by ion exchange (qv), for example, complexes form with citric acid, ethylenediaminetetraacetic acid (EDTA), and hydroxyethylethylenediaminetriacetic acid (HEEDTA) (see Chelating agents). The complex formation is pH-dependent. Oil-soluble compounds ate used extensively in the industrial separation of rate earths by tiquid—tiquid extraction. The preferred extractants ate catboxyhc acids, otganophosphoms acids and esters, and tetraaLkylammonium salts. 

Nloha.tes, Niobic acid is amphoteric and can act as an acid radical in several series of compounds, which are referred to as niobates. Niobic acid is soluble in solutions of the hydroxides of alkaH metals to form niobates. Fusion of the anhydrous pentoxide with alkaH metal hydroxides or carbonates also yields niobates. Most niobates are insoluble in water with the exception of those alkaH metal niobates having a base-to-acid ratio greater than one. The most weU-known water-soluble niobates are the 4 3 ad the 7 6 salts (base acid), having empirical formulas MgNb O c, (aq) and M24Nb2202y (aq), respectively. The hexaniobate is hydrolyzed in aqueous solution according to the pH-dependent reversible equiHbria (130), when the pH is ca 9. 

For both coordinated and congruent control, the pH depends upon the phosphate concentration and the sodium to phosphate ratio. Generally, however, phosphates are unsuitable for use at boiler pressures above 100 bar as their low solubility and high concentration factors developed lead to corrosive conditions. 

Extraction and partial purification of photoprotein. The solubility and general luminescence characteristics of the S. luminosa photoprotein are similar to those reported for the S. oualaniensis photoprotein the protein is soluble in buffer solutions containing 0.6-1.0 M salt but not in solutions containing 0.1-0.2 M salt, and the luminescence is pH-dependent. In the extraction of S. oualaniensis,... 

Before leaving the subject of polarity and in relation to uptake and distribution, mention should be made of weak acids and bases. The complicating factor here is that they exist in solution in different forms, the balance between which is dependent on pH. The different forms have different polarities, and thus different values. In other words, the values measured are pH-dependent. Take, for example, the plant growth regulator herbicide 2,4-D. This is often formulated as the sodium or potassium salt, which has high water solubility. When dissolved in water, however, the following equilibrium is established ... 

Solutions of polyelectrolytes contain polyions and the free (individual) counterions. The dissociation of a polyacid or its salt yields polyanions, and that of a polybase or its salt yields polycations, in addition to the simple counterions. The polyampholytes are amphoteric their dissociation yields polyions that have anionic and cationic functions in the same ion and often are called zwitterions (as in the case of amino acids having HjN and COO groups in the same molecule). Such an amphoter will behave as a base toward a stronger acid and as an acid toward a stronger base its solution properties (particularly its effective charge) will be pH dependent, and an isoelectric point (pH value) exists where anionic and cationic dissociation is balanced so that the polyion s charges add up to zero net charge (and solubility is minimal). 

Zwitterionic character is notable in several therapeutic area series, e.g. in angiotensin-converhng enzyme inhibitors, quinolone anhbacterials and thrombin inhibitors. The aqueous solubiUty measurement of zwitterions is very pH dependent as might be expected. The relationship of aqueous solubiUty to ionization state is extraordinarily complex if the zwitterion is of the type capable of an equi-Ubrium between true zwitterion and formally neutral forms (e.g. as in a quinolone antibacterial). For these types of complex equilibria, salt effects on solubility may be unexpectedly large, e.g. solubility unexpectedly may track with the chaotropic character of the salt... 

S. O. Prediction of pH-dependent aqueous solubility of druglike molecules. J. Chem. Inf. Model. 2006, 46, 2601-2609. 

Many synthetic water-soluble polymers are easily analyzed by GPC. These include polyacrylamide,130 sodium poly(styrenesulfonate),131 and poly (2-vinyl pyridine).132 An important issue in aqueous GPC of synthetic polymers is the effect of solvent conditions on hydrodynamic volume and therefore retention. Ion inclusion and ion exclusion effects may also be important. In one interesting case, samples of polyacrylamide in which the amide side chain was partially hydrolyzed to generate a random copolymer of acrylic acid and acrylamide exhibited pH-dependent GPC fractionation.130 At a pH so low that the side chain would be expected to be protonated, hydrolyzed samples eluted later than untreated samples, perhaps suggesting intramolecular hydrogen bonding. At neutral pH, the hydrolyzed samples eluted earlier than untreated samples, an effect that was ascribed to enlargement... 

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