Solubility measurements

The solubilities of the various gases in [BMIM][PFg] suggests that this IL should be an excellent candidate for a wide variety of industrially important gas separations. There is also the possibility of performing higher-temperature gas separations, thanks to the high thermal stability of the ILs. For supported liquid membranes this would require the use of ceramic or metallic membranes rather than polymeric ones. Both water vapor and CO2 should be removed easily from natural gas since the ratios of Henry s law constants at 25 °C are -9950 and 32, respectively. It should be possible to scrub CO2 from stack gases composed of N2 and O2. Since we know of no measurements of H2S, SO, or NO solubility in [BMIM][PFg], we do not loiow if it would be possible to remove these contaminants as well. Nonetheless, there appears to be ample opportunity for use of ILs for gas separations on the basis of the widely varying gas solubilities measured thus far. 

Infrared, X-ray diffraction, DTA, TG, electrical conductivity and solubility measurements have been used to investigate the mechanisms of tribochemical reactions between solids [385,386],... 

Solubility measurements and complex formation in solution. L. Johansson, Coord. Chem. Rev.,... 

The complexation of Pu(IV) with carbonate ions is investigated by solubility measurements of 238Pu02 in neutral to alkaline solutions containing sodium carbonate and bicarbonate. The total concentration of carbonate ions and pH are varied at the constant ionic strength (I = 1.0), in which the initial pH values are adjusted by altering the ratio of carbonate to bicarbonate ions. The oxidation state of dissolved species in equilibrium solutions are determined by absorption spectrophotometry and differential pulse polarography. The most stable oxidation state of Pu in carbonate solutions is found to be Pu(IV), which is present as hydroxocarbonate or carbonate species. The formation constants of these complexes are calculated on the basis of solubility data which are determined to be a function of two variable parameters the carbonate concentration and pH. The hydrolysis reactions of Pu(IV) in the present experimental system assessed by using the literature data are taken into account for calculation of the carbonate complexation. 

The study of carbonate complexes of Pu is complicated by various experimental difficulties. The low solubility of many carbonates (7), leaving a very dilute Pu concentration in solution, results in difficulties to the experiments with electrochemical or spectrophotometric methods. However, the radiometric method with solvent extraction or solubility measurement is easily applicable for the purpose. Unlike the solution with anions, like Cl, N03 etc., the concentration of which can be varied at a constant pH, the preparation of solutions with varying carbonate concentration accompanies indispensably the change of pH of the solution. As a result, the formation of carbonate complexes involves accordingly the hydrolysis reactions of Pu ions in solutions under investigation. It is therefore prerequisite to know the stability constants of Pu(IV) hydroxides prior to the study of its carbonate complexation. 

The present study is conducted under consideration of thus mentioned difficulties. The solubility measurement is applied to the present investigation, selecting the pH range 6 v 12 in which the carbonate concentration can be maintained greater than 5xl0 6 M/l. The carbonate concentration and pH of experimental solutions, both being mutually dependent in a given solution, are taken into account as two variable parameters in the present experiment and hence the final evaluation of formation constants is based on three dimensional functions. For calculation purpose, the hydrolysis constants of Pu(IV) are taken from the literature (18). In order to differentiate the influence of hydrolysis reactions on the carbonate complexation so far as possible, the calculation is based on the solubilities from solutions of carbonate concentration > 10-1 M/l and pH > 8. 

The postulation of the +4 oxidation state of cobalt is necessary to account for the retarding influence of Pb(II). The existence of a dimeric species of Co(II) acetate is required by the rate law and is confirmed by spectrophotometric and solubility measurements. The existence of ionic species of the reactants is inferred by the rate increase on addition of sodium acetate, an observation which cannot be attributed to a salt effect because sodium perchlorate produces a rate decrease. On this scheme an explanation of the effect of water on the stoichiometry is that the step... 

A relative scale of the standard Gibbs energies of ion transfer or the standard ion transfer potentials can be established based on partition and solubility measurements. The partition eqnilibrium of the electrolyte can be characterized by a measnrable parameter, the partition coefficient P x-... 

The evaluation of the apparent ionization constants (i) can indicate in partition experiments the extent to which a charged form of the drug partitions into the octanol or liposome bilayer domains, (ii) can indicate in solubility measurements, the presence of aggregates in saturated solutions and whether the aggregates are ionized or neutral and the extent to which salts of dmgs form, and (iii) can indicate in permeability measurements, whether the aqueous boundary layer adjacent to the membrane barrier, Umits the transport of drugs across artificial phospholipid membranes [parallel artificial membrane permeation assay (PAMPA)] or across monolayers of cultured cells [Caco-2, Madin-Darby canine kidney (MDCK), etc.]. 

There are other soUd states which sometimes confuse the measurement and definition of solubiUty. The dmg may crystaUize as a hydrate, i.e. under inclusion of water molecules. If the hydrate form is more stable than the pure form it may be difficult to measure the intrinsic solubility of the drug at all. Often drugs tend to precipitate in an amorphous form, often under the inclusion of impurities. As with metastable polymorphs, such amorphous precipitates may lead to erroneously high solubility measurements. CommerciaUy, drugs are often crystallized in salt form, e.g. as the hydrochloride salt, a cation with a chloride anion. In these co-crystallized salts, a much lower solubility than the intrinsic solubility will typi-... 

Delaney [4,14] and Klamt [16] argued that for drug-like compound datasets only about 20% of the variance of log S arises from AG s. This is further confirmed by the study of Wassvik et al. [15] in which 77% of the variance is due to the solubility of the supercooled liquid. Hence, applying crude estimates by mean values or by QSAR approaches we can reasonably expect that the inaccuracies introduced in dmg solubility prediction by our theoretical ignorance of AG s is less than, or at least not much bigger than, the inaccuracies introduced by the estimates of the larger park i.e. the liquid solubility, and by the experimental difficulties in solubility measurement. 

Experimental methods for virtually all types of solubility measurements have critically been evaluated [38]. 

Quite often a compound is rather unstable in aqueous solution. Hence the long exposure to liquid required for traditional solubility measurements will cause decomposition, and the resulting solubility results will be unreliable. In this particular case a method known as Nogami s method may be used. If a solution experiment is carried out as a dissolution experiment with samples taken at equal time intervals, 8, it can be shown [20] that when the amount dissolved at time t + 8 is plotted versus the amount dissolved at time t, a straight... 

Lipinski et al. [12] and Pan et al. [463] compared several commonly used methods of solubility measurement in early discovery, where samples are often introduced as 10 mM DMSO solutions. Turbidity-based and UV plate scanner-based detections systems were found to be useful. The methods most often used in discovery and in preformulation will be briefly summarized below. 

Solubility measurement at a single pH [37-39] under equilibrium conditions is largely a labor-intensive procedure, requiring long equilibration times (12h-7 days). It s a simple procedure. The drug is added to a standard buffer solution (in a flask) until saturation occurs, indicated by undissolved excess dmg. The thermostated saturated solution is shaken as equilibration between the two phases is established. After microfiltration or centrifugation, the concentration of the substance in the supernatant solution is then determined using HPLC, usually with UV detection. If a solubility-pH profile is required, then the measurement needs to be performed in parallel in several different pH buffers. 

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 concept of the A shift in HTS solubility measurements is quite exciting. It means that DMSO can be used in solubility measurements and the measured values later corrected to DMSO-free conditions. So we can have speed and accuracy at the same time The pharmaceutical industry needs speed and accuracy, and will need these more in the future. In silico methods are no better than the data used to train them. 

Semiquantitative schemes, like the maximum absorbable dose (MAD) system described by Curatolo [53], can be made more predictive by applying solubilities measured by clinically-relevant protocols and PAMPA permeabilities. 

The BCS scheme can be made more useful by incorporating a further improved basis of physicochemical profiling. For example, the role of pH in permeability measurements could be better defined. The use of simulated intestinal fluids for solubility measurements could be better promoted. The effects of fed/fasted states on absorption could be better address, in methods that have optimum clinical relevance. 

When determining the solubility and dissolution rate of amorphous or partially crystalline solids, the metastability of these phases with respect to the highly crystalline solid must be considered. While the low diffusivity of the molecules in the solid state can kinetically stabilize these metastable forms, contact with the solution, for example during measurements of solubility and dissolution rate, or with the vapor, if the solid has an appreciable vapor pressure, may provide a mechanism for mass transfer and crystallization. Less crystalline material dissolves or sublimes whereas more crystalline material crystallizes out. The equilibrium solubility measured will therefore approach that of the highly crystalline solid. The initial dissolution rate of the metastable form tends to reflect its higher... 

Three methods were used in this research to measure the extent of binding of organic pollutants to dissolved humic materials. They were equilibrium dialysis, solubility measurements and changes in sorption behavior in the presence of humic materials. Other authors have used solubility measurements, ultrafiltration and volatilization measurements. The methods will be described in the following paragraphs. 

High-throughput solubility measurements have been developed which can be used in early discovery [9, 20-22]. 

This chapter is not simply a treatise on the highest capacity methods for measuring aqueous solubility in a discovery setting that most closely approximate a lower capacity thermodynamic solubility measurement. Rather it is the author s viewpoint that dealing with the problem of poor drug solubility in an early discovery setting requires an appreciation of recent changes in three related but distinct areas. The areas to be considered are ... 

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