Solubility turbidity method

The earliest chemical methods developed for the assay of polyacrylamide were based on turbidimetric methods in which the polymeric material was reacted with a reagent to form a barely soluble turbid compound. A method based on the reaction of hydrolysed polyacrylamide with a quaternary ammonium cation was proposed by Michaels and Morelos (1955). This method was later modified by Grummet and Hummel (1963), and it has been applied and automated for determining polyacrylamides and other anionic... 

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. 

Very recently a new method was developed that opens the possibility to polymerize even hydrophobic monomers in aqueous solution. This method is based on the finding that hydrophobic monomers can be made water-soluble by incorporation in the cavities of cyclodextrins. It has to be mentioned that no covalent bonds are formed by the interaction of the cyclodextrin host and the water-insoluble guest molecule. Obviously only hydrogen bonds or hydrophobic interactions are responsible for the spontaneous formation and the stability of these host-guest complexes. X-ray diffraction pattern support this hypothesis. Radical polymerization then occurs via these host-guest complexes using water-soluble initiators. Only after a few percent conversion the homogeneous solution becomes turbid and the polymer precipitates. 

Similar dependencies on concentration are observed for the osmotic pressure or the electrical conductance of the solution. If we look at the optical turbidity of the solution the trend is opposite. At low concentration the solution is transparent. When the concentration reaches the CMC many solutions become opaque. In parallel, a property, which is of great practical relevance, changes the capacity to solubilize another hydrophobic substance. At concentrations below the CMC of the surfactant, hydrophobic substances are poorly dissolved. At the CMC they start being soluble in aqueous solution. This capability increases with increasing surfactant concentration. There may be small systematic differences in the concentration at which the specific property abruptly changes and the CMC determined by different methods may be different. However, the general trend and the dependency on external parameters such as temperature or salt concentration is always the same. 

The methods that do not contain steps to ensure the establishment of equilibrium can be considered nonequilibrium methods. In the past few years, several methods commonly used for solubility measurements in the early discovery setting have been reported (Curatolo, 1996 Lipinski et al., 1997 Pan et al., 2001). These methods typically begin with dimethylsulfoxide (DMSO) solutions or with amorphous material. Turbidity and ultraviolet detection are commonly used because they easily can be designed into high-throughput instrumentation. 

The expression of results in analytical chemistry is mostly in SI units (all base units except the candela and many derived units). The principles to be followed to achieve the comparability and traceability of measurements to the SI have been clearly stated [1,2]. However, certain types of measurements are expressed in conventional units. Turbidity evaluation in water quality analysis, determination of soluble content of fruit and vegetable products by the refractometric method, measurement of caking power of hard coal by the Roga test, determination of the octane number of fuel and seric protein analysis are some examples. 

PURPOSE AND RATIONALE In vitro testing of drug candidates and combinatorial chemistry lead to an increase of lipophilic compounds with poor solubility (Lipinsky). Poor solubility itself may lead to poor oral availability of a potential drug. The growing demand for solubility data in lead phase of drug discovery is answered by a variety of simple solubility assays, which allow the classification of a compound without real quantification (see previous section). One of the easiest way to detect saturation in a solvent is the turbidity of the solution if precipitation occurs. The turbidity caused by precipitation of a poorly soluble compound can be detected by a couple of detection methods (Van de Hulst, Hongve). Lipinsky describes the first methodology, which use UV as detection method and is able to screen hundreds of compounds a day with one instrument. 

Conductometric titration — A -> titration method in which the electrical conductivity of a solution is measured as a function of the volume of -> titrant added. The method is based on replacing an ionic species of the - analyte with another species, corresponding to the titrant or the product of significantly different conductance. Thus, a - linear titration curve is plotted to obtain the - end point. This method can be used for deeply colored or turbid solutions. It does not require knowing the actual specific conductance of the solution, and only few data points far from the end point are necessary. This is to avoid effects such as hydrolysis or appreciable solubility of the reaction product that give rise to curvature in the vicinity of the end point [i]. 

Volumetric Methods.—Nickel may be conveniently estimated volu-metrically in the absence of cobalt, copper, silver, gold, and the platinum metals by means of potassium cyanide.4 The solution containing the nickel is, if acid, neutralised with ammonia and some ammonium sulphate is added to render the indicator more sensitive. A little ammonia is now added, and a few drops of potassium iodide and silver nitrate. The solution becomes turbid in consequence of the precipitation of silver iodide. The liquid is now titrated with potassium cyanide solution until the turbidity just disappears. The reaction consists in converting the nickel salt into the double cyanide, Ni(CN)a.2KCN, after which any excess of potassium cyanide attacks the silver iodide, yielding the soluble double cyanide, AgCN.KCN. The disappearance of the turbidity therefore indicates the complete conversion of the nickel salt. A slight correction is necessary for the silver introduced. 

Solubility in Alcohol Determine as directed under Solubility in Alcohol, Appendix VI. One milliliter of sample dissolves in 1 mL of 90% alcohol, often with turbidity, and remains in solution on further addition of alcohol to a total of 10 mL. Specific Gravity Determine by any reliable method (see General Provisions). 

Solubility in Alcohol Proceed as directed in the general method, Appendix VI. One mL dissolves in 4 mL of 95% ethanol, sometimes with slight turbidity. The age of the oil has an adverse effect upon solubility. 

Cold Stability of Refined Sunflower Oil Sunflower oil waxes are fatty alcohol esters of fatty acids. Their melting point is around 75°C, and their solubility in the oil is low, leading to the appearance of turbidity in the refined oil with decreasing temperature. An oil s cold stability is usually assessed by means of the cold test (method AOCS Cc 7-25). Oils passing the cold test will remain clear—without the appearance of turbidity—after 5.5 hours permanence at 0°C. The solubility of waxes in sunflower oil is shown in Figure 21 as a function of... 

A simple turbidimetric method for the determination of the solubility of acids and bases in buffers of different pH can be used. Solutions of the hydrochloride (or other salt) of a basic dmg, or the soluble salt of an acidic compound, are prepared in water over a range of concentrations. Portions of each solution are added to buffers of known pH and the turbidity of the solutions is determined in the visible region. Typical results are shown in Fig. 5.4. Below the solubility limit there is no... 

The phase diagrams were prepared at room temperature by the usual method, where a weighed aliquot of the surfactant/ cosurfactant mixture (E) was diluted with known amounts of water (W) and then titrated with oil (0) to turbid and clear endpoints. Alternatively, the dilution of E could be made with oil and titration with the water. Generally, fifteen to thirty titrations were sufficient to roughly outline the phase maps. Solubility limits were also determined by titration of the solvent with the solute (or solute solution) to a cloudy endpoint. 

Diphenylurea has a solubility of 5.5 mg in 100 cm 3 of saturated aniline solution [1560], and for improved accuracy in phosgene determinations it is recommended that phosgene is passed into the aniline solution until a small amount of precipitate is formed. This is then filtered off, and the clear filtrate (now saturated with diphenylurea) is subsequently used for the phosgene determination [1560]. Although traces of phosgene can be readily detected by the appearance of slight turbidity in diphenylurea-saturated aniline solutions, the filtration and weighing of sueh precipitates is impractical, and the method is not as accurate as the iodine titration method (Section 3.2.1.2) [1560]. 

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