Solubles, analysis

Topal, U. et al.. Extraction of lycopene from tomato skin with supercritical carbon dioxide effect of operating conditions and solubility analysis, J. Agric. Food Chem., 54, 5604, 2006. 

Several collaborating laboratories (usually five participating laboratories) test the proposed substance using a variety of techniques. The relative reactivity or relative absorbance of the impurities present in a substance must be checked when a nonspecific assay method is employed, e.g. by colorimetry or ultraviolet spectrophotometry. It is particularly important to quantify the impurities when a selective assay is employed. In such a case, it is best to examine the proposed substance by as many methods as practicable, including, where possible, absolute methods. For acidic and basic substances, titration with alkali or acid is simple but other reactions which are known to be stoichiometric may be used. Phase solubility analysis and differential scanning calorimetry may also be employed in certain cases. 

Phase solubility analysis is a technique to determine the purity of a substance based on a careful study of its solubility behavior [38,39]. The method has its theoretical basis in the phase mle, developed by Gibbs, in which the equilibrium existing in a system is defined by the relation between the number of coexisting phases and components. The equilibrium solubility of a material in a particular solvent, although a function of temperature and pressure, is nevertheless an intrinsic property of that material. Any deviation from the solubility exhibited by a pure sample arises from the presence of impurities and/or crystal defects, and so accurate solubility measurements can be used to deduce the purity of the sample. 

The experimental procedure for conducting phase solubility analysis is rather simple it consists of mixing increasing amounts of sample with a fixed volume of solvent and then determining the mass of sample that has dissolved after each addition. It is not necessary to exceed the solubility limit of the analyte species, but attainment of this condition makes it easier to recognize trend within the plots. An experimental protocol for phase solubility analyses is available [39]. The data are most commonly plotted with the system composition (total mass of sample added per gram solvent) on the x axis, and the solution composition (mass of solute actually dissolved per gram of solvent) on the y axis. 

Schirmer has succinctly summarized the strengths and limitations of phase solubility analysis [40]. The principal advantages are that (1) a reference standard known purity is not required, (2) the number and types of impurities in the sample need not be known, (3) all required solubility information is obtained from the analysis, (4) the technique can be applied to the analysis of any solute that can be dissolved in some solvent, (5) the deduced results are both precise and... 

A basic exposition of Gibbs phase rule is essential for understanding phase solubility analysis, and detailed presentations of theory are available [41,42]. In a system where none of the chemical species interact with each other, the number of independently variable factors (i.e., the number of degrees of freedom, F) in the system is given by... 

Table 4 Phase Solubility Analysis of Fluphenazine Dihydrochloride in Absolute Ethanol...

For phase solubility analysis, acetonitrile appears to be the most suitable solvent. A typical plot is given in figure 13 along with the experimental conditions. 

Figure 13. Phase Solubility Analysis Plot of Bromocriptine Mesilate, dried in High Vacuum for 15 Hours. Solvent dry Acetonitrile, Vibration for 24 hrs. in the Absence of Light. Slope 1.41 0.05 %.

Figure 20 Generation of solvent candidates through ProCAMD based on the solubility analysis with SoluCalc.

The total yield of the crude precipitation obtained in the above manner comprising about 1 kg is then dissolved in chloroform so as to form a 15% solution of a crude penicillin salt. To the filtered chloroform solution is added ethyl acetate slowly and with agitation until the solution becomes turbid as crystallization begins. Thereafter crystallization is allowed to proceed undisturbed for about 30-60 minutes in a cold room having a temperature of about 5°C. Sufficient ethyl acetate is slowly added to provide a final concentration of about 50% ethyl acetate and the mixture is allowed to stand in the cold room for one hour to complete crystallization. The precipitate is filtered and washed with about 750 ml of ethyl acetate and thereafter washed with the same volume of ether. The crystals are dried in vacuo and a yield of about 900 g of N,N -bis-(dehydroabietyl)-ethylenediamine-dipenicillin G is obtained. The penicillin product melts with decomposition at a temperature of 170°C to 172°C on a Kofler hot stage. Solubility analysis of the product shows the product to be 95.3% pure. 

Fig. 13 Solubility of CBZ NCT cocrystal (1 1) and single component crystal of CBZ(III) at 25°C as a function of total NCT concentration in ethanol, 2-propanol, and ethyl acetate. The solid lines represent the predicted solubility, according to Eq. (28) with values for Ksp and Kn in Table 5. Filled symbols are experimental cocrystal solubility values in ( ) ethanol, (a) 2-propanol, and ( ) ethyl acetate. The dashed lines represent the predicted solubility of CBZ(III) based on Kn values calculated from the cocrystal solubility analysis. Table 5. Open symbols are experimental CBZ(III) polymorph solubility values in pure solvent. (Reproduced from Ref. l)...

Fig. 13 Broadening effect of the melting curve of P-hydroxy-propyltheophylUne due to impurities. PSA = phase solubility analysis. All batches have the same TLC purity results. (From Ref. )...

Phase-Solubility Analysis Phase-solubility analysis is the quantitative... 

William J. Mader. Phase Solubility Analysis, Critical Reviews in Analytical Chemistry, 2 193-215, 1970. 

United States Pharmacopoeia Rev. 25 and National Formulary Rev. 20. 2002 General Test (1171) Phase Solubility Analysis, p. 2122. 

Of the impurity/degradant enhancement techniques available, the phase-solubility analysis technique requires minimal sample handling from the... 

USP 24 (1171) Phase-solubility analysis, The United States Pharmacopeia Convention, Inc... 

Grdinic, V., Jaksevac-Miksa, M., Bezjak, A., Radaic, A. and Briski, D. Importance of factors for ruggedness test in phase solubility analysis. Eur. J. Pharm. Sci. 2(4) 293-6, 1994. 

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