Phase-solubility analysis is the quantitative determination of the purity of a substance through the application of precise solubility measurements. At a given temperature, a definite amount of a pure substance is soluble in a definite quantity of solvent. The resulting solution is saturated with respect to the particular substance, but the solution remains unsaturated with respect to other substances, even though such substances may be closely related in chemical structure and physical properties to the particular substance being tested. Constancy of solubility, like constancy of melting temperature or other physical properties, indicates that a material is pure or is free from foreign admixture except in the unique case in which the percentage composition of the substance under test is in direct ratio to solubilities of the respective components. Conversely, variability of solubility indicates the presence of an impurity or impurities.

Phase-solubility analysis is applicable to all species of compounds that are crystalline solids and that form stable solutions. It is not readily applicable to compounds that form solid solutions with impurities.

The standard solubility method consists of six distinct steps: (1) mixing, in a series of separate systems, increasing quantities of material with measured, fixed amounts of a solvent; (2) establishment of equilibrium for each system at identical constant temperature and pressure; (3) separation of the solid phase from the solutions; (4) determination of the concentration of the material dissolved in the various solutions; (5) plotting the concentration of the dissolved materials per unit of solvent (y-axis or solution composition) against the weight of material per unit of solvent (x-axis or system composition); and (6) extrapolation and calculation.

Solvents

Apparatus*

Constant-Temperature Bath— Use a constant-temperature bath that is capable of maintaining the temperature within ±0.1 and that is equipped with a horizontal shaft capable of rotating at approximately 25 rpm. The shaft is equipped with clamps to hold the Ampuls. Alternatively, the bath may contain a suitable vibrator, capable of agitating the ampuls at 100 to 120 vibrations per second, and equipped with a shaft and suitable clamps to hold the ampuls.

Ampuls— Use 15-mL ampuls of the type shown in the accompanying illustration. Other containers may be used provided that they are leakproof and otherwise suitable.

Solubility Flasks— Use solubility flasks of the type shown in the accompanying illustration.

Procedure

note—Make all weighings within ±10 µg.

System Composition— Weigh accurately, in g, not less than 7 scrupulously cleaned 15-mL ampuls. Weigh accurately, in g, increasingly larger amounts of the test substance into each of the ampuls. The weight of the test substance is selected so that the first ampul contains slightly less material than will go into solution in 5 mL of the selected solvent, the second ampul contains slightly more material, and each subsequent ampul contains increasingly more material than meets the indicated solubility. Transfer 5.0 mL of the solvent to each of the ampuls, cool in a dry ice–acetone mixture, and seal, using a double-jet air-gas burner and taking care to save all glass. Allow the ampuls and their contents to come to room temperature, and weigh the individual sealed ampuls with the corresponding glass fragments. Calculate the system composition, in mg per g, for each ampul by the formula: in which W2 is the weight of the ampul plus test substance, W1 is the weight of the empty ampul, and W3 is the weight of ampul plus test substance, solvent, and separated glass.

Equilibration— The time required for equilibration varies with the substance, the method of mixing (rotation or vibration), and the temperature. Normally, equilibrium is obtained more rapidly by the vibration method (1 to 7 days) than by the rotational method (7 to 14 days). In order to determine whether equilibration has been effected, 1 ampul, i.e., the next to the last in the series, may be warmed to 40 to produce a supersaturated solution. Equilibration is ensured if the solubility obtained on the supersaturated solution falls in line with the test specimens that approach equilibrium from an undersaturated solution.

Solution Composition— After equilibration, place the ampuls vertically in a rack in the constant-temperature bath, with the necks of the ampuls above the water level, and allow the contents to settle. Open the ampuls, and remove a portion greater than 2 mL from each by means of a pipet equipped with a small pledget of cotton membrane or other suitable filter. Transfer a 2.0-mL aliquot of clear solution from each ampul to a marked, tared solubility flask, and weigh each flask plus its solution to obtain the weight of the solution. Cool the flasks in a dry ice–acetone bath, and then evaporate the solvent in vacuum. Gradually increase the temperature to a temperature consistent with the stability of the compound, and dry the residue to constant weight. Calculate the solution composition, in mg per g, by the formula: in which F3 is the weight of the flask plus residue, F1 is the weight of the solubility flask, and F2 is the weight of the flask plus solution.

Calculation

100 – 100S.

Purification Technique

Topic/Question	Contact	Expert Committee
General Chapter	Horacio N. Pappa, Ph.D. Senior Scientist and Latin American Liaison 1-301-816-8319	(GC05) General Chapters 05

USP32–NF27 Page 687