White Paper on Solubility: Importance, Measurement & Applications

The solubility of a compound in organic solvents or water is equally important for screen design and later for process development. For designing a screen, for instance around cooling crystallization, you need to select solvents that have sufficient solubility and that have a high dependency of solubility on temperature. In addition, a selection of solvents and mixtures that spans the range of possible chemical functionalities will maximize the chances of finding new, interesting and developable solid forms. This white paper covers two dynamic methods for effective and reproducible solubility data generation: the temperature variation (TV) and solvent addition (SA) methods. These methods can be easily applied by making use of the turbidity probes integrated in the Crystal16 and particle viewer cameras of the Crystalline.

The TV method is the most suitable method for determining the temperature dependent solubility line of a compound in a solvent. Upon heating a suspension of known composition, the temperature at which all crystals are dissolved marks a point on the solubility line. After a recrystallization step through cooling, the measurement can be repeated. An additional benefit of these cyclic measurements is that during the cooling stage the temperature at which the first crystals reappear can be recorded as the cloud point. The collection of cloud points give the metastable zone width (MSZW), which is used to determine the operation range of the process and indicates the tendency towards primary nucleation.

When solubility data is required at constant temperature, which is often the case in multicomponent mixtures, SA is the method of choice. Additionally, the method is very useful for systems in which the solubility is not strongly dependent on temperature or where the MSZ is wide. However, the MSZW is not measured in this method. In the solvent addition method, the temperature is kept constant. Upon dilution of a suspension of known composition by the addition of solvent, a clear point is detected when the equilibrium concentration is reached.

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 For further information please check our publications database for the white paper  document or the Crystal16 & Crystalline leaflets. Additionally, you may contact Technobis  Crystallization Systems on +31 72 3020040 or info@crystallizationsystems.com.