Common Ways to Reduce Solubility and Drive Crystallization

This is the second blog post in a series dedicated to crystallization.  In case you missed the first in the series, you can find it here: Introduction to Crystallization and Precipitation.

Reduce Solubility and Drive CrystallizationThe starting point for most crystallization processes is a saturated solution. Crystallization is generally achieved by reducing the solubility of the product in this solution by cooling, antisolvent addition, evaporation* or some combination of these methods. Another common method used to drive crystallization is via a chemical reaction where two or more reactants are mixed to form a solid product insoluble in the reaction mixture; a common example of this would be the reaction of an acid and a base to form a salt.

The method chosen can vary depending on a number of factors. For example, protein crystals are temperature-sensitive ruling out cooling and evaporation and leaving antisolvent addition as the most common crystallization method. For many crystallization processes, cooling can be advantageous as it is reversible; the saturated solution can be reheated in the event of a non-optimal outcome. For the desalination of seawater (essentially the crystallization of salt!) in hot climates, it makes sense to take advantage of the power of the sun to drive an evaporation crystallization process.

Saturated Solution and Solubility:
At a given temperature, there is a maximum quantity of solute that can be dissolved in a given solvent. At this point, the solution is saturated. The quantity of solute dissolved per unit of solvent at this point is the solubility.

Units: Solubility is usually reported as

  • g of solute/100 g of solvent
  • g of solute/L of solution
  • mole fraction
  • mole %

The plots below, commonly known as a solubility curve, neatly illustrate the solvent and temperature dependence of solubility for a given material. By plotting temperature vs. solubility, scientists begin to develop the framework needed to develop the desired crystallization process. In the example below, the solubility of the given material in Solvent A is high – meaning more material can be crystallized per unit volume of solvent. Solvent C has a low solubility at all temperatures, indicating it could be a useful antisolvent for this material. Solubility curves also reveal the theoretical yield for a given crystallization process. Below, if a saturated solution containing 50g of product per 100g of solvent is cooled from 60°C to 10°C then 10g of product per 100g of solvent will remain in solution. In other words, exactly 40g of product per 100g of solvent will crystallize. This allows crystallization scientists and engineers to compare the theoretical yield with the actual yield and define the efficiency of the crystallization process.

reduce solubility & drive crystallization

Many techniques can be used to measure solubility curves and recent research aimed at predicting solubility in different solvents is showing promise. The references below offer a good starting point for a more in depth study of the topic:

Gravimetric Analysis:

Howard K. Zimmerman, The Experimental Determination of Solubilities, Jr. Chem. Rev., 1952, 51 (1), pp 25–65

Granberg and Rasmusson, Solubility of Paracetamol in Pure Solvents, J. Chem. Eng. Data, 1999, 44 (6), pp 1391–139

Dynamic Methods:

P. Barrett and B. Glennon, “Characterizing the Metastable Zone Sidth and Solubility Curve Using Lasentec FBRM and PVM,” Trans ICHemE, vol. 80, 2002, pp. 799-805.

Innovative Approach:

M. Barrett, M. McNamara, H. Hao, P. Barrett, and B. Glennon, “Supersaturation tracking for the development, optimization and control of crystallization processes,” Chemical Engineering Research and Design, vol. 88, Aug. 2010, pp. 1108-1119.

*It should be noted that crystallization via evaporation usually occurs as a result of removing solvent, not by reducing solubility. Depending on the system, with the solvent removal and change in solution composition during the crystallization, the boiling point can increase and solubility can increase as well. Only in the case where antisolvent gets selectively distilled out, solubility is reduced; but such case is rare in practice.

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