Mixed-solvent recrystallisation

If a compound is known to crystallise conveniently from a particular solvent mixture (e.g. 50% aqueous ethanol), then this solvent mixture can be employed, in exactly the same way as a single solvent would be. The main problem that can arise is that the two solvents will likely boil at different temperatures, hence heating a mixture of the solvents to near boiling point will usually cause one solvent to evaporate faster than the other, hence the mixed solvent composition will gradually change, with consequences for the solubility of the compounds. There are notes on developing a solvent ratio mixture below.

Solvent/Antisolvent recrystallisation

The solvent/antisolvent approach is more common. In this technique, the “solvent” (i.e. the solvent which readily dissolves the compound) is used first. The compound is dissolved in the minimum volume of hot solvent. The “antisolvent” (i.e. the solvent which doesn’t dissolve the compound) is then added, carefully, dropwise. This has the effect of reducing the solubility of the compound in the hot solvent mixture. The antisolvent is added until the solution begins to appear turbid (i.e. cloudy), which indicates that the compound is starting to come out of solution. Whilst this solution could be allowed to cool at this point, better crystals are usually acheived by redissolving the material at this point, so that crystallisation (rather than precipitation) fully occurs. There are two ways to acheive this:

• The solution can be reheated to dissolve. The antisolvent is usually added cold which has the effect of slighly cooling the solution. Heating the solution up results in the turbidity dissapearing and the solution becomes saturated again. For solutions which require large amounts of antisolvents, this approach is unsuitable as the solution will cool too much and warmed antisolvent should be used.

• A few drops of solvent are then added until the solution regains its clarity; at this stage, the solution is saturated, so it can be set aside to cool and crystallise.

Since this technique involves adding solvents to other hot solvents, it is important to be aware of the associated hazards, and consider the boiling points of the solvents. For example, if diethyl ether and acetone are used as a solvent pair, addition of diethyl ether to a hot acetone solution would cause the ether to immediately boil and vaporise.

Developing a solvent ratio for recrystallisation

Solvent/antisolvent recrystallisations are often the stepping-stone to determining a ratio mixture for recrystallisation. If a recrystallisation is going to be carried out a number of times it is worth investing the time to develop a ratio mixture as this is often easier to carry out and is more reproducible than a solvent/antisolvent approach. Usually, the solvent/antisolvent pair are determined as described above and then different ratios of the solvent/antisolvent are tested to find the optimal ratio. Increasing the amount of antisolvent should result in requiring a larger volume of solvent to dissolve the compound and vice-vesa. Aim for a solvent ratio that requires sufficient volume of solvent to be required that allows high quality crystals to grow and can be collected easily, but without generating large quantities of waste solvent.