Making a Good Recrystallization Process Step Better

Recrystallization can efficiently purify organic solids.  The weakness of the method for devising optimal synthetic processes is that a good recrystallization cannot be predicted based on molecular structures of starting materials, co-products, by-products, and product to the same extent one can predict, for example, the results of acid-base extractions or methyl alcohol/heptane solvent partitioning.

It is for this reason that in synthesis planning for chemical process development Kilomentor gives preference to intermediates that are acids, bases, or salts.

Nevertheless, many process intermediates will be compounds that offer no practical alternative to purification by recrystallization and so it is useful to consider simple ways to increase the recovery from recrystallization steps. 

Recrystallization separates impurities in two ways during the operation. Typically, the solid is first dissolved in the minimum amount of a hot solvent.  The temperature for dissolution is most often the boiling point of that solvent, although for high boiling solvents a lower temperature, such as steam bath temperature, may be used.  These temperatures are convenient because there is no problem holding a solution at these points.  The hot solution is then filtered to remove insoluble substances. This filtration is the first phase separation from extraneous insoluble solids. Very often this purification opportunity is not properly recognized because a good solvent usually dissolves essentially everything when warmed or, in instances where it does not, some kind of filter aid is added, obscuring the presence of insolubles.  Then, in the second stage, the clear solution (i) may be cooled to a lower temperature (ii) is mixed with an anti-solvent to reduce its solubility or (iii) is treated in both ways together. Thereafter, a crystalline solid phase appears, is separated by filtration, and the impurities are retained in the mother liquors.

In the most frequently used techniques, recrystallization is conducted from a single solvent or a mixture of two solvents by dissolving the solid hot, filtering hot and then cooling to recover a crop of crystals.

When more of the recrystallizing solvent mixture is needed to completely dissolve the crude solid prior to filtering than is needed to effectively hold impurities in solution after cooling, good product is likely being lost using this simple process.

The following simple test can easily show whether a part of the product is being unnecessarily lost in any particular recrystallization situation. Instead of recrystallizing the solid in a single charge, divide it into two equal homogeneous portions. Recrystallize the first portion as usual with the only difference that if the crystals are washed on the filter, keep the wash liquid separate from the regular filtrate. Dry, and weigh this first portion. Now recrystallized the second portion of crude using as solvent only the mother liquors from the first portion. Again dry and weigh the product and analyze both for purity.

If  the recovery from the second portion is greater than from the first at the same time as the purity profiles of the two portions are not significantly different, changing your processing methodology will save you product.

At scale, recrystallization in two portions rather than one will save product but double processing costs.  The same result, however, can usually be obtained by dissolving and filtering the entire crude amount in a single charge and then reducing the volume by half before cooling and recovering the solid.  When the two conditions are met, the two-stage laboratory experiment provides the proof that you only need half the solvent to efficiently dissolve away the impurities. The second half of the solvent was more than anything else just dissolving away your product.

Note that in order to practice this method without problems the hot solution of crude solid must be stable to any extended boiling during the concentration stage.  Of course, if there is a stability problem, the concentrating can be done under reduced pressure to lower the heat requirement.

To proceed further with the same thought, one should first place the crude solid into a poor solvent such that not the entire mass dissolves.  It is important however that this solvent is more volatile than the good solvent in which one is planning to recrystallized as above. Filtering the mixture partially dissolved in this poorer solvent will remove some material as sludge on the filter. Adding the good solvent and heating to boiling will remove this poorer solvent because it is more volatile. After hot filtering, the last traces of this poorer solvent will be removed when the volume is boiled down to one half.