The terms digestion and trituration seem to be used interchangeably by many chemists. In my KiloMentor articles, I consider digestion to be hot trituration.
Trituration
Pure hydrocarbons are used frequently for trituration because in the cold they dissolve much less of most products compared to more polar organic solvents yet they can substantially reduce impurities that are present in small amounts. Thus digestion with hydrocarbon solvents can be used for initial purification of a crude mixture, so long as it is not an oil. If it is an oil, trituration may still succeed so long as enough hydrocarbon triturant is used so that any liquid impurity is only a small portion of the liquid phase.
A rule of thumb might be to triturate mixtures of high molecular weight compounds and distill or co-distill low molecular weight ones before trying to crystallize either one.
The purity of solvents used in crystallization is important because solvent impurities, even other solvents, can retard the rates of both crystal nucleation and crystal growth just like other higher molecular weight reaction impurities can. Because solvent changes on scale are done by solvent exchange rather than by evaporation to dryness and replacement with the new solvent, on scale the residue of the first solvent can be more substantial than one would experience in the laboratory.
Besides the physical property difference between homologous alcohol solvents: methanol, ethanol, propanol, etc., process chemists might be wise to keep in mind that only ethanol has denaturants added to make the ethanol unsuitable for beverages. These denaturants are different for different grades and can interfere with the crystallization kinetics.
Water is the most omnipresent impurity in crystallizations, so much so that in many cases efforts to work free of it are doomed to failure. Poly-hydroxyl compounds such as sugars and glycosides are the common materials most dramatically affected by the presence of water. To illustratw, sucrose of 72% purity has been shown to crystallize twice as fast as a 70% pure sample but only one-fifteenth as fast as the pure sugar. [A. R. Nees and E.H. Hungerford, Ind. Eng. Chem., 28, 893 (1936)].
Water frequently forms a solvate with a compound of interest and this can be helpful, or not, depending upon the properties sought.
Digestion
Digestion is hot trituration with the minimum amount of a poor solvent required to cover a crude solid and make it stirrable. Digestion as a purification method at scale requires some means to obtain an initial crude solid without evaporation to dryness. Digestion is typically done by refluxing the liquid making up the slurry in order to equilibrate the impurities with the solvent.
In addition to water and saturated hydrocarbon as liquids likely to dissolve only a small amount of the main product in a trituration or digestion, the following azeotropic mixtures, which are either hydrocarbon or water-rich, are suggested. None have been tested.
97.0% water 3.0% acetic acid azeotrope bp 76.6 C
91.0% water 9.0% Benzyl alcohol azeotrope bp 99.9ºC
87.1%heptane 12.9% water azeotrope bp 79.2 ºC
94.4%hexane 5.6% water azeotrope bp 61.6ºC
95.5% hexane 4.5% allyl alcohol azeotrope bp 65.5ºC
97% hexane 3% 1-butanol azeotrope bp 67.0ºC
91.5% Cyclohexane 8.5% water azeotrope bp 69.8ºC
83.7% acetonitrile 16.3% water azeotrope bp 76.5 C
72.9% Allyl alcohol 27.1% water azeotrope bp 88.2ºC
66% Allyl cyanide 34% water azeotrope bp 89.4ºC
77.5% Formic acid 22.5% water azeotrope bp 107.1ºC
Digestion from an Inert Support
KiloMentor has already written about direct isolation on a solid support.
An idea that synthetic organic chemists have apparently not considered up until now is the evaporation of a reaction mixture onto an inert solid material from which byproducts can be digested away using poor solvents followed by dissolving the main product with a good solvent and filtering away from the inert solid support material. One possible reason for this is that synthetic chemists are not familiar with the properties of pharmaceutically acceptable supports that could be used as the inert material for such evaporations.
The inert solids can be pharmaceutically acceptable tablet excipients such as microcrystalline cellulose, crospovidone, cross-linked polystyrene, calcium sulfate, calcium carbonate, calcium phosphate. They could be heated and stirred to just above the temperature of the solvent in which the reaction mixture is dissolved and the solution of the reaction mixture added to it.
The solvent would be expected to flash distill out of the reactor and could be collected for destruction or reuse. The method would have a particular advantage in that it could be used for recovering dipolar aprotic solvents which are more difficult to remove.
Similar things have been done. Evaporation of a solution of a reaction mixture onto chromatography media such as silica or alumina has been done to prepare a concentrated band of material that can be spread on the top of a chromatographic column to be eluted with a series of increasingly polar solvents.
Treatment of a solution of a crude reaction mixture with charcoal has often been done to remove small amounts of non-polar high molecular weight impurities. A paper has been published that illustrates the work-up of a chromic acid oxidation by pouring the crude reaction mixture onto a column of cross-linked, unfunctionalized polystyrene and eluting the column with methanol-water mixtures to remove first the inorganic salts and then the organic products. In this process, the solvent of the reaction mixture is simply diluted with the methanol-water eluate.
In the slightly different process, I am contemplating. The reaction mixture would be added to stirred, warm, cross-linked polystyrene so that the reaction solvent evaporates and leaves the crude product in the solid resin. Then the inorganic components would be removed by digestion or trituration with methanol/water mixtures. Thereafter, the organic compounds would be eluted with a less polar solvent mixture.
Since charcoal has been used as an additive to consume excess oxidant, the first step after reaction completion could be treatment with a small amount of charcoal and filtration followed by evaporation onto free flowing non-functionalized cross-linked polystyrene.
If we can obtain the crude solid solvent-free, we can also adopt the other digestion technologies using poor solvents for the principle product.
Evaporation of a reaction mixture onto a solid polymer is one means to evaporate to dryness; something that cannot be done on-scale in a large stirred reactor.
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