The Problem of Oiling Out in Chemical Process Development

kilomentor | 09 January, 2013 18:03

It is often called LLPS (liquid-liquid phase separation). This could be good if you are performing a liquid-liquid extraction and are concerned about emulsions. When you are trying to perform a crystallization or recrystallization LLPS is bad news because it is what we practitioners call oiling out. As Kilomentor has often repeated, when devising a process, chemists are really guessing when they try to assess how well and how easily they will be able to purify those solid intermediates they need to recover by crystallization. One of the mantras of the Kilomentor blog is: Choose process schemes that incorporate rugged scaleable phase switches that either improve purity before a final crystallization or enable process step telescoping that avoids entirely some of these crystallizations.
Having the substance you are trying to crystallize oil out is high on the list of those things you don’t want to happen, particularly on large scale, because you are working in a vessel with a stirrer that does not scrape the walls and where you can’t easily follow what is happening. Because oiling out occurs down inside a poorly illuminated reactor, in the situation where that oil eventually solidifies, you may never learn what happened. All that may be evident is that the purification failed and the impurities are not uniformly distributed in the product.
Even in the most rugged reaction sequences successful crystallization of solid intermediates will be important and reducing the likelihood of oiling out in crystallizations of low melting solids will be needed to avoid a major dislocation.
Only one article ever accepted by the Journal of Organic Process Research & Development contained ‘oiling out’ in its title [ Jie Lu et al. Org. Process Res. & Dev. 2012, 16, 442-446]. Only three pages in Niel Anderson’s, Practical Process Research & Development, First Edition pertain to oiling out problems in crystallization (Sorry – I can’t afford to pay for both First and Second Editions).
In the one example treated at pg. 280, Anderson cites the case of a pharmaceutical product isolation where oiling out is avoided by adjusting processing to make sure that plenty of seeds are available. The drug captopril was crystallized by first forming a thick seeding suspension of some previously isolated captopril solid , acetic acid, and sodium chloride all together in water and then followed by adding slowly and simultaneously (i) the strongly basic hydrolyzate obtained by first treating S-acetyl captopril methyl ester with 3.3 equivalents of sodium hydroxide and (ii) aqueous HCl the latter in such amount that the crystallizer contents always remained acidic. By forming the captopril in situ in the presence, throughout the entire nucleation, of many preformed captopril crystallites, oil was not formed even though there was a high concentration of sodium chloride in the water.
The oiling out phenomena has been categorized by two parameters. The first parameter is temperature. As far as the first classification is concerned, oiling out near or above the solute’s melting point should not be surprising at all. Separation of solid should not be expected if the solution saturation is exceeded at a temperature where that substrate should be a liquid. The solution is too concentrated for work at that temperature. There is oiling out that occurs near and above the melting point of the main solute and there is oiling out that occurs below that melting point.
The second parameter pertains to the solvents. There is oiling out from a single solvent or from a solvent combination. It seems to me that oiling out from a single solvent below the anticipated melting point of the substrate most often arises simply because the rate of phase separation is faster than the rate of nucleation. The antidotes should be one or both slower cooling and seeding. Oiling out from a solvent combination appears more frequently and is more obvious in explanation. The emerging solute causes different solvents to demix and phases separate. This situation would be most common when the solvent mixture is composed of solvents of quite different polarities; for example ethanol-hexane.
Another scenario could arise when the main impurities begin to separate before the desired product and they contaminate the emerging product enough to reduce its melting point below the solution temperature. This is likely to arise when trying to purify a main substance with more polar impurities by crystallizing from a strongly apolar solvent or purifying a main substance with predominantly less polar impurities from a strongly polar solvent.
It would seem to me that this is the situation in the Jie Lu et al. example cited earlier. Idebenone http://en.wikipedia.org/wiki/Idebenone comprises a dialkyl-dimethoxyl-p-quinone with a primary hydroxyl in the side chain. The two impurities of concern in the Liu paper each have one or the other of the methoxyls demethylated to a phenolic hydroxyl. Thus these impurities are distinctly more polar than idebenone itself yet the idebenone is being recrystallized from methylene chloride-hexane, a rather non-polar medium. From my own experience working with idebenone, I know that it can be recrystallized in high yield from ethanol-water and this would most likely be a preferred method for getting rid of these phenolic impurities without any risk of oiling out.