kilomentor

Improving the Purity of Product from a Good-Enough Process

kilomentor | 17 January, 2013 19:03

 

Distinctively Different Impurities

In developing a process, optimization may proceed to a outcome satisfactory for a particular purpose by only modifying a few of the possible reaction variables.  Yet, in so doing, the situation may sometimes arise that an unidentified impurity can remain persistently and invariantly at a low but still unacceptable level as a contaminant. This occurs when the variables that worked well for optimizing the overall reaction yield and isolation do not purge the impurity. 

When such an impurity has an unknown structure, it is not easy to construct a hypothesis for its formation and thereby predict conditions that could reduce its occurrence.  The usual approach in this situation is to use very sensitive analytic methods, such as HPLC/MS/MS to try to get some indication of the structure and then advance the purification using this knowledge.  Sometimes, however, the apparent impurity concentration will be exaggerated by the analytical method. This occurs in the situation where the detector is much more sensitivity to the impurity than to the desired product. The impurity can then be present at lower concentrations  than it appears from the analysis. This occurs in HPLC with UV detection for example when the impurity has very much the stronger absorption at the detecting wavelength.  Even though the actual impurity concentration may in fact be low enough to be innocuous for regulation purposes, because the compound is structurally unknown, one cannot prove to regulatory authorities that the impurity is at that low and acceptable level without identifying it.

 

Rather than processing large amounts of product using laborious treatments to obtain a concentrated crude sample of unknown for standard preparative chromatographic separation, Kilomentor has found that a further investigation of the synthetic reaction using statistical design methods to test the influence of some of the previously unchecked reaction variables can often quickly provide a solution to this problem. The solution arises from either of two outcomes. Investigating the new parameters, while holding the previously optimized parameters at their optimized levels, can often produce a condition where the proportion of the impurity in the product is significantly changed. If this leads to new conditions that are still acceptable with respect to yield and that reduce the level of this impurity below the level of concern, then the impurity can be left unknown. This is an easily understand strategy and outcome. It is the second possibility however that makes the investigation more likely to solve the difficulty. In the alternative but less frequently imagined outcome, the investigation of the effect of new parameters leads to conditions that very substantially increase the amount of the unknown impurity. But this also is a useful result! Now using these conditions, useful amounts of the unknown can be much more readily prepared.  These larger amounts are more easily separated, purified, and the substance identified using standard methods. With the structure now available and with parameter(s) that affect the concentration of the substance known, controlling the purity level is well on the way to being solved.

 

As has been mentioned above, the impurity of concern in this scenario is usually much more sensitive than the desired product to the mode of detection. It logically follows that most often such impurity has a structure quite different from the product itself.  Thus the impurity is unlikely to be a diastereoisomer or a geometric isomer of the product.  The more common sources of such quite different impurities is a distinctly different substance that is an impurity in one of the immediate starting materials of the product. A common cause of these impurities is local concentration effects related to stirring inefficiencies  or variations in the ratios of reactants and products during their combination in the synthesis.

 

Distinctively Similar Impurities

Impurities that are very similar in structure to the desired compound are a quite different situation. Most often these arise from other impurities already present in the starting materials; particularly homologs and isomers of the purchased starting substances. These usually have almost the same sensitivity to a detector as the desired product so the estimate of their amount is usually good but they are the most difficult to purge by changing reaction conditions and the most likely to become trapped and to co-crystallize with the product. These impurities are most easily identified and purged by purifying the starting materials that typically are much smaller molecules. Nevertheless, process chemists need to constantly keep in mind that it is a great waste to spend resources performing a purification if the later steps in the process sequence themselves provide means to keep the impurity or the impurities derived by its transformation out of the final product. This automatic purification provided by the processing itself is commonly called purging. It is difficult however to distinguish between an impurity that is remove by subsequent processing and the impurity that is further transformed in parallel and is carried along becoming impossible to detect analytically as it is further transformed.

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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.  

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