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.

Chemical terms compound | solution | substance | yield

Comments

Re: Improving the Purity of Product from a Good-Enough Process

Christian | 20/02/2013, 20:32

"unidentified impurity can remain persistently and invariantly" that reminds me of how Pedersen discovered the crown ethers. For me as a scientist, the only acceptable solution would be isolation, purification and identification of this impurity.

Isolation diffculties

marto | 14/03/2013, 00:20

Dear Kilomentor,

I am trying to isolate CF3COAr (80% w/w assay) derivative compound from the ArBr (10% w/w and Piperidine COCF3 derivative (10% w/w) mixture . CF3COAr derivative is low melting solid (mp ~ 52 °C) and I dont have the distillation data of the same. I just would like to know whether bisulfite adduct isolation can be attempted on 25 kg scale or which method you would suggest. Small scale preparation involves isolation by precipitation (~ 50 % receovery) in cylcohexane at lower temp (- 20 °C).
Please suggest me if you have any experince

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