Unknown Intransigent Chemical Impurities in Pharmaceuticals: Their Qualities and their Treatments

The Intransigent Impurity

In developing a process, improvement very often only proceeds to an outcome satisfactory from a cost, scale, and safety perspective.  This can be by only modifying a few of the possible reaction variables.  Yet, in so doing, an unidentified impurity remains may remain persistent and invariant at a very low but still unacceptable level as a contaminant. The constancy of physical properties may indicate high purity but analytical methods still show contamination. This occurs when the variables that worked well for improving(optimizing) the overall reaction yield and isolation, cannot purge the impurity. 

With such an impurity having an unknown structure, constructing a hypothesis for its formation is not easy.  Predicting conditions that could reduce its occurrence have no compass.

  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. 

The apparent impurity concentration has been exaggerated by the analytical method. This occurs in HPLC with UV detection, for example, when the impurity has very much stronger absorption than the desired product 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 the unknown to be subjected to 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. 

This solving arises from either of two outcomes. Firstly, investigating the new parameters while holding the previously optimized parameters at their optimized levels, can 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 reduces the level of this impurity below the level of concern, then the impurity can be left unknown. This is the more easily understood useful outcome. 

It is the second possibility, however, that combined with the probability of the first, makes the investigation quite likely to ressolve the difficulty. In this 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. This perhaps surprisingly is also 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.

Distinctively Dissimilar Impurities

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 are a distinctly different substance that is an impurity in one of the immediate precursor 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 display different characteristics. Most often these arise from 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 eliminated by purifying the starting materials. The starting materials are typically much smaller molecules and distillation is often applicable. Also, a different commercial supplier may sell the material minus the impurity of concern, since the impurity is often related to their route of synthesis.

Purging of Impurities

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 overall 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 removed by subsequent processing and the impurity that is further transformed in parallel and is carried along becoming harder and harder to detect analytically as it is further transformed. and becomes part of a larger and larger molecule.