Drying of Process Intermediates

In performing a single step process, the product is typically dried to constant weight because for a final product you want a uniform consistent material that will have reproducible physical properties every time it is made.

Process intermediates do not automatically need to be consistently dried. Process intermediates are dried because measuring the dry weight of the isolated product is a way to get the percentage yield. It is not necessary to dry the entire amount of the intermediate to get a yield so long as a representative sampling can be taken. Similarly, to measure purity only a representative sample needs to be dried. The problem is being sure that your sampling is representative. The process chemist needs to be able to calculate what the weight of a completely dried intermediate would be so the quantities of reagents and solvents for the subsequent step can be calculated. Because achieving representative sampling is so uncertain, drying to constant weight is most often followed. 

Solvent drying is also necessary when the next process step requires a different solvent; particularly when the previous step's solvent would interfere.

Drying an intermediate to negligible further weight loss is not a simple task working with kilograms of material. Because drying is very often required after isolation from every step, if one is working different steps of a process in parallel, drying capacity can easily be exceeded. It is, therefore, important to do whatever one can to increase the rate of drying. This will reduce the overall time to complete a run for a particular intermediate and increase the rate at which a campaign can proceed. Not recognizing the capacity limitations of the plant's drying ovens is a serious shortcoming with process chemists.

When the filtrate from which crystals are removed is inconveniently high boiling, there can be advantages to washing with a lower boiling anti-solvent before moving it to a drier because this can substantially reduce the drying time. It is important, however, to retain at least one wash with the same solvent mixture as the filtrate before any further wash with low boiling anti-solvent, because, otherwise, you can precipitate impurities caught in the droplets of the original filtrate that are still coating the wet cake. 

Drying proceeds both on the filter and in the drying oven. A longer period sitting with air being sucked through a solid cake on the filter will reduce the time required in the drying oven.

     The length of time required for drying is a function of (i) the volatility of the liquid being evaporated, (ii) the temperature of the incoming gas, and (iii) the degree of vacuum in the dryer. Water is among the most difficult solvents to remove.

     Small crystals occlude more solvent than larger ones, but small crystals trap comparatively fewer chemical impurities in their lattices. Therefore, there is a trade-off in deciding whenever there is a choice of crystal size. Digestion of organic precipitates can change the crystal habit by dissolving smaller particles and growing the larger ones. 

Tray drying is very irregular. To get a reasonable estimate of the residual solvent, portions of a sample for weight-loss testing must be taken from different locations among the several trays and combined. When tray drying a thick layer of a lower melting solid, it can partially melt in the tray, even though no problem is evident with smaller quantities in a thinner layer. One test for possible melting is to pack a wet solid into a glass test tube and place it, without stoppering in the same oven to dry. This will simulate a thicker layer.

      When convection air drying is being used a higher inlet air temperature can substantially reduce the drying time.  The inlet temperature can be higher at the beginning of drying because the chemical substance is protected by cooling from the more rapid solvent evaporation. That is, the actual temperature inside the solid mass is lower than the inlet air temperature.

     In the laboratory, the drying oven is very large compared to the amount of material to be dried so there is the possibility of underestimating the drying time required. On the other hand, in the laboratory, solids are most often put into the dryer in the late afternoon and left until the next morning. This may substantially overestimate the required drying time.  Long drying times or limiting oven capacity can profoundly affect throughput and process chemists need to be aware of this! 

Improving Recovery from Crystallization

KiloMentor consistently advocates a preference for scaling-up processes that are designed, as much as possible, to use intermediates that can be protonated or deprotonated at pH levels accessible in water and that, therefore, can utilize 'phase switches' as part of their purification. Such proposed paper syntheses are rugged to the extent that they do not depend for purification on the crystallization of hypothetical intermediates, whose physical properties are unknown when the route is being planned. Despite this bias against neutral isolated intermediates, once the molecular weight of intermediates in a proposed route exceeds what can be practically distilled, crystallization must remain the predominant isolation and purification method for these neutral, unionizable intermediates.

Indeed, crystallization is of such importance that it is taught at the early undergraduate stage in what still remains of laboratory training in universities. The disadvantage is that such early treatment is elementary and actual scientists who will work in the lab during their careers never seem to get around to more sophisticated discussions of it, but learn what more they can through experience - both good and bad.

Quite a bit of what I offer here is taken from a manual that soon will become an authentic antique: Laboratory Technique in Organic Chemistry, Avery Adrian Morton, McGraw-Hill Book Company, Inc. 1938! 

Trying to crystallize without first applying other methods of purification is a common error. Because the deleterious effect of impurities upon the rate and completeness of crystal formation is so great, crystallization of crude products should never be attempted until other methods of purification have been applied. Although immediate crystallization will usually reduce impurities dependably when crystals do form, the extent of crystallization achieved in a reasonable time is almost always far less than it would be with a purer starting sample. 

Thus it is wise to triturate high molecular weight compounds and distill or co-distill low molecular weight ones before trying to crystallize them.

Consideration should be given to first distilling in vacuo; co-distilling with another solvent (triethanolamine, quinoline, kerosene, glymes, fatty acids ); steam distillation with or without the presence of salt; superheated vacuum steam distillation; exhaustive digestion with a poor solvent or a hydrotrope; trituration with a poor solvent; extraction in a Soxhlet apparatus; passage through a plug of a solid adsorbent; or acid/base extraction. The last of these has utility even when the desired compound is neutral because the extraction can remove acidic or basic impurities. Other applicable methods are treatment with insoluble polymeric derivatizing reagents to trap identified or guessed impurities, or partitioning between two immiscible organic solutions. If the compound is a Lewis base, a cocrystal with another compound such as bis-N,N’-(3-nitrophenyl)urea may be possible. Specific KiloMentor blog articles treat many of these methods and these may be found using the blog's search tool.   

The influence of heat on solute solubility is marked. At higher temperatures, differences in the solubility of a substrate between different solvents are leveled. A purified hydrocarbon fraction is often as good a solvent when hot as, say, nitrobenzene. The only advantage of nitrobenzene in such a situation might be that it could hold back impurities from solidifying when the solvent is cooled while the hydrocarbon would often hold back little.

Besides impurities derived from reaction procedures, more thought needs to be given to the purity of the solvents used in crystallizations themselves because solvent impurities, such as other solvent residues, can retard the rate of crystal nucleation and crystal growth just like other higher molecular weight reaction impurities can. Because solvent changes at scale are done by solvent exchange rather than by evaporation to dryness and replacement with the new solvent, the residue from the reaction solvent at scale can be higher than in the laboratory.

Besides the physical property difference between homologous alcohol solvents: methanol, ethanol, propanol, etc. process chemists need to be heedful that only ethanol has denaturants added to make the ethanol unsuitable as a beverage. These denaturants are different for different grades of alcohol and can change 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.  Polyhydroxy compounds such as sugars and glycosides are common materials affected dramatically by the presence of water in the crystallization environment. For example, 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 when it crystallizes and this can be helpful, or not, depending upon the properties sought.

Digestion

Digestion is hot trituration with just 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 to equilibrate the impurities with the solvent solubility.

In addition to water and saturated hydrocarbon solvents, liquids unlikely to dissolve  a large amount of the main product can be applied in trituration. The following constant boiling azeotropic mixtures which are either hydrocarbon or water-rich might serve:

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

A concept that synthetic organic chemists have not given sufficient consideration to 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 excipients that could be used as the inert material for such evaporations. Inert solids such as microcrystalline cellulose, crospovidone, cross-linked polystyrene, calcium sulfate, calcium carbonate, calcium phosphate, etc. 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 onto 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 difficult to remove.
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. Trapping of an intermediate on a polymeric support for isolation has been examined by Frans Muller and Brian Whitlock, An Alternative Method to Isolate Pharmaceutical Intermediates, Organic Process Res. & Dev., 2011, 75, 84-90.

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 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 principal product.

Advantages Filtering Solids at Scale

Crystallization in the laboratory is rarely performed under an inert atmosphere. Most commonly, crystal filtration is done in the open air on a Buchner filter followed by washing with ice-cold wash liquid and then partially dried by sucking air through the filter cake using water-aspirator vacuum.

Because lab filtrations are most commonly conducted in this fashion, the final crystallization temperature and the temperature of the wash liquid are rarely taken below zero degrees Centigrade. If lower temperatures could be used, recoveries could be higher but this would cause moisture from the air to contaminate the solvents used and/or to condense on the porcelain or glass filter funnel.  Furthermore, if the Buchner filter is not sufficiently cold, it becomes more difficult to draw off the mother liquors and the wash solvent without partially redissolving the filtrand. Thus, laboratory filtration in the air has upper and lower temperature bounds. This limitation does not exist at-scale. In the plant, both the solution and the solid crystalline cake are always inerted and since water vapor can't get into the reactor to condense, the clarified solution can be cooled to -20 C to force out more crystals. In the same way, wash liquid to wash the material on the filter is conveniently cooled to a sub-zero temperature while excluding moisture throughout.

Black's Rule [F.L. Muller, M. Fielding and S.N. Black, Org. Process Res. Dev. 2009, 13, 1315-13231] states that solubility doubles every 20 C°. Sometimes struggles to find a suitable solvent system for recrystallization that depends upon the difference in solubility between two different temperatures can be replaced with a low-temperature recrystallization from hexane, pentane, or other hydrocarbon liquid. The larger temperature ranges between these liquids' boiling points and -20°C diminishes the need for a dramatic difference in solubility between some refluxing hot solvent and that same solvent at 0°C. 

However, special laboratory equipment for the laboratory is necessary to explore such an approach. Roger Giese described such an apparatus and its mode of use in the Journal of Chemical Education, 45, 610 (1968). Step-by-step instruction is provided. The apparatus is sufficiently simple that it can be put together by modifying a chromatography column that has a fritted glass disc as the plug. Because it operates with its own jury-rigged cold bath made from a plastic bottle, it does not need to fit in a Dewar for cooling, unlike the apparatus described by C. Frank Shaw, III and A. L. Alfred in Journal of Chemical Education, 47, 165 (1970).

Using Giese's apparatus it would be interesting to see what kind of improvements in yield and purity could be achieved in important crystallizations.

Swishing and Swish TLC: The Most Important Analytical Paper Ever for Chemical Process Development

In KiloMentor’s assessment, the most important analytical paper in the literature in terms of usefulness to process development chemists is almost unknown.  George B. Smith and George V. Downing wrote a note called Phase Solubility Analysis as the Basis of a Separation Method [Anal. Chem. 51(13) 2290-2293 (1979).]

In this article, the authors describe a polishing purification technique for essentially pure chemical solids used at Merck Sharpe & Dohme laboratories informally called “swishing.” 

The technique is not readily applicable to small samples. Swishing is actually an exhaustive equilibrium trituration.

Swish purification of several grams or several hundred grams of material is accomplished by overnight equilibration in a suitable liquid (an anti-solvent or very poor solvent), with magnetic stirring on a small scale or with mechanical agitation in a Morton flask for large quantities. This is followed by filtering, separating, and retaining the filtrate. 

Separating the trituration liquid from the residual solid results in a highly purified solid phase on the one hand and a solution in which many minor impurities are dramatically concentrated on the other.  It is the enriched impurities in the filtrate that are of particular interest here. When thin-layer chromatography (TLC) is used to see the pattern and intensities of the impurities, the combined method is called Swish TLC. 

If the solid mixture of impurities and main compound from one swishing is now subjected to a second swish purification, the impurities may be even further concentrated, often sufficient to provide samples of one or more impurities, which are often of previously undetermined structure. The technique is a powerful resource to identify and characterize minor impurities, for a Drug Master File, for example. Very often swish TLC can reveal impurities that are otherwise below the limit of detection of the standard analytical method. 

Swish TLC is also a forensic method by which patterns of impurities 'fingerprint' a particular process used to manufacture a substance.

Swish purification and swish TLC could usefully be studied using constant boiling azeotropic mixtures which are predominantly either water or hydrocarbons but contain small amounts of other solvents which would provide a useful boost to the overall solvency.

It strikes me, although I can find no experimental implementations, that using a blender to macerate the solid in the antisolvent might make the technique more efficient. 

Byproducts, Side-products, and Co-products.

A co-product is defined in the KiloMentor Blog as follows; A co-product is a product created according to the stoichiometry of a balanced chemical equation representing a chemical transformation when it is not the material of interest.
 It is created in a defined ratio with respect to the material of interest and is an unavoidable result of that chemical reaction.

William Watson writing online has tried calling a material satisfying this definition a ‘byproduct’. The KiloMentor does not think this is a wise choice of terminology because 'byproduct' already has a contradicting meaning in common parlance. Byproduct according to one dictionary definition is “a secondary or incidental product, as in a process of manufacture” When we look up ‘incidental’ we find it defined as “1. happening or likely to happen in fortuitous or subordinate conjunction with something else. 2. Likely to happen or naturally appertaining (usually followed by to). 3. Incurred casually and in addition to the regular or main amount.”

Thus, in the common usage of ‘byproducts’ there is the implication that these can be prevented from occurring in some instances and the product retained. In contradiction, in Watson’s chemical usage, chemicals created in reactions, which he would call byproducts, are inevitable, since they are dictated by the particular stoichiometry. In my alternative, the word co-product contains this idea of inevitable relationship or complementarity. ‘Co’ is a prefix meaning complement of. The complement completes something; in this case, product and co-products complete the right-hand side of the chemical equation.

‘By the bye’ means incidentally. Incidental products or side products,  KiloMentor can accept these to identify products that are not dictated by the equation that represents the pertinent reaction creating the product. For further clarity in their identification, side products are substances that, at least in principle, can be reduced or eliminated by optimizing the reaction conditions.


Thus, in the common usage of ‘byproducts’ there is the implication that these can be prevented from occurring in some instances and the product retained. In contradiction, in Watson’s chemical usage, chemicals created in reactions, which he would call byproducts, are inevitable, since they are dictated by the particular stoichiometry. In my alternative, the word co-product contains this idea of inevitable relationship or complementarity. ‘Co’ is a prefix meaning complement of. The complement completes something; in this case, product and co-products complete the right-hand side of the chemical equation.
‘By the bye’ means incidentally. Incidental products or side products,  KiloMentor can accept these to identify products that are not dictated by the equation that represents the pertinent reaction creating the product. For further clarity in their identification, side products are substances that, at least in principle, can be reduced or eliminated by optimizing the reaction conditions.

Separation as the Focus of Chemical Process Development

KiloMentor | revised 6th  January 2009 republished February 17/2017

This is a revision of one of the earliest articles from the KiloMentor archives. The original was written in 2007.  It restates for new readers the core idea of the KiloMentor process development philosophy and teaches an approach that KiloMentor thinks leads consistently to valuable ideas. for improving process throughput.

In synthesis, we talk about assembling, building, or constructing a molecular structure. This is a misleading metaphor because we are comparing an activity in the nano-world to an activity in the macro-world. Operating in the macroscopic world, for example in building a house, we handle the pieces, we position the pieces, and we join the pieces.

In chemical synthesis, we do none of these. The substructures we are endeavoring to unite are atomic in scale: too small to touch, to align, or even to see.

In chemical synthesis, the chemist adjusts macroscopic conditions: solvent ratios, stoichiometry, stirring, temperature, duration of exposure, etc. Then the chemist presents the proposed reaction partners, to each other under the orchestrated conditions and they interact, as their nature dictates; but, hopefully, this is also as we have planned.  How is this perspective different from the conventional one?  Chemical process development is simply making these parameter choices that cause nature’s choice to comply with what we want the outcome to be, efficient. Nature to be commanded must be obeyed.

According to the academic synthetic chemistry tradition, synthetic accomplishments are scored based on the number of synthetic steps, the yield per step, and the overall yield for the combination of steps. High yields are good. A short sequence is good. The combination is elegant. According to this traditional perspective, the focus is on the reactants, the plan for reactant transformation, and the overall yield output from that plan. Separation of unreacted starting materials, by-products, co-products, catalysts, solvents, salts, and other excipients and processing chemicals are in the background (the attitude is that work-up/purification can be done and will be done BUT these are not important criteria to evaluate the quality of the synthesis).  The give-away phrase of those who harbor this philosophy is “the product was isolated in the usual way.”

From the KiloMentor perspective, in this age of online substructure searching, coming up with creative transformations with strong literature analogies is no longer the domain of the synthetic genius but has come within the scope of good synthetic chemists. We do not have to depend upon our neuronal computers alone anymore. Now it is creative ideas for separation and purification that are not easy to search for and have become the greater artist skill of the project. The deconstruction of the chemical soup and the fishing out of the desired product in an adequate state of purity is paramount.

Is there any particular value in this way of looking at processes that surpasses the traditional way which focuses on the series of chemical reactions while taking the separation of intermediates as an obvious technical work? My perspective emphasizes:

• The work involved in setting up and controlling the necessary reaction conditions.
• The work involved quenching the reaction condition/then working up the reaction and finally isolating and purifying the desired product.

The value in this perspective is that in chemical synthesis, the money, manpower, and resources consumed during the reaction step phase, ie. while A & B are reacting with each other, is minuscule compared to the money, manpower, and resources expended preparing for the reaction and recovering pure product from the reaction.

The clash of these perspectives leads to the question, “Which would I rather do- a four-step synthesis in which every conversion has many parameters that must be rigorously controlled and from which each intermediate must be isolated by gradient column chromatography and evaporated to a foam OR an eight-step synthesis which is rugged and forgiving of process deviations and from which each intermediate can be cleanly extracted in a separatory funnel or crystallized or distilled to give an adequate practical purity intermediate."

People have personal preferences and this is as it should be in a pluralistic society BUT I pick the second sequence and as the need for larger quantities and higher quality intensifies, I increasingly prefer the second route.

Please note- I am not saying the number of chemical steps doesn’t matter. I am not saying that the overall yield does not matter. I am saying that elegance also encompasses simplicity, ruggedness, time economy, and scalability.

OK, so what. How does this insight change our behavior in the synthetic laboratory, office, or library? Based on an examination of what really goes on in a chemical process step a method of rating the difficulties of the separation is proposed as a quantitative tool to rank the challenges of a process scale-up.

We should evaluate or rate synthetic schemes using more criteria:

1. Number of Chemical Steps
2. Isolated overall Yield
3. Yields of the Individual Steps.
4. Difficulty Rating for Each Reaction Mixture Separation

The fourth point comprises the new insight. How could we execute this new difficulty rating? We could classify work-ups:

A. The product can be separated practically pure by simply liquid-liquid extraction (ie acid-base pH or other phase switching)

B. Product can be separated by crystallization of precipitation as a filterable solid.

C. Product can be separated by atmospheric or vacuum distillation based on a projected difference in boiling points (based on molecular weights)

D. Product can be separated based on chemical reactivity (formation of reversible simply separable derivative, or destruction of contaminant by reaction)

E. The product seems likely only to be separable in practical purity by chromatography.

Clearly, as process chemists, we want to face more A-C separations and fewer D-E type separations.

The KiloMentor blog will highlight methods to augment isolations and purifications so chemists can improve their ability to assign these ratings and take them into account when designing synthetic chemical processes that can be readily and ruggedly scaled up into the plant.

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.