For simplification in the operation of the plant, chemical engineers prefer a standard cleaning protocol no matter what process step has preceded it. This is often possible but for it to be workable without exception is wishful thinking. A standard protocol cannot take into account different substrates, different products, different processing conditions, different materials of construction, and the variety of different pieces of equipment in the reaction/isolation/purification train.
Because chemical engineers cannot as easily detect strongly adhering contamination in the larger equipment, they often learn about a problem far along in the development. The process chemists, in contrast, often working in transparent equipment that they clean themselves can be aware at an early stage when a cleaning difficulty is likely. Furthermore, so long as they know the standard cleaning protocol in the plant they are in a perfect position to know that it is likely to be seriously challenging.
Discovering an optimized reactor cleaning protocol can be regarded as unsophisticated stuff but it makes nonsense of our efforts to improve throughput with optimal processing conditions if, in fact, the reactor cleaning takes an order of magnitude more time to perform than the entire process! It very often can be easier and cheaper to improve throughput by reducing cleaning time by improving the cleaning protocol.
Reactor cleaning in API production is the most obvious situation where the process chemist can alert the engineers. It is in the reaction zone where highly insoluble, often polymeric, often baked or charred materials can become attached to the equipment. It is such impurities that provide the greatest challenge to cleaning methods because they cannot usually be treated by the physical abrasion of scrubbing. If an impurity can transfer either in solution or as a particulate downstream into the isolation/purification equipment that ability to migrate suggests an upper limit to the cleaning difficulty. Since it could be moved down the equipment chain it should be able to be moved out of the equipment entirely!
Neil G. Anderson in his monograph, Practical Process Research & Development, says nothing about reactor cleaning other than providing a reference to the article by I.I. Valvis, W.L. Champion Jr. “Cleaning and Decontamination of Potent Compounds in the Pharmaceutical Industry.”
Org. Process Res. Dev. 1999, 3, 44. This latter article pertains to cleaning the residues from final products of known activity rather than unknown mixtures of compounds of unknown but probably low activity. Although the gunk that is tenaciously retained in the reactor zone is physically intractable it is likely not bioavailable.
The process chemist can do laboratory experiments in a fashion that will be more likely to show up such a gunking problem at an early stage. These difficult contaminants are often created when the reactor contents splash onto the vessel walls above the surface covered by solvent. This occurs in the plant because the entire wall of the reactor is heated not just up to the level of the reaction solvent. If in the laboratory the reaction flask is only lowered into the oil bath up to the solvent line, there will be no corresponding surface for this gunking to occur on and it might not be observed. To mimic more closely the process reactor both portions of the flask below and above the solvent line need to be heated.
When at the end of the reaction period the reaction vessel is visibly contaminated to an extent where hot reaction solvent will not make it visually clean, a scale-up problem is possible and potential solutions need to be considered in advance.
At the very least the process chemist should record and retain information about what was tried and what seemed useful in removing the visible impurities. It would also be useful to know at what point the impurities became apparent, whether they were deposited above the solvent level, below it, or in both places. Sometimes the gunk is more concentrated near the point of addition of some reagent or it may accumulate on the stirring paddle or the stirring shaft to a greater extent.
The chemist may be able to make some useful guesses about the mechanism for producing the impurities and whether, for example, the impurities derive from a co-product (which will not be reduced in the optimization) or from a byproduct that could be reduced by optimizing. Since very often these dark-colored, low solubility substances are polymeric, consideration might be given to how a radical chain inhibitor might change things.
Polymers can also often be reduced by technologies that create an environment of high dilution for one or more of the reactants.
Definitions
Full cleaning is the more thorough cleaning protocol used when a different process step or a different product is going to be produced next in the reactor being cleaned. This is also referred to as decommissioning cleaning.
Partial cleaning is the less thorough cleaning protocol that is applied when the same process step is to be repeated next in the equipment. Some residual detectable contaminants are acceptable since they are the same as will be produced by the repetition of the step.
Boil outs, rinses, and swabs are three different methods for obtaining a sample to analyze to determine the extent of the cleaning.
A boil out is performed by refluxing a solvent in a closed reaction system in order to clean its interior surfaces and provide a sample of the residues in solution. The cleaning effectiveness of a boil out is a function of dissolution, mixing shear, and vapor extraction all resulting in an exponential dilution cleaning profile.
A rinse sample is performed using spraying or misting nozzles to send solvent where boil out would typically be impossible as for example in piping or portable equipment.
A swab sample is obtained by wiping a surface with solvent-moistened cotton gauze and it is used to grossly quantify the presence or absence of a contaminant.
Since boil outs result in exponential dilution profiles, equal results from two consecutive boil outs are sufficient to validate cleanliness.
The most common solvent to use in boil outs is methanol. Because it is miscible with water it does not form two phases even if the reactor is a bit wet. Although it is a good cleaning solvent for drugs since to be bioavailable they must have some solubility in water and hence likely some in polar organics, it is not necessarily good for process intermediates that may be very hydrophobic.
Acetamide is a solid at normal pressure mp 81℃ but it is liquid under reduced pressures: bp760 222℃; bp100 158℃; bp40 136℃; bp20 120℃ ; bp10 105℃ ; or bp5 92℃ . According to the Merck Index, 1 gram of acetamide dissolves in 0.4 ml of water, 2 ml of alcohol, or 6 ml of pyridine. It is also soluble in chloroform, glycerol, and hot benzene. Merck reports molten acetamide is reported to be an excellent solvent for many organic and inorganic compounds. It has been reported to be the most universal of all solvents. The high temperature required for melting and vaporizing the material will increase the dissolution. Under vacuum, the conditions for a boil-out are obtained in the reactor. Molten acetamide or condensing acetamide vapor can be expected to dissolve both organic and inorganic compounds.
Another idea for removing gunk would be to reflux the azeotropic mixture of diisobutylketone (isovalerone) and water. The minimum azeotrope boils at 97.0 C. When the azeotropic composition condenses it splits into two immiscible phases: 53.4% relative volume of >99% diisobutylketone and 46.6% of >99% water. Thus it is possible to boil out with a constant boiling mixture that applies a pure organic liquid of low surface tension to all the equipment surfaces.
Alternatively, using the azeotropic composition of the diisobutylketone reduction product, 2,6-dimethyl-4-heptanol and water (29.6% alcohol and 70.4% water) a constant boiling azeotrope can be boiled out in the system that upon condensation returns to immiscible alcohol and water phases.
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