Models for Ideal Chemical Processes

Any process has the possibility of continual incremental improvement but practically a point will be reached when it is not worth further effort and one’s time and talents are better expended elsewhere. 

 In process development how does one judge the good and the better?  A good process meets its quality and quantity requirements. The better process does this and goes further. The better process must be rugged. In a rugged process, if human error, mechanical failure, or equipment inadequacy creates some small deviations from the prescribed procedure, the result does not suffer seriously either in quality or quantity.

We judge a process by its costs and these include the labor expended, the time utilized in the special equipment, the price of the starting materials, and the price of waste disposal or recycling. A costing not only provides an indication of the efficiency with which inputs are used but it also provides a running assessment on the specific shortcomings that contribute most to the overall expense. A preliminary costing is an important tool in developing any process because it ranks areas where one might invest whatever limited time one has to achieve improvement.  

Trost has philosophized that the ideal process would be a single step and that there should be no co-product. That is, all the atoms in the reacting substances are retained in the products. Nothing then is thrown away. This is an interesting idea to contemplate.  It dramatically highlights that atom economy, as he calls it. It has the benefit of high weight throughput and low waste disposal but it is far from reality in terms of what can be actually practiced.  Every process is indeed ideally only a single transformation but the problem is starting materials for this ideal process are not commercially available- and because of this, the process creator must move retro-synthetically one step at a time until we do reach such commercial precursors.

Another useful idealized conception of a process is a sequence of chemical steps in which the reaction mixture from each step is simply treated over and over again with the reagents for the next transformation until the material which is the synthetic goal is present in the mixture; then, in one isolation operation, this product is separated pure from the complete complex mixture containing all the by-products and co-products of all the prior steps. This model dramatizes that it is most important to eliminate isolations because it is isolations that usually consume the most time and resources in a process.   In practice, of course, there are very valid reasons for performing isolations before the final isolation.

Valid reasons for isolation are:

1. To remove non-productive mass (ballast)
2. To change solvent for reaction optimization
3. To achieve needed purification through phase shifting
4. To correct stoichiometry and so save reagents
5. To provide convenient stopping points for campaign processing
6. To provide rework opportunities for rugged processing

Advanced Manufacturing Ideas Can Be Applied to Fine Chemicals/ Pharmaceuticals

 

In their August 12th, 2023 issue pg. 63-64, the Economist magazine describes the advanced manufacturing of first, computer chips and then, cordless electric drills. Reading this brief report suggested to KiloMentor possible parallels with future advances in the scale-up for the manufacturing of complex organic chemicals.

The article points out that “chips are designed using software that directly links to the automated hardware which fabricates them.” The efficiencies that this unlocks derive from the consequence that “the constraints of the production line- even fiddly details like the positioning of screws— are encoded in their CAD (computer-aided design) programs.”

Well, how does this have any analog implications for chemical processes for making sophisticated chemicals? We don’t have automated production facilities and we don’t work out the details of process steps in computer programs.

The research laboratory functions as our design tool and the pilot plant functions as our automated fabrication hardware and our problem is too often that our designing is not sufficiently linked to our manufacturing. The problem is how do “even [these] fiddly details”, like the constraints of large-scale production get signalled back to the laboratory before valuable time is wasted?

In advanced manufacturing, these constraints are wired into computer-aided design programs. For our projects, there are two possibilities. Either our process design chemists must have these limitations wired into their chemical know-how or the whole company must adopt some form of what has been termed ‘full process vision’. I have written previously about this idea in the blog, Avoiding the Screw-up from Left Field with a Full Process Vision.

Since it is difficult to impossible to find this article I have reprinted it below.

"Some process chemists will find themselves as small cogs in large teams whose goal is to develop new specialty chemicals or pharmaceuticals.  As a scientist whose contribution is to apply highly specialized knowledge, you may be bunkered in a rather isolated trench or silo within your organization. Your mission may be defined for you rather narrowly so your undoing may come from an irrefragable requirement that comes from outside your silo and that is imposed so late in your work plan that it really means starting over.    

A powerful organizing structure for pharmaceutical product development is presented in an article by Pradir K. Basu, Ronald A Mack, and Jonathan M. Vinson, “Consider a New Approach to Pharmaceutical Process Development“ Chem. Eng. Prog., 95(8), 82 (1999).  It seems intended to reduce the likelihood of the above misfortunes.  

Process chemists, as knowledge managers, need to press at an early stage in their work for some mechanism within the wider team so that these must-have ‘requests’ from outside your core group reach you before your work is too far advanced. 

Much of the referenced article presents no more than standard reminders of the importance of cost considerations throughout discovering a synthetic method, scaling it up, and putting it into production for a process to manufacture a new pharmaceutical. This is the pharmaceutical business with the marketing, selling, and regulatory functions stripped away. Its importance to corporate profitability does not engender much debate. The importance of the article is that their concern is broader. 

The authors are concerned about the efficient execution of a plan that starts after identifying a candidate to be a commercial drug with a salutary effect on a biological target and proceeds to the validation of manufacture for that molecule at a commercial scale. 

The enhanced approach that they propose identifies what they call ‘process vision’ as the core organizing principle. The definition and exemplification of the expanded concept of ‘process vision’ is the article’s significant accomplishment. 

The authors help us understand different aspects of this 'process vision' at different points in the article. For me, I cannot say I adequately grasped what they were getting at until I drew particular phrases together from my notes. Some of these quotes, drawn from different parts of the essay are: 

 “The process vision satisfies all essential requirements, including those for safety, quality, waste minimization, cost, time, and operability”. 

“The process vision is neither the process with maximum yield nor the one that gives maximum product purity…..it is neither a chemist’s vision nor an engineer’s vision; it is not even the vision of the chemists and engineers together.” 

“It is a vision that all stakeholders in development, manufacturing, and marketing can share…..” 

Reading between the lines and amplifying certain aspects, the process vision emerged as a policy statement that provided, as a starting point, standards by which team members coming from each stage of the organization's endeavor (laboratory process, kilo lab, pilot plant, and manufacturing facility) could satisfy downstream colleagues’ concerns from the outset of their own work. The authors' specific examples of the unique orientation and emphasis that players at the different stages have and which they want to see addressed from the very outset reinforce my interpretation. 

This early overview, whose importance they emphasize, can be expected to show up inevitable cross purposes and improve the odds for early compromise and conflict resolution. 

They write:

 “Chemists think in terms of steps, reactions, yield, purity, and so on; engineers in terms of unit operations, physical properties, heat load, and the like; manufacturing personnel in terms of throughput, waste control issues, and plant modifications that may be required to run a process; and marketing people in terms of the net present value of the product, how much it can sell for, etc.” 

“It is important ….to get stakeholders to develop….agreed-upon objectives of process development.” 

“communication among….personnel is critical during process development.” 

“We need to…. provid[e] development team members with systems or tools to facilitate communications among different disciplines.”

“Unless the manufacturing team is involved in the process development, they will not have confidence in the scale-up”. 

“…manufacturing and commercial input at this stage [late stage discovery] are essential for choosing the optimum processing route”. 

“Team members need to be involved in setting targets for cost, manufacturability, waste and emission loads, development time….” 

“These alternatives must be evaluated based on….criteria agreed upon by all stakeholders….” 

“If stakeholders are involved in planning experiments, it’s likely that more useful data could be collected from fewer experiments.” 

For me, the management tool the authors recommend for achieving this widely held ‘process vision' is Panglossian. 

The authors propose that even at the experimental program level one should try to bring together a diverse project team including representatives all the way out to marketing, frequently enough to work out priorities and make decisions. This is what they recommend. 

This seems excessively optimistic as regards human nature. Instead, I suggest, one could establish a 'process vision' statement establishing some sort of median or normal starting-point performance criteria that would address recurring diverse concerns of process development, manufacturing, regulatory affairs, and marketing and that would chevvy the most common interests of the downstream project teams on the upstream collaborators. In this implementation, the process vision would be via a statement delivered with full corporate authority that would continuously challenge upstream groups with the standard core concerns of the downstream members. 

The authors illustrate marvelously this challenging interaction throughout their article. What I interpret them to be saying is that the problem is not that different elements of the project team have concerns that inevitably seem to operate at cross purposes; but that the team members can reach solutions that satisfy all parties, so long as the areas of tension are discovered early enough. 

KiloMentor has a strong preference for its alternative. The use of a process vision statement as a proxy for the perspectives and concerns of downstream project groups seems preferable to using large frequent group meetings to actually direct even the collection of particular data. For a company’s drug product projects to be successful and on time, any process’s strategy must not conflict too greatly with the psychological needs and private professional goals of the individual team members. The people downstream in the project, whether they be in late-stage process development, manufacturing, or marketing, simply will not give a project the attention it needs until it arrives at the phase where they are being held singly and personally responsible. They are too busy concentrating their attention on what is on their plate already and extinguishing the fat that is already on fire. This is human nature! Besides, pharmaceutical product projects can go on so long that some participants can realistically expect to no longer be involved when a late-stage discovery project limps into manufacturing or marketing. People may hope or plan to outrun the difficulties. Only unambiguous corporate endorsement can get everyone to give a thought to early-stage projects.

Equally problematically, the upstream professionals, working at a particular phase of the work on their own turf, would require an uncommon personal modestly to accept without rancor face-to-face demands that particular questions be answered on a priority basis. 

A corporate ‘process vision’ statement takes the personalities and egos out. At the same time, the standards proposed by a process vision statement would command authority and yet not be carved in stone. They would exist to bring a persistent awareness of particular concerns. They would bring those different needs, which may be pulling at cross purposes to early attention, and they can be expected to bring the affected team members together as needed to create or negotiate a solution." 

The Half- Addition In-Process Check (IPC)

 Smart laboratory practice can save process development time and make a chemist more valuable to his or her employer. What kind of synthetic organic chemist would be taking a thin-layer chromatography sample when only 1/2 of the reagent has been added into a reaction? As KiloMentor will explain below: a smart one.

The gradual addition of one of the reactants into a reacting system is typical. The purpose is to avoid an exothermic runaway reaction. 

If the analysis of a quenched reaction mixture at the half-addition point shows both significant product along with either a substantial temperature increase inside the reactor or the need for cooling to prevent such an exotherm, then the need for the precaution is proven.

When this is observed, it signals that the processing is likely sensitive to the rate of addition of the reactant being added because a lot of the reacting is occurring under conditions where the reactant being added is depleted in the reactor compared to its stoichiometry as represented in a balanced equation. If the actual average ratio of reactants is different from that specified by the balanced equation for the desired transformation then in some instances a different chemical outcome can arise from a different mode of reacting. This is convoluted to put in words but simple to illustrate.

Suppose one is attempting to execute the transformation

 1.0 A + 1.0 B reacts to form 1.0 A-B 

where the integers identify the number of moles of A, B, and the adduct A-B.  The transformation issuing conducted by adding gradually, drop by drop A into the entire mole of B. The reaction is exothermic and external cooling must be applied to keep the mixture at a safe temperature. As small portions of A mix together with all of B, A—B is quickly formed, in fact so quickly that essentially no A remains in the mixture between aliquots of addition. All that is in the mixture one could conclude is the formed A—B and the remaining B.

The actual average ratio A: B at any point is far from 1:1!

Now suppose that another reaction in solving A—B is possible. Suppose A—B can react with a second molecule of B:

A—B reacts with B to give B—A—B. Then this overall transformation can be represented as

1.0 A reacts with 2.0 B giving 1.0 B—A—B

This is more consistent with what the actual stoichiometry is and is likely promoted by this need for the gradual addition of A.

What we can conclude is that the gradual addition of one reactant to the other may favor side reactions with other stoichiometries more consistent with the actual average ratio of reactant that occurs in the reactor. Substantial formation of product at the 1/2 addition point is a warning that this may be occurring.  

If the gradual addition is to control the heat of mixing or some other preliminary reaction equilibration then it is OK to see no product at this half-addition stage.

If this misfortune is occurring what can be done? In the example we have looked at the gradual addition of B to A is likely to minimize the formation of B—A—B. In other instances, the gradual simultaneous addition of both A and B at the same rate may be examined. This way the actual ratio of A to B is held more closely constant near 1:1 through the reaction time.

But these solutions are made pertinent only after the 1/2 addition IPC has warned the researcher that they may be particularly needed.

The Purpose of Standard Operating Procedures (SOPs) in Chemical Manufacturing

 The Purpose of Standard Operating Procedures (SOPs) in Chemical Manufacturing

Chemists with post-graduate educations including experimental laboratory training are expected to know a variety of safe and effective ways to achieve common chemical goals. As well, they are expected to have document research skills sufficient to find approved methods for unfamiliar operations. They do not need standard operating procedures. In fact standard operating procedures may be fatal to new discoveries.

  Chemical processes are executed by operators, who are trained differently. Operators are most valued because they can follow instructions of a process in a totally reproducible and detailed fashion while watching and reporting anything unusual. Often they may not know the theoretical basis behind the exact operations that they need to perform.

It is desirable to provide every possible means to assist them to do their work methodically so that an operation is performed precisely the same way each time whether it is part of one process or another and no matter which operator is in charge. This is the purpose of Standard Operating Procedures (SOPs) in the manufacturing environment. SOPs can also be written for operations for analyses, for receiving, for shipping, for reporting accidents, for filling out batch sheets etc. SOPs help to achieve faithful and exact repetition of a procedure wherever a specific action is called for. It is not the basis for a decision between alternate actions. What sets an exceptional operator or analyst apart from an ordinary one are two things- detailed exact repetitive execution and the ability to observe small differences in what happens, remember them, and report them.  

Reaction Addition Modes: Controlling Chemical Reaction Stoichiometries

 

  A + B  Gives C + D

Most chemical reactions are either unimolecular or bimolecular in their kinetics. They are either addition/condensations where there is only one product, ie C and no D, or in other instances, some transformation also provides a coproduct, D, created along with C.

Reactions proceed when the energy supplied to a system is appropriate for the free energy of the reaction. More energy being supplied to the system can cause the reaction to proceed faster and/or it can promote alternative transformations that compete with the desired one. Applying excess energy for longer than necessary can degrade any of A, B, C, or D.

If any of the reactions

 C + (A or B) gives (E or H)

or 

A + A gives F  

or

B+ B gives G

can occur, then having the correct stoichiometry present throughout the time when the system experiences the required activation energy becomes important. If the stoichiometry is wrong then starting reactant polymerizations or overreaction modes can compete to the detriment of the desired outcome. A procedure that keeps the reactants in the correct stoichiometry throughout that period when adequate activation energy is supplied is likely to give a cleaner reaction.

Standard Chemical Processing

Now in the standard mixing procedure, a solution either of reactant A or B is added slowly to a solution of the complete charge of B or A already stirring in the reactor. If the reaction proceeds so quickly that it overheats, the addition is slowed or stopped allowing the rate of reaction to slow down as the reactant being added gets consumed and no more is being added. That is, the reaction is prevented from running out of control by letting the stoichiometry inside the reactor change radically. To control an exotherm the operators in such instances are forced to let the concentration of the reactant being added into the vessel fall towards zero.

For greater clarity and to emphasize the necessary safety issue let us perform the thought experiment of mixing all of the charge of these same A and B in methylene chloride and starting to heat the reactor. When the reaction between A and B sets in, the methylene chloride will start to reflux but as the temperature rises towards the boiling point of the methylene chloride the reaction between them goes faster and faster. The methylene chloride now boils faster than it can be condensed and gaseous methylene chloride blows liquid methylene chloride and all the rest of the reactor’s content out of the reactor and probably onto the roof of the plant building!

Identifying Reactions that Could be Affected by Stoichiometry

The standard mixing procedure is unlikely to be adversely affected by the ‘in situ’ stoichiometry if the reaction rates of all steps occurring in the reactor are slow compared to the addition time. This is easily determined. When one-half of the addition of the controlling reactant has been added, an in-process check should be done. If either the product or any reaction intermediates are significant compared with unreacted starting materials then the transformation is likely to be sensitive to the reaction’s stoichiometry. If nothing significant besides unreacted starting materials (or substances produced during the quenching of the reaction before analysis) are present, then it is very unlikely that the yield will be affected by stoichiometry. When hardly any change can be detected in this test it indicates that almost the reacting occurs mainly after the reactant being added is completely in the reactor and the stoichiometry is therefore essentially fixed throughout the actual reacting period.

Importance of the Enthalpy of Reaction Calculation

If you are going to perform experiments in which all the reactants are mixed together at once, you must take appropriate precautions. 

You must do a calculation of the enthalpy of reaction based on standard bond energies; however, the enthalpy of reaction (∆H) is only a crude approximation to the free energy of reaction (∆F) since ∆F = ∆H - T∆S. The change in entropy of the reaction (∆S) also contributes to the reaction’s driving force. For example, if the reaction leads to more moles of products than the moles of reactants, the entropy change is most likely going to be positive and the overall free energy decidedly more negative because of (-T∆S). The reaction will be faster than the approximation.  It will be necessary to absorb the net free energy of reaction through the agency of first- the temperature rise of the reactor contents ( mostly solvent),  then the energy absorbed in vaporizing some part of the reaction solvent, and finally by the energy drained off by the refluxing of a part of the solvent.

Absolute Necessity for Small Scale Trials in a Laboratory Fume Hood

Theory is just theory. If you are going to perform a reaction in which all the reactants are to be mixed together and then reaction initiated (either by heat or catalyst), you must try out the method at a scale where even if you have miscalculated there will be no more than a mess to clean up, not a laboratory disaster! The reaction which you have examined might not even be the reaction that occurs. Something much more energetic could surprise you.

Get Emergency Control Means Ready

Of course, your reaction vessel must be equipped with a means to directly in real-time read the internal temperature. Otherwise, you won’t be alerted soon enough that you have a problem.

If despite your calculations the temperature of the reactor accelerates in an unexpected way you want to be prepared to intervene to slow things down. Having a cold -bath ready into which the reactor flask can be plunged often can tame a reaction that is misbehaving. The advantage of this form of moderation is that it can be removed when the danger passes and the experiment continued.

Some reactions need to be quenched by injection. In many cases that quench material can be as simple as water. Of course, such an experiment is wasted but a runaway condition is avoided. 

When a runaway reaction is the least bit possible, the experimentalist should both wear appropriate personal protective equipment and have a fire extinguisher handy. It is important to prepare by imagining what might happen. For example, are there other chemicals in the hood you will be using that could exacerbate your runaway? 

Well then—can we actually mix reactants A and B together safely so that the correct stoichiometric is maintained at all times and a runaway exotherm is prevented?

 Two Simultaneous but Separate Additions

Simple in concept but mechanically difficult would describe the simultaneous addition to one reactor of two separate solutions, one carrying the A reactant and the other carrying the B reactant. The two addition rates of each need to be controlled so that the same required molar amount of each reactant is delivered throughout the addition time. If unwanted exothermicity occurs in the reactor both reactant streams need to be slowed the same amount or stopped simultaneously. Technically this is a big ask and practically it will only be approximately successful but even if it is only achieved approximately it can provide a closer approximation to constant ideal stoichiometry. This method of reactant addition, even if performed somewhat imperfectly, can give the experimentalist an indication of whether getting better stoichiometry using a different but more practical method is likely to deliver a useful benefit.

Storage Solvent and Reaction Solvent Method

Both reactants can be dissolved together completely in a volatile solvent (storage solvent) at a temperature and concentration at which reaction will not proceed and that solution can be added in a controlled fashion to a higher boiling solvent (reaction solvent) preheated to below its own bp. but above the bp. of the addition solvent so that the storage solvent will flash distill as it is added and the reaction between A and B will occur at the set stoichiometry in the reaction solvent solution.

Flow System Method

A continuous flow system may be possible where the reactants are bled separately but in the proper stoichiometry into a heated reaction zone and the product is continuously removed from the reaction zone. The problem with the flow technique is that for many reactions operating at the lowest normal reaction temperature, the heated zone would be quite long. Such specially configured equipment is not typically available. This can be solved by operating at a higher temperature in a higher boiling solvent treated in the reaction zone near the higher boiling point of this alternative solvent. 

For example, suppose it is known that A will react with B in refluxing dichloromethane and the reaction is essentially complete in three hours. The same reaction however might proceed equally cleanly in hot propylene carbonate in one minute. Then mixing two solutions one of A and the other of B; each dissolved in hot propylene carbonate so that a correct stoichiometric ratio and delivering it into the hot reaction zone in a flow reactor so that the transition of material through that zone was one minute could produce C more cleanly than heating much longer in dichloromethane because the correct stoichiometry has been more faithfully observed and the reaction period is very abbreviated.  If the reaction time is lessened, the reaction zone length can be shortened and some standard equipment may suffice. Now, whether creating the advantage of having the correct stoichiometry throughout the reaction period outweighs the disadvantage of applying more energy to the system than is actually required to get reaction can only be answered by experiment.

Reactants- All-In Method

Another means to achieve the same result would be to mix the correct stoichiometric quantities of A and B in the bottom of a reactor and then add a high-boiling solvent to it; in our example above this would be the propylene carbonate. The reactor is then heated to start the reaction. Normally mixing all of the reactants together and then heating to start their reaction is never done at scale because, as already pointed out, the exothermicity of the reaction is likely to cause a runaway wherein the entire contents of the reactor including any solvent would overheat and potentially even explode; however, using a sufficient quantity of a high-boiling solvent with a significant heat capacity and large enough heat of vaporization will allow any exothermicity to be absorbed first by the heating of the high-boiling solvent and subsequently by the heat of vaporization (refluxing) of a small portion of this solvent.

Using High-Boiling Solvents to Control Exothermic Reactions

The advantage to using a high-boiling solvent for such a reaction is not primarily its ability to dissolve the reactants and bring them together homogeneously. Good low-boiling solvents can do that. The high-boiling solvent can use its higher heat-of-vaporization, as well as its heat capacity, as a heat sink to soak up the exothermicity of the reaction.

In fact, the high-boiling liquid in which the reaction is being conducted does not need to be able to dissolve the reactants for it to be effective as a heat sink. So long as the reactants can blend together without solvation help the liquid medium does not have to dissolve them. Reactions ‘on-water’ for example are of this type. If at least one of the reactants is itself liquid there will be a reduced need for a dissolving type solvent. Another purpose for using a high-boiling liquid medium in which the reactants are insoluble is to provide sufficient bulk volume to satisfy the minimum stirrable volume requirement for the reactor.