kilomentor

June 13 and 14^th just passed  I was generously provided a Press Pass to attend the Cambridge Healthtech Institute’s  6^th International Current Process Chemistry Conference in Princeton New Jersey.

This meeting is attended predominantly by very experienced scale up scientists who usually are the team leaders of a group or the directors of a department specializing in process scale up. The content is focused at a level  suitable for persons who could write this blog rather than those who are most likely to benefit from reading it! Nevertheless, the general nature of the subject matter being discussed helps me see the trends of the research big pharma and contract research organizations are doing today and the types of background preparation upcoming process development chemists and chemical engineers are going to need.

Most speakers provided a narrative description of the particular issues that arose in the scale up for preparing a particular structure. The emphasis here is on rapid, fit-for-purpose, scale up. This means that the processes were not really optimized in the sense of using a multivariable statistic design to find the overall best combination of all the variables.  Rather, in the typical instance, a processes was modified by eliminating  potentially serious risks such as the potential difficult in removing metal impurities or immediately vetoing potentially dangerous methodologies or making appropriate provisions to deal with questions about late stage genotoxic impurities. (Issues relating to genotoxic impurities came up regularly throughout the meeting. There are certain functional groups which increase the likelihood that the intermediate or reagent containing  them will be found genotoxic.  Genotoxic substances cause changes in the transmission of the genome and affect genetic inheritance and must be held below very stringent impurity levels. They do not follow a dose response relationship so there is no completely safe dose. Just developing analytic methods showing that a process controls genotoxic impurities below these levels is difficult. As a result scale up chemists often simply avoid routes that use these late stage intermediates or reagents.)

The main concern of these specialists was as I said fit-for-purpose scale up. The dominate concern was to provide the correct number of kilograms of product, of the required purity, on the required date. The only long range requirement of the method was that there should be no reason why the method could not be run larger and more intensively to provide commercial quantities.

There wa very little mention of minimizing cost at this stage, for these people, except the minimization of solvent usage where it reflects the greenness of the process. Minimization of solvent use of course also helps increase throughput and influences the time needed to deliver their kilograms of drug candidate.  It seems that the cost reduction strategies that grind down the costs of API to the lowest level possible are found more among the generic drug substance chemical community.

Another keen interest of these fit-for-purpose process chemists was identifying and demonstrating the effect of critical process variables.  It appears still very important for developing process chemists to have an understanding of what constitute critic process parameters. This is part of process validation. Kilomentor has written an article about process validation from a process chemist’s perspective which the emphasis of this conference seems to further recommend. http://kilomentor.chemicalblogs.com/55_kilomentor/archive/1375_the_importance_of_understanding_process_validation_for_pharmaceutical_process_chemists.html

Government regulators are interested in guaranteeing the public’s safety when they take the actual medicine. Therefore, they are only interested that manufacturers control variables which can deleteriously affect the quality of the final drug substance. The companies that make drug substances, on the other hand,  are also very interested in parameters that have an impact upon the cost of the drug substance. Although the percentage  yield of a drug intermediate is may have no effect on the quality of the final product, a low yield can and most likely will make the ultimate process uneconomic. Thus the companies are very concerned about these parameters which affect the economics. Parameters that do not affect the final product quality but do affect the economics are called key parameters as opposed to critical parameters. Incidentally regulators are interested in knowing about varying yields,  even if the yield of a particular intermediate is only a key parameter because it shows that there is at least one significant uncontrolled variable in the process. Unidentified sources of process variation are signs of inadequate process knowledge and potential product difficulties in the future. 

In Organic Synthesis Coll. Vol. II pg 279 there is a procedure for monomethylation of ethyl malonate (diethyl methylmalonate). The crude, neat diester product is “shaken for exactly one minute with a cold solution of 10 g. of sodium hydroxide in 30 cc. of water.” The corresponding note  reports that “[t]he ester is treated in this manner to remove any unchanged ethyl malonate [diethyl malonate].  Michael¹ has shown that this treatment will completely remove unchanged ethyl malonate [diethyl malonate] while hardly attacking ethyl methylmalonate. No ethyl dimethyl-malonate is formed when methyl bromide is used as the methylating agent….A separation of the desired product from traces of unchanged starting material and from ethyl dimethylmalonate cannot be accomplished by distillation as the boiling points of the three esters lie within three and one-half degrees of one another.” The notes contain this additional information. “Michael found that unchanged malonic ester can be removed completely by taking advantage of the greater ease with which it is hydrolyzed by alkali ….”The references are Michael, J. Prakt. Chem. (2) 72, 537 (1905) and Fieser and Novello, J. Am. Chem. Soc. 62, 1856 (1940).
 This appears to be an extraordinary example of separation by competitive reaction using heterogeneous media. For this to work the rate of hydrolysis of the starting material under these conditions must be at least one hundred times faster than that for the monomethyl product. Why would this be and how can other separations take advantage of this? It might be that the deprotonation and extraction into the aqueous basic phase of ethyl malonate in a vigorously agitated two phase mixture is much faster for an unsubstituted ethyl malonate than for one that is substituted, even with a very small group like methyl. It is very much less likely to relate to a difference in solubility between the ethyl and ethyl methyl malonates or even of their respective monoanions.  Once ethyl malonate gets deprotonated and carried into the aqueous phase it is probably quickly further hydrolyzed to give carboxylates which keep it there. Kilomentor has given other examples of such ‘phase switching hydrolysis’ separating esters where there is a free phenol in only one component of a binary mixture and calls the method. http://kilomentor.chemicalblogs.com/55_kilomentor/archive/1011_extractive_and_phase_switching_hydrolysis_in_chemical_process_development.html
 

If the hypothesized explanation is correct this technique would be generally applicable in any monoalkylation of ethyl malonate with a hydrophobic side chain. It would mean that an excess of the inexpensive ethyl malonate could be used in such alkylation to speed up the overall rate in the knowledge that the excess ethyl malonate could be easily removed by alkaline hydrolysis and a water wash. This would also allow the amount of dialkylation to be reduced to essentially nothing.

Vis-a-vis my last post, I am responding to Bender’s questions. Whether one gets an interview for a job depends both upon the degree of urgency that the employer faces and the quality of the competition. Does reading kilomentor prepare one for a process chem job better than actual experience in process chem? No. Definitely no. It can supplement but not replace. Does it prepare one better than having no process exposure at all? Definitely. Does it prepare a graduating chemist  better than most of what is offered as process chemistry in academia?  I think so. I’m trying hard. As it stands right now, I think kilomentor can replace academic training in its present form but can’t replace process development experience. Kilomentor can give new chemical graduates a leg up for an entry level position.   

As far as the overall usefulness of organic synthesis as preparation for other chemical functions, I have seen throughout my career synthetic organic chemists switching with outstanding success into other jobs- analytical, regulatory affairs, and in my own case, solid dosage formulation. I have seen none move the other way. My conclusion is that thinking about any chemical problem from a base perspective of structure and reactivity has tremendous advantages. I entered solid dosage formulation with no academic training; just several weeks working with an old formulator, two days of those intensive classes, a textbook, and the chemical literature! A synthetic background is the best preparation for any of these jobs in my experience.

The Kilomentor educational blog is likely to have even more visitors starting next week. A letter from the author appearing in the letters section of the Journal of Chemical & Engineering News wil comment on the utility of blogs for educational purposes.  Therefore, a review of the history, purpose, and perspective of the blog may be appropriate.

The Kilomentor blog was begun in 2006. The goal was to provide training and updating in the methods for chemical process development, emphasizing scale up of organic synthesis, particularly for high value pharmaceutical products. The author recognized that there were textbooks, symposia, and courses for this purpose but they were expensive and not equally available anywhere in the world. Moreover, in academia, the treatment of chemical process development was neither widespread nor generally thorough enough. The Kilomentor blog would be free, have post graduate content, and be available wherever access to the world wide web was possible.

The particular perspective of this blog was that designing synthetic routes selection has become easier than in in the past. Today, ever since electronic sub-structure searching became readily available, finding promising potential schemes has been simplified. What has not been made easier is choosing between these hypothetical process routes and finding rugged/fast methods of isolating process intermediates. Kilomentor has chosen to highlight techniques that both work on scale and make isolating clean intermediates easier. The articles encourage development chemists and chemical engineers to choose processes for scaling that comprise more of such easily purified intermediates. It has suggested that routes containing more of these rugged intermediates may even be preferable to processes with fewer apparent steps. Thus routes that can have higher throughput tend to win out over routes that just have fewer ‘ on paper’ transformations.

The Kilomentor blog has been well received. It has had more than 184,000 visits since its start and there are now more than 115 separate blog articles. Visits, in 2012, have reached about 200 per day. A search tool on the site will look for key words and identify relevant articles.

Thanks for participating; and if you are new, then welcome!     

I have talked about a number of recyclable reagents, such as lasalocid, in the previous blog. The title compound to-day can be used either as a salt forming reagent or as an appendage or protecting group.
It has a structure containing three phenyl groups strung together,  end to end, through their para positions with an n-pentyloxy cap at one terminal and a carboxylic acid function at the other. All three rings are therefore para disubstituted. This acid, after coupling with the echinocandin B macrocycle, gives a product with excellent pharmaceutical properties. The substructure compound, as an amide derivative, is part of the drug anidulafungin. Since this linkage would be broken during the drug’s metabolism and since the drug has been found to be safe, this would seem to establish that this acid component is fairly nontoxic to the human metabolism.

This compound is a high melting solid and would be predicted to give high melting salts and other covalent derivatives. For example, the esters and amides are more likely to be solids using this rather than other carboxyl functionalities. The rigidity of the carbon skeleton might be expected to cause it to have a significant steric effect even remote to the point of attachment with another substructure. The expense of this potential protecting group would be ameliorated because the acid could be easily recovered and recrystallized to a dependable purity for recycling. Its use might be particularly promising where the process intermediates are expected to be liquids, oils, or waxes, such as in prostaglandin synthesis.  

When performing a chiral resolution at scale it is important  whether the resolving agent can be re-isolated, crystallized to a consistent purity  and thus practically  reused. When the resolving agent is a carboxylic acid, this is simpler when the the carboxylate salt of an alkali or alkaline earth metal is soluble in water while the free acid precipitates from water. Two common chiral acids have this characteristic: lasalocid and (-)DAG.

Lasalocid

Lasalocid sodium is a veterinary pharmaceutical available in large quantities. It is a chiral carboxylic acid that can be used to form diastereomeric salts with racemic amines. Based on tested examples it is predicted to work most dependably for primary amines that have their chiral centre at the alpha or beta position as well as tertiary amines with a proximate chiral centre with respect to the nitrogen atom. The ligand is capable of multipoint binding with the amine as it forms hydrogen bonds to many different oxygens. The ligand contains many different chiral centres. The molecule is made by fermentation.

The acid is relatively inexpensive. It was covered by US 4,129,580 which expired in 1998.

(-)-2,3;4,6-di-O-isopropylidene-2-keto-L-gulonic acid hydrate also called (-)-DAG

(-)-DAG is also a water insoluble chiral organic acid that can be used to resolve chiral asymmetric amines.

It is a relatively inexpensive compound that is used  an intermediate in the synthesis of Vitamin C.  It was first prepared by Reichstein et al. Helv. 17, 311 (1934). Its use for resolution was taught in the expired US patent 3,682,925 (1972).

James Myslinski has asked me to elaborate on the technique of purification by ‘exhaustive digestion’. This is a phrase that I used in my blog entitled, Crystallization and Recrystallization Particularly On Scale. In this blog I make the point that chemists scaling up a laboratory process often fail to do adequate preliminary purification of a solid and as a consequence get a lower recovery than is possible if a preliminary treatment is done. I propose ‘exhaustive digestion’ as one pretreatment before recrystallization. I don’t know whether there are any widely accepted differences between digestion and trituration but, when used in my blogs, first, the noun trituration can be taken as applying equally to oils or solids while digestion will only apply to solids. Second, trituration can be taken to be done with ambient temperature or cold solvent while trituration and particularly exhaustive trituration is more often done with hot liquids, usually rather poor solvents for the desired product.

In the old literature, the progress of purification by digestion on the laboratory scale is followed by observing the change in boiling point in the digesting solvent or solvent mixture using a Beckmann thermometer, which is a thermometer that can measure differences as small as one tenth of one degree. I don’t know how long it has been since I have seen anyone use a Beckmann thermometer but, at least in Phys. Chem., it was done quite often in my younger days. The range of a Beckmann thermometer can be adjusted by removing or adding mercury to the column of mercury used for measurement by moving mercury back and forth from an attached mercury reservoir.

I will illustrate exhaustive digestion by quoting from an experiment taken from Laboratory Technique in Organic Chemistry  by Avery Adrian Morton, First Edition , McGraw-Hill, 1938,  pg. 128-229.
“The apparatus consists of a tube or flask of such size that a large part of the bulb is covered by the solid material being extracted , a thermometer graduated in tenths of a degree, a reflux condenser, and a water or oil bath. Place the sample in the container, insert the thermometer so the bulb is immersed in or covered by the sample, and add solvent to cover the solid and the thermometer bulb. The solvent is usually one that will dissolve impurities without appreciable quantities of the desired material. Petroleum ether or ligroin is often suitable. A mixture of solvents may be employed without effecting their utility in this experiment, as long as the composition of the mixture is not varied . Reflux the solution [I think slurry is intended] using a water or oil bath as a source of heat. After about 20 minutes the temperature has reached a constant level. Usually no trouble will be experienced from superheating as long as solid phase is present, although a little agitation with the thermometer is sometimes needed. Filter either by pouring into a Buchner funnel or by using a filter stick. Add more of the same solvent, reflux once more, and observe the temperature after equilibrium conditions have been reached. Continue the operation until the temperature of two or more successive operations are identical. The more soluble impurities have now been removed, and the solution contains only the pure compound or the compound with [less soluble type] impurities that have not been entirely removed…. The operation may be continued, if desired, until all the product has been dissolved. A change of solvent [may be implemented at some point for further purification]….. Constancy in the boiling points of successive portions constitutes further evidence of the purity of purity of the material, whereas a drop in the boiling point is evidence of the exhaustion of still another component. Usually the final portions of exhaustive digestion are pure materials.”

In light of the current interest in PAT, I cannot resist including the  short paragraph that followed the quote from this 1938 text.

“Use the same apparatus to follow the progress of a reaction in which a solid phase is present, e.g., conversion of a triarylcarbinol to the chloromethane compound while under a mixture of petroleum ether and acetyl chloride.”

 By continuously measuring and recording the changes, in real time, of the boiling point without any sampling this is an early application of a PAT technology. With the improvements in the size and sensitivity of temperature measuring devices, this following of small changes in boiling point under conditions where superheating does not occur perhaps deserves more frequent consideration.

Exhaustive digestion if used at-scale would require some more rugged method for measuring small changes in the boiling point of the slurry than A Beckmann thermometer loaded with mercury. Stirring using the thermometer as described in the above laboratory procedure of course out of the question. In a small amount of a thick slurry, the volume could easily fall below the minimum stirrable volume in the reactor so a plow type stirrer might be needed.

Remember guys, during the idea generation stage of problem solving criticism is supposed to be put on hold!

Now what can we get by playing with the idea of reaction of the impurity? What distinguishes the undesired impurity from the bulk? Molecular weight. The presence of silicon. The presence of a silicon oxygen bond. The presence of carbon-silicon bonds. The presence of silicon in the impurity seems to jump out at me. What is the strongest bond that silicon can form because that is what I want to do if I am going to drive this product into some other substance? The strongest silicon bond is one to fluorine. So perhaps the ion exchange resins that are being contemplated should have fluoride ion loaded on them. The conversion R₃SiOEt + F^- + H₂O going to  R₃SiF + H-OEt + OH^-  would have an enthalpy advantage of about 27 kcal/mole. Hydrolysis in contrast has no enthalpy advantage, I think.

Anyway, problem solving is a combination of a good statement of the problem, a non-critical atmosphere for generating ideas, and most important well loaded retrievable associative memory banks. Note that you cannot come up with good ideas based on stuff you can’t recall but need to look up. Looking stuff up can be used to refine ideas but it cannot help to create them.  You need to know things well enough that they can be recalled by associative memory when presented with the clues offered by the problem itself.   

 

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