January 31, 2021

Speculations on Covid-19 Vaccine Production Bottlenecks.

The paper I'll discuss in this post is this one: Optimization of Lipid Nanoparticle Formulations for mRNA Delivery in Vivo with Fractional Factorial and Definitive Screening Designs (Kevin J. Kauffman, J. Robert Dorkin, Jung H. Yang, Michael W. Heartlein, Frank DeRosa, Faryal F. Mir, Owen S. Fenton, and Daniel G. Anderson
Nano Letters 2015 15 (11), 7300-7306)

Recently on this website, I described how I cheered up my doctor by relaying to him "war stories" from the scale up of HIV protease inhibitors in the 1990s, of which I am a "veteran" of sorts. It's here: I hope I cheered my doctor up.

This morning I attended a (Zoom) lecture by an astrophysicist at Princeton University Professor Cristiano Galbiaiti who works on neutrino and dark matter detectors which rely on highly purified gases, who used his expertise and knowledge of them to rapidly design a new ventilator that was cheap, easy to manufacture, and proved to be highly effective for the treatment of Covid-19. It obtained the fastest approval, from conception to patient use, of a new medical device by the USFDA, 45 days.

It is an example of how "impractical science," the discovery of neutrinos in space, allows for "practical" innovation, much as the 1960's space program allowed for the development of small portable computers, on which many of us now rely.

If you member, in the early days of Covid, there was a huge shortage of ventilators, and the Canadian government, which funded the design and manufacture of the ventilators, ordered many tens of thousands of these new ventilators, which were delivered. The end result is interesting: There is now an oversupply of them, and the partners working on this project are now working to get Western governments to donate ventilators to Africa, where, predictably, ventilators are still in short supply.

I have to see my doctor again this week, and I decided to look into the manufacturing process of RNA vaccines, so I could further cheer my doctor up, with some more detailed insights into the manufacture of these vaccines, about which I have a sense of regulatory requirements, but not the actual details.

I am not currently in anyway involved in the manufacture of Covid vaccines, but I have had professional conversations about nucleic acid formulations, and have had other conversations relating to, and sometimes supporting, related "lipid nanoparticle" work, notably liposomes. Anything I say in this post will, however, be largely guesswork and should be taken with a grain of salt.

The HIV protease inhibitors are drugs that are considered "peptidomimetics" and they depended on access to certain amino acids as starting materials, in particular cysteine and phenylalanine (depending on the protease inhibitor in question). Since many chemical synthesis steps were involved in converting them into "isosteres" of peptides, these starting materials were unregulated commodity items required only to meet certain specifications subject to somewhat limited specifications.

What was involved was large chemical reactors, performing organic synthesis on a multi-ton scale, in some cases utilizing fairly dangerous reagents. (Phosgene was one.) Ultimately these were utilized to make the "API" - the active pharmaceutical ingredient, the protease inhibitor.

The situation with respect to the API of nucleic acid drugs is somewhat different, I expect.

Nucleic acids, such as DNA and RNA, are self replicating molecules of course, and so in theory, their production can (and does) proceed exponentially. This is the technology behind forensic and commercial (as in "23 and me" and related companies) "PCR" (Polymerase Chain Reaction) technology. It is the design of the nucleic acid that matters.

A nice overview of the design and some information about production of the API can be found in an open source article that is somewhat, but not, I think, overly, technical: The promise of mRNA vaccines: a biotech and industrial perspective. A cool feature of the design of these vaccines, with which I was unfamiliar, is the realization that they not only encode for the immunogen protein of the SARS-CoV-2 virus, the famous "spike" protein, but they also encode for some proteins designed to aid with the transcription of the RNA to generate the proteins.

I really can't say very much intelligent about the scale up of the API and potential bottlenecks, since these are involved more with biological systems than synthetic systems and I personally have far less exposure (mainly osmotic exposure) to these than I do to synthetic systems. I would imagine that the chief bottleneck might be having useful enzymes for transcription from the DNA parent the RNA, as well as nucleic acids themselves, although, as opposed to amino acids, which in living systems have 20 basic components (actually a few more because of "post translational modifications" ) there are only 8 nucleic acids in living cells, making separations more straight forward. I would imagine (but do not know) that these are synthetically available without isolation from natural sources (as are some amino acids) from ribose, deoxyribose (almost certainly obtained by fermentation) and the nucleobases which are readily available commodities lacking stereocenters. I know for a fact, that enzymes, including certainly the enzymes responsible for nucleic acid transcription are readily available from biological fermentation facilities. It is possible there has been some strain on these supplies, but basically a vast infrastructure exists.

So my guess is that the API's are not much of a bottleneck at all, beyond, it would seem, some industrial scale chromatography in at least some steps; I would imagine, perhaps, affinity chromatography, which is much, much cleaner than other types of chromatography, perhaps even at the level of solid phase affinity extraction. (These are all speculations; I have no information.)

My guess is that the real issue, the biggest bottleneck, is the formulating agents.

Nucleic acids are charged species, hydrophilic species, that is they are soluble in water and other polar solvents. All cell membranes, by contrast, are lipids, aka "fats." The basic rule that "like dissolves like" applies, which is why cells like blood cells are able to stay intact; their membranes are insoluble in water. Therefore the trick is to get the charged nucleic acids through the membrane, and into the cell. This requires amphiphilic lipids, which have hydrophobic properties on one end of the molecule, and hydrophilic properties on another end. The most famous of these are soaps, with which everyone is familiar.

In fact, the SARS-CoV-2 virus is coated with a lipid, and this is why soap, regular hand soap, is so effective at inactivating it, since it strips away the lipid layer on which the virus depends.

Fats are readily available from multiple sources, so much so that they have been utilized as fuels, biodiesel, in automobiles and trucks by the so called "renewable energy" industry, which has succeeded in destroying large swathes of Asian rain forest for palm oil plantations in part to make diesel fuel for German cars and trucks.

I want to be clear on something in this context, since I am about to discuss lipids, the amount of palm oil required to make the world supply of Covid vaccines (if palm oil is a basic source at all, which it may not be) will surely be trivial when compared to produce other commodities, including biodiesel and the palm oil utilized in foods. There is really no legitimate rationale for destroying the South Asian rain forests for commercial interests. The very special lipids that are likely utilized in Covid vaccines might have just as easily utilized corn oil as palm oil, since it is likely that the starting materials, saturated and unsaturated straight chain fatty acids are present in both sources, and perhaps other temperate zone agricultural products such as canola oil or soybean oil.

Anyway.

The lipids in question are amphiphilic, but they are very special lipids of a type, which are widely found in living systems, but which are also synthetically complex except by enzymatic routes.

To give a feel for the complexity of lipids beyond the straight chain fatty acids, here is a chart showing types of a class of lipids that are found prominently in skin, the ceramides:



Some of the lipids described in the paper cited at the beginning of this post are isosteric (similarly shaped) to sphingosines.

The key point in this development is the concept of "ionizable lipids," which address the transport of a charged species, RNA, across the lipid membranes of cells.

(At this point, it behooves me to mention a post in this forum by our leader, pointing to the career of a famous lipid chemist in the early days of lipid chemistry: Watch for NOVA's rerun of "Forgotten Genius" in your area ... or watch it online ...

From the introduction to the paper cited at the outset:

The authors developed a combinatorial approach using chemical libraries (compounds modified and mixed in a controllable but different way) to screen lipid formulations.

There are many hundreds of papers on the topic of lipid particles utilized in nucleic acid drug development, but for this brief post, we'll just look at the pictures produced here, and return to figure one for further discussion:



The caption:





The caption:



EPO here, is one of the early protein drugs on the market, one that got Lance Armstrong and other athletes busted, the anti-anemia drug erythropoietin, which jacks up hemoglobulin in the blood. The idea here is to insert RNA into cells in such a way that rather than being produced in a reactor, it is produced within the blood itself. (I would imagine that tracing this would make anti-doping efforts somewhat more challenging.



The caption:





The caption:



The experimental portion of the paper, by the way, describes the synthesis of the mRNA itself that was used in this study; it is very "PCR" like, an exponential growth system. Certainly some clean up is involved, but I suspect this is not a bottle neck.



Now I'ld like to return to figure 1, which I repeat for conveninence, and make some comments.



Without having sourced it myself, I would imagine that cholesterol is easy to get from a variety of sources.

What are interesting are the other three molecules (which may represent classes of molecules in real cases or similar cases).

These I would imagine (and in one case, I know) are chemically synthesized in chemical reactors.

First the "ionizable lipid." There is an element of pseudosymmetry in this molecule, inasmuch as all the long carbon chains are C12, and are almost certainly obtained from lauric acid, the C12 fatty acid, which I know from experience is available in high quality from a number of sources. The core of the molecule is piperazine, the cyclic molecule in the center with two nitrogen atoms in the ring on opposite sides, also a commercially available reagent. Nevertheless, there is symmetry breaking inasmuch as the spacers in the two nitrogens on the piperazine ring have different spacers. This means to make the molecule, one must protect one (and only one) of the nitrogens, which is not entirely straight forward, or otherwise synthesize the ring in such a way that one nitrogen is protected, eliminating the advantage of using very cheap and readily available piperazine. My organic synthesis muscles are no longer strong enough to offer a route off the top of my head to the OH group that is one carbon removed from the amino nitrogens in those side chains, but I'm quite sure if one looks, one can find such a route.

Nevertheless, although very large reactors for making this "ionizable lipid" are certainly available under regulated ("GMP" ) conditions, this would be a bottleneck, if this particular (or a similar) "ionizable lipid" were utilized in formulating either the Moderna or the Pfizer vaccines.

The DSPC is a derivative of phosphocholine, which is found in many foods, notably eggs, and is fact found all over living organisms. In theory it can be made from one of the cheapest industrial chemicals there is, glycerol, a side product of the soap and biodiesel industries which is so cheap that people often dump it rather than sell it if they are far from a facility that uses it. The DSPC is a chiral molecule exhibiting "handedness" (being non-superimposable, like right and left hands). I'm sure that there are lots of enzymatic routes to making phosphocholine, but still, after one has it, one has to acylate the two oxygens with steric acid, also a commodity produced from things like palm oil, corn oil, canola oil...etc...etc. Still one needs a reactor to do this.

Finally there is there is "lipid anchored" "PEG," polyethylene glycol, which is also a derivative of phosphocholine, in fact, it is a derivative of DSPC. It is the PEG side chain that matters. The thing that disturbs me a little bit is the designation, at least in this paper, of a fixed length. PEG in most drugs - it is commonly used in many protein drugs to prevent their rapid breakdown in the body - is a polymer, and generally has a molecular weight distribution centered around a specific molecular weight, and also containing some molecules of higher and some of lower molecular weight. It is generally made by the polymerization of ethylene oxide (oxirane). I would hope that the formulations of the lipids in the vaccines do not actually in real life involve this restriction, since this would be problematic and represent a real bottle neck.

But even if it was...

One of the largest selling drugs in the world for many, many, many years was atorvastatin (Lipitor). It was discovered and initially developed at a company that no longer exists, Parke Davis. Here is the structure of atorvastin:



I was told a story about atorvastatin that I heard; it may or not be true. This drug was developed in the 1980's when industrial chiral synthesis was still somewhat problematic - it was a problem generally solved by the time HIV protease inhibitors came around - but early on it wasn't. I was told that Park Davis felt that atorvastatin would never be a big seller, because it was too expensive to make on an industrial scale, because of the seven carbon side chain with the two hydroxygroups on it, both of which are present as chiral centers. In the early days of scale up of the drug, the cost of the side chain was said to be over $1000/kg in 1980s dollars. I know people who were selling it for $800/kg in the 1990s.

Every chiral organic chemist in the world, both industrial and academic, looked at that side chain and figured that they could make a killing by making it cheaper; everybody in the world was going to get rich making it for $500/kg. Companies were founded on this expectation.

So many people exercised their genius to make the molecule cheaper that it ultimately became a commodity, and everybody was trying to undercut everyone else, because everyone's cheaper route made for an oversupply. I heard, that the cost of the side chain, before the expiry of the Park Davis successor company(ies) (ultimately Pfizer) the side chain was priced well under $100/kg, I heard $50, out of India and China.

So what's the story, morning glory?

Yeah, right now, there are bottlenecks, but they aren't going to last very long. Within a year, maybe sooner, these vaccines are going to be commodities, because, right now, there is clearly intellectual and almost certainly physical infrastructure to do it.

And that's a good thing. In the end, it will come down to logistics and little else.

Cheer up. We have a smart and energetic President who actually gives more than a rat's ass, vastly more than a rat's ass, as opposed to his orange predecessor, and we will beat this thing.

Some suggested further reading:

Martin A Maier, Muthusamy Jayaraman, Shigeo Matsuda, Ju Liu, Scott Barros, William Querbes, Ying K Tam, Steven M Ansell, Varun Kumar, June Qin, Xuemei Zhang, Qianfan Wang, Sue Panesar, Renta Hutabarat, Mary Carioto, Julia Hettinger, Pachamuthu Kandasamy, David Butler, Kallanthottathil G Rajeev, Bo Pang, Klaus Charisse, Kevin Fitzgerald, Barbara L Mui, Xinyao Du, Pieter Cullis, Thomas D Madden, Michael J Hope, Muthiah Manoharan, Akin Akinc, Biodegradable Lipids Enabling Rapidly Eliminated Lipid Nanoparticles for Systemic Delivery of RNAi Therapeutics, Molecular Therapy, Volume 21, Issue 8, 2013,

Dynamic PolyConjugates for targeted in vivo delivery of siRNA to hepatocytes
David B. Rozema, David L. Lewis, Darren H. Wakefield, So C. Wong, Jason J. Klein, Paula L. Roesch, Stephanie L. Bertin, Tom W. Reppen, Qili Chu, Andrei V. Blokhin, James E. Hagstrom, Jon A. Wolff, Proceedings of the National Academy of Sciences Aug 2007, 104 (32) 12982-12987; DOI: 10.1073/pnas.0703778104

Semple, S., Akinc, A., Chen, J. et al. Rational design of cationic lipids for siRNA delivery. Nat Biotechnol 28, 172–176 (2010). https://doi.org/10.1038/nbt.1602

Many, many, many more papers may be found by calling these papers up in Google Scholar, and clicking on the citations list.

I hope you will have a safe and enjoyable Sunday.

January 30, 2021

Has anyone here ever eaten a fruit called Durian?

I'm catching up on my reading, and I came across a paper titled thus: Food Waste Durian Rind-Derived Cellulose Organohydrogels: Toward Anti-Freezing and Antimicrobial Wound Dressing (Xi Cui, Jaslyn Lee, Kuan Rei Ng, and Wei Ning Chen, ACS Sustainable Chemistry & Engineering 2021 9 (3), 1304-1312).

It contains this text:

Famous all over the world?

Serious problem to the environment?

Never heard of Durian...

Anyone?

January 30, 2021

PPPL Science on Saturday: From studying the Sun, to searching for dark matter, to fighting Covid.

PPPL's science on Saturday lecture tomorrow morning by Princeton University Professor Professor Cristiano Galbiaiti giving a talk entitled: From studying the Sun, to searching for dark matter, to fighting COVID-19

Sign up here:

Science on Saturday, on Zoom

Almost always the talks are fascinating. Although, the Princeton Plasma Physics Lab is an National Physics Lab, the talks, while often involving physicists (as tomorrow's will), also include, biologists, geologists, chemists, social scientists, oceanographers, climate scientists, etc.

They are hosted by the charming and fun Dr. Andrew Zwicker, head of science education at the lab, who also moonlights as the Democratic NJ Assemblyman in the NJ Legislature.

In previous years, the talks were held at PPPL with a very nice social hour before hand featuring coffee, donuts (great donuts!) bagels and interesting conversation.

As with Covid, the talks have moved to Zoom, they are now accessible around the world. They are held at 9:30 am EST, with a Q&A session after the talks ending usually by 11:30. The talks themselves are about an hour generally.

Check it out!

January 28, 2021

A fabulous soporific horror book.

I'm a chronic insomniac, but I just found a great tool for going to sleep which isn't pharmaceutical.

I remember when I was 18, having my first college adventure, the arguments between the Trotskyites and the Leninists in the student center, with a few Maoists thrown in the mixture just for fun.

It was New York; what can I say?

I had no idea whatsoever what it was all about, having been raised to think a commie was a commie, and being something of a Rube, it all seemed so excitingly sophisticated. I never did learn to tell the difference.

Eventually arguing over Trotsky and Lenin fell out fashion, thankfully, but in the back of my mind, as an old man, I found myself wondering, what the hell all that passionate stupidity was all about. I mean, I knew it was stupid somehow, but never knew why.

Lately I've been reading Dmitri Volkogonov's Stalin, Triumph and Tragedy. Volkogonov was a Soviet Colonel General who was charged with psychological warfare, and who, given access to the Soviet archives before the fall of the Soviet Union, became a historian. When he died, donated his papers to the US Library of Congress.

It's fascinating, because it gives a behind-the-scenes account of the rise of Stalin who, by aligning himself with Lenin's dead body, defeated Trotsky via the duplicitous manipulations of the weather vane duo Zinoviev and Kamanev who, as sophisticates, felt they could manipulate and control the rise of either Stalin or Trotsky. It was a bad bet. Zinoviev and Kamanev were executed by Stalin in the 1936 Purges.

However, one cannot read Soviet history, especially as it involves Soviet Marxist theology/"theory" without eventually thinking of conversing with Brezhnev about wonderful Soviet tires made of concrete and licorice. Three of four pages, tops, and your eyes are heavy. By the fifth page, you're asleep. Better than Ambien, safer too.

The rise of Stalin is, of course, a horror story, and one feels trepidation because you kind of know the ending, but it is fascinating because Stalin rose by seeming reasonable. I'm coming up on the great Ukrainian famine. It's scary, if one can stay awake through it.

I'm just getting to the point where we learn of "Socialism in one country," of which I've heard in reference to Stalin, but I never actually understood the background and how it differed from Trotskyism.

I wish I was 18 again, and could join in the fun in the student center.

I wouldn't care, but I do need to sleep in order to work well.

January 28, 2021

I hope I cheered my doctor up.

I had to go see my doctor for a problem not related to Covid-19. As it happened, my son had seen him earlier, whereupon my son reported that he was basically freaking out about the vaccine/mutation situation.

Apparently he was thinking it was never going to end, and was extremely stressed about the vaccine supply apparently because the State of New Jersey had a disconnect with the status of his vaccine supplies and the people who could get it and now he was forced to field a lot of calls from anxious and sometimes angry people. He was worried about the mutants.

So after the exam was done, I asked him, cheerfully, if he was having "fun" with Covid. He looked really frazzled and said, "No! No!"

Happily - unhappily because it was a disease - I am a veteran of the industrial scale up of HIV protease inhibitors, and was intimately aware of what people go through under such a circumstance, a circumstance wherein a logistical screw up, or perhaps, a regulatory or process screw up means, literally, that people will die. So you do everything you can to do everything right.

It's serious, a huge responsibility, but in those times, one in which pharmaceutical teams, I'm happy to say, rose to the occasion - you saw the best in people mostly, and very little of the worst. I was very, very, very proud of the opportunity to have been involved.

"Look," I told my doctor, "for about a year, I was dealing with people begging me for supplies and then, all of a sudden, the whole thing dried up, because so many players rushed in that eventually there was an over supply."

As for mutations, I said, I know, I know, I know, retroviruses suck because they mutate so rapidly. But I told him, and of course he knows this, that this is reason we now give HIV protease inhibitor cocktails, because any virus with a single nucleotide polymorphism, or even a polynucleotide polymorphism is going to be hit by one or the other.

We saw these SNP's and PNP's all the time, but lives are still, almost 30 years later, being saved with protease inhibitors.

I told him about the glycosylation patterns on the coronavirus, contrasting them with HIV, and letting him know that this was a different, easier, ball game and finally about how these nucleotide drugs are easy to re-engineer to a moving target.

"Look," I said, "it's going to be, at the worst case, ultimately, like when you ask me to get a flu shot every year. You're going to ask me did I get my annual Covid shot. The infrastructure will be there, and sales guys will be calling on you to tell you why their vaccine is better than the other guy's, begging you to use theirs."

Expecting a doctor to really know about the industrial operations of the pharmaceutical industry is rather like expecting your car mechanic to know about how an auto parts plant works. Your mechanic doesn't need to know about the metallurgy of a water pump to fix your car. He just needs to know if the part fits and if it works.

I felt my doctor felt better. I hope so. He's under a huge amount of strain, and I could see it.

I feel better because adults are in charge of the country again, which makes everything better automatically. It doesn't mean we're "there yet," but at least we know where we're going.

Life is interesting, and then you die.

January 26, 2021

Why cats go crazy for catnip.

The following is a news item in the premier scientific journal Science. It should be open sourced, and is here: Why cats are crazy for catnip (Sofia Moutinho, Science, January 20, 2021).

Some excerpts:

It appears, however, that nepetalactol also repels mosquitos:



If you have a cat, and have seen him or her around catnip, you knew, at least intuitively, that it acts on opioid receptors. I didn't know about mosquitos however. I might try some myself.

The full scientific paper to which this article refers is here, and is, I believe, open sourced: The characteristic response of domestic cats to plant iridoids allows them to gain chemical defense against mosquitoes (REIKO UENOYAMA, TAMAKO MIYAZAKI, JANE L. HURST, ROBERT J. BEYNON, MASAATSU ADACHI, TAKANOBU MUROOKA, IBUKI ONODA, YU MIYAZAWA, RIEKO KATAYAMA, TETSURO YAMASHITA, SHUJI KANEKO, TOSHIO NISHIKAWA, MASAO MIYAZAKI, SCIENCE ADVANCES 20 JAN 2021 : EABD9135)

Nepetalactol:

January 24, 2021

The cabinet page at Whitehouse.gov

When I need to be happy and confident in the future, I'll look at it.

This is America:

The Cabinet, Whitehouse.gov

January 24, 2021

Recovery of Trivalent Lanthanides and Transplutonium Actinides with Resin Supported Diglycomides.

The paper I'll discuss in this post is this one: Scaling Trivalent Actinide and Lanthanide Recovery by Diglycolamide Resin from Savannah River Site’s Mark-18A Targets (Kevin P. McCann, Mark A. Jones, Edward A. Kyser, Tara E. Smith, and Nicholas J. Bridges Industrial & Engineering Chemistry Research 2021 60 (1), 507-513).

The elements in the two rows below the "main" periodic table are collectively called the "f elements." The row beginning with the chemical symbol Ln (lanthanum) are called "the lanthanides" - and somewhat more commonly in an annoying and misleading term, "rare earths" - and the row beginning with the chemical symbol Ac (actinium) are called the "actinides." They are placed below the main elements of the periodic table only to make the table fit nicely in the width of a sheet of paper. Properly drawn they represent another "step" in the step shapes in the main part of the table, properly the table should have 32 columns, not 18, although the congener relationship in purely chemical terms between, say protactinium and praseodymium is weak and not all that worthy of consideration.

The lanthanides, with some exceptions, generally exhibit the +3 oxidation state, the "trivalent" state, because the "f orbitals" which are being filled across the row do not participate to any appreciable extent in chemical bonding because of shielding effects.

This is not true for the lower actinides before americium, only actinium itself exhibits only the trivalent state. For a very long time, until the 1940's, when interest in actinide chemistry exploded - no pun intended - thorium was thought of as a congener of hafnium and zirconium, because like them, its most common oxidation state is +4, and protactinium was considered a congener niobium and tantalum because its common oxidation state is +5, and uranium, a congener of molybdenum and tungsten because of its common oxidation state of +6.

Actinium, thorium, protactinium, and uranium all occur naturally in weighable amounts, thorium and uranium on a billion ton scale - their decay is largely responsible for the internal heat of the Earth - actinium and protactinium occur in trace amounts, in concentrations so low that they are best accessed not by isolation from the ores in which they occur, but by the use of nuclear reactions, neutron or proton bombardment.

In 1940's, as he worked on the discovery of new synthetic elements in the periodic table, especially neptunium, plutonium, americium and curium, Glenn Seaborg had the insight that the chemistry of these elements could be discerned by recognizing that they were, in fact, "f elements" as opposed to "d elements" like hafnium, tantalum, and tungsten.

The actinides become "lanthanide-like" at americium. Although americium can be oxidized to higher oxidation states, it's major oxidation state is +3; this is also the case with curium, berkelium and californium.

When I was a kid, the first mass spec with which I was used by one of the companies for which I worked had a californium ionization source; I'm an old guy. (Modern mass specs have other types of ionization inductions, notably electrospray ionization (ESI) for which John Fenn won the Nobel Prize.) The californium where I worked (in California) was the 252 isotope, which has a half-life of about 2.64 years, decaying both by spontaneous fission and by alpha decay to curium-248. The spontaneous fission of californium-252 made it a useful source of neutrons, and it was widely used in chemical analysis using neutron activation analysis, which has been mostly displace by high sensitivity ICP/MS instruments that for most elements can record parts per trillion.

Perhaps a current motivation, particularly in the days of antibody payloads is in neutron boron therapy, where small portable Cf-252 sources might displace the need for expensive accelerators, particular in rural or remote regions: Boron neutron capture therapy: Current status and future perspectives (Dymova, M.A., Taskaev, S.Y., Richter, V.A. and Kuligina, E.V. (2020), Cancer Commun., 40: i-i.)

In the 1960s and 1970's an effort was made to produce large (large being milligram quantities) of californium-252 as a neutron source and as an ionization source. (Mass specs in space robots generally use curium sources because of their longer half-lives.)
Another important isotope is plutonium-244, which has a half-life of 80 million years, and which is used as an internal standard in actinide analysis, and as a target for super-heavy element analysis.

The United States is running out of plutonium-244, and the paper listed above is about recovering it, as well as the transplutonium elements therein. The introduction to the paper covers things on which I touched above:

The Reillex HPQ resin is an anion exchange resin, a polyvinyl-N-methylpyridinium resin, that intereacts with the anionic plutonium (IV) hexanitrate anion (-2). In Reillex 402, the methyl group is replaced by a proton, in other N-pyridinium alkyl primary ammonium groups of various chain lengths to give a dicationic species.

The structure of these complexes are nicely shown in this cartoon:



Molecularly Engineered Resins for Plutonium Recovery

(S. Fredric Marsh, D. Kirk Veirs, Gordon D. Jarvinen, Mary E. Barr, and Eddie W. Moody, Los Alamos Science 26 (2000) 454-463)

The Los Alamos people note that some of the designed resins may also extract transplutonium nitrate complexes, but it would appearl that straight up Reillex HPQ (the methyl pyridinium is selective toward tetravalent plutonium nitrate complexes) and thus can be utilized in the current setting, where the target are trivalent species, specifically transplutonium actinides and lanthanides.

To save the world, the required inventory of plutonium - even in the "breed and burn" scenario where only a critical mass (realistically a little more) is required for start up - is on the order of hundreds of metric tons, and it is unrealistic that Reillex HPQ would be of much use on that scale.

These charged resins thrill, perhaps in the form of ionic liquids, the imagination about the possibility of electroprocessing.

I recall that when I was writing over in the E&E forum a lot, an anti-nuke of the particularly dull sort announced that nuclear energy was "too dangerous" because a tunnel at the Hanford site which had been abandoned collapsed. Pretty typically this person who is happily on my ignore list was far less interested in the 7 million people who died last year from air pollution while dumb guys get wedgies in their underwear about tunnels built in the 1950's which may contain (gasp) radioactivity. On investigation, it turns out that the tunnel contained some old abandoned chemical reactor vessels for plutonium purification ob rail cars, with trace plutonium on their surfaces. The number of lives lost associated with the collapsed rail tunnel was zero.

Reillex HPQ would be good to decontaminate the decontamination wash solutions to clean off the chemical reactors such as may exist from reprocessing efforts, but not for large scale processing. Let's be clear though, on a scale of risk, when compared with the very real and rising catastrophe of dangerous fossil fuels, unless one is a complete idiot - and sadly complete idiots exist - plutonium stains on a 50 year old chemical vessel is a non starter.

But in the case of the Mark-18A targets, these contain curium on a scale of a few hundred grams, and thus the resins have much to recommend them. Since the quantities are relatively small, but extremely valuable, column scale separations are entirely acceptable.

The authors note that during the last campaign to milk the Mark-18A targets for their valuable components, which took place in the early 1970s, a Dowex anion exchange resin was utilized. A difficulty with this resin, although it was clearly workable, was the release of sulfate from the sulfonylphenyl groups on which this relatively primitive anion exchange resin was based. Sulfates tended to contaminate the eluted products and raffinates, requiring additional clean up steps. Moreover, combustion of the used resins was problematic.

The more modern resin under discussion here contains only carbon oxygen and thus can be readily destroyed in an appropriate oxidation setting designed to contain residues.

The historical separation process is described as follows:



To prevent leaks, the authors were looking for a way to avoid the use of pressure, hence the evaluation of a new approach to the separations. All of the fermium and einsteinium in the targets has now decayed to lower actinides, of course, so they are no longer relevant to the case.

They write:



Although I do not have access to the exact structure of the commercial DGA resin, the structure of these resins is probably something along these lines:



(cf Mohapatra et al., RSC Adv., 2014,4, 10412-10419)

The authors conducted two tests, one using non radioactive fission product simulant with neodymium standing in for the actinides, and a second, also loaded with a fission product simulant spiked with the actinide americium.



The flow chart calls for the dissolution of the aluminum clad targets with caustic (which dissolves aluminum), leaving behind a solid residue of oxides which are then dissolved in 7M nitric acid. It is the nitrate complex which is separated as anionic species by the resin.


Some pictures from the text:




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A new wrinkle in this method as opposed to the method utilized in the 1970s also concerns the detection. For the purposes of these experiments, the complexes were monitored by their UV absorption spectra.



The caption:






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The authors conclude as follows:



Cool paper I think, with some application, for cleaning chemical reaction vessels used in the essential - if we are to save the world - separation of the higher actinides.

I trust you are enjoying, as much as I am, the first weekend in the already magnificent Presidency of Joe Biden, and are doing so safely.

January 24, 2021

Conspiracy (2001), Kritzinger's Warning.

The Wannseekonference took place on January 20, 1942. The conference lasted about 2 hours, and was conducted as a lunch meeting. It was held to plan the murder of the Jews of Nazi occupied Europe, and discussed plans for the murder of Jews in countries that had not yet been conquered by Germany, Great Britain, for instance.

The participants were highly educated and efficient men.

The conference was organized by Reinhard Heydrich, a talented musician, skilled athlete who was educated at a German Naval Institute. He later became the "protector" of Moravia and Bohemia, where he was assassinated by British trained Czech partisans several months after the Wannsee conference. Heydrich is considered by historians to have been one of the purest embodiments of pure Nazi evil.

Notes from the meeting were discovered in 1947 from the files of Martin Luther, a minor Nazi official, probably the lowest ranking figure at the meeting, who had, in fact, ended up in a concentration camp himself before the war was over.

Several films, including documentaries have been made about the Wannsee conference, one in German in 1984, another in English in 2001, called "Conspiracy." It stars Kenneth Branagh in a chilling portrayal of Heydrich.

If one has ever been to a high level executive meeting in any capacity, one can recognize the tenor of the meeting as portrayed in "Conspiracy." The goal is to "get things done" while schmoozing in a genial way, juggling for position, clarifying issues, coming to a final agreement and understanding.

In this sense it is frightening, and I advise young people "on their way up" in their careers to study it in this light, to see how easy it can be to slip into a kind of officiousness that is divorced in every way from morality, how easy it is to divorce one's self from ethics by "going along," "not making waves." There is surely an element of that in all kinds of business meetings, including those where the business is criminal.

A scene in the film came to mind, because I have felt myself being consumed with rage and anger and, yes, frankly hatred over the last four years.

The scene comes at the end of the film, after all of the participants in the conference have left, after agreeing in an affable business-like sense to murder all of Europe's Jews in a two hour meeting. Heydrich (Branagh), Adolf Eichmann (played by Stanley Tucci), and Heinrich Mueller, head of the Gestapo, sit together to have a drink and commiserate about the outcome of the meeting. They discuss a story told by Friedrich Wilhelm Kritzinger, a State Secretary in the chancellery, who is portrayed in the film as having had reservations about the murder of the Jews, although it is not clear in the historical record that this actually was the case for the real Kritzinger.

The scene has stuck in my mind for many years as a kind of warning should one let oneself be consumed and defined by hatred.

No one here, I'm convinced, is consumed by race based hatred like Heydrich's Eichmann's and Mueller's hatred of the Jews, but I know for myself, I have repeatedly felt consumed by perhaps a more justified hatred over the last 4 years, which, irrespective of its origins and its justifications, is hatred all the same.

Speaking only for myself, in these days of liberation and relief, I want to let go of it; as hard as it is, I want to let go of the hatred. It does nothing good for me.

January 23, 2021

Still high...

Amanda Gorman's poem deepens my conviction that this coming generation is going to a great generation like none we've seen, and Yo Yo Ma, the beautiful comforting voice, the happiness, the Amazing Grace.

And then there's that old white guy, sprinting around the White House filled with fire, as if with a magic wand, expelling demons.

That old white guy makes me feel so much better about being an old white guy, which has been something of an embarrassment of late.

Suddenly I feel, at least, the joy of youth.

Yo Yo Ma, how beautiful, how unbelievably beautiful:

This old man is glad to have lived to see this!!!!!