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Drug Synthesis In Printed Reactors

I’m still trying to get my bearings with this new paper from the Cronin group at Glasgow. What it proposes is a new style of API (active pharmaceutical ingredient) production. Instead of being done in bench- or process-scale lab glassware or in production-plant reactors, these syntheses take place in 3D-printed reactors, connected together in ways so that the whole process can be moved forward with solvent and/or nitrogen pressure.

That’s a pretty ingenious idea. They have various modules for things like filtration, lighter-than-water (and heavier-than-water) extraction, etc., as shown in the scheme and photograph at right (in the photo, the various reactors are built already connected). These are produced by 3D printing with polypropylene, which gives a good intersection between “printability” and chemical reaction capability). Those of us who have taken up all kinds of nasty reagents over the years in the commonly available PP syringes can attest to its durability. One disadvantage, as noted in the text, is that the rough surfaces inherent to current 3D printing techniques lower the recovery from each vessel somewhat as compared to similar glass reactors (on the other hand, you can’t shatter the things). Overall, I find this  printed-small-reactor idea more interesting than I do the drug synthesis part. I hope that 3D printing will allow the development and prototyping of all sorts of new lab apparatus, and I don’t want to take away from that aspect of this paper at all.

But as written, the paper is more aimed at drug synthesis. It demonstrates several (known) synthetic pathways to common drug substances, such as two steps to lamotrigine, three steps to zolimidine, and four steps to baclofen, starting from available industrial precursors. I should note that these synthetic steps require numerous operations, though (addition, mixing, heating, cooling, extraction, filtration, transfer into the next vessel and so on), and they seem to have these working quite well in the PP reactor suites.

A natural next question is why one would want to do API synthesis this way. Here’s the paper’s rationale:

The distribution model for fine and specialty chemicals, such as the APIs implied by this approach, would lead to a decentralizing of logistical approaches to chemical manufacture. Here, any location with access to a sufficiently diverse market of chemical precursors and suitable cartridge fabrication facilities could be used to produce chemical products, which could previously be achieved only in a fully equipped synthesis laboratory with highly trained staff. This approach not only holds promise for eventually delivering on-demand personalized medicines manufactured at, or near, the point of use, but also has short-term potential applications in the synthesis of APIs that are currently out of production. . .

. . .Our methodology will have the most rapid impact for chemicals that are currently produced on demand in small batches and that occupy a gap in the market where the demand for a product is sufficient for it to be commercially viable but insufficient to justify plant-scale production. This gap lies between the high cost of bench-scale versus reactor- scale synthesis, and thus the digitization benefit of compounds in this zone is high

I’m not completely convinced by this, for several reasons. My first impulse is that any region with a sufficiently diverse market of chemical precursors and cartridge fabrication facilities may be able to make APIs in the “traditional” ways. If not, then I come to the same question I had about the Jamison lab’s compact flow machinery for DARPA: if you can ship that machine and the reagents needed for it (or in this case, if you can ship the reagents and the 3D printer and its supplies), then you can ship in APIs, too, for less cost and trouble. I understand that Cronin et al. are picturing a situation where these machines and this technology are already distributed, ready to be configured for what syntheses may come, but I’m not sure how we get to that world from the one we’re in now.

In other words, if you’re in a location where there’s a bottle of methyl p-chlorocinnamate on the shelf, that shelf could usefully also hold a bottle of baclofen as well, which is what you’d make from that precursor. Similarly, if it’s a place where someone can ship you a supply of the cinnamate, they can ship you a supply of baclofen, too, and relieve you of the trouble of keeping all the other reagents around that are needed for its synthesis. Another thing to remember is that the number of reagents, solvents, and precursors needed for a reasonably-sized pharmacopeia is actually quite large.

Here’s another, much larger consideration: if someone ships you a bottle, crate, or shipping container of baclofen, it’s probably going to be baclofen tablets. Not the powder that comes right out of the reactor suite. There is usually a difference. The words “formulation”, “tablet”, “capsule”, “excipient” and “particle size” do not appear in this paper, and those are just the kinds of words and concepts that are usually needed to take you from a bulk chemical to a drug that’s suitable for patients to put in their mouths. Now, if I’m in a real medical jam, I’m going to happily swallow whatever API powder I can get, washed down with any liquid to hand. But that’s not how you want to run things if you can help it. This is certainly not an insurmountable problem, but it is a problem, and the paper sort of glides over it.

To Prof. Cronin’s credit, though, the paper does address another problem: regulation:

The regulatory framework necessary to produce complex materials in this fashion will need thorough attention; indeed, our approach would require a completely new system for the regulation of API manufacture. This system would have to be developed alongside the evolution of this approach as a method for pharmaceutical synthesis, which we have presented here in proof- of-concept form; however, we can envision a situation in which regulatory agencies certify specific cartridge or module designs as soon as a digitized process is fully established (including the embedded quality-control protocols.

That’s a tall order, and it’s worth remembering that it will only happen if there’s enough perceived utility and enough demand. Let’s go back to the chemistry, then, for another thought. What scale are these APIs being made on? The baclofen synthesis starts with 200mg the cinnamate and produces 98mg of API, and that seems to be what’s envisioned here:

This approach not only holds promise for eventually delivering on-demand personalized medicines manufactured at, or near, the point of use, but also has short-term potential applications in the synthesis of APIs that are currently out of production. An immediate impact of digitization is that the cost for synthesis at the bench scale (milligrams) could decrease markedly owing to savings in labor and infrastructure with only a one-off digitization cost (and allow operators to make 5 to 10 different products at the same time).

That paragraph (to my mind) is mixing two different things. Bench-scale synthesis of milligram amounts is (or can be) a very different thing than the synthesis of APIs that are out of production. Put simply, these reactors will need further work if they’re to be scaled up. As any industrial chemist knows, the procedures for mixing, heating and cooling, filtration, extraction, and transfer become quite different as you move to larger scales, and if you’re starting on the 200mg scale they’re going to become different pretty quickly. (That’s not to mention the likely need for a completely different model of 3D printer in order to make the reactors themselves). The paper does suggest using smaller reactors in parallel, although I should note that that complicates things under the current regulatory framework.

I bring this up because the demonstrated synthesis of baclofen is enough to make four or five tablets (if you had the facilities to make tablets, that is). There may well be benefits to making such compounds at the point of delivery, but there are significant benefits to making them on scale, too. I note in passing that baclofen itself is available from at least 13 suppliers (although, to be sure, I don’t know if they’re all making it themselves).

And that leads to another large argument I have with this idea. As the quotes above show, one of the propositions behind this work is that manufacturing costs are a key barrier to the availability of drugs. But in my experience, that is rarely the case. To be sure, I have not spent my career in the generic-compound end of the industry, and the low margins in that business can make manufacturing costs more of a factor. But the barriers to generic drug availability are more often regulatory and legal ones than they are manufacturing ones. It’s true that the cost per milligram for such compounds could come down through this small-reactor technique, but only if you just need milligrams. If you need much more compound, then it becomes far less expensive to make it on scale in a defined batch and ship it somewhere.

So here’s my question, and it’s a similar one to what I had with the DARPA-funded synthesizer work: can someone lay out a general situation where this sort of point-of-use drug synthesis would be the best way to go? I don’t mean in general terms; the paper itself does that. But does the real world overlap with those general terms, and if so, how? What APIs are currently produced “on demand and in small batches” where that part itself is the limit on availability? I’m willing to be convinced, but I’m not convinced yet.

Note: there have been a couple of clueless headlines about this work that talk about “3D printed drugs”, but the paper itself makes no such claims. of course. It’s been a safe bet for some years now that any press coverage with that phrase in it was written by someone who has no idea what they’re talking about, and that rule still holds.

42 comments on “Drug Synthesis In Printed Reactors”

  1. Martin says:

    “On demand/small batches” – maybe radiolabelled molecules?

    1. John Wayne says:

      That is a great idea Martin.

    2. Barry says:

      That the author doesn’t mention radioisotope work–which is the killer application for this idea–suggests that he’s working on a second manuscript/patent for just that. D.L.J.Clive has been doing this (albeit with swagelocks, rather than 3-D printing) for years.

      1. sf says:

        what are you talking about?

    3. Jamil says:

      Short lived PET radiotracers for parenteral administration are already being produced on disposable cassette based chemistry systems in clean rooms (see GE FASTlab as an example). To make different radiotracers on the same chemistry system we have to do risk assessment then cleaning validations. The regulatory demands add most of the cost and I really cannot see how this type of system would be cost effective for API manufacture.

      1. former radiochemist says:

        I would agree with Jamil about the PET applications being limited. PET has plenty of assembled cartridge systems already, making them by your self sounds like more of a pain in the arse than anything else. Especially as these systems are very difficult to develop as they must work >99% of the time and delivering a non-sterile or contaminated sample will get your lab shut down.

        As for long lived isotope radiosynthesis (e.g. C14), I can’t see how it would help, you need to make you compound quickly to a deadline, not play around with your 3D printed flow system for 3 months! Similarly to normal org chem, you also make a very wide variety of compounds so having bespoke stuff for one compound isn’t that useful if it only lets you do synthesis on a small scale.

  2. Uncle Al says:

    A repeated gram/dose is questionable. If one seeks a pharmacological rainbow of curated milligram doses – (upscale) recreational pharmaceuticals – or are exploratory, it makes sense DCF/ROI. Portability is important re Breaking Bad, capital investment being largely in compact printers not bulky fragile apparatus.

  3. PrintingBad says:

    You asked for an example where this point-of drug use would be useful? Didn’t you just earlier write an article about a hospital that wanted to make its own drugs due to availability problems?

    1. b says:

      “But the barriers to generic drug availability are more often regulatory and legal ones than they are manufacturing ones.”

      The exact same point was made in both the post you cite and this one. The availability problems are generally not those of supply. I assumed he meant an example of point-of-use in which supply is the problem. Radiolabelled compounds would be a good example, as Martin states above.

    2. Derek Lowe says:

      Ah, but that was a whole group of hospitals who wanted to band together and make the compound(s) in bulk (or contract someone else to make them) to save money. This is very close to the opposite, which is why I can’t figure out where it fits in.

  4. bill says:

    ” savings in labor and infrastructure”

    My experience of flow chemistry & cont. manufacture at scale is that you need more chemists, engineers and operators, who are more highly skilled (expensive), contrary to belief that these technologies reduce cost. Perhaps applies here

  5. NJBiologist says:

    “I bring this up because the demonstrated synthesis of baclofen is enough to make four or five tablets (if you had the facilities to make tablets, that is).”

    Derek, it’s worse than you realize. As the patient accommodates to the side effects, baclofen doses for spasticity can get to 80 mg/day. If you make that patient 200 mg, they’ll be back on day 3, wondering where you’ve got their lunchtime dose.

  6. Anon says:

    Centralized manufacturing and distribution was invented to improve the poor efficiencies of DEcentralized manufacture and distribution. So basically, this guy has taken a perfectly good solution to a long-forgotten problem, and reinvented the original problem for it!

  7. anon the II says:

    This is actually very simple. It’s obvious to about anyone who reads this blog that this is an insanely stupid way to deliver drugs to people. However, if you are a chemist who is playing around with a 3D printer and has always been fascinated by flow style chemistry AND you need a publication, then why not spin this as a way to “put it to the man”, the man being the greedy pharmaceutical industry. It worked very well. He got the pub and the press he wanted. And you’re all arguing about the technical details of what was an obvious publicity stunt.

    Having said all that, the paper showed a lot of clever stuff and, maybe as Martin suggested, there could be some utility for niche applications.

  8. tlp says:

    It sounds useful for a fantastic chemogenomics world where each patient is getting their genome sequenced, personal drug designed, and where each phenotype is rare enough (or even completely new) for pharma to bother to produce drugs on scale. For point-of-care synthesis of baclofen it doesn’t make sense.

  9. MoMo says:

    Printer ink is more expensive than gold.

    Those are going to be some expensive cartridges!

  10. Peter Kenny says:

    As a way to deliver (legal) drugs this doesn’t currently look viable. There may be opportunities in PET field.

  11. tt says:

    As an experienced process chemist, I agree with all the aforementioned criticisms made in the post…It boggles the mind why this paper was published in Science and is a great example of salesmanship and academic research / hype at its worst. The only possible utility of this is to simply prototype and test reactor designs and even that is a bit of a stretch considering scale effects (mass transfer, heating, mixing, etc…) are best explored through modeling and simulation. My first reaction to this paper was why…as in if I live somewhere with access to lots of chemicals, why couldn’t I just order a bunch of cheap glassware with valves and connectors (setting aside the question of why not just order the fully formulated drug in the first place). At least the Jamison/DARPA work in flow is more of a good test bed to push the limits of the tech and invent new stuff (rather than its stated goals to make drugs), and there are already companies that 3D print flow reactors.

    From a regulatory/safety standpoint, this is a terrible idea as one would still need QC oversight and spec setting on regulated starting materials (as well as reagents/solvents), control systems to prevent deviations from acceptable operating space, in-process analytics, release criteria with validated assays to ensure product quality (as well as no deadly impurities are present), and of course correct crystal form and particle size that is suitable for formulating. All of these analytical needs and testing as well as formulating immediately swamp any perceived benefit/cost associated with 3D printing a simple reaction vessel. These regulations and tests exist for very good reasons, namely patient safety by ensuring product quality and hence provide a very strong rationale for centralized production (not to mention the economy of scale and reliable supply chains on key RMs). I find that all of the authors claims to utility are laughable at best, but kudos to both his use of buzzwords and ability to generate hype. Science should also be ashamed…did any actual, working industrial chemists (or even better, chemical engineers) with knowledge of pharmaceutical production actually review this paper? I could keep going with both criticism of the actual work as well as its stated potential…but my typing fingers grow weary.

  12. cyn says:

    This Cronin paper is a turd, no matter how many ways you polish it up.

    1. Regular Joe says:

      You may not be able to polish a turd but you can roll it in glitter

      1. Peter Kenny says:

        Dietary fiber is the key to delivery of polishable turds

  13. Yvar says:

    Polypropylene syringes are great one-use items, but I’d have a lot of concern about synthesizing different drugs in the same reactor with contamination of the vessels. And if these are one-use items, disposal will be a nightmare since they’ll all be hazardous waste (not to mention radioactive if used to make PET imaging agents). I really don’t understand what you do with these reactors after you’ve made the first batch.

    1. John campbell says:

      Radioactivity of PET reagents is effectively zero after a few days.

  14. Isidore says:

    How about developing a single platform instrument that will carry out all QC release tests (UV/Vis, FTIR, TLC, pH, dissolution, LC-MS, and whatever else small molecule people do, I work on proteins myself). I think this would be much more useful than any synthesis machine. And probably easier to develop, build and validate.

    1. Shane says:

      Now we re talking, it doesn’t how big or small the production run is, product validation by chemical analysis and loads of paper work will always exsist (except in the zombie Apocalypse)

  15. cynical1 says:

    I think all of you are forgetting about the zombie apocalypse. Then and only then will this find it’s true niche in “society” when both the number of humans and their access to medicines approach zero. Fire this puppy up and voila: You have 200 mg of baclofen. Actually, you could use the baclofen on the zombies too! From what I can tell, it would appear as if baclofen might be the first drug to try on them with all of those jerky movements.

    1. Derek Lowe says:

      Gotta devote some thought to your endpoints here. Do you really want the zombies to be able to move more around more effectively?

      1. cynical1 says:

        Well, hypothetically, if you watch The Walking Dead, you will find that, at times, one has to use zombies to attack one’s enemies in the post-apocalyptic world. And zombies are awfully easy to kill when they’re lurching and bumbling around. So a nice bolus of baclofen might increase your odds of success at using them as weapons. (All of this predicated on the rampant demise of the moral and ethical fabric of society at the onset of the zombie apocalypse. Probably a safe bet.)

        1. WD-most-overrated-POS-ever says:

          If you watch the Walking Dead, you should know that zombies are a plot device that can be easily killed or even ignored when it is convenient, only to become an insurmountable threat at other points in the episode, for no reason other than to facilitate an ailing plot.

  16. J Campbell says:

    I don’t have access to the full paper but I am not sure how it differs from other small scale flow systems as reviewed by Steve Ley here:!divAbstract

  17. Sean Fearsalach says:

    But it might be useful ror the OTHER pharmaceutical industry.

  18. Ben says:

    One potential use case I can see for this is in locations with unstable electricity: if you can start from shelf-stable reagents and synthesize small batches of APIs that would require refrigeration to be regularly stocked, you can run your synthesis when the power is on and work in small batches that are consumed before their non-refrigerated shelf life expires. I don’t know enough about pharmaceuticals to name any specific candidates, unfortunately.

  19. Todd Knarr says:

    I think the only possible niche would be for drugs where the precursors or base components are readily stored and shipped but the drugs themselves are either perishable or difficult to transport to an extent that makes shipping from a central large production facility impractical. That’s what you need for region where some drugs are needed often enough that one-off bench synthesis can’t produce as much as needed but there isn’t enough demand within the viable service area to justify a large-volume production facility.

    1. tt says:

      I can’t think of a single marketed drug where this is the case…

  20. DrOcto says:

    I think I recall a dodgey HIV antiviral sales effort in Africa a while back. The flaw was the drug needed to be stored refridgerated, but was being stored and shipped to patients at African room temp.
    So in the hypothetical situation that you have a site that can’t afford a fridge, but has access to high tech 3D-printing, internet, and a steady supply of raw materials, …..perhaps…..maybe?

  21. gippgig says:

    If commercial 3D printers-for-rent facilities don’t already exist they soon will.
    It shouldn’t be too hard to 3D print capsules to put the API in. (hmm… I wonder if the standard PLA is digestible?)
    Where would this be useful in the real world? Well, if you consider it real world, a manned Mars mission… maybe.

    1. Thomas McEntee says:

      3D printing service bureaus are in business to print-to-order: Send them a STL file, specify your material, and they’ll print whatever and how many copies you want. They’re all over the US and elsewhere in the world. Collectively, they work with all of the common 3D printing polymers as well as metals, including Ti6Al4V for aerospace applications and medical implants, various nickel-based superalloys, cobalt-chromium, aluminum alloys, etc.

      With respect to polymers, the common polymers are poly(lactic acid) (PLA), ABS, polycarbonate, polyamides, and less commonly, polysulfone-based materials. 3D Systems offers “polypropylene-like” material, something that is based on isobornyl acrylate, but I haven’t come across actual (“real”) PP. But this is a technology driven by innovation and experiementation so the sky is the limit in what people will experiment with in materials.

      In the aerospace business, Boeing, Lockheed Martin, and Northrop Grumman have been building aircraft parts for the past 20 years…but the qualification process for FAA airworthiness certification is a long and slow haul. 3D printing has the advantage of reducing titanium usage as compared to subtractive manufacturing processes: Subtractive manufacturing (e.g. milling) leads to generation of 4-5 kgs of scrap for every kg of finished parts. GE is presently building fuel injectors for their LEAP engine using a cobalt-chromium alloy and also is building aircraft turbine engine blades using 3D printing with a carefully-modified titanium aluminide alloy. The investments needed to gain manufacturing proficiency are large: GE reportedly has invested more than a billion USD in 3D printing (additive manufacturing)

  22. Paul Brookes says:

    A key issue here is the availability of solvent-resistant plastics to print with. Most hobbyist/consumer 3D printers use PLA (ploylactic acid, aka bioplastic), which is biodegradable and not stable to THF or methylene chloride. The more expensive consumer models (heated print bed) can use ABS which dissolves in acetone.

    In-fact, one way people smooth out their printed objects to remove horizontal lines leftover from FDM style printers is with “vapor polishing” (i.e. suspend the object in a chamber filled with solvent vapor). It’s scary to think there’s a hefty amount of THF in non-fume -hood settings in basement hobbyshops all over the world!

    Sure, it is “technically” possible to 3D print in stainless steel, titanium, etc. (see GE’s printed airplane turbine blades) but the machinery to do that is priced far beyond the reach of most.

  23. eagleon says:

    his is out there, but: Try making borosilicate on Mars. Sourcing a high-quality silica source and heating it to the temperatures required is a tall order. This provides an option in-situ for production of rare drugs that MC couldn’t foresee needing to ship, or which would face expiration problems far away from a steady supply, and might require less energy and water if the reactor materials can be efficiently purified and recycled. Making more pp from ethanol to replace stock contaminated beyond recovery is a stretch, granted, but if they’re shipping a pp-capable printer, it’s probably being put to other use and there’s enough to go around. Yes, you could just ship glassware (how much is enough?), but this could still be a pretty nice backup for inevitable breakage.

  24. Dr Doom says:

    My next submission to Science shall outline my new line of modular custom reactors for drug synthesis I shall name it QUICKFIT and we shall demonstrate the synthesis of SNAKE OIL :-@

  25. Okemist says:

    Possession of an unlicensed tableting machine is a felony, you could use it to formulate a number of regulated controlled substances. But this whole Gizmo has already been done, see Milkshakes blog on poly propylene production of meth in “Shake” chemistry.

    1. eagleon says:

      You’re talking about ? Unless there’s some other statute, the law fully takes into account intent, listing imprinting a counterfeit marking, possessing while knowing it will be used by you or someone else for producing a controlled substance, or for export or sale to someone who will. Read: it’s fine to own one, so long as you’re not making chewable oxycontins with it, or selling drywall plaster as off-brand tylenol. If this law worked that way, GNC would be facing life in prison for selling gelatin capsules to people taking creatine without wanting to gag.

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