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Perverse Polymorphism

I mentioned polymorphs the other day, and no mention of those should go by without a reference to the classic 1995 article on “disappearing polymorphs” and its 2015 follow-up. This is a controversial area, but what everyone can agree on is that there are numerous cases where some particular crystal form of a compound has been prepared and characterized, but later on becomes far more difficult to obtain at all. There are various values for the terms in that statement, but as the case of ritonavir shows, you can have a compound that has been worked on for years and produced commercially in bulk that hits upon a more stable solid phase. And since these more stable crystal forms tend to have very different solubilities, the effect on a drug development program (or in ritonavir’s case, a drug that is already rolling off the manufacturing line!) can be extremely unwelcome.

When this happens, it can seem as if the original crystal form is going extinct and never to be seen again, an effect that seems almost supernatural. But as these papers note, the “unintentional crystalline seed” hypothesis is surely the explanation. Organic chemists are well acquainted with the idea of seed crystals being added to a solution, but we’re adding them all the time whether we realize it or not. That’s both likely and plausible when you do the numbers:

Many laymen are initially skeptical about a phenomenon caused by particles that cannot be seen, although very few would accept an invitation for a casual—and unprotected— visit to the pneumonia ward at their local hospital. The approximate limit of visual detection for the naked eye is a crystal that weighs approximately 10-6g. We pointed out earlier that a speck of that size contains approximately 1016 molecules and while there are various estimates of the size of a critical nucleus that could act as a seed even the largest— a few million molecules[23]—would mean that an invisible particle could contain up to 1010 of such unintentional seeds.

What’s more, a given cubic foot of air could easily contain a million or so particles under a half-micron size without anyone noticing at all. Consider also that such too-small-to-see particles can lurk in what looks like a clear solution, and you have plenty of opportunities to spread a given polymorph around by what seems like magic. The 2015 paper tracks down several examples of the spread of such material

It’s also not true that polymorphs can truly go extinct, either, although it’s understandable that it might appear that way. There are always conditions out there to obtain the old crystalline form, although there is no requirement that these be easy to find (!) Indeed, the original form of ritonavir was recovered and brought back into production after a great deal of effort, although not before HIV-positive patients had seen their medicine disappear from the shelves for months (and not before Abbott had lost a quarter of a billion dollars along the way). But as the authors point out, every one of these situations really is unique; that adjective is used here in its exact sense. There are compounds for which only one crystalline form has ever been reported, and there are others with two dozen polymorphs (and when that’s happening, you can be pretty sure that there are some others that haven’t shown up yet). Only one polymorph of aspirin was known until 2005, when another turned up, Since we are still no good at predicting polymorphs and crystallization conditions in general, anyone working on such a problem will have to prepare for a great deal of experimentation, both wide-ranging and precise, which is not such an easy combination to realize.

The 2015 paper goes into detail on several cases from the drug industry, and you will not be surprised to hear that this squarely intersects with patent issues. The legal landscape in this area is something of a mess, or at least that’s my impression. People sue claiming that Patent X is invalid because it didn’t actually cover useful polymorph number 18, and are countersued by the original holders claiming that there is no way that the procedures described could have produced what the plaintiffs are claiming, and on and on. Various legal teams have staked out positions over the years that range from “everything in the world is covered in microscopic seed crystals of everything” all the way to “there is no evidence for crystal seeding whatsoever”, depending on the issues at hand, which is of course what lawyers are paid to do. But there’s quite a bit of room between those two(!), and  the “every single case is unique” aspect of crystallization does not blend well with the legal need for fundamental principles and rules that apply across different situations. Consider that the law not only has to deal with polymorphs but with hydrates and solvates as well (crystal forms that have water or other solvents as part of their lattice) and that those can form polymorphs all their own, and it’s no surprise that all this is still such a tangle in the courts. And on the lab bench!

20 comments on “Perverse Polymorphism”

  1. luysii says:

    Ice-9 – -https://en.wikipedia.org/wiki/Cat%27s_Cradle

  2. Cato says:

    Great article!

  3. loupgarous says:

    There are references in Richard Rhodes’ popular-audience book on the slow encephalopathies and their transmission Deadly Feasts to a chemical plant which somehow got “infected” with a chemical “seed” that made an unusable polymorph of the plant’s main product, EDTA, and had to be decommissioned.

    Is there anything to that? Rhodes’ source seems to be the late Carleton Gajudsek, Nobel Prize (Physiology or Medicine, 1976) laureate.

    I can’t find that incident described anywhere else. Does anyone here know about that?

  4. Ted says:

    Hi all:

    When I joined Upjohn Process in ’93 I had a hallway conversation with one of the older scientists that stuck with me. He told me about a more stable polymorph coming up post drug approval. The API failed a dissolution release before they realized what had happened. At first it was just some reworks, but then they couldn’t get the original even with heavy seeding – which blew most of their seed stock. They started moving the process from building to building, but eventually the “new” polymorph would take over. They transferred the process to France, but after a few months the new form predominated. The last ditch was to move it to Puerto Rico, and when they started failing there they resorted to refiling. It sounds a lot like the Ritonavir story, although a few years too early and the wrong company.

    Does this ring a bell for anyone else?

    best,

    -t

  5. colintd says:

    I think you might be referring to the Bell Labs problem. Before the hydrothermal method for growing quartz crystals, Bell Labs spent several years producing commercial quantities of the piezoelectric crystals of ethylene diamine tartrate for use as oscillators. Then one day they started getting “parasitic growths” on their lovely clean crystals. Investigation showed it was a previously unknown monohydrate form.

    Despite developing a cunning way to reducing the impact of the monohydrate https://patents.google.com/patent/US2592729 volume production never resumed. Partly this was due to the development of ways to grow artificial quartz, but if it wasn’t for the monohydrate it may well have been we’d be using EDT crystals in our digital devices to this day.

    The first time I came across this was a reference in the Oct 1960 issue of “Analog Science Fact to Fiction”, which has a great article on crystals and crystal growing (I read an old copy as a child in the 70s). This was later extended into the wonderful https://www.amazon.co.uk/Crystals-Crystal-Growing-MIT-Press/dp/0262580500 by Alan Holden. I would recommend this book to anyone interested in crystals.

  6. colintd says:

    In the Analog Science Fiction article there is also an interesting story about crystallising glycerine and seed crystals, with one lab able to do it, and another only able to produce a super-cooled syrup, until a seed crystal is sent from the first lab, after which they can never recreate the super-cooled state.

    I’ve just checked and for those who are interested there is a complete scan here https://drive.google.com/file/d/1mP4ULPwpUxlpiTqJep1Gjepf_B_sMCqh/view . Article (titled “The self-repairing robot”) starts p83, the Glycerine story is bottom of p87, Bell Labs EDT problems on p88)

    1. Derek Lowe says:

      For many years, fructose was known as the “uncrystallizable sugar”. Finally, a seed-with-everything effort gave some; as I recall, the vial that was nucleated with pentaerithritol crystallized, so all the crystalline fructose in the world is presumably derived from that!

      1. Colintd says:

        That I didn’t know. Happy Thanksgiving.

      2. A Nonny Mouse says:

        Sounds like a “Barton-ism”….. “I’ve known perfectly respectable sugars take years to crystallise….”

    2. loupgarous says:

      Thanks much – finding a firm source for that drove me crazy, and it’s a notable addition to wikipedia’s article on EDTA.

  7. Some idiot says:

    I have had personal experience of very many promising processes which died/became problematic later on due to the appearance of another crystal form (not necessarily restricted to polymorphs). My advice (and personal practice) is to try and induce the crystallisation of irritating forms as early possible in the process (the relevant word here is “try”: there is absolutely no guarantee you can, even if it can/will exist!!!). Not (necessarily) because I am a masochist, but rather because I prefer to get bad news earlier in development, and not in the middle of a critical campaign…!
    On the other hand, I have experience of production processes which have run for some years before some intermediate crystallises out. Although potentially irritating in the short term, it is generally a very useful thing!!!

    1. colintd says:

      I remember from my undergrad days one professor who had a jar full of mixed up dirt he’d collected from all the labs he’d ever worked at. When he couldn’t get something to crystallise, he’d add a pinch from the jar, and surprisingly often those magic crystals would form. The downside, however, with that particular jar would set any geiger counters merrily clicking away, as one of the labs he’d been in dealt with processing of uranium ores…

  8. colintd says:

    And just for completeness this article in the 1950 Bell Labs journal is probably the original source of the description of the problem https://www.americanradiohistory.com/Archive-Bell-Laboratories-Record/50s/Bell-Laboratories-Record-1950-01.pdf (p13 “The case of the barnacled crystals”), which includes photographs of the anhydrous crystals with the monohydrate “barnacles”.

    It in turn references this Dec 1947 article https://www.americanradiohistory.com/Archive-Bell-Laboratories-Record/40s/Bell-Laboratories-Record-1947-10.pdf which gives wonderful details of the EDT crystal growing production plant (pre-monohydrate problems) used to produce crystals for war time SONAR use.

    1. loupgarous says:

      Thanks, again. This may be the first documented incident in which unintentional crystal polymorphism became economically and technically important.

      1. Colintd says:

        Glad to have helped. When Derek wrote this article the EDT problem came immediately to mind, and I was glad that I was able to go back further and find the now online Bell Labs journals.

  9. aairfccha says:

    Could the composition of pretty much omnipresent background trace contaminants have an effect beyond seeding by pushing the process of crystallisation towards another form as a catalyst? For example, there should be much less lead compounds from gasoline around now than decades ago.

  10. DoesNotMatter says:

    Fascinating.

    I am admittedly somewhat below interested amateur in most science matter – days only so long etc. – but I thought I got the broad strokes mostly.

    I had no idea that this was/is a problem, nor that it is, going by what I’ve read now, such a puzzle to replicate controllably.

    You never can say you know enough.

    1. loupgarous says:

      DoesNotMatter: “You never can say you know enough.”

      Which is why I keep reading this blog and others like it. I’m over 60, and keep seeing new things other folks have found out.

  11. Jim Hartley says:

    From “Public relations footnote” in the “2015 followup” paper:

    “There was no gradual trend. Something occurred that caused the new form to occur…There was no early warning.”

    “We, quite honestly, have not been able to pinpoint the precise conditions which led to the appearance of the new crystal form. We now know that the new form is, in fact, more stable than the earlier form, so nature would appear to favor it…Form II is new.”

    “We did not know how to detect the new form. We did not know how to test for it. We did not know what caused it. We didn’t know how to prevent it. And we kept asking the question, why now?…We did not know the physical properties
    of the new form…We did not know how to clean it, and we did not know how to get rid of it.”

    “…our initial activities were directed toward eliminating Form II from our environment. Then we finally accepted that we could not get rid of Form II. Then our subsequent activities were directed to figuring out how to live in a Form II world.”

    “This is why all of us at Abbott have been working extremely hard throughout the summer [of 1998], often around the clock, and sometimes never going home at night. We have been here seven days a week and we will continue to do so. We have cancelled vacations and asked our families for their understanding and support. This is not an issue that we take lightly.”

    “There were several sub-teams of three to 600 people per team working full time in different areas. We also called on as many resources as we could.”

    “We tried everything. We conducted countless experiments. We reconditioned our facilities. We rebuilt facilities and new lines. We looked at alternative sites. We visited a number of [other] organizations around the world…to see if we could start clean in a new environment free of Form II.”

    “In a matter of weeks—maybe five or six weeks, every place the product was became contaminated with Form II crystals.”

    Question: “You are a large multinational company. Your scientists are obviously smart. How could this happen?”

    Answer: “A company’s size and the collective IQs of their scientists have no relationship to this problem…This obviously has not happened to every drug. But it has happened to other drugs.”

  12. JimM says:

    We visited a number of [other] organizations around the world…to see if we could start clean in a new environment free of Form II.”

    “In a matter of weeks—maybe five or six weeks, every place the product was became contaminated with Form II crystals.”

    I’m sure in hindsight it’s occurred to them that the former might have had something to do with the latter.

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