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Down At the Crystal Surface

If you’re at all involved in producing solid forms of compounds, you’re familiar with the concept of a polymorph. That, put simply, is a different crystalline form, and any given substance can have several. Or a lot more than several. I don’t know what the record is for any single compound, but it’s way up into the dozens, and you never know when a new one might show up. You can get these different forms through all sorts of variations in the way the compound is crystallized or precipitated: different solvents, different temperatures, different types of stirring (yes indeed), different concentrations. . .and we haven’t even gotten to hydrates and solvates, where molecules of water or other solvents are incorporated into the crystal structure as it forms. And those can have polymorphs in turn, or different ratios of water and solvent, and there’s just no end to it.

Polymorphs can behave completely differently from each other. The same substance, completely pure, can come out looking like several unmistakable crystal types (rods, prisms, plates), in different crystalline space groups, with completely different melting points and solubility behavior. Past blog posts on this are here, here, here, and here, and as that last one illustrates, this is definitely not something of just theoretical interest. The saga of the anti-HIV drug Ritonavir is the classic example. That altered solubility behavior is of tremendous importance for drug dosing, and in Ritonavir’s case, a more stable (and less desirable!) polymorph appeared and threatened to disrupt the entire supply of the drug, because after a while, it was appearing more and more in the production line. “More stable”, of course, can easily mean “so stable it would rather not dissolve and get into the bloodstream”. Polymorphs themselves can be patented separately over such meaningful differences, as can methods for their production.

Even very simple compounds can show grindingly complex behavior. Aspirin, for example, exists in two polymorphs (so far) that are so similar that they can both show up in the same single crystal, and it takes good X-ray data (and a good X-ray crystallographer) to work out what’s going on. One of those past blog post links is about the trickiness of phenylalanine, a substance you’d think had been studied to pieces by now. But as that link shows, D-ribose is in the same category: the crystallographic literature for years was all over the place.

How about something even more simple than those? I refer to the most simple amino acid of all, glycine. This new paper has some details on its polymorphs, and the ridiculously subtle effects that cause them to form. There are three that form under “normal” conditions from aqueous solution, and while the gamma one is the most thermodynamically stable, the alpha one is kinetically favored. Adding small amounts of simple alcohols to the aqueous solution starts producing mixtures of the alpha and beta forms, though, and eventually, as the alcohol concentration goes up, you only get the beta form. All classic polymorph behavior. But why? Here’s what the authors found:

Herein, by applying extremely sensitive pyroelectric measurements and impedance spectroscopy at different temperatures, we discovered that methanol, unlike water, is incorporated in a polar mode within the bulk of the growing a-polymorph. Consequently, the solvent molecules create polar domains, which exhibit pyroelectricity (i.e., they develop temporary voltage when exposed to temperature changes). As a result, it follows that the incorporated solvent molecules operate as conventional “tailor-made” inhibitors of this polymorph.

It appears that the alpha-form starts growing in a pyramidal shape, just as it usually does, but then starts incorporating methanol-solvated glycine molecules into its growing lattice. This buries methanol molecules into the crystal as it continues forming, and creates zones of higher polarity because of the different orientation of those solvated glycines (and the slight deformations in the nearest neighbor glycine arrangements as well). The normal arrangement in the crystal is a sort of “canceled-out” glycine dimer, but that gets disrupted into a more polarizable form. That’s the origin of the pyroelectric effect they’re able to detect.

Once this starts happening, that developing surface of the crystal ends up “poisoned”, as some molecular dynamic simulations suggest, by the methanols incorporated into the lattice. The new surface doesn’t recognize the usual glycine-dimer form so readily, and further growth is inhibited – you see truncated pyramids of the alpha-form that have stopped in their tracks. Meanwhile, the beta-form end up with one surface (a more hydrophilic one) similarly poisoned and inhibited, but another one (a more hydrophobic one) is totally unaffected, so the crystal grows more rapidly along that face and produces long rods of the beta-form.

This level of detail answers some questions and raises others. There are probably all sorts of metastable crystal forms (and crystal surfaces) showing up in complex polymorph situations, and the ability to see and characterize these things will (as in this case) give us a better physical picture of what’s going on. But predicting such behavior is another thing entirely. You’d hope as we start to pile up enough detail that predictive power will start to emerge (hello, machine learning). That’s a reasonable hope, but there’s no reason that things have to work out that way. The whole “Big Data” effort across various sciences is putting that view of the world to the test, and sometimes it’s going to work out and sometimes it isn’t. Stay tuned!

7 comments on “Down At the Crystal Surface”

  1. AvidBiotech says:

    Interestingly the concept of what it means to be crystalline featured in ongoing litigation between a biotech and potential generic entrant – original patent for the biotech had defined crystalline polymorph and generic had originally intended to construe as implying a long range order that potential generic lacked (therefore not violating patent). They had proposed XRPD to resolve. I wonder how better characterization might inform these kinds of debates!

  2. Some idiot says:

    Nice piece of work… Reminds me of Richard Kellog’s work on kinetic crystallization inhibitors, leading to (apart from other things) control of polymorphism and single enantiomer crystallization. Plus the later work which included racemisation catalysts in order to obtain a single enantiomer in essentially 100 % yield from a racemic starting material… In my opinion the most likely origin for “handedness” of amino acids….! And all from considering what is happening on a molecule by molecule basis on a growing crystal surface… Lovely stuff!!!

    (-:

  3. DLIB says:

    I’ve seen this kind of thing in reverse as well…the selective inhibition of an etch plane during the etching of single crystal Si….It’s a way to get a perfectly mirror finish on the edge of etched 100 Si. Using Iso
    in the etch solution.

  4. Torchwood says:

    I am underwhelmed by the number of comments here for a great post and a great paper. Usually there are 10, 20 or more comments posted everyday here (100 if it’s about GSK). Some related things to add to your list of polymorphs, hydrates and their polymorphs, solvates, ….
    1. The paper reminds me a little of inorganic crystals where you can change the habit (not polymorph) with ppm quantities of similar inorganics such as thiosulfate blocking some faces in sodium chlorate crystals. Mullin’s book has more cool examples.
    2. Conformers and that weird phenomena of heating a supersaturated system to make it nucleate
    3. Conformational isomers and cagey crystals that form synthons with water or solvents or counterions or all of the above and with non integer stoichiometry, all resulting in similar XRD patterns that can confuse the heck out of you
    4. Some polymorphs have different colors too!
    I feel crystallization is still an under-resourced area that gets little attention in Pharma. The crystallization field is growing rapidly for all the above phenomenological reasons. I’ve seen crystallization or form controlling steps jammed in at the end of a synthesis, hurried to meet timelines, assumed it can be done by your run-of-the-mill chemist or CMO and not given as much respect as other synthetic steps. The polymorph is a CQA, you want to show you can control it even if there is only one known form.

  5. A Nonny Mouse says:

    What isn’t too well know is that polymorphs of polymerisation catalysts can lead to quite different polymer structures; I was once involved with a company that was trying to get round a patent in this area.

  6. Anon says:

    Folks may be interested in this (open access) paper from the Continuous Manufacturing and Crystallisation group in the UK describing a workflow for designing/controlling continuous crystallisation from initial investigations up to manufacturing scale
    http://pubs.rsc.org/en/Content/ArticleLanding/2018/ME/c7me00096k#!divAbstract

  7. NJBiologist says:

    OK, I admit: I got a laugh out of the idea of crystals getting methanol poisoning (would that make crystallographers blind to structure…?).

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