Movers and shapeshifters in the world of solid state chemistry
Have you ever left a bar of chocolate for a long time only to find, disappointingly, that it is covered in a white layer and doesn’t taste quite right?
This white layer is caused by a change in crystal form of the chocolate. Over time, the molecules in the chocolate crystals rearrange. This causes a partial melting of fats which rise to the surface causing the white bloom. The white layer is not mould, but “fat bloom”.
Chemicals that can exist in different crystal forms are said to exhibit polymorphism. Different polymorphs can have differing physical properties, such as thermal stability, solubility, colour, hardness and melting point. Chocolate can exist in at least six different crystal forms, known as Forms I-VI.
Many given polymorphic substances have a single polymorph that is preferred for its specific properties. In the case of chocolate, Form V is favoured because of its melting point (33.8 ˚C – approximately mouth temperature) and its shininess. The tempering process used by chocolatiers, which involves cooling the chocolate slowly, serves to increase the amount of Form V chocolate in a finished product.
Chocolate’s Form VI, however, is the most stable. Left long enough, all other crystal forms of chocolate will eventually convert to Form VI. Sadly, Form VI is also more brittle and melts at a higher temperature than Form V… that’s why old chocolate is dry and powdery.
Polymorphic drugs
Chocolate is just one example where polymorph selection is key. Polymorphs play an important role beyond matters of taste and colour. In the pharmaceutical industry, for example, polymorphism is highly significant. This is because the crystal form can affect characteristics of the drug, like solubility, which in turn affects bioavailability.
In one of the most famous examples to date, the anti-retroviral drug Ritonavir underwent temporary market withdrawal due to interconversion of crystal forms. It was found that stocks of ritonavir originally created as capsules and containing the Form I crystal were spontaneously converting to the previously undiscovered, and less bioavailable, Form II [1].
The issue was eventually solved by reformulation of the capsules into a refrigerated gelcap. Needless to say, having a full understanding of the various crystalline lattices exhibited by a given molecule is pertinent, across many fields in chemistry.
Navigating the crystal maze
Recently, two research groups working independently have demonstrated new ways to find previously uncovered crystal forms of even the most studied molecules.
In a research group at the University of Montreal [2], elemental replacement was used to create molecules that mimic the shape of a target molecule but have some atoms replaced with different elements. Those augmented molecules can then be incorporated into seed crystals of mixed composition. When placed in supersaturated solutions of the target molecule, the mixed-seed crystals induced small conformational changes that led to the production of previously unseen crystal forms.
A second study at Newcastle University used a different method altogether. Nanolitre droplets containing a solution of a target molecule in organic solvent were suspended in inert oil. Hundreds of these suspended droplets, representing different crystallization conditions, were created and monitored in parallel by robots. The use of oil encapsulation is a handy trick resulting in the slow loss of solvent from the nanodrop, up to and beyond the point of saturation for the target molecule. This leads to the perfect conditions for crystallization. The sheer volume of conditions that could be tested meant that one set was found to lead to a new crystal form altogether.
The first method is effective due to designed changes to the crystallization process. That said, the second has the merit of applying the brute force of high-throughput techniques to the problem of polymorphism.
Both of these research groups studied an interesting small molecule known as ROY (for the numerous red, orange and yellow crystal forms it exhibits). Already known to crystallize in twelve distinct forms, these two studies separately uncovered new polymorphs of ROY, bringing the total number of known crystal structures for ROY to an impressive fourteen.
Entropy-neurial spirit
Given their importance and sometimes surprising properties, polymorphs frequently feature as the subject of patents. For small molecule drugs, marketing authorization is often given for a specific polymorph.
Therefore, a patent which claims the marketed polymorph provides relatively strong protection. Polymorphism is typically studied at a much later point than when the earliest patents are filed for a drug (relating to the compounds themselves). Accordingly, polymorph patents can play a highly important role in the lifecycle management of pharmaceuticals because they often provide protection for a marketed product that extends beyond the lifetime of the first patents.
At the European Patent Office (EPO) there is a mass of case law surrounding polymorph patents. Briefly, for pharmaceuticals, when no polymorphs are yet known, it is expected that a research team will undertake a systematic investigation to screen for polymorphic forms. The inevitable results of such a routine screening program - i.e. the mere discovery of a crystalline form, when previously none were known - will often be considered obvious and hence not patentable. However, if a particular polymorph has surprising, unexpected, and advantageous characteristics then it may well be considered inventive. This is especially the case where one or more polymorphs have previously been reported for that compound. In that scenario, in the eyes of the EPO, a skilled person typically has no motivation to seek out new, even better, polymorphs and hence a later-discovered polymorph having improved properties is much more likely to be deemed inventive.
It is also worth noting that the techniques for finding polymorphs in themselves, to the extent that they are novel and non-obvious, can also be protected with patents. Clearly, such methods will be of great interest to the pharmaceutical industry and beyond!
[1] Bauer J, Spanton S, Henry R, et al. Ritonavir: an extraordinary example of conformational polymorphism. Pharm Res. 2001;18(6):859-866. DOI:10.1023/a:1011052932607
[2] Alexandre Lévesque, Thierry Maris, and James D. Wuest, Journal of the American Chemical Society 2020 142 (27), 11873-11883. DOI: 10.1021/jacs.0c04434
