Periodic Reporting for period 3 - CONTROL (Laser control over crystal nucleation)
Reporting period: 2022-09-01 to 2024-02-29
Crystals are enormously important in day-to-day technological applications from semiconductors used for solar energy generation, through paint, to pharmaceutical drugs. Crystals of a particular molecule typically come in a number of variants referred to as “polymorphs” and it is often important which polymorph is formed when a crystal nucleates. For example, in the case of pharmaceutical drugs, different polymorphs will dissolve at different rates, which implies that a particular drug may dissolve in your stomach, your belly, or not at all, which could mean that it kills you, cures you, or does nothing. So, controlling crystal nucleation and controlling which polymorph is formed is a very practically important issue. Unfortunately, crystal nucleation is still poorly understood and even more poorly controlled.
In the late 1990s and early 2000s, it was shown that a pulsed laser can be used to induce nucleation of crystals in a supersaturated solution. Most excitingly, it was reported that the laser polarisation could be used to control which polymorph would nucleate, promising an unprecedented degree of control. In the 2010s, it was shown that non-pulsed and therefore much cheaper lasers could be used to nucleate crystals and also control the polymorph. This suggested that cheap lasers might one day be used in industry to crystallise compounds of commercial interest.
However, it was not at all clear how laser-induced crystal nucleation worked, what the physics behind it is. Without understanding the physics of a process, you cannot predict what it will do, how it will work, or how to improve it. First it was suggested that the laser could simply line up molecules through an effect discovered in 1875 by Glasgow scientist the revered John Kerr. However, this effect is much too weak on the level of individual molecules. In the 2010s, it was suggested that the laser might interact with clusters of molecules. But where would these clusters come from?
In 2018, we figured out that you could exploit separation of phases, a bit like separating oil and water. Oil and water don’t normally mix but would mix at a high enough temperature. At the precise temperature and concentration point where the phases start to mix, is the so-called critical point. Near this critical point, it is really easy to manipulate matter, for example, with a laser. This idea formed the basis of the CONTROL research programme.
In the late 1990s and early 2000s, it was shown that a pulsed laser can be used to induce nucleation of crystals in a supersaturated solution. Most excitingly, it was reported that the laser polarisation could be used to control which polymorph would nucleate, promising an unprecedented degree of control. In the 2010s, it was shown that non-pulsed and therefore much cheaper lasers could be used to nucleate crystals and also control the polymorph. This suggested that cheap lasers might one day be used in industry to crystallise compounds of commercial interest.
However, it was not at all clear how laser-induced crystal nucleation worked, what the physics behind it is. Without understanding the physics of a process, you cannot predict what it will do, how it will work, or how to improve it. First it was suggested that the laser could simply line up molecules through an effect discovered in 1875 by Glasgow scientist the revered John Kerr. However, this effect is much too weak on the level of individual molecules. In the 2010s, it was suggested that the laser might interact with clusters of molecules. But where would these clusters come from?
In 2018, we figured out that you could exploit separation of phases, a bit like separating oil and water. Oil and water don’t normally mix but would mix at a high enough temperature. At the precise temperature and concentration point where the phases start to mix, is the so-called critical point. Near this critical point, it is really easy to manipulate matter, for example, with a laser. This idea formed the basis of the CONTROL research programme.
The CONTROL team started out by building a microscope system to carry out the main experiments on. It consists of a relatively standard microscopy core equipped with sample temperature control and multiple way to image samples in real time. In addition, two “optical tweezing” lasers (pulsed and not pulsed) can be focussed in the samples; these lasers are one of the main methods to trigger the crystal nucleation process. A third (low power but very pure) laser is focussed into the samples to carry out Raman spectroscopy: this technique allows one to observe the characteristic vibrations of the molecules in the sample. These vibrations will change depending on whether you are looking at a solution or a crystal or perhaps something in between.
Simultaneously, the CONTROL team started investigating the basic physical properties of solutions and liquids that could be used to investigate crystal nucleation (or lack thereof). We determined temperatures at which crystallisation takes place or at which the sample solidifies into an amorphous glass. We investigated the effects of a third component, sometimes referred to an anti-solvent, and its role in crystal nucleation. We carried out various spectroscopic investigations: femtosecond optical Kerr-effect spectroscopy to detect the vibrations of clusters of molecules that are associated with the very first steps of nucleation; Raman spectroscopy to observe the folding and unfolding of side groups as molecules (try to) fall into the regular packing of the crystal; and fluorescence spectroscopy as a marker of crystallisation. The Diamond Light Source in Oxford was used to scatter a narrow beam of x-ray radiation off samples to learn about the evolving structures as molecules try to crystallise. Collaborators carried out atomistic molecular-dynamics simulations on super computers to understand the supramolecular structures that form, solid-state nuclear magnetic resonance (ssNMR) spectroscopy to determine the shape of molecules, and calorimetry (heat measurements) to temperatures as low as just 1 degree above the absolute of zero.
All this to discover that nature does not actually work the way you expected…
Simultaneously, the CONTROL team started investigating the basic physical properties of solutions and liquids that could be used to investigate crystal nucleation (or lack thereof). We determined temperatures at which crystallisation takes place or at which the sample solidifies into an amorphous glass. We investigated the effects of a third component, sometimes referred to an anti-solvent, and its role in crystal nucleation. We carried out various spectroscopic investigations: femtosecond optical Kerr-effect spectroscopy to detect the vibrations of clusters of molecules that are associated with the very first steps of nucleation; Raman spectroscopy to observe the folding and unfolding of side groups as molecules (try to) fall into the regular packing of the crystal; and fluorescence spectroscopy as a marker of crystallisation. The Diamond Light Source in Oxford was used to scatter a narrow beam of x-ray radiation off samples to learn about the evolving structures as molecules try to crystallise. Collaborators carried out atomistic molecular-dynamics simulations on super computers to understand the supramolecular structures that form, solid-state nuclear magnetic resonance (ssNMR) spectroscopy to determine the shape of molecules, and calorimetry (heat measurements) to temperatures as low as just 1 degree above the absolute of zero.
All this to discover that nature does not actually work the way you expected…
The CONTROL team set out to reproduce previous work and to investigate the role of hidden liquid-liquid critical points. However, we were unable to reproduce this older work and annoyingly the samples appeared to contain dust. This “dust” turned out not to be dust at all (nor bacteria, nor fungus) but an amorphous (“glass” like) form of the molecules we were trying to crystallise using the laser. When these amorphous particles are touched by the laser, they turn into crystals. There are now a number of reports in the scientific literature showing the presence of similar amorphous clusters that play a role in the nucleation of crystals. A review of the literature on laser-induced nucleation shows that most of these require the samples to age, which we showed causes the formation of the amorphous particles. Therefore, this is likely to be a more general phenomenon.
While investigating the basic physical properties of solutions and liquids, we serendipitously stumbled upon a family of liquids that can either crystallise or form a glass, while the molecules have a very simple symmetric shape. This simple molecular shape allowed us to measure a spectral feature that represents exactly those structures that prevent the liquid from crystallising. Combining a large number of experimental techniques and simulations showed that these structures are caused by densely packed molecules tending towards but prevented from actually attaining crystalline structural order. In light of the discovery of the role of amorphous particles in crystallisation, understanding the amorphous phase is clearly very important.
In the second half of the project, we are expecting to characterise the amorphous particles in a much larger range of systems. We have already found molecules that form many more amorphous particles and have made some slow progress in concentrating them in order to analyse them using techniques such as x-ray scattering and transmission electron microscopy and diffraction. The next step would be to improve our understanding through modelling in order to understand the role of laser light in promoting one polymorph over another. Preliminary work on another family of liquids has shown that some of these behave like rubber, which is novel for liquids of small molecules, and we hope will change our view of liquids near the glass transition. Hopefully the second half of the project will be less affected by pandemics.
While investigating the basic physical properties of solutions and liquids, we serendipitously stumbled upon a family of liquids that can either crystallise or form a glass, while the molecules have a very simple symmetric shape. This simple molecular shape allowed us to measure a spectral feature that represents exactly those structures that prevent the liquid from crystallising. Combining a large number of experimental techniques and simulations showed that these structures are caused by densely packed molecules tending towards but prevented from actually attaining crystalline structural order. In light of the discovery of the role of amorphous particles in crystallisation, understanding the amorphous phase is clearly very important.
In the second half of the project, we are expecting to characterise the amorphous particles in a much larger range of systems. We have already found molecules that form many more amorphous particles and have made some slow progress in concentrating them in order to analyse them using techniques such as x-ray scattering and transmission electron microscopy and diffraction. The next step would be to improve our understanding through modelling in order to understand the role of laser light in promoting one polymorph over another. Preliminary work on another family of liquids has shown that some of these behave like rubber, which is novel for liquids of small molecules, and we hope will change our view of liquids near the glass transition. Hopefully the second half of the project will be less affected by pandemics.