by Gry Christensen was a 15-year-old year 11 student when she took part in a “citizen science” project to understand how the different crystals in mussel shells form. But unlike most school experiments, scientists then blasted the samples she and her 1,000 middle school classmates had prepared in a particle accelerator using X-rays 10bn times brighter than the sun.
“It was an eye-opener,” Christensen says of the study, called Project M, which involved students from 110 schools. They prepared various samples of calcium carbonate (the main component of mussel shells) which were then examined by scientists at the UK’s national synchrotron (a type of circular particle accelerator), the Diamond Light Source in Oxfordshire. The aim was to help scientists better understand how to form different types of crystal structures from the same chemical. “I was more interested in chemistry after that,” says Christensen, who went on to study agricultural science at Gråsten Landbrugsskole in Denmark. “Chemistry really helped me gain insight into the natural world.”
But while such an approach may be new, understanding how crystals form is an old problem with serious consequences. Crystal structure can affect the strength of steel, and even the therapeutic activity of medications developed to treat AIDS and Parkinson’s disease.
Calcium carbonate is the main compound in rocks such as chalk, limestone and marble, which comes from organic materials including shells. It is responsible for those annoying limescale stains around faucets, as well as useful applications from antacid tablets to concrete blocks. “Calcium carbonate is all around us,” says Dr Claire Murray, a chemist who led Project M in 2017 with a colleague and fellow chemist at the Diamond Light Source, Dr Julia Parker. But one challenge that remains unsolved is controlling its crystal forms.
The results were not only scientific: school participants who were enthusiastic about chemistry later turned up for internship interviews
A crystal is a solid in which components are arranged in a highly ordered and repeating pattern, and the shape of this pattern – the crystal structure – determines the properties of the material. A common example of the crystal structure effect is carbon – useful for jotting down notes when the atoms lie in sheets of honeycomb lattices in pencil lead (graphite), but much more difficult, and much more expensive, when which the atoms are arranged in. the cubic crystal lattice that forms a diamond.
In other materials, gaining control over the substance’s possible crystal structures – or “polymorphs” – was a matter of life and death. In the early 1980s, life expectancy after an AIDS-related diagnosis was less than two years. Patient outcomes improved significantly by the mid-1990s, thanks to the development of antiretroviral treatments, including a drug called ritonavir. However, two years after its initial release in 1996, the drug was withdrawn from the market due to issues with the stability of its crystal structure.
The ritonavir capsules were first dispensed with the active ingredient in a highly concentrated solution. Unfortunately, these conditions caused the active drug to change structure, becoming less soluble than the original and therefore much less effective as a drug. Further drug development has since solved the problem. However, similar problems with the Parkinson’s drug rotaginin and a less soluble crystal structure emerged in 2008, prompting a batch recall in Europe and in the US the drug was listed as out of stock until 2012, when drug developers found a reformulation.
“There are many recent examples, but not all of them are public,” says Dr. Marcus Neumann, CEO and scientific and technical director of Avant-garde Materials Simulation (AMS), a German company that develops software to predict crystal structure. “Examples are made public when they interfere with a drug that is already on the market. And thankfully, that doesn’t happen often.”
For more than 20 years, AMS has been making improvements to computer code that can predict what crystal structures can form for a given chemical compound, helping drug companies catch problematic polymorphs before a drug is brought to market. In 2019, AMS showed that its code could predict the appearance of a problematic form of rotigotine. Recent updates to the algorithm incorporate the effects of temperature and humidity, and also use comparisons with crystal structure data from drug companies AMS has worked with including AstraZeneca, Novartis, AbbVie (which now produces reformulated ritonavir), and UCB Pharma (which produces the restoration. rotigotine patches).
However, identifying the experimental conditions required to produce a specific crystal remains challenging, as different structures can occur with little change in conditions, and one structure can transform into another. You can think of it like oranges stacked in a box. You can lay out a square grid of oranges and balance each orange in the layer above directly on top of the orange below, and they will balance out perfectly for a while. However, just a tap will nest the oranges on top in the swim between oranges in the row below – the most stable structure.
“There is still a lot of need for experimentation because many factors are not 100% understood in how to achieve certain crystal structures,” says Dr. Adam Raw, head of materials science R&D in the life science division at Merck. He emphasizes the “large number of factors that can come into play” when introducing additives to push the system towards a certain crystal structure, precisely the approach that Project M investigated.
Calcium carbonate has three possible crystal structures: aragonite, vaterite and calcite. A mussel selectively grows what it needs – the most durable calcite for the outer shell, for example – and “without the use of harsh chemical conditions,” says Dr Julia Parker. “Just additives, organic molecules.” Parker and Murray wondered if the right additive at the right concentration would help them control the growth of vatarite versus calcite.
At the Diamond Light Source, the pair could quickly distinguish small changes in the crystal structure of hundreds of samples by examining the paths of X-rays from the synchrotron as they scattered from each crystal’s lattice. (The synchrotron accelerates electrons, which emit X-rays as they change direction to move around it.) The mess was preparing all the samples – to test factors including the additive used, the concentration and the mixed time – until the idea of working with the UK ended. schools, taking advantage of similarities in the laboratories and environmental conditions.
Christensen and classmates at Didcot Girls’ School, located near Diamond, were the first to try out the sample preparation kits and helped guide Parker and Murray to the equipment and instructions needed in each kit. . The data required to characterize each sample was collected in one day at the synchrotron.
The results, published in January of this year, help to shed light on the conditions that greatly favor or discourage the formation of vaterite, and provide insight into the ways in which these crystals form. “I think they have made progress in showing which factors are most likely to respond to biomining [living creatures making minerals] and forming these calcium carbonate crystals in biological applications,” says Raw. “But of course there is much more work to be done.” The results of the project were not just scientific results, however: school participants who were enthusiastic about chemistry appeared at Diamond for internship interviews.
“With the project it was like you were doing something for the real world, not just an experiment at school,” says Christensen.
