Gry Christensen was a 15-year-old grade 11 student when she participated in a “citizen science” project to understand how different crystals in mussel shells form. But unlike most school experiments, the samples he and 1,000 of his fellow middle school students prepared were then blasted by scientists in a particle accelerator using X-rays 10 billion times brighter than the sun.
“It was a bit of an eye-opener,” Christensen says of the study, called Project M, in which students from 110 schools participated. They prepared different samples of calcium carbonate (the main component of mussel shells), which the scientists then examined at Britain’s national synchrotron (a type of circular particle accelerator) at the Diamond Light Source in Oxfordshire. The goal was to help scientists better understand how to create different types of crystal structures from the same chemical. “Later I became more interested in chemistry,” 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. The crystal structure can affect the strength of steel and even the therapeutic effectiveness of drugs developed to treat AIDS and Parkinson’s disease.
Calcium carbonate is the main compound in rocks such as chalk, limestone, and marble, derived from organic materials including crusts. Besides being responsible for those pesky lime stains around taps, it has useful applications from antacid tablets to concrete blocks. His colleague and fellow chemist at Diamond Light Source, Dr. Chemist Dr. D., who led Project M with Julia Parker in 2017. “Calcium carbonate is all around us,” says Claire Murray. But one notable challenge is controlling crystal forms.
The results weren’t just scientific: school participants excited about chemistry then attended internship interviews
A crystal is a solid in which the components are arranged in a highly regular and repeating pattern, and the shape of this pattern (crystal structure) determines the properties of the material. A common example of the effect of crystal structure is carbon; It is useful for taking notes when the atoms are arranged in honeycomb-shaped lattice layers in pencil lead (graphite), but it is much harder and much more expensive when the atoms are arranged in a regularly arranged manner. the cubic crystal lattice that forms the diamond.
In other materials, control over the possible crystal structures or “polymorphs” of a material has been a matter of life and death. In the early 1980s, life expectancy following an AIDS-related diagnosis was less than two years. Thanks to the development of antiretroviral treatments, including a drug called ritonavir, patient outcomes began to improve significantly in the mid-1990s. However, two years after its initial launch in 1996, the drug was withdrawn from the market due to problems with the stability of its crystal structure.
Ritonavir capsules were initially distributed with the active ingredient in a highly concentrated solution. Unfortunately, these conditions caused the active drug to change its structure, becoming less soluble than its original and thus much less effective as a medicine. Since then, further drug development has solved the problem. However, the Parkinson’s drug rotigotine faced similar problems with a less soluble crystal structure emerging in 2008, triggering a mass recall in Europe, while in the US the drug was out of stock until 2012, when drug developers came up with a reformulation .
D., CEO and scientific and technical director of Avant-Garde Materials Simulation (AMS), a German company that develops software for crystal structure prediction. “There are many recent examples, but not all of them are publicly available,” says Marcus Neumann. “When samples affect a drug that’s already on the market, it becomes public. And fortunately, that doesn’t happen very often.”
For more than 20 years, AMS has been developing computer codes that can predict what crystal structures might form for a given chemical compound to help pharmaceutical companies catch problematic polymorphs before a drug is launched. In 2019, AMS demonstrated that its code could predict the emergence of a problematic form of rotigotine. Recent updates to the algorithm include the effects of temperature and humidity, and also use comparisons with crystal structure data from pharmaceutical companies AMS works with: AstraZeneca, Novartis, AbbVie (now producing reformulated ritonavir) and UCB Pharma (producing reformulated ritonavir). rotigotine patches).
However, determining the experimental conditions required to produce a particular crystal remains challenging, as different structures can form with small changes in conditions and one structure can transform into another. You can think of it like oranges lined up in a box. You can place a square grid of oranges and balance each orange in the layer above directly on top of the orange below; they stabilize well for a while. However, just a touch will cause the oranges on top to nestle at the bottom between the oranges in the layer below; This is a more stable structure.
Head of materials science R&D at Merck’s life sciences division, Dr. “There is still a lot of need for experimentation, as many factors regarding how to obtain certain crystal structures are not 100% understood,” says Adam Raw. While additives are added to push the system towards a specific crystal structure, exactly the approach Project M is investigating, he highlights “the multitude of factors that can come into play.”
Calcium carbonate has three possible crystal structures: aragonite, vaterite, and calcite. Dr. Julia Parker says she selectively grows what a mussel needs (for example, the more durable calcite for its outer shell) and “does not use harsh chemical conditions.” “Just additives, organic molecules.” Parker and Murray wondered whether the right additive at the right concentration would help them control the formation of vaterite versus calcite.
At the Diamond Light Source, the pair were able to quickly distinguish small changes in the crystal structure of hundreds of samples by examining the paths of X-rays from the synchrotron scattered through each crystal’s lattice. (The synchrotron accelerates electrons and emits X-rays as the electrons change direction to move around it.) Until the idea of working with England came up, the bottleneck was preparing all the samples to test factors such as the additive used, concentration and mixing time. schools by taking advantage of similarities in laboratories and environmental conditions.
Christensen and other students at Didcot girls’ school near Diamond were the first to try the sample preparation kits and helped guide Parker and Murray through the equipment and instructions needed in each kit. The data needed to characterize each sample were collected in just one day at the synchrotron.
The results, published in January this year, help shed light on the conditions that significantly favor or inhibit vaterite formation and provide insight into the ways these crystals form. “I think they’ve made progress in showing which factors most correspond to biomineralization [living creatures making minerals] and the formation of these calcium carbonate crystals in biological applications,” Raw says. “But of course there’s more work to be done.” But the results of the project weren’t just scientific: School participants excited about chemistry later came to Diamond for internship interviews.
“With the project, it was like you were doing something for the real world, not just an experiment at school,” Christensen says.