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Understanding crystallisation: a key to more reliable medicines

Geneva, March 27, 2025 - Dr Pierrick Berruyer.

At the end of the 90s, a pharmaceutical company suffered a colossal loss of over 250 million dollars when it was forced to temporarily withdraw one of the first HIV drugs, ritonavir, from the market. The cause? A crystallisation problem. This incident reminded the scientific, academic and industrial community of the crucial importance of understanding and controlling solid-state matter and pharmaceutical products. The molecular structure of an active molecule and the purity of its manufacture are not in themselves a guarantee of the drug's ultimate efficacy.Ìý

In an article published in March 2025 in theÌýProceedings of the National Academy of SciencesÌý(PNAS), T. Adachi, assistant professor in the School of chemistry and biochemistry at the AV¶ÌÊÓƵ, and his team rationalised the effect of an additive (sodium chloride) on the initial stages of glycine crystallisation. Additives are commonly used in the pharmaceutical industry to control the crystallisation of active molecules. Thanks to an innovative method developed by the group, it is now possible to observe, describe and understand previously unexplored phenomena. In the case of glycine, their observations contradict a widely accepted mechanism of γ-glycine formation in salt water, and the results provide a crucial advance towards the rational control of polymorphs.

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Time-lapse videos of the formation of γ-glycine crystals from a single β-glycine crystal in salt water (clips 1 and 2). Video of a crystal showing the coexistence of α- and β-glycine, followed by dissolution of the β-glycine.

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WHEN DRUGS LOSE THEIR EFFECTIVENESS: THE ROLE OF CRYSTALLINE FORMS

The crystalline state, a widespread form of the solid state, sees molecules arranged in an orderly, repetitive manner, like the bricks in a well-built wall. However, the same molecule can crystallise in different ways, a phenomenon known as polymorphism. Although they are the same molecule, polymorphs can have distinct chemical properties, such as solubility, thermal stability and bioavailability. In the case of ritonavir, the appearance of an unknown polymorph on the production lines contaminated them, forcing a temporary halt to production. This new polymorph, which was not very soluble in water, greatly reduced the drug's efficacy.

Understanding and controlling the crystallisation process is essential for guaranteeing the quality and efficacy of pharmaceutical products. Prof. Adachi, from the Department of Physical Chemistry and principal investigator of this study, explains:Ìý

« The phenomenon of crystallisation remains largely misunderstood; it is still a mystery how molecules assemble into a specific crystalline pattern. In general, we crystallise and observe the end result, without really controlling nucleation. It is known that crystallisation conditions and additives can influence the final crystal, but the rationalisation of these processes is still in its infancy and the end result remains speculative.Ìý»

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RATIONALISE CRYSTALLISATION FOR CONTROLLED PRODUCTION

In this research, the group sought to understand how an additive (sodium chloride) influences glycine crystallisation. To do this, the team relied on a method developed in 2022, which makes it possible to observe a single crystal being formed at the pre-nucleation stage:Ìýsingle crystal nucleation spectroscopyÌý(SCNS), based on Raman spectroscopy with an optical trap. Dr Johanna Brazard, researcher and author of the study, explains:Ìý

« This unique method, developed by our laboratory, gives us a considerable lead. We are one of the few chemists in the world who can accurately observe a single crystal in the process of formation.Ìý»

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The SCNS allows us to observe glycine nucleation in aqueous medium for the first time, with or without sodium chloride (NaCl). Glycine can crystallise in several forms: alpha-, beta- and gamma-glycine. With or without NaCl in the water, beta-glycine crystals always appear first. Without NaCl, these are rapidly transformed into alpha-glycine and do not evolve any further. In the presence of NaCl, the researchers show that the beta-glycine crystals persist, and then gamma-glycine forms on the surface of the beta-glycine. The beta-glycine eventually dissolves again. Their precise observations made it possible to attribute the final formation of gamma-glycine to the stabilisation of beta-glycine by NaCl. In the absence of NaCl, beta-glycine disappears too quickly for gamma-glycine to form. Although absent in the final state (with or without NaCl), it is the formation of beta-glycine and whether it is stabilised by NaCl that plays a key role here.

The SCNS method developed by Prof. Adachi's group makes it possible to clearly attribute the role of the additive (NaCl) in the crystallisation of glycine in an aqueous medium. It provides crucial information for accelerating the study of the early stages of crystallisation and rationally controlling polymorphisms. By mastering these stages, chemists could abandon costly and risky trial-and-error methods, rationalising the crystallisation of molecules more precisely and efficiently. This would reduce costs and increase the reliability of drug manufacturing processes. This breakthrough could transform the development of pharmaceutical products, offering faster and safer solutions for the production of essential medicines. It is a promising step towards a better understanding and control of crystallisation phenomena.