Crystallisation: Doing more with less

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The pharmaceutical industry relies on crystallisation experiments to study impurities and assess product quality. The problem is, it faces significant challenges in the availability of active pharmaceutical ingredients (APIs), forcing it to conduct frequent and complex crystallisation experiments with less material. Here, Dr. Carmen Guguta, global head of business development and marketing at Technobis Crystallization Systems, explores how laboratories can do more complex experiments with small amounts of material by using benchtop analytical technology.

Key insights:

  • Geopolitical factors and the logistical effects of Brexit, have driven up manufacturing and transport costs, placing an ever-heavier burden on laboratory research budgets.
  • By reducing the mass of active pharmaceutical ingredient (API) required in experiments, scientists can free up more of their vital funding for other spending.
  • If laboratories were to upgrade their workflow using innovative benchtop equipment, running multiple, complex experiments simultaneously with small sample sizes would become easy.

For years, laboratories have been able to access cheaper raw materials from across the world, but recent disruptions have made this more difficult. For example, a report by the European Parliament concluded that 60 to 80% of APIs are manufactured in India or China. However, pandemic travel restrictions across these regions, as well as other geopolitical issues like Brexit and the Ukraine-Russia conflict, have disrupted the supply of these materials, forcing many laboratories to look elsewhere.

As a result, API prices have soared, having a knock-on effect on drugs like paracetamol, meropenem and metformin, which have increased in price by 139%, 127% and 124%, respectively. Transportation prices have also soared. In some cases, the cost of shipping per kilogram of freight has increased by up to 360%.

This has placed heavy financial burdens on companies, who must carry out frequent and complex crystallisation experiments, such as evaporation and vapour diffusion, to obtain X-ray quality single crystals, with smaller amounts of material. If laboratories were to upgrade their workflow using innovative benchtop equipment, running multiple, complex experiments simultaneously with small sample sizes would become easy.

Effortless experimentation

Conducting a full crystallisation screen, where parameters are carefully controlled to obtain X-ray quality single crystals, typically requires about one gram of sample. However, due to the challenges affecting API availability, this isn’t always feasible for laboratories.

Laboratories need an instrument capable of carrying out a full screen with less material. For example, they can benefit from single benchtop instruments that carry out slurry experiments, thermocycling, slow cooling, and sublimation with real-time turbidity readings, using just one milligram of sample. It is now even possible to run vapour diffusion and evaporation crystallisation experiments on these instruments, adding to their versatility. These are more advanced processes that involve carefully controlling vacuum pressures, temperatures and stirring speeds to obtain X-ray quality single crystals for structural determination of the API.

Traditionally, many of these experiments were conducted separately, requiring multiple machines, often spread over different labs. As a result, it could take several days to grow single crystals of an X-ray quality. Transporting samples to different machines also increases the risk of cross contamination as well as requiring more manual labour.

Using benchtop equipment like Technobis’ CrystalBreeder, which can conduct up to 32 parallel experiments at working volumes of 0.06–0.10 milliliters, means that X-ray quality single crystals can be grown within four hours. This helps to reduce the time to market for any company that relies on crystallisation research for its products. Performing these experiments in one place also reduces manual labour and avoids contamination.