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Improving crystallisation research for drug development

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Here Dr. Carmen Guguta, global head of business development and marketing at crystallisation technology provider, Technobis Crystallization Systems, explains how new technology is streamlining crystallisation research.

Key insights:

Crystallisation research plays a crucial role in drug development as more than 90 per cent of APIs are synthesised as a crystalline product. Traditionally, several challenges have interfered with scientists’ ability to deliver crystallisation research effectively.

Crystallisation research is necessary from the start of the drug development process to find either the most thermodynamically stable form or the right polymorphic form of a drug. It is one of the oldest separation methods in the world and has contributed to the efficient production of high-value, life-saving drugs for decades. Crystallisation is commonly used to help define the solid-state landscape and avoid unwanted issues such as poor solubility or permeability, which can cause the failure of promising chemical entities.

Initial considerations when testing crystallisation conditions

Chemists must be able to describe their compound by testing a wide range of crystallisation conditions, such as solvent systems, compound concentrations, counter-ions, and temperature profiles. Understanding the solubility of the compound in different solvents is necessary for scientists to design ongoing experiments. Once a temperature dependent solubility study has taken place, the scientists will have more information about the physico-chemical properties of the compound, its polymorphic behaviour of the compound and how to design future solid state screening studies.

However, achieving this is not without challenges. Scientists must be able to control their laboratory environments to avoid interference in experiments, cope with copious amounts of data, and perform several experiments with sometimes only milligrams of material.

Controlling temperatures in the lab

Creating crystals using traditional methods involves using a hot plate with a magnetic stirrer to experiment with different solvents. However, this equipment presents various challenges. Firstly, it’s potentially a safety hazard and secondly, experiments on hotplates will be affected by ambient atmospheres. As an example, a lab in Malaysia will have a much warmer, more humid ambient atmosphere than a lab in The Netherlands. This can also be a problem if the laboratory uses air conditioning, which will create a cooler ambient environment.

As a result, compound behaviour may differ depending on the location of the lab, or even the weather on the day of the experiment. This is the reason that temperature-controlled reactors are important in crystallisation research. The greater temperature control scientists have when conducting crystallisation experiments, the more reproducible each experiment is.

Laboratory technology is evolving to help solve this problem. Laboratories can now access table-top multi-reactor systems that allow scientists to heat and cool samples in a controlled manner. The Crystal16 V3, for example, controls the temperature of four block reactors from -20 to 150 degrees Celsius with a precision of 0.5 degrees. Scientists that require even lower temperatures of around -25 degrees Celsius can achieve this, for all four blocks in parallel, using a chiller. Therefore, ambient temperatures are less likely to affect the outcome of crystallisation research.

Streamlining laboratory processes

Before innovations in technology, crystallisation research was a time-consuming task. Previously, scientists determined solubility using HPLC, which could take several days to complete — valuable time that could be used elsewhere in the lab. Now, scientists can use 16 parallel reactors to generate solubility curves for four solvents in just two hours, with less than 100 mg of material.

With an increased demand for scientists in the pharmaceutical industry to analyse more samples in less time to accelerate drug launches, laboratory equipment must be designed to increase throughput. New technology means scientists can perform up to 16 different crystallisation experiments on the same device, generating simple phase diagrams and solubility curves, in a way that improves efficiency and reduces laboratory operating costs.

The result of such an increase in throughput is naturally a growth in data. Innovations in software have led to the creation of laboratory automation tools that help scientists to better organise, manage, and analyse their findings. Now, the examination of solubility and transmissivity data for all block reactors can be examined on the same interface, making data analysis more efficient.

We’ve also seen the introduction of more user-friendly new drag and click software packages. This software includes features such as predefined temperature profiles and integrated transmissivity technology. Scientists can easily determine cloud and clear points, obtaining solubility and metastable zone width data at an early stage.

Making the most out of materials

Sometimes, laboratory staff may only have access to a few milligrams of material, for reasons such as cost or lab space, despite needing to conduct several experiments. Innovations in lab technology mean that systems, like Crystal 16 V3, have enlarged measurement windows where scientists can screen crystallisation conditions at the 1 ml scale. This means that labs can conduct even more experiments than thought possible with smaller amounts of material.

Innovations in laboratory technology are necessary to support scientists as they develop new API formulations. How industry challenges are tackled, for some labs, is the difference between a successful drug that goes to market and one that fails in the development stages. As a result, innovation must come from scientists, who truly understand the every-day problems they face in the lab and their consequences.

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