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Reducing drug time to market with new wave of crystallisation technology

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Dr. Carmen Guguta, global head of business development and marketing, Technobis Crystallization Systems, describes the time-consuming challenges of current crystallisation process and how innovative analytical instruments are massively reducing the time it takes to develop drugs to market-ready status.

Key insights:

A drug’s journey to fully approved, market-ready status is a long one. After identifying an active pharmaceutical ingredient (API), chemists must determine the best way to administer it, and the most stable morphology for industrial-scale manufacturing and storage in different conditions. Pre-clinical and clinical phase trials, regulatory approval and manufacturing all contribute to a process that takes years from start to finish.

Furthermore, existing methods of ascertaining these basic properties have some drawbacks. Long waiting times inhibit progress in the lab, multiple assays use up potentially expensive reagents and utilities, and variance in conditions can hamper reproducibility. Additionally, research companies have their patent lifetimes to worry about. By investigating as many experimental conditions as possible, they maximise the value of their proprietary molecule.

Challenges in the field

One such method is High/Ultra-High Performance Liquid Chromatography (HPLC/UHPLC), often used to find solubility. Reverse-phase HPLC is the most common type and involves passing polar solvents through a column filled with silica particles, made less polar by attaching long-chain hydrocarbon molecules.

Extremely high pressure is applied to drive the solution through the column. Different solutes are separated by the time taken to pass through, known as the retention time, tR. which is dictated by the solute’s affinity for the now non-polar silica particles.

This is incredibly time-consuming because the equilibration and experimentation phases require days to generate one solubility figure. As this figure is temperature-dependent, the accumulated time taken to plot a solubility curve could be up to 112 hours.

Furthermore, the demands of running multiple consecutive assays are not only time-related. The consumption of chemical reagents and utilities, like the high pressure, can be very costly. In cases where only a small amount of the test subject is available at all, it can even be prohibitive to research. The pressures involved with HPLC, the expensive solvents needed to run assays, and machine maintenance costs are all considerations researchers must make.

Due to the expense involved, crystallisation studies are sometimes scheduled later in the process. However, if the drug is then found to have untenable properties, then the whole project up to that point must be abandoned.

These properties might be unsuitable solubility at a specified temperature or pH, or an unscalable crystal formation process. This is the worst-case scenario for the researcher and their investors, as reverting to the API identification stage means their previous efforts were wasted.

A new direction

Fortunately, new solutions are coming into focus, as advanced analytical instruments have reached the lab apparatus market. These are often quicker, more cost-effective, and helpful in mitigating the risk inherent to drug development.

Multiple reaction chambers can run in parallel, escaping the limitations of consecutive assays and boosting the reproducibility of the data collected. Furthermore, integrated transmissivity technology can analyse a sample by passing light through it as crystals form, giving you the required information on its structure and pharmacological properties smaller analysis vessels dramatically reduce the volume of reagent required to investigate the relevant properties.

One example of a benchtop analysis machine that offers all these innovations is the Crystal16 version 3 from Technobis Crystallization Systems. With 16 reaction chambers, the Crystal16 can generate solubility curves for four different solvents in under four hours. In this instance, the experimentation is performed concurrently with molecular analysis, which allows the scientist in question to be sure of the contents of their vial in real time.

Lower process costs allow researchers to investigate solubility earlier, reducing the chance of expensive losses later in the development pathway. Technobis Crystallization Systems has even found a way to reduce the material needed for investigation. For example, enlarged measurement windows mean that laboratory workers can analyse just one millilitre of sample.

The same crucial data is produced in hours, not days, with half the amount of material previously required and for a smaller cost to pharmaceutical manufacturers than ever before. By embracing these technological innovations, researchers can maximise efficiency in this foundational stage of drug development and get their products to the patients who need them in record time.

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