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Discovery & Development Formulation, Small Molecules, Quality & Compliance, Ingredients

As Clear as Crystallization

Over the past few decades, immeasurable resources have been spent trying to understand the crystallization process. But despite research efforts, a delicate balance of several influencing factors continues to make crystallization a difficult problem for medicine makers to deal with. Crystallization is crucial in the pharmaceutical industry as a separation process for intermediates and as the final step in the manufacture of active pharmaceutical ingredients (APIs) – precise control of crystallization is vital to ensure polymorphic purity and batch-to-batch product consistency. Because different crystal forms (polymorphs) of APIs exhibit different physicochemical properties and can behave very differently once inside the body, understanding the factors affecting crystallization is vital to manufacturers hoping to control the process.

Studies have revealed that the outcome of a crystallization process is dependent on a crystallization triangle of solvent conditions, nucleation initiators, and process conditions (including stirring, geometry of vessel, flow pattern, etc.) of the system.

Many researchers have reported that special glass surfaces have the potential to nucleate crystals of therapeutic proteins. However, in a recent study, Jerry Heng and his colleagues at the Department of Chemical Engineering, Imperial College London, have demonstrated that even a normal glass surface – when modified through surface treatments – can trigger nucleation of specific crystal forms of a small-molecule API (1). Polymorph control in pharmaceutical crystallization is typically ensured by seeding the solution with the desired crystal form and by operating the process at a preset solute concentration. “However, variations in the properties of seed crystals and solution conditions, at times, result in crystallization of unwanted polymorphs,” says Heng. “The current work is important for the understanding of selective nucleation of polymorphic forms on different chemically-modified surfaces.”

The researchers used computational molecular modeling methodology to understand how the glass interacts with the API crystal. “Contrary to conventional wisdom, this study has shown that intermolecular interactions between the template surface and the crystalline phase impact the polymorphic outcome,” says Heng. He suggests that the molecular modeling calculations outlined in the study could be used to predict the propensity for preferential nucleation on new engineered surfaces.

With further development of the results, Heng hopes the approach could be used by manufacturers to have additional control over the crystallization process by improving predictability of the outcome and to ensuring product consistency.

Moving forward, Heng hopes to develop design rules to engineer new templates for other crystallization systems, making his approach easily acceptable and applicable for newer drugs, and to explore means of applying his findings to large scale production processes, and to next generation therapeutics – such as biomacromolecules.

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  1. J. Heng et al., “Establishing template-induced polymorphic domains for API crystallization: the case of carbamazepine,” CrystEngComm17, 6384-6392, 2016.
About the Author
James Strachan

Over the course of my Biomedical Sciences degree it dawned on me that my goal of becoming a scientist didn’t quite mesh with my lack of affinity for lab work. Thinking on my decision to pursue biology rather than English at age 15 – despite an aptitude for the latter – I realized that science writing was a way to combine what I loved with what I was good at.


From there I set out to gather as much freelancing experience as I could, spending 2 years developing scientific content for International Innovation, before completing an MSc in Science Communication. After gaining invaluable experience in supporting the communications efforts of CERN and IN-PART, I joined Texere – where I am focused on producing consistently engaging, cutting-edge and innovative content for our specialist audiences around the world.

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