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BACG Annual Lecture: Susan M. Reutel-Edens

Pharmaceutical Crystallization: BIG Lessons from Small Molecules

Solid form screening to crystallize a molecule for the first time or in a suitable solid form that can be reliably delivered to patients is the first significant milestone along the path to transforming a molecule into a medicine. With challenges and continuous learning from the experience of crystallizing ever more complex molecules, what have we learned and where do we go from here? In this talk, big lessons – scientific and beyond – from the experience of crystallizing small molecules in early pharmaceutical development will be shared.



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Franziska Emmerling

Federal Institute for Materials Research and Testing, Berlin, Germany

Investigating the mechanism and kinetics of the mechanochemical synthesis of multi-component systems

Mechanochemistry is a promising and environmentally friendly approach for synthesizing (novel) multicomponent crystal systems. Various milling parameters, such as milling frequency, milling time, and ball diameter have been shown to influence the mechanisms and rates of product formation. Despite increasing interest in mechanochemistry, there is still limited understanding of the underlying reactivity and selectivity mechanisms.

Various analytical techniques have been developed to gain insight into the mechanochemical transformations, including powder X-ray diffraction, X-ray adsorption spectroscopy, NMR, Raman spectroscopy and thermography. Using these techniques, we have studied the formation of (polymorphic) cocrystals, organometallic compounds and salts, and elucidated the influence of milling parameters and reaction sequences on the formation mechanism and kinetics.

For example, our study of the mechanochemical chlorination reaction of hydantoin revealed that normalisation of the kinetic profiles to the volume of the grinding ball clearly showed that physical kinetics dominate the reaction rates in a ball-milling transformation. Attempts to interpret such kinetics in purely chemical terms risk misinterpretation of the results.

Our results suggest that time-resolved in situ investigation of milling reactions is a promising way to fine-tune and optimise mechanochemical processes.





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Kevin Girard

Chemical Research & Development, Pfizer, Inc., Groton, CT, USA

Building a Continuous Crystallization, Isolation, and Drying Capability at Pfizer

Continuous processing of pharmaceuticals is a growing area of interest, with many companies engaged in the effort for both “flow chemistry” and continuous drug product manufacture.  A critical missing link between these mor popular areas of study is continuous crystallization, isolation, and drying (CCID).  Recognizing this essential need, Pfizer have begun developing a CCID capability to provide a critical bridge between synthetic steps as well as enable a “raws in, products out approach,” creating a fully connected continuous processing chain from starting materials to drug products.  The approach is based on several distinct pillars: Workflows, Equipment (Lab and Plant scale), PAT, Process Modeling and Control, and Nucleator Design.  Each will be discussed in turn and within the context of Pfizer projects.  Challenges in these pillars will be discussed, as well as several opportunities to enhance the capability of the kit.  Finally, a modular CC skid for manufacturing in a kg/day scale plant will be presented, showing elements from all the pillars of the platform. 





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Klaas Wynne

School of Chemistry, University of Glasgow, UK

General role of amorphous aggregates in crystal nucleation

Nucleation of crystals from solution is traditionally described in the framework of classical nucleation theory. However, it has been challenged by observations of nanoscale and mesoscale metastable solute species in supersaturated solutions. In one case, these were found to be an intermediate in laser-induced crystal nucleation.1 Here, we will show that a wide range of amino acids as well as di- and tripeptides in supersaturated aqueous solution form aggregates and investigate their role in laser-induced nucleation. Using light scattering, we demonstrate that these aggregates are far from monodisperse but have a wide range of sizes, while in situ Raman spectroscopy confirms their amorphous nature. Mass spectrometry is used to confirm that the solute molecules cluster over a very wide range of sizes. All but one of the samples investigated shows aggregate-assisted laser-induced nucleation. These results suggest a general role of amorphous aggregates in crystal nucleation and a universal role in laser-induced nucleation. The wide range of observed sizes of the aggregates is inconsistent with both classical and non-classical theories involving liquid–liquid phase separation, requiring a new theory of crystal nucleation.

  1. Liao, Z. & Wynne, K. A Metastable Amorphous Intermediate Is Responsible for Laser-Induced Nucleation of Glycine. J. Am. Chem. Soc. 144, 6727–6733 (2022).




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Noushine Shahidzadeh

Institute of Physics, Van der Waals-Zeeman Institute, University of Amsterdam, The Netherlands

Self-organizing crystallization induced by evaporation

Salt crystallization by evaporation is widely used in industrial processes, but is also a natural phenomenon occurring frequently around us whenever salt solutions are present and the water evaporates. This can lead to very spectacular natural landscapes but is also a major cause of the weathering of artworks, buildings, soil solification and corrosion of outdoor electronics. I will discuss the dynamics of crystal growth during evaporation when salt creeping occurs and show the mechanism behind this self-amplifying process that leads to ‘salt trees’. I will also show how by changing the wettability and/or the porosity of the surface in contact with the salt solution, self-organized crystallization with a fractal morphology spontaneously develops upon drying. I will discuss the importance of the ion advection and diffusion on the crystallization patterns that develop and relate our results to salt crystallization damage observed in our cultural heritage and for works of art.



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