Any fans of the Great British Bake Off will know the precision needed to succeed in chocolate week and gain a Paul Hollywood handshake for making perfectly tempered chocolate. Tempered chocolate refers to a specific arrangement (known as Form V) of cocoa butter molecules which give it the perfect glossy texture and famous snap. This is formed by allowing melted chocolate to cool just below 35°C such that Form V crystals seed and grow. Importantly, the chocolate must be cooled slowly enough to prevent any unwanted secondary chocolate forms from crystallising1. Each form of the chocolate is called a polymorph. Polymorphs are ways to describe different possible crystal arrangements of molecules which themselves are chemically identical. However, chocolate isn’t the only thing that has many polymorphs. In the pharmaceutical industry, the stakes go further than star baker. Polymorphs of drugs can have different stabilities and therefore may behave differently in the body. It is important to observe these polymorphs to understand the conditions under which they form.2 One way to investigate these differences is using electron diffraction, an electron microscopy technique, which is where my research comes in.

Figure: Chocolate has 6 polymorphs https://www.rciscience.ca/blog/science-of-chocolate

It is not possible to use an optical microscope to resolve individual atoms. This is because the wavelength of visible light (300 – 700 nm) is too large compared to the size of an atom (~ 0.1 nm). Electrons, however, can be accelerated to high enough energies such that they have wavelengths comparable to the size of an atom. Using this radiation, we can now resolve objects at the atomic scale. In the technique of electron diffraction, an electron beam is fired at a sample. Depending on the type of atoms in the sample and their positions, some of the electrons are diffracted which means that they change direction. After this interaction, the electrons are detected below the sample and form a diffraction pattern. Based on the position and the magnitude of the signal measured, these diffraction patterns tell us information such as crystalline structure and orientation of the sample.3 In this way, we can tell the difference between one polymorph or another. Currently, X-ray diffraction (XRD) is one of the dominant techniques used in industry for these tasks. Due to a stronger (Coulombic) interaction with a sample, electron diffraction offers the potential to explore much smaller crystals than would be possible with XRD. In my research, we are trying to increase the feasibility of widespread adoption of electron diffraction as a new technique for crystallographic investigation of active pharmaceutical ingredients in the pharmaceutical industry.

References:

  1. Afoakwa, E. O. Chocolate Science and Technology. (2010).
  2. Gardner, C. R., Walsh, C. T. & Almarsson, Ö. Drugs as materials: valuing physical form in drug discovery. Nat. Rev. Drug Discov. 2004 311 3, 926–934 (2004).
  3. Gemmi, M. et al. 3D Electron Diffraction: The Nanocrystallography Revolution. ACS Cent. Sci. 5, 1315−1329  (2019)

Helen Leung

NanoDTC Associate, a2021