One method to improve the solubility, stability, and bioavailability of a poorly soluble drug is to combine it with another molecule to form a cocrystal. When in a cocrystal, the physicochemical properties of the drug are dependent on the overall structure, including the hydrogen bonding between the molecules.
In this study, published in PCCP, the researchers used multiple analytical techniques, including neutron scattering, to characterise the structure of a cocrystal of the fungicide pyrimethanil, a proxy for new drug delivery vectors that are currently under development.
“Understanding and harnessing the nuances of hydrogen bonding in pharmaceutical cocrystals is essential for tailoring their behaviour, stability, and therapeutic performance," explain the study authors.
This study formed part of Ramandeep Dosanjh's PhD project, which was joint between ISIS, Johnson Matthey and the University of Glasgow. The aim was to determine whether Fourier transform infrared spectroscopy in attenuated total reflection mode (FTIR-ATR), could be used for studying the hydrogen bonding in the crystal structure of a representative cocrystal.
First, they needed to fully characterise the cocrystal before comparing their results with those from FTIR-ATR to check its validity. They began their characterisation by doing single crystal diffraction studies using X-rays and then neutrons on the SXD instrument at ISIS. Their X-ray studies provided useful geometric parameters, but to resolve the positional ambiguities of the hydrogen atoms they needed to use neutrons.
Neutron diffraction provides enhanced sensitivity to hydrogen atoms because the scattering power depends on the neutron scattering cross-section, not the number of electrons as for X-ray scattering. Working with beamline scientist Matthias Gutmann, they were able to measure the localisation of hydrogen atom positions more precisely.
“The integration of neutron and X-ray data exemplifies the complementary nature of these techniques. Together, they provided a cohesive structural basis for our subsequent computational and vibrational analyses."
The team used their diffraction data as a basis on which to carry out computational modelling to predict the vibrational properties of the cocrystal. They were then able to measure the vibrational modes experimentally using inelastic neutron spectroscopy on Tosca, working with beamline scientist Stewart Parker.
Again, the inherent sensitivity of neutrons to the hydrogen atoms in the system was extremely useful. It enabled the team to assign the hydrogen-bonding deformation modes and use these as a basis for the analysis of the FTIR-ATR and Raman spectroscopy.
They found that Raman spectroscopy would not be a useful tool, but that there was greater diagnostic capability afforded by the FTIR-ATR.
“Our study shows how vibrational spectroscopy could be used to supplement investigations on the structure and form of this cocrystal as a potential drug delivery vector for this fungicide."
The full paper can be found at DOI: 10.1039/D5CP02802G
