Understanding solid form stability with Hydrogen Bond Statistics
September 23, 2021
We’re pleased to present a new structural analysis tool in our latest release: Hydrogen Bond Statistics. Used in combination with the other solid form risk assessment tools in CSD-Materials, this allows you to understand how different characteristics influence stability in your solid-state material. Here we explain how Hydrogen Bond Statistics works.
How to assess solid form stability
Hydrogen bonds are an important class of intermolecular interactions that influence the overall stability of a solid. In the context of a pharmaceutical product, this could affect thermal stability or the likelihood of polymorphism. For this reason, hydrogen bonding is assessed during solid form development, to identify potential risks, and ultimately to ensure that the selected crystal form is sufficiently stable.
The Hydrogen Bond Statistics tool examines the geometry of the observed hydrogen bonds in a given structure in comparison to relevant known structures in the Cambridge Structural Database (CSD). This assessment of hydrogen bond statistics allows you to understand packing preferences, assess if a system is polymorphic or monomorphic, explore polymorphic systems, examine phase transitions, and generally assess risks in your solid form material. The concept was built in close collaboration with our Solid Form Design Centre partners at Pfizer.
This is part of the family of Solid Form Assessment tools we offer together with the Hydrogen Bond Propensity, Aromatics Analyser, and Full Interaction Maps (FIMs) components. All are available with a CSD-Materials or CSD-Enterprise licence (this includes full academic CSD licences).
The different tools available in CSD-Materials to support Solid Form Risk Assessment with informatics.
How to use the Hydrogen Bond Statistics component in CSD-Materials
The Hydrogen Bond Statistics tool is found under the CSD-Materials menu in Mercury, and it can also be accessed in the CSD Python API.
Once selected, it compares the geometry of the hydrogen bonds in your structure to known structures in the CSD.
In this example below, we can see that the distance of the N1…O4 hydrogen bond is not unusual, but the angle of the N1…O4 hydrogen bond in our chosen structure is categorized as unusual based on comparison to CSD statistics. The distance histogram, angle histogram, and distance/angle heat map (coloured by frequency) show the distributions of this type of hydrogen bond in the CSD. On the heat map, the white lines represent the specific hydrogen bond geometry in our structure under analysis.
The Hydrogen Bond Statistics display shows the distance, angle, and relative frequency of this type of hydrogen bond in the CSD so you can see usual or unusual characteristics which impact stability.
Update to the 2021.2 CSD Release to access this feature. You can update directly in Mercury.
Download our whitepaper here for a more detailed exploration of solid form informatics and how it was used to assess the stability of three pharmaceutical products in development at Pfizer.
CSD System (49)
Hydrogen Bond (1)
Release 2021.2 (2)