How to Analyse Hydrogen Bonding
November 29, 2022
Hydrogen bonds (H-bonds) are the most important directional intermolecular interactions. They drive a huge number of observed bulk properties, from alternative polymorphs to changes in stability, melting point, and more.
CCDC software allows you to assess H-bonds in a number of ways, to deeply understand how these forces are impacting your structure of interest. Here we explain the hydrogen bond assessment tools available, how they differ, and when they can be applied.
Hydrogen bonding can impact solid-form structures in numerous ways. The formation of H-bonds can make the difference between a polymorph which does or does not have the required properties. In pharmaceuticals, this can mean the difference between an effective drug and one which is ineffective — the most famous case is that of Ritonavir, an HIV drug which had to be withdrawn from the market at great cost to patients and the manufacturer, because of an unexpected polymorph (Bauer et al, Pharm Res, 2001).
CCDC software has been used to assess for such changes, for example in this work by Pfizer, with a range of in silico H-bond analysis tools.
All the software features described here base their calculations on data from the CSD, the Cambridge Structural Database. This means that the results are all informatics-based, or derived from real, experimentally-observed results, collated from the literature and direct data-sharing since 1965.
Hydrogen Bond Propensity
This component identifies possible hydrogen bond networks which could contribute to observed polymorphs. It lets you assess possible alternative H-bond networks, and how likely they are to be observed. The results are all based on observed hydrogen bonds in the CSD, so they are based on real-life observed experimental results.
The hydrogen bond propensity tool produces results in chart and table forms, so you can review and assess further.
This tool is best when you have a molecule capable of hydrogen bonding, in a crystal structure, and you want to know if there are other, more likely, networks available.
This tool was used in work published in Crystal Growth and Design which identified novel polymorphs of the anti-inflammatory drug Flunixin — read the case study here.
Hydrogen Bond Statistics.
This component looks at the observed geometry of hydrogen bonds in a given structure and compares them to relevant, experimentally observed structures in the CSD. It is a useful component of a risk assessment of the packing in the solid form.
The outputs are given as a histogram, showing the geometry of your bond of interest vs relevant structures in the CSD as a whole, so you can see if your structure is unusual.
This tool is best for an initial assessment of the hydrogen bonding present in your structure.
Full Interaction Maps
This component visually plots a molecule’s interaction preferences in one click.
The breadth of molecular interactions observed in the Cambridge Structural Database (CSD), across a wide variety of conditions, allows us to understand where interactions are most likely to occur using knowledge derived from experimentally observed structures. The distributions of CSD interactions are extracted into a knowledge-based library of interactions; IsoStar.
The Full Interaction Maps tool uses this to calculate where chemical probes are likely to be found around a molecule. It produces a visual 3D map to show where functional group interactions are likely based on the geometry of the molecule, allowing you to see if these are satisfied in the packing environment.
The tool is best used for a qualitative assessment of the packing environment of the target molecule.
Learn how to use Full Interaction Maps in our free online course here. It includes video demos, examples to follow, and a quiz to get a certificate.
Solid Form Informatics (7)