A to Z of polymorphs related by proton transfer

Woods-Ryan, Amy; Doherty, Cheryl L.; Cruz-Cabeza, Aurora J.

Abstract

The occurrence of tautomeric polymorphism in the Cambridge Structural Database (CSD) was established to be very rare in a previous study by A. J. Cruz-Cabeza and C. R. Groom (CrystEngComm, 2011, 13, 93). A decade has now elapsed and the CSD has seen a significant increase in its total number of crystal structures, useful CSD subsets have been introduced and the CSD Python API has been developed to allow for complex data mining. Given this, we wanted to revisit tautomeric polymorphs in the CSD alongside other polymorphs related by proton transfer and compare these results with those from an in-house pharmaceutical database in order to assess their prevalence and significance for pharmaceuticals. From A (amine–imine tautomeric polymorphs) to Z (zwitterionic polymorphs), here we study different types of polymorphs related by proton-transfer in the CSD, the CSD drug subset (DrugCSD), the single component drug subset of the CSD (SDrugCSD), and the GSK small molecule crystal structure database (GSD). First, we assess the potential of compounds to exist as tautomers. Whilst 51% of compounds in the CSD are capable of tautomerism, this number increases to 73% and 70% for the SDrugCSD and the GSD respectively. Tautomerism potential is, thus, more prevalent in pharmaceuticals than in common organic compounds in the CSD. Second, in mining the CSD we identify a total of 95 families of polymorphs related by proton transfer which can then be classified into six different categories depending on the type of proton transfer observed and the ionisation of species involved. The most common of such category is that of tautomeric polymorphs followed by zwitterionic polymorphs. The rarest type of proton transfer polymorphs is that of multi-zwitterionic polymorphs where two different zwitterions of the same compound are found in two different crystal structures. Overall, 3% of polymorphic compositions in the DrugCSD are found to be related by proton transfer which, although not very common, is of relevance to pharmaceuticals and drug development due to the potential impact on physical properties. Specific examples of each of the categories are discussed with calculations of lattice energies presented and consideration of ΔpKa values and likelihood of proton transfer and ionisation.

Citation

Woods-Ryan, A., Doherty, C. L., & Cruz-Cabeza, A. J. (2023). A to Z of polymorphs related by proton transfer. CrystEngComm, 25(19), 2845-2858. https://doi.org/10.1039/d3ce00216k

• Journal Article Type: Article
• Acceptance Date: Apr 25, 2023
• Online Publication Date: May 3, 2023
• Publication Date: May 3, 2023
• Deposit Date: Aug 11, 2023
• Publicly Available Date: Aug 11, 2023
• Journal: CrystEngComm
• Publisher: Royal Society of Chemistry
• Peer Reviewed: Peer Reviewed
• Volume: 25
• Issue: 19
• Pages: 2845-2858
• DOI: https://doi.org/10.1039/d3ce00216k
• Keywords: Condensed Matter Physics; General Materials Science; General Chemistry
• Public URL: https://durham-repository.worktribe.com/output/1715842