Du, Jonathan, Lai, Felcia, Váradi, Linda, Williams, Peter, Groundwater, Paul, Platts, James A.  ORCID: https://orcid.org/0000-0002-1008-6595, Hibbs, David and Overgaard, Jacob
2018.
Monoclinic paracetamol vs. paracetamol-4,4'-bipyridine co-crystal; what is the difference? a charge density study.
Crystals
8
(1)
, -.
10.3390/cryst8010046
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Abstract
Paracetamol (PCM) has two well-documented polymorphic forms at room temperature; monoclinic Form I is more stable than the other orthorhombic Form II. Form II exhibits improved tabletting properties compared to Form I due to low shearing forces; however, difficulties in its manufacture have limited its use in industrial manufacture. Previous studies have found that the introduction of a co-former to form co-crystals would allow the PCM molecule to exist in a conformation similar to that of the orthorhombic form while being more stable at room temperature. Experimental charge density analysis of the paracetamol-4,4′-bipyridine (PCM-44BP) co-crystal system, and its constituent molecules, has been carried out to examine the forces that drive the formation and stabilisation of the co-crystal, while allowing PCM to maintain a packing motif similar to that found in Form II. It is hoped studies on this well-known compound will help apply the knowledge gained to other drug molecules that are less successful. The PCM molecules in the co-crystal were found to exhibit similar packing motifs to that found in Form I, however, intercalation of the 44BP molecule between the PCM layers resulted in a shallower angle between molecular planes, which could result in the required lateral shear. Topological analysis identified more weak interactions in the co-crystal compared to the individual molecules, thus allowing for greater stability as evidenced by the lattice energies. Weak interactions in the PCM-44BP co-crystal were found to range in strength from 4.08–84.33 kJ mol−1, and this variety allowed the PCM-44BP planes to be held together, while a weak π–π interaction (15.14 kJ mol−1) allowed lateral shear to occur, thus mimicking the planes found in Form II PCM and offering the possibility of improved tabletting properties. A comparison of integrated atomic charges between partitions of the PCM molecules in the single and co-crystal found that the hydroxyl and amide groups were involved in greater hydrogen bonding in the co-crystal, resulting in a charge redistribution across the molecule evidenced by a larger molecular dipole moment (µ = 12.34D). These findings, in addition to the co-crystal having the largest lattice energy, form a potential basis with which to predict that the co-crystal exhibits improved solubility and stability profiles. It is anticipated that these findings will contribute to improvements in the formulation and other physical properties of PCM and other pharmaceutical compounds.
| Item Type: | Article |
|---|---|
| Date Type: | Publication |
| Status: | Published |
| Schools: | Schools > Chemistry Professional Services > Advanced Research Computing @ Cardiff (ARCCA) |
| Publisher: | MDPI |
| ISSN: | 2073-4352 |
| Date of First Compliant Deposit: | 23 January 2018 |
| Date of Acceptance: | 15 January 2018 |
| Last Modified: | 05 May 2023 04:36 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/108365 |
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