4.6 Article

Monoclinic Paracetamol vs. Paracetamol-4,4 '-Bipyridine Co-Crystal; What Is the Difference? A Charge Density Study

期刊

CRYSTALS
卷 8, 期 1, 页码 -

出版社

MDPI AG
DOI: 10.3390/cryst8010046

关键词

paracetamol; charge density study; tableting performance; co-crystals

资金

  1. University of Sydney Bridging Support Scheme
  2. University of Sydney
  3. Faculty of Pharmacy
  4. Danish National Research Foundation (Center for Materials Crystallography) [DNRF-93]

向作者/读者索取更多资源

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 pi-pi 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 (mu = 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.

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