Relationship Between Crystal Structure and Mechanical Properties in Cocrystals and Salts of Paracetamol

Oral tablets are convenient and widely administered drugdosage forms.The mechanical properties of a drug substance such as plasticity, ability to cohere into compacts and friction/adhesion are important in the development of a tablet formulation. Crystal engineering is an interesting and viabletool for improving or optimizing these technical properties of a drug substance.The creation of a lternative polymorphic forms, cocrystals, salts or hydrates of a drug substance can result in structural variations in the molecular packing of the crystals and, thereby, can alter the deformation behavior of the materials.Knowledge of the relationships between crystal modifications and the technical properties in multicomponent systems is limited, but represents a possibility to predict mechanical properties based on crystalstructure that facilitates engineering particles for the optimal processing performance. The overall objective of this thesis is thus to gain better understanding of the relationships between the crystal structure features and the mechanical properties of cocrystals and salts. Paracetamol form I, its cocrystals with oxalic acid and 4,4´-bipyridine, and its hydrochloride salt were selected as model systems in the study.The materials were scaled-up using rational crystallization methods and the physical purity was confirmed. The relevant properties of these powders were determined.Tablets were then made at applied pressures of50-250 MPa under controlled conditions.The tabletability and compactability of the powders were determined. The compression mechanics of the powders were the investigated according to a material classification protocol.Slip planes were identified by visually observing the crystal structures and based on the attachment energies calculated using different force fields in the materialsstudio.The tensile strengths of the powders increased with increasing pressure and the tabletability decreased in the order oxalic acid>paracetamol-hydrochloride salt≈paracetamol-oxalic acid>4,4´-bipyridine>paracetamol-4,4´-bipyridine.The tensile strength of the tablets decreased exponentially with increasing porosity,with some exceptions.Ingeneral, the cocrystals and the salt displayed intermediate compression characteristics as compared to the reference substances.The elastic recovery of the cocrystal and salt forms of paracetamol was not markedly different from that of paracetamol.It was found that slip plane prediction based on the attachment energies was not reliable. While it was possible to explain the improved tableting properties of powders based on the crystal features (i.e. the presence of slip planes and flat layers), no clear relationship was found with yield pressure. This may be attributed to possible brittle material characteristics and the surface energies of the crystals,which need to be further studied.Thus, cocrystallization and salt formation introduced structural features that were responsible for changes in the compaction and compression properties of drug substances. In future work, we intend to extend these studies to provide a clear picture of structure-mechanical property relationships in organic molecular crystals over multiple length scales;molecules to crystals to bulk powder.Key words Crystal engineering, solid forms, cocrystals, salts, tableting, crystal structure, mechanical properties, compression analysi