Successful tablet manufacturing is greatly dependent on good flow and compaction behaviour of the active pharmaceutical ingredient (API) and excipients. These are governed by the physicochemical and mechanical properties of the materials. Like most organic crystalline materials, APIs are highly anisotropic, with weak van der Waals interactions often yielding needle-like, brittle crystals with poor flow and compaction. Additionally, the API-excipient ratio further impacts the processability and quality of the final tablet. Studying multi-component systems can prove challenging as API-excipient interactions are complex, and decoupling interparticle cohesion-adhesion and their impact on flow and compaction can be difficult to determine. This is especially true for modern formulations with low-dose excipients. Robust predictive models for formulation optimisation and processability remain limited. Thus, the need to utilise tools which enhance the understanding of how composition affects tabletability, ultimately optimising the manufacturing process.
This PhD combines computational and experimental methods to investigate the interplay between physicochemical and mechanical properties of the drug mefenamic acid (MA) and excipient d-mannitol (DM), and their impact on flow and compaction.
Molecular modelling successfully predicted the thin platy morphology of MA, driven by its anisotropic hydrogen bonding at its capping faces, and the columnar prismatic particles of DM, due to its homogenous distribution of -OH interactions. Predictions of their surface interactions revealed MA to have stronger cohesivity driven by strong dispersive interactions (93.53 %) and DM stronger adhesivity, displaying a better balance of dispersive to polar interactions (75.29 % and 24.71 % respectively). Prediction of their mechanical properties revealed both compounds to be brittle in nature; however, DM's extensive h-bond network allows for the occurrence of plastic deformation.
The predictions correlated well with experimental results. MA displayed poor flow (HR: 1.37, AOR: 44.55°), no plasticity (Py: 357.14 MPa), high porosity (E: 0.22) and low tensile strength (0.095 MPa). On the contrary, DM displayed good flow (HR:1.13, AOR 39.20), good compressibility (E: 0.03) and plasticity (Py: 65.79 MPa) and high tensile strength (1.07 MPa). Binary mixtures of 50-50, 65-35 and 75-25 MA to DM were examined in the same manner. The 50-50 blend provided the best balance between flow, compressibility and tensile strength. Whilst increasing the amount of MA, the blend's properties increasingly resembled those of pure MA. The findings were further validated through X-ray computed tomography (XCT), where powder flow, consolidation patterns, tablet compressibility and particle orientation were examined.
