Pharmaceutical tablet compaction : product and process design

Abstract

This thesis explores how tablet performance is affected by microstructure, and how microstructure can be controlled by selection of excipients and compaction parameters. A systematic strategy for formulation and process design of pharmaceutical tablets is proposed. A modified nanoindenter method was used to test the mechanical behavior of diametrally compressed excipient granules. X ray micro computed tomography and Terahertz pulsed spectroscopy (TPS) and imaging (TPI) were used to analyze the microstructure of the tablet core and detect internal defects. Granule failure mechanisms are found to be consistent with tablet microstructure. MCC granules deform plastically when tested and X ray images show individual granules undergoing increasing deformation in tablets as higher compaction forces are used. A highly interconnected pore-structure limited tablet hardness and led to bursting behavior during dissolution. No effect of compaction force or speed was observed in dissolution profiles. Lactose granules fracture at strains less than 5%, forming monolithic structures with no evidence of initial granule shape or size. Pore size decreases as compaction force is increased for DCL 11 tablets. A decreasing pore size corresponds to increasing THz refractive index, tablet hardness and dissolution time. DCL 11 and DCL 14 tablets compacted under the same conditions have the same pore size distributions and hardness, although DCL 14 granules are weaker than DCL 11, and DCL 14 tablets dissolve up to four times slower than DCL 11 tablets. No difference was observed between the THz spectra of tablets made from the two grades of lactose.

(cont.) Further work is needed to understand the physical significance of the THz measurements. TPI can detect laminated tablets and is faster than X ray micro CT. In order to develop a rational design methodology, two key areas for future research are building a process model for compaction and developing quality testing methods that can be analyzed mechanistically. The capstone project explores strategic decision making for innovator firms and generic drug manufacturers in the period surrounding patent expiry. Statin products were used as an illustrative case of a pharmaceutical technology experiencing commoditization. A system dynamics model was used to simulate historic results and explore options for products still under patent protection. Current models of technology market dynamics apply to statins, but regulation and legislation play a large role in controlling market entry, leading to strong sequencing effects.