University of Minnesota Ph.D. dissertation. 2015. Major: Pharmaceutics. Advisor: Changquan Sun. 1 computer file (PDF); 322 pages.Adequate mechanical strength is a critical requirement to the successful development of a tablet product. Before tablet compression, powders are often engineered by various processes including wet granulation and surface coating, which may improve or adversely affect the powder tableting performance. Such effects, commonly, result from a change in either particle mechanical properties or particulate (size, shape) properties. In this work, tableting performance is interpreted based on the qualitative bonding-area and bonding-strength (BABS) model. The tabletability of the microcrystalline cellulose (MCC) granules deteriorates rapidly with increasing amount of granulating water and eventually leads to over-granulation at high water level. Granule surface smoothing, size enlargement, granule densification and shape rounding are the dominant factors leading to the tabletability reduction of plastic MCC. Incorporation of increasing amounts of brittle excipients, such as lactose or dibasic calcium phosphate reduces the rate of tabletability reduction by promoting more granule fragmentation, introducing more surface area available for bonding. When a sufficient amount of brittle excipients is used, the over-granulation phenomenon can be eliminated. Surface coating of incompressible MCC pellets with highly bonding polymer leads to sufficient surface deformation and adhesion to enable direct compression of the pellets into tablets of adequate mechanical strength. This improvement is enhanced by the presence of moisture, which plasticizes the polymer to allow the development of a larger bonding area between coated pellets. The relationship between mechanical properties and tableting behavior is systematically investigated in polymeric composites using celecoxib-polyvinylpyrrolidone vinyl acetate solid dispersions. Mechanical properties such as indentation hardness of the solid dispersions were measured using nanoindentation. Incorporation of celecoxib up to 60% by weight hardens the polymers, which reduces bonding area but increases bonding strength. On the other hand, moisture softens the solid dispersions and facilitates deformation under pressure to improve tablet mechanical strength. In summary, insights into the deteriorated tabletability of wet granulated powders have been developed and strategies for improving tabletability have been demonstrated. Also, the relationship between particle mechanical properties and tableting performance has been examined using solid dispersions. The BABS model has been further developed to enable its widespread application in interpreting complex tableting behavior
