Maryam Tofiq: Tableting performance of dry granulated particles: Significance and assessment of compression mechanical properties

Abstract

Dry granulation (DG) is often utilized as an intermediate process during tablet manufacturing, for improving flow characteristics of the powder blend and/or reducing segregation issues related to the active pharmaceutical ingredient (API). The resulting granules exhibit typically irregular shapes with rough surfaces and their mechanical properties are related to the feeding powder and the process parameters used during the DG. Most frequently, a reduced tabletability of the dry granulated particles is reported compared to the feed powder, referred as loss of tabletability (LoT). A sufficient mechanical strength of the tablet is required to survive further handling, processing and packing. In this thesis the LoT has been addressed by structure-property-performance interrelationships. To achieve this, dry granulated particles were prepared with controlled physical properties, utilizing systematically variated starting powders of a typical brittle (crystalline α-lactose monohydrate) and a typical plastic material (microcrystalline cellulose). Consequently, the granule mechanical properties ranged from an extensive brittle character to a plastic character. In addition, analytical powder compression was employed to understand the overall compression mechanisms of dry granulated particles during tableting and to determine descriptors (parameters) that reflects the granule mechanical property which controls the LoT. 

The compression mechanisms of dry granulated particles were found to occur in a series of phases in sequence. In the first phase, at very low compression pressure, rearrangement of the granules occurred until a jamming point was reached. The second phase was dominated by granule fragmentation which occurred at relatively low pressure with a high compression rate. The third phase was dominated by plastic deformation and occurred at high pressure with a decreased compression rate. Finally, the compression mechanisms ceased at the highest tableting pressure (300 MPa) which involved an elastic deformation of the formed tablet. Among the compression parameters studied, the Adams parameters were found to be the most valuable descriptors of granule fragmentation and deformation. Thus, it was concluded that both granule fragmentation and deformation affect the LoT depending on the tablet pressure. At low tablet pressure (up to 100 MPa) the degree of granule fragmentation was found to be the critical mechanism controlling LoT, which depended on the brittleness of the granules. Conversely, at higher pressure (above 100 MPa) the degree of granule deformation was the critical mechanism controlling LoT, which depended on the plasticity of the granules. In conclusion, the LoT was dependent on granule structure and granule mechanical property.