TWIN SCREW GRANULATION: IMPROVING THE MIXING OF HYDROPHOBIC AND HYDROPHILIC POWDERS

Powders are ubiquitous to the pharmaceutical industry and represent a large proportion of formulated products i.e. granules, tablets, capsules. The quality of the formulated product is a function of the primary powder’s physical properties i.e. size, shape, density, strength, morphology, wettability and granulation process parameters. In recent years, powders which are synthesized as either excipients and/or active pharmaceutical ingredients are increasingly becoming hydrophobic (as defined by the contact angle). This property makes it difficult to design, troubleshoot and predict the wet granulation process due to the complex interactions between the liquid binder and primary powder particles. Moreover, traditionally the granulation process is conducted in batch mode. However, efforts are being made to move to continuous twin screw granulation (TSG). Continuous TSG is attractive to the pharmaceutical industry as the equipment can be run for longer periods, thus promoting increased productivity. Continuous TSG aids fast development of product from lab scale to pilot scale thus reducing product development time and cost to market. However, understanding of the continuous TSG process and its interplay with complex hydrophobic powders is not well understood to enable effective development of process design space to yield product with desired quality attributes i.e. uniformity, flowability, strength, stability etc. The primary objective of this thesis was to improve understanding on how the initial interaction between the liquid binder and primary powder particles influence the granulation mechanisms taking place in TSG when using a hydrophobic component in the formulation composition. Experimental investigations were two-fold (1) initial static liquid-primary powder interactions and (2) dynamic mixing in continuous TSG. Initially a study of spreading of single liquid droplets on powder beds is investigated from an experimental and theoretical point of view, paying particular attention to competing spreading mechanisms. The existence of two competing single liquid droplet spreading mechanisms on powder beds is shown: a) d_h spreading describes the length the liquid droplet travels horizontally across the powder bed and b) the d_v imbibition is the length the liquid droplet travels vertically into the powder bed. The spreading mechanisms are distinct from those reported in literature because the d_h spreading is shown to be dominant when spreading is driven by capillary forces resulting in fast wetting and nucleation kinetics. In contrast, the d_v imbibition is shown to be dependent on interfacial tension between the solid and the liquid droplet where the wetting and nucleation kinetics are slow. Experimental findings are presented on the dependence of the equilibrium contact angle on the chemical composition of the powder bed. It was found that the experimental data is inconsistent with existing Cassie-Baxter model for two-component mixtures. A new dimensionless surface coverage wetting model that predicts the contact angle behavior of two-component mixtures has been proposed. The key aspect of the model is the consideration of particle surface coverage and its relation with the contact angle behavior. In fact, it is believed that this proposed theory is necessary as mixtures consist of components with different particle sizes making surface coverage of one constituent over another inevitable. Finally, the static liquid-powder bed behavior was linked to ‘real’ continuous TSG to assess how key granulation mechanisms (wetting & nucleation, consolidation & coalescence and breakage & attrition) affect mixing and segregation behavior within the TSG process. This link was achieved by using: a) specific mechanical energy and proposed dimensionless mixing number and b) results from Residence Time Distribution and Near Infra-Red Chemical Imaging. When the static behavior between the liquid droplet and powder bed particles was driven by capillary forces this led to more rapid granulation resulting in greater extent of granulation and formation of stronger granules. However, in the interfacial tension driven regime the granulation behavior was very slow resulting in larger amounts of un-granulated fines. Granulation in this regime was successful when mechanical dispersion was applied as the stress was able to force the distribution of the liquid binder through the powder bed, resulting in improved granule properties i.e. extent of granule formation and strength. This contribution is expected to make it possible to design, control, troubleshoot and optimize the TSG granulation process, to allow for better control of final granular properties