Yes / Twin screw granulation (TSG) has been applied to wet granulation, although its application in melt granulation has been more limited. This work explores potential advantages of hot melt granulation using twin screw extrusion. Four main operating and formulation parameters were investigated: screw speed, number of mixing elements, temperature, and binder percentage. Combinations of these factors were then studied to determine their impact on the quantity and characteristics of granules within the desired size range of 125 - 1000 µm. A screening design of experiments (DOE) study was used with each factor set at three levels, to investigate individual factor effects and interactions. Two types of mixing elements were studied: kneading block (KB) and chaotic elements. The type and number of mixing elements were found to be paramount in contributing to the quantity and characteristics of granules formed. Results obtained agreed with previous findings in literature on the influence of different screw elements on the characteristics of granules formed by twin screw granulation. Additionally, the study revealed the unique impact which different mixer elements have on both granule production and characteristics. Depending on the specific need or use of granules in required applications, the granulation process can be effectively designed to meet the end product quality and outcome.

Continuous wet granulation using a twin-screw extruder has attracted considerable attentions in pharmaceutical industry as it ensures consistent tablet quality at a high production rate. However, challenge still exists in controlling desired granule properties especially when different sized twin-screw granulators are used. This study therefore explored the potential of scalability of two sized twin-screw extruders and the how raw materials affect granules properties in two twin-screw extruders. The first study focuses on aspects of scaling using two twin-screw extruders, 18mm and 27mm. Dimensionless groups including Fr Number, Powder Feed Number and Degree of Fill (<30%) were studied to observe their influences on granule attributes. It was found that these dimensionless groups demonstrated inconsistent effects on granule properties and the effect of Powder Feed Number was highly dependent on Degree of Fill. Different extruder still exerts significant impact on granule properties. A scaling rule was established for median granule size (d50) only, but only moderate degree of fit was found. Although a considerable number of studies have been published on controlled-release and extended-release excipients, little attentions have been given to the influence of microcrystalline cellulose (MCC) grades in twin-screw wet granulation. The second study therefore investigated the processability of five grades MCC from the Avicel® PH family using two twin-screw extruders again, 18mm and 27mm. Granule attributes including particle size, density, moisture, and strength were tested and it was found that MCC inherent density has the most significant impact on granule properties while particle size of MCC has minor positive effect on granule size. This study also concluded that better granule flowability and uniformity can be achieved by using low moisture, larger particle size and high density MCC as excipients. / Thesis / Master of Applied Science (MASc)

Twin screw wet granulation (TSG) has been studied as a continuous manufacturing alternative to batch granulation for nearly twenty years. One of the main differences between batch granulation and TSG lies in the exiting granules being presented as a bimodal particle size distribution (PSD) in the latter case. Current process analytical technologies (PAT) can monitor a monomodal distribution well but there have been no techniques disclosed in the public domain so far that can accurately monitor this unusually shaped PSD. Acoustic emissions (AE) has been identified as a PAT of interest due to its ease of use (lack of calibration), low cost, and non-invasive design relative to other PATs used for monitoring PSDs. Hence the goal of this thesis was to develop AE as a process analytical technology (PAT) capable of estimating the full distribution of produced granules by TSG in real time. The first research study of this thesis focused on the development of the new technology. The AE PAT consisted of an acoustic sensor, an impact plate, and software to convert the time-domain signal of particle collisions into a time-averaged frequency-domain spectrum to be subsequently used to estimate a weight-averaged particle size distribution. A novel and much required addition to the PAT was inclusion of a digital filter based on particle mechanics parameters to overcome auditory masking which hindered accurately converting the cumulative sounds of impact into a PSD. The PAT was tested in this study with granulated lactose monohydrate and with the new digital filter, obtaining a maximum error of 1 wt% across all particle sizes tested. In the second research study, as more formulations commonly used in the industry were tested, the filter proved unable by itself to account for the differences in impact mechanics and therefore needed to be modified to incorporate the more inelastic behaviour now being seen. Two micromechanical models were explored, and the Walton-and-Braun model was found to be the most suitable for the AE PAT – reducing its error from 8 wt% down to 2.75 wt% across four formulations producing coefficients of restitution from 0.79 to 0.24. In the last research study in this thesis, the now-functional inline PAT was used to reveal mechanistic details related to the transition state in granulation as a TSG starts up, to improve the field’s understanding of the granulation mechanism. The technique was able to estimate the PSD over much shorter periods of material collection compared to sieving, allowing the evolution of the PSD as a function of time to be examined for varying degrees of fill (DF) and liquid-to-solids ratios. It was determined that the time to steady state, at both DF tested, occurred at approximately 5 times the mean residence time of the process by both PAT and sieving analyses. Particle sizes between 102-2230 μm were then tracked as a function of time below 120 s and variations of granule growth were seen for each degree of fill which added to the understanding of the granulation mechanism. This PAT shows great promise as a monitoring tool to implement quality by design principles for TSG in pharmaceutical manufacturing. / Thesis / Doctor of Philosophy (PhD)

Twin screw wet granulation has been proved as a feasible alternative for traditional batch granulation process due to its continuous processing feature; considered as a significant processing method especially in the pharmaceutical industry. This thesis will explore the processibility of twin screw wet granulation with various formulations. The first section of the thesis focused on examining the processibility of wet granulation in a twin screw while using various grades of hydroxypropyl methylcellulose (HPMC) as an extended-release excipient. The method to find the processibility was by modifying the liquid-to-solid ratio for each formulation. The process window was defined by examining the amount of granules that fall in a pre-determined acceptable size range. This part focused on three substitution types of HPMC (Type 2910, Type 2208, and Type 2906) that varied in molecular weights. It was found that only Type 2910 HPMC showed a shift in the process window (also known as granulation range) in relation to the molecular weight of the formulations. A higher demand for binder liquid was found for higher molecular weight Type 2910 HPMC in order to form granules with acceptable sizes. The second part of this thesis was focused on understanding the process variables that might influence the processibility of the HPMC formulations. This part examined the impact of feed rate on the granulation range of Type 2910 HPMC specifically was examined. Multiple feed rates were tested, and it was found that the granulation range for lower molecular weight Type 2910 HPMC was easier to shrink when higher feed rates were applied. A transition in the granule formation method from liquid-bridging to compaction with respect to the feed rate was found for low molecular weight HPMC, whereas the high molecular weight HPMC always formed granules through compaction at all feed rates due to strong water retainability. / Thesis / Master of Applied Science (MASc)