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A twin-screw granulator (TSG), a promising equipment for continuous high shear wet granulation (HSWG), achieves the desired level of mixing by a combination of the appropriate screw configuration and a suitable set of process settings (e.g. feed rate, screw speed, etc.), thus producing a certain granule size and shape distribution (GSSD). However,...
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... is a process aiming at enlarging powder particles, which can be advantageous for many reasons. The size enlargement results in gravity forces exceeding the van der Waals forces, thereby contributing to better flow properties required for improved processability and accurate dosing in further downstream processing. Especially in the pharmaceutical industry, where often highly potent drugs are processed, the amount of dust generated by powder handling is reduced by granulation, resulting in improved safety. Also, segregation (demixing) can be minimized along with the improved downstream processing characteristics of the granules. Therefore, wet granulation is an important process for the particle enlargement during the formulation of solid dosage forms in the pharmaceutical industry (Ennis, 2010). Vervaet and Remon (2005) extensively reviewed continuous granulation techniques. The high shear twin-screw granulation system has received most attention in the last decades due to its inherent benefits, including ease of use in continuous operation and the potential to integrate the TSG with other operations (Kumar et al., 2013). The high shear wet granulation (HSWG) process in the twin-screw granulator (TSG) can be divided into several stages (Fig. 1). A number of different mechanisms, including nucleation, growth, aggregation, and breakage, which ultimately determine the characteristics of the produced granules, typi- cally drive the dynamics of wet granulation. Although details about the precise sequence of growth and breakage mechanisms during TSG are not available from the literature, growth and breakage of granules are expected to occur simultaneously due to the inhomogeneous shear force distribution inside the TSG barrel (Dhenge et al., ...
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... in batch HSWG the granulation time is in the order of minutes, while, in a TSG, it is limited to a few seconds (Kumar et al., 2014). The short granulation time is, although desirable from the productivity point of view, challenging for micro to meso scale rate processes in HSWG (Fig. 1). The rate processes of wet granulation are required to occur during the short granulation time before the material leaves the TSG. Thus, ...
Citations
... Larger agglomerates contained a higher amount of binder liquid. During the wetting phase of hydrophilic formulations, the binder liquid can easily penetrate into the pores of the hydrophilic powder bed to form highly saturated nuclei with relatively smaller amounts of binder liquid at the edges (Kumar et al., 2014). Consequently, smaller particles that break off from the edges of the initial agglomerates contain a lower amount of binder liquid. ...
... The effect of L/S ratio has been reported as much higher than that of SS and MFR in several lines of continuous wet granulation (Verstraeten et al., 2017;Matsunami et al., 2020). While a critical interaction between L/S ratio and MFR was reported in a different line (Miyazaki et al., 2020), it was not relevant in the Con-siGmaTM-25 unit (Kumar et al., 2014). Experimental conditions were defined based on three steps. ...
Population balance models (PBM) have been widely used to model the twin-screw wet granulation (TSWG) in the continuous manufacturing of solid dosage forms. However, some knowledge gaps, such as material properties and process parameters, remain, which hampers the applicability of new drug developments. This work presents a hybrid model of a compartmental one-dimensional PBM and partial least squares (PLS) towards a generic model. The PBM that considers aggregation and breakage was calibrated with experimental data of ten different formulations with different liquid-to-solid ratios. The PLS models were built to predict the PBM parameters based on the material properties and liquid-to-solid ratio. The proposed model was validated by testing it with four formulations containing new active pharmaceutical ingredients (APIs) using maximum mean discrepancy. The model captured the peak of each granule size distribution for all formulations. This approach has the advantage that the hybrid model of the PBM and PLS can compute the resulting granule size distribution without granulation experiments. This work enhanced the applicability of PBM, which can reduce experimental efforts in new drug development.
... The effect of the L/S ratio on granule properties in twin screw granulation has been widely reported in literature in the past few years indicating that in general, an increase in L/S ratio leads to larger and denser granules (Seem et al., 2015;El Hagrasy et al., 2013;Kumar et al., 2014;Lute et al., 2016). Fewer papers have looked at the direct effect of the L/S ratio on the tensile strength of the tablets with findings indicating that it is formulation dependant (Gabbott et al., 2016;Megarry et al., 2020). ...
The pharmaceutical field is currently moving towards continuous manufacturing pursuing reduced waste, consistency, and automation. During continuous manufacturing, it is important to understand how both operating conditions and material properties throughout the process affect the final properties of the product to optimise and control production. In this study of a continuous wet granulation line, the liquid to solid ratio (L/S) and drying times were varied to investigate the effect of the final granule moisture content and the liquid to solid ratio on the properties of the granules during tabletting and the final tensile strength of the tablets. Both variables (L/S and granule moisture) affected the tablet tensile strength with the moisture content having a larger impact. Further analysis using a compaction model, showed that the compactability of the granules was largely unaffected by both L/S and moisture content while the compressibility was influenced by these variables, leading to a difference in the final tablet strength and porosity. The granule porosity was linked to the L/S ratio and used instead for the model fitting. The effect of moisture content and granule porosity was added to the model using a 3d plane relationship between the compressibility constant, the moisture content and porosity of the granules. The tablet tensile strength model, considering the effect of moisture and granule porosity, performed well averaging a root mean squared error across the different conditions of 0.17 MPa.
... As the screw speed increases the energy supplied per unit time per unit mass to the powders increases (E s ). An increase in screw speed leads to an increase in axial velocity of particles which ultimately decreases the mean residence time of particles inside the system [6,49,50]. In this study, impact velocity is calculated as the square root of the energy supplied per unit time per unit mass (E s ). ...
... Feed rate has competing effects on holdup and fill level, and as shown in Equation (7) it has a direct positive effect on hold up. However, it also affects MRT such that an increase in feed rate leads to a decrease in MRT [21,44,50]. This is attributed to the increase in powder throughput force with an increase in feed rate, and this decreases the occurrence of back mixing and eventually leads to an increase in axial velocity and decrease in MRT. ...
... Mundozah et al. [51] and Meier et al. [36] showed that even though there is a decrease in MRT with an increase in feed rate, the increase in the holdup and fill level prevailed. This can be attributed to the nature of the effect feed rate has on MRT and holdup,which are also dependent on other factors such as screw speed and screw configuration [50], which decreases the influence of feed rate on MRT. Hence an increase in feed rate has a net positive effect on holdup, and an increase in hold up leads to an increase in the torque of the system. ...
Twin screw granulation (TSG) is a continuous wet granulation technique that is used widely across different solid manufacturing industries. The TSG has been recognized to have numerous advantages due to its modular design and continuous manufacturing capabilities, including processing a wide range of formulations. However, it is still not widely employed at the commercial scale because of the lack of holistic understanding of the process. This study addresses that problem via. the mechanistic development of a regime map that considers the complex interactions between process, material, and design parameters, which together affect the final granule quality. The advantage of this regime map is that it describes a more widely applicable quantitative technique that can predict the granule growth behavior in a TSG. To develop a robust regime map, a database of various input parameters along with the resultant final granule quality attributes was created using previously published literature experiments. Missing data for several quality attributes was imputed using various data completion techniques while maintaining physical significance. Mechanistically relevant non-dimensional X and Y axis that quantify the physical phenomena occurring during the granulation were developed to improve the applicability and predictability of the regime map. The developed regime map was studied based on process outcomes and granule quality attributes to identify and create regime boundaries for different granule growth regimes. In doing so breakage-dominant growth was incorporated into the regime map, which is very important for TSG. The developed regime map was able to accurately explain the granule growth regimes for more than 90% of the studied experimental points. These experimental were generated at vastly different material, design, and process parameters across various studies in the literature, this further increases the confidence in the developed regime map.
... The sievers were vibrated for 20 min with 60 Hz vibration speed. A particle size distribution curve was created with the desired low amount of fines by the granulation process (Kumar et al. 2014). ...
The research was conducted to analyze the effect of different types and concentrations of the acid source on the physical characteristics and chemical stability of black soybean (Glycine max (L.) Merr.) Detam I variety effervescent granules. Effervescent granules were made in three different acid sources, which are 15% citric acid for formula I, a mixture of 5% citric acid and 10% tartaric acid for formula II and a mixture of 8% citric acid and 16% tartaric acid for formula III, respectively. The granules’ physical characteristics were obtained by particle size distribution, specific density, bulk density, moisture content, flow time, angle of repose, and effervescent time. Total phenolic content was evaluated for 28 days and the samples were collected at 0, 1, 4, 7, 14, 21, and 28 days. The sample was then measured using a visible spectrophotometric method at 505.5 nm wavelength. The results showed that granule effervescent with formula III was selected as the best formula in all parameters measured, except on the particle size distribution result. In addition, total phenolic in the formula I was the highest content with a better stability profile, compared to formula II and III. It showed that the formula with a combination of 8% citric acid: 16% tartaric acid is the most optimum formula physically, even for further research, adsorbent use or binder ratio in the formula, and moisture resistant of the primary packaging must also be considered.
... De Simone et al., [30] optimized the low shear granulation process of hydroxypropyl methylcellulose using DIA. Kumar et al., [31] and Madarász et al., [32] used DIA to analyze the size and shape of granules in the twin screw granulation process. ...
The aim of the work was to analyze the influence of process parameters of high shear granulation on the process yield and on the morphology of granules on the basis of dynamic image analysis. The amount of added granulation liquid had a significant effect on all monitored granulometric parameters and caused significant changes in the yield of the process. In regard of the shape, the most spherical granules with the smoothest surface were formed at a liquid to solid ratio of ≈1. The smallest granules were formed at an impeller speed of 700 rpm, but the granules formed at 500 rpm showed both the most desirable shape and the highest process yield. Variation in the shape factors relied not only on the process parameters, but also on the area equivalent diameter of the individual granules in the batch. A linear relationship was found between the amount of granulation liquid and the compressibility of the granules. Using response surface methodology, models for predicting the size of granules and process yield related to the amount of added liquid and the impeller speed were generated, on the basis of which the size of granules and yield can be determined with great accuracy.
... For this reason, theoretical [57,58] and experimental [43,[59][60][61] approaches have been introduced to understand the transport, mixing and the fundamental mechanisms in twinscrew wet granulation. As shown in Figure 8, the dry powder is fed in the barrel through the feeding zone while the granulating liquid is added using two nozzles (for each screw). ...
Twin-screw granulation (TSG) is a pharmaceutical process that has gained increased interest from the pharmaceutical industry for its potential for the development of oral dosage forms. The technology has evolved rapidly due to the flexibility of the equipment design, the selection of the process variables and the wide range of processed materials. Most importantly, TSG offers the benefits of both batch and continuous manufacturing for pharmaceutical products, accompanied by excellent process control, high product quality which can be achieved through the implementation of Quality by Design (QbD) approaches and the integration of Process Analytical Tools (PAT). Here, we present basic concepts of the various twin-screw granulation techniques and present in detail their advantages and disadvantages. In addition, we discuss the detail of the instrumentation used for TSG and how the critical processing paraments (CPP) affect the critical quality attributes (CQA) of the produced granules. Finally, we present recent advances in TSG continuous manufacturing including the paradigms of modelling of continuous granulation process, QbD approaches coupled with PAT monitoring for granule optimization and process understanding.
... In the first kneading zone, the nuclei are forced between the barrel wall of the granulator and the flight tip of the kneading elements in compartment 2. According to Pradhan et al. and Mundozah et al. this breakage of the oversized nuclei occurs simultaneously with consolidation and the further agglomeration of ungranulated powder due to the process of layering (Hagrasy and Litster, 2013;Verstraeten et al., 2017). Since consolidation and layering are favoured at higher L/S ratio (Kumar et al., 2014;Verstraeten et al., 2017), a more narrow GSD was obtained at higher L/S ratio (Fig. 2C), compared to lower L/S ratio ( Fig. 2A). The change in GSD was concomitant with a significant increase in torque for both experiments (Fig. 2B, 2D; orange). ...
... At high MFR and high L/S ratio, a heavy wetted powder mass was created, enhancing the level of shear mixing with high friction forces and resulting in a sluggish flow of the wetted mass with a longer residence time. Therefore, more energy is required to convey the mass and higher torque values are recorded (Fig. 2D) (Dhenge et al., 2012a;Kumar et al., 2014). Fig. 5 shows the amount of fines (Fig. 5B) and oversized (Fig. 5A) granules in the wetting zone (blue) and after the first kneading zone (orange) as a function of the torque increase, the torque increase of compartment 3 being the combined increase in torque caused by compartments 1 to 3 compared to the baseline torque. ...
... A different change in GSD was observed after the second kneading zone (i.e., compartment 5) as the GSD change depended on the available amount of granulation liquid. This is illustrated by experiments 2 (low L/S) and 13 (high L/S) in Fig. 2. At low L/S ratio, weaker liquid bonds between the powder particles were formed in compartment 3 (Kumar et al., 2014;Verstraeten et al., 2017). Therefore, more brittle granules were formed in the first kneading zone and breakage of those brittle granules occurred when passing through the second kneading zone. ...
The potential of torque as in-process control (IPC) to monitor granule size in twin-screw wet granulation (TSG) was investigated. An experimental set-up allowing the collection of granules at four different locations (i.e., in the wetting zone, after the first and second kneading zone and at the end of the granulator) of the granulator screws was used to determine the change in granule size, granule temperature and the contribution of each compartment to the overall torque for varying screw speed, mass feed rate and liquid-to-solid ratio. The only observed correlation was between the granule size and torque increase after the first kneading zone because the torque increase was an indication of the degree in granule growth which was consistently observed with all applied granulation process parameters. No correlation was observed in the other locations as changes of torque were accompanied to either granule breakage and/or growth. Moreover, torque increase was correlated to higher granule temperature, suggesting that energy put into the granulator was partly used to heat up the material being processed and explains additionally the lack of correlation between granule size and torque. Therefore, this study showed that torque could not be used as IPC to monitor granule size during TSG.
... In continuous twin-screw granulation, the wetting stage is physically separated from the granule consolidation, growth, breakage and attrition stages (Dhenge et al., 2012;Kumar et al., 2014). For most studies on twin-screw granulation, the granule quality attributes have been investigatedafter passing the complete screw configurationat the outlet of the granulator. ...
... Consequently, the influence of individual granulation stages upon final granule quality attributes cannot be determined. A few studies investigated the evolution of the granule properties along the barrel length (Dhenge et al., 2012;Kumar et al., 2014;Verstraeten et al., 2017;. The methodologies described in these studies allow to analyse granules from the different screw compartments (i.e., wetting zone, kneading zones and end of the granulator). ...
Wetting is the initial stage of wet granulation processes during which the first contact between the powder and the liquid occurs. Wetting is a critical step to allow granule growth and consolidation, but also to ensure uniform active pharmaceutical ingredient (API) distribution over all granule size fractions. A physical understanding of the wetting stage is therefore crucial to design a robust granulation process. In twin-screw granulation, wetting is physically separated from granule consolidation, growth, breakage and attrition. The present study used this particularity to investigate the wetting step in such a way that the fundamental mechanisms governing the wetting can be linked and understood. A modified granulator barrel was used allowing the collection of granules immediately after the wetting. A low drug-loaded pharmaceutical formulation containing a poorly soluble and poorly wettable API was used for this investigation. Granules obtained after the wetting zone were analysed for granule size distribution, API distribution over the different size fractions and granule temperature. It was found that “wetting efficiency” (i.e., fraction of powder being nucleated during the wetting stage) could be predicted using an energy balance based on in-line measurement of the granule temperature. Wetting efficiency could moreover be linked to final granule quality attributes (i.e., granule size distribution) at the outlet of the granulator. It was further demonstrated that granule growth and consolidation could only be achieved when complete wetting was achieved in the wetting zone of the granulator. This study suggested a methodology based on in-line temperature measurements to quickly determine wetting efficiency. The described methodology could therefore be used as a tool to gain more fundamental understanding of the wetting stage during twin-screw granulation as well as to define suitable formulation and process ranges for further granulation process development.
... In the lactose/PVP formulation (Fig. 4), relevant influences were observed for the barrel temperature and screw speed, which were not observed for other formulations: more oversized granules were measured at higher barrel temperature, due to the higher solubility of lactose (Rowe et al., 2009). Furthermore, at higher screw speed the reduction of oversized granules was attributed to the lower fill level of the granulator barrel (Kumar et al., 2014). In contrast, screw speed and barrel temperature showed a limited effect on the particle size of the other formulations, similar to the findings of Dhenge et al., who evaluated the effect of screw speed on a formulation consisting of αlactose monohydrate (73.5%), microcrystalline cellulose (20%), croscarmellose sodium (1.5%) and hydroxypropyl cellulose (1%) (Dhenge et al., 2010). ...
