Scale-up in twin-screw wet granulation: impact of formulation properties.

The focus of this study was to investigate the sensitivity of different drug formulations to differences in process parameters based on previously developed scale-up strategies. Three different formulations were used for scale-up experiments from a QbCon® 1 with a screw diameter of 16 mm and a throughput of 2 kg/h to a QbCon® 25 line with a screw diameter of 25 mm and a throughput of 25 kg/h. Two of those formulations were similar in their composition of excipients but had a different API added to the blend to investigate the effect of solubility of the API during twin-screw wet granulation, while the third formulation was based on a controlled release formulation with different excipients and a high fraction of HPMC. The L/S-ratio had to be set specifically for each formulation as depending on the binder and the overall composition the blends varied significantly in their response to water addition and their overall granulation behavior. Before milling there were large differences in granule size distributions based on scale (Earth Mover's Distance 140-1100 µm, higher values indicating low similarity) for all formulations. However, no major differences in granule properties (e.g. Earth Mover's Distance for GSDs: 23-88 µm) or tablet tensile strength (> 1.8 MPa at a compaction pressure of 200 MPa for all formulations with a coefficient of variation < 0.1, indicating high robustness for all formulations) were observed after milling, which allowed for a successful scale-up independent of the selected formulations.

Influence of granulation temperature on particle size distribution of granules in twin-screw granulation (TSG).

This study investigated an influence of granulation temperature during twin-screw granulation (TSG) on particle size distributions (PSDs). The influence of the granulation temperature on granule size distributions varied, depending on the liquid to solid (L/S) ratio, the kind of binders, the method of binder addition, and the filler material. The PSD of granules was broad and bimodal at a barrel temperature of 30 °C. Granules size distributions became narrow and second height decreased at high barrel temperature. While the L/S ratio had an effect on the sharpness of granule size distributions, this effect was minor compared to the granulation temperature. Granule size distributions were influenced by binder addition methods. When the binder was added as solution, PSD became broad. In formulations using lactose as filler, PSD became broad and bimodal at 90 °C. Much lactose was dissolved in granulation solution at high temperature, because the solubility of lactose rises significantly with the solution temperature leading to higher effective L/S ratio in the granulator. Hence, granulation was proceeded and large granules were formed. From these results, the granulation temperature is one of important parameters to obtain mono-modal PSD in TSG.

Continuous Twin-Screw wet granulation process with In-Barrel drying and NIR setup for Real-Time Moisture Monitoring.

The purpose of this study was to evaluate if wet granule formation and drying could take place in a single operation by utilizing in-barrel drying. The drying kinetics of the formulation were studied in order to select appropriate processing parameters and assess feasibility with short residence times in the extruder. The 18-mm extruder was operated in a 40:1 L:D ratio with 8 zones. The first two zones were used for material feeding and wet granule formation and the remaining zones were used for drying at elevated temperature. The impact of screw configuration as well as screw speed, feed rate, and residence time were all studied to optimize the drying process. Due to limitations of temperature and residence time, vacuum was added to enable sufficient drying. In-line NIR spectroscopy was incorporated into the twin-screw wet granulation (TSWG) process to monitor the moisture content of wet granules in real-time. The set-up was optimized and a predictive model was developed for future experiments. This study demonstrated the success of this technique on a pilot-scale (18-mm) extruder for the first time. Granules were formed and dried to a target loss on drying (LOD) of less than 2 % at moderate temperatures (100 °C - 110 °C) with one single operation. Streamlining wet granulation and drying into one unit operation can have a profound impact on pharmaceutical manufacturing reducing time, footprint, and environmental exposure due to reduced product transfers.

Comparison of scale-up strategies in twin-screw wet granulation.

The aim of this study was to compare different scale-up strategies in twin-screw wet granulation and investigate the impact of the selected strategy on granule and tablet properties for a defined formulation. For the scale-up, a granulation process was transferred from a QbCon® 1 with a screw diameter of 16 mm to a QbCon® 25 line with a screw diameter of 25 mm. Three different scale-up strategies were introduced based on differences in process parameters and their resulting effects on various aspects. such as the powder feed number as a surrogate for the barrel fill level or the circumferential speed. Both are highly dependent on screw diameter and screw speed (SS), while the barrel fill level also depends on the overall throughput. Granules produced on the larger scale were significantly larger due to the larger gap size in the granulator, however, these differences were eliminated after milling. Despite major differences in powder feed number, circumferential speed, overall throughput and SS, product properties for both tablets and granules were strikingly similar after milling on both scales and with all applied strategies. For the selected formulation the effect of varying liquid to solid ratio at the same scale was much higher than the differences between scale-up strategies. The results of this study are promising for future process scale-up from lab scale to production scale in twin-screw wet granulation, as they are indicating towards a robust granulation process leading to similar tablet properties afterwards.

A Semi-Mechanistic Prediction of Residence Time Metrics in Twin Screw Granulation.

This work is concerned with the semi-mechanistic prediction of residence time metrics using historical data from mono-component twin screw wet granulation processes. From the data, several key parameters such as powder throughput rate, shafts rotation speed, liquid binder feed ratio, number of kneading elements in the shafts and the stagger angle between the kneading elements were identified and physical factors were developed to translate those varying parameters into expressions affecting the key intermediate phenomena in the equipment, holdup, flow and mixing. The developed relations were then tested across datasets to evaluate the performance of the model, applying a k-fold optimization technique. The semi-mechanistic predictions were evaluated both qualitatively through the main effects plots and quantitatively through the parity plots and correlations between the tuning constants across datasets. The root mean square error (RMSE) was used as a metric to compare the degree of goodness of fit for different datasets using the developed semi-mechanistic relations. In summary this paper presents a new approach at estimating both the residence time metrics in twin screw wet granulation, mean residence time (MRT) and variance through semi-mechanistic relations, the validity of which have been tested for different datasets.

Fluidization characterization in the ConSigma 25 dryer via process data - A method of advanced quality assurance in continuous manufacturing.

Wet granulation lines in pharmaceutical manufacturing facilities typically comprise a dryer that removes the excess moisture content after wet granulation. In this study, a semi-continuous dryer installed in the ConsiGma 25 wet granulation line was investigated. The goal was to highlight specific characteristics of this type of dryer, utilizing the available process data and the corresponding data obtained via material characterization. This paper addresses typical effects and issues associated with the dryer's setup and operation (e.g., unexpected cell temperature profiles, the effects of air flow and temperature on the granule properties, variations in the granule moisture between the dryer cells). Since in many situations the liquid-to-solid ratio is based on the properties of granules after the granulation step, the selection of inlet air flow rate and the inlet air temperature of the dryer as well as the overall line throughput (affecting the cell fill level in the dryer) are of particular interest from a practical point of view. This paper discusses these issues and provides suggestions on how to address them when setting up the process. A novel approach for characterizing the fluidization inside the dryer by means of quantifying the "smoothness" of the temperature profile is proposed. The paper should be viewed as a hands-on guideline, which highlights possible pitfalls during the process setup and offers solutions.

Native starch as in situ binder for continuous twin screw wet granulation.

The use of native starch as in situ binder in a continuous twin screw wet granulation process was studied. Gelatinization of pea starch occurred in the barrel of the granulator using a poorly soluble excipient (anhydrous dicalcium phosphate), but the degree of gelatinization depended on the liquid-to-solid ratio, the granule heating and the screw configuration. Furthermore, the degree of starch gelatinization was correlated with the granule quality: higher binder efficiency was observed in runs where starch was more gelatinized. SEM and PLOM images showed experimental runs which resulted in completely gelatinized starch. Other starch types (maize, potato and wheat starch) could also be gelatinized when processed above a critical barrel temperature for gelatinization. This barrel temperature was different for all starches. In situ starch gelatinization was also investigated in combination with a highly soluble excipient (mannitol). The lower granule friability observed using pure mannitol compared to a mannitol/starch mixture indicated that starch did not contribute to the binding, hence starch did not gelatinize during processing. The study showed that native starch can be considered as a promising in situ binder for continuous twin screw wet granulation of a poorly soluble formulation.

The impact of channel fill level on internal forces during continuous twin screw wet granulation.

The forces experienced by the particles inside a twin screw granulator (TSG) are one of the most difficult parameters to measure quantitatively. However, it is possible to perform accurately this measurement through the use of dye containing calibrated microencapsulated sensors (CAMES) whose rupture is directly dependant on their experienced shear stress. The current study measures the extent of local stresses in the transformation from powder to granules at different channel fills during TSG processing. Channel fill has shown good potential as a design tool, however, its validity for predicting particle size distributions has yet to be demonstrated in an 11-mm TSG. The results of this study showed that the particles within the twin screw granulator experienced stresses in the range of 350-1000 kPa and this value was not linear with the specific mechanical energy applied by the granulator. It was observed that the majority of these stresses were produced by material transport processes rather than the granulation in itself. In addition it was determined that the torque required by the TSG increases exponentially after a certain channel fill a feature that requires to be considered in order to design safer, predictable and reliable granulation workspaces.

Transfer from high-shear batch to continuous twin screw wet granulation: a case study in understanding the relationship between process parameters and product quality attributes.

A twin screw to high-shear batch granulation technology switch was evaluated for a pharmaceutical development project. Differences in granule (particle size distribution and porosity) and tablet (dissolution) quality attributes were analysed for both continuous and batch technologies. Liquid to solid (L/S) ratio, screw configuration and screw speed parameters on the twin screw granulator were varied, with output granule and tablet properties characterised. L/S and screw configuration were found to influence the granule particle size distribution, porosity and tablet dissolution. At 0.15 L/S, the particle size distribution showed a significant proportion of ungranulated material in the output granule. As the L/S is increased, the level of ungranulated material decreased. An increase in L/S and the number of kneader elements caused a decrease in granule porosity and tablet dissolution. Twin screw and batch granulation technologies generated different granule properties (size and shape) at a constant L/S. A lower L/S in twin screw granulation was needed to achieve similar tablet attributes. It is concluded that differences in liquid addition and therefore initial granule nucleation caused differences in granule properties, which impacted tablet attributes and manufacturability.