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Average relative density of the powder bed after dosing of material as a function of the container angle for Lactohale 100.
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The manufacturing of the majority of solid oral dosage forms is based on the densification of powder. A good understanding of the powder behavior is therefore essential to assure high quality drug products. This is particularly relevant for the capsule filling process, where the powder bulk density plays an important role in controlling the fill we...
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Citations
... The variability was predicted for a variety of pellet sizes and shapes. Other newer works under investigation report feasibility of terahertz reflection measurements to predict relative densities of packed powders and capsule fill weight [7]. ...
... In Figure 5a-c plots of CFW vs. bulk (pb) or tap (pt) density and FWV vs. Kawakita's a and CC% are presented. A linear increase in CFW with pb (circles) or pt (squares) is notable in Figure 5a, which was expected from the results of earlier works [3,7]. Although the correlation coefficients were relatively high (R 2 0.975 and 0.982, respectively) the scatter of the data restricted an accurate prediction. ...
Plain or coated pellets of different densities 1.45, 2.53, and 3.61 g/cc in two size ranges, small (380–550 μm) and large (700–1200 μm) (stereoscope/image analysis), were prepared according to experimental design using extrusion/spheronization. Multiple linear regression (MLR) and artificial neural networks (ANNs) were used to predict packing indices and capsule filling performance from the “apparent” pellet density (helium pycnometry). The dynamic packing of the pellets in tapped volumetric glass cylinders was evaluated using Kawakita’s parameter a and the angle of internal flow θ. The capsule filling was evaluated as maximum fill weight (CFW) and fill weight variation (FWV) using a semi-automatic machine that simulated filling with vibrating plate systems. The pellet density influenced the packing parameters a and θ as the main effect and the CFW and FWV as statistical interactions with the coating. The pellet size and coating also displayed interacting effects on CFW, FWV, and θ. After coating, both small and large pellets behaved the same, demonstrating smooth filling and a low fill weight variation. Furthermore, none of the packing indices could predict the fill weight variation for the studied pellets, suggesting that the filling and packing of capsules with free-flowing pellets is influenced by details that were not accounted for in the tapping experiments. A prediction could be made by the application of MLR and ANNs. The former gave good predictions for the bulk/tap densities, θ, CFW, and FWV (R-squared of experimental vs. theoretical data >0.951). A comparison of the fitting models showed that a feed-forward backpropagation ANN model with six hidden units was superior to MLR in generalizing ability and prediction accuracy. The simplification of the ANN via magnitude-based pruning (MBP) and optimal brain damage (OBD), showed good data fitting, and therefore the derived ANN model can be simplified while maintaining predictability. These findings emphasize the importance of pellet density in the overall capsule filling process and the necessity to implement MLR/ANN into the development of pellet capsule filling operations.
... Of particular interest is the relationship between THz transmission properties and tablet dissolution (Figure 16) [98], because dissolution time is a critical parameter in drug delivery. The behavior of powder during the manufacturing process and the effects of density variations in the final product have also been studied [102]. ...
This paper is a survey of existing and upcoming industrial applications of terahertz technologies, comprising sections on polymers, paint and coatings, pharmaceuticals, electronics, petrochemicals, gas sensing, and paper and wood industries. Finally, an estimate of the market size and growth rates is given, as obtained from a comparison of market reports.
While measurement and monitoring of powder/particulate mass flow rate are not essential to the execution of traditional batch pharmaceutical tablet manufacturing, in continuous operation, it is an important additional critical process parameter. It has a key role both in establishing that the process is in a state of control, and as a controlled variable in process control system design. In current continuous tableting line operations, the pharmaceutical community relies on loss-in-weight feeders to monitor and understand upstream powder flow dynamics. However, due to the absence of established sensing technologies for measuring particulate flow rates, the downstream flow of the feeders is monitored and controlled using various indirect strategies. For example, the hopper level of the tablet press is maintained as a controlled process output by adjusting the turret speed of the tablet press, which indirectly controlling the flow rate. This gap in monitoring and control of the critical process flow motivates our investigation of a novel PAT tool, a capacitance-based sensor (ECVT), and its effective integration into the plant-wide control of a direct compaction process. First, the results of stand-alone experimental studies are reported, which confirm that the ECVT sensor can provide real-time measurements of mass flow rate with measurement error within -1.8 ∼ 3.3 % and with RMSE of 0.1 kg/h over the range of flow rates from 2 to 10 kg/h. The key caveat is that the powder flowability has to be good enough to avoid powder fouling on the transfer line walls. Next, simulation case studies are carried out using a dynamic flowsheet model of a continuous direct compression line implemented in Matlab/Simulink to demonstrate the potential structural and performance advantages in plant-wide process control enabled by mass flow sensing. Finally, experimental studies are performed on a direct compaction pilot plant in which the ECVT sensor is located at the exit of the blender, to confirm that the powder flow can be monitored instantaneously and controlled effectively at the specified setpoint within a plant-wide feedback controller system.
Oral solid dosage forms, the most widely used pharmaceutical products, are typically manufactured through a series of processes that transform a blend of drug and excipient particles into a densified product with consistent quality attributes. While the densification of powder during processing is crucial and directly impacts the quality of the drug product, there is still scarcity of non-destructive and fast sensor systems that provide access to the powder density at critical process stages. This review discusses methods for monitoring density variations of particulate matter by describing their principles and presenting application examples. The techniques discussed range from common in-line methods such as near-infrared spectroscopy, acoustic emission and ultrasonic methods as well as techniques with potential to be more frequently applied in a pharmaceutical manufacturing line, i.e. terahertz spectroscopy and imaging, microwave technique, electrical tomography and X-ray based methods. This review also compares these techniques in terms of measurement and data processing time, resolution and its ability to be integrated in a process.
