(T1330-10-54) Continuous Manufacturing: Rheological Powder Characterisation of Excipients to Understand Their Behaving during the Feeding Step

Purpose: Continuous manufacturing (CM) is getting more and more popular in the pharmaceutical industry. In regular CM lines, the first and key tools are represented by feeders. Thus, a good flowability performance of the products is necessary to ensure a smooth feeding process. Especially during the feeding step, powders are undergoing several physical environments requiring different behavioral properties. ^[1,2]. Hence the characterization of the powder flow is essential to screen and predict powder performances. A FT-4 powder rheometer is as example a very good tool to analyze critical attributes to take in account during the feeding. L-HPC is an excellent candidate for taking first steps in rheology analysis as grades with various particle sizes and shapes are available (Table 1). In this study, the flow properties of three different L-HPC grades measured with the FT4 powder rheometer will be correlated with feeding trials conducted at Coperion (Switzerland).

Methods: The powder rheology of LH-11, LH-31, and NBD-021 was measured with the FT4 powder rheometer. The methods we used in this study were related to the feeding step and included stability and variable flow rate as dynamic- and shear cell as shear-methodology.^[3,4] A 25ml glass vessel, the two blade stirrer for the dynamic method, the vented piston and shear head for the shear cell method were used. For the feeding trials we used the Coperion QT20-twinscrew feeder with a 2D 20 l funnel, twin concave fine (TCF) screws and a horizontal agitator. The refill was done manually. The feeding rates used were 1, 5 and 20 kg/h.

Results: The Stability and variable Flow Rate method measures the energy which is required to move the rotating blade through the powder in vertical downward direction. The measurement is divided into 2 parts: the first 7 data points represent the stability test with a constant blade tip speed of 100 mm/s; test 8-11 represent the variable flow rate test with a decreasing blade tip speed from 100 mm/s to 10 mm/s, typically more energy is consumed as the blade passes at a slower speed (Fig. 1. A). LH-11 needs the highest total energy to become fluidized, whereby LH-31 needs the lowest. The total energy decreases from LH-11 > NBD-021 > LH-31 which can be explained by the particle size distribution; the finer the powder, the lower the total energy. Another explanation can be the particle shape; LH-11 contains the highest amount of fibers, NBD-021 has more spherical particles and less long fibers besides a more narrow PSD which results in a lower energy consumption (Fig. 1. A, Table 1). Shear properties are important for understanding how easily a previously at rest, consolidated powder will begin to flow; the higher the shear stress for a given normal stress, the less likely the powder will yield and begin to flow if entrapped in a e.g. funnel under a similar setting stress. The obtained data could be used to apply a number of mathematical models. One of this models is the calculation of the Flow Function, a parameter which is used to rank the flowability, below 4 the powder is cohesive and denoting poor flow, between 4 and 10 the powder is easy flowing and above 10 it is free flowing. ^[3,4] According this model, LH-11 and NBD-021 are easy flowing whereby LH-31 is cohesive (Fig 1. B). According the feeding trials. all grades were easy to feed with a feed rate of 1 and 5 kg/h. The lowest deviation in the mass flow could be observed for NBD-021, whereby LH-11 showed the highest. At a feed rate of 20 kg/h some differences occurred. Still, LH-11 showed the highest fluctuation in mass flow besides the lowest feed factor, LH-31 was not able to feed till the end (Fig. 2). Due to electrostatic charge, LH-31 showed a powder build up towards the feeder outlet. The feeder outlet was also covered with a powder layer which was not observed for LH-11 and NBD-021.

Conclusion: The FT-4 measurements have shown that micronized powders tend to create problems regarding cohesiveness even if the total energy necessary to fluidize the powder is very low. LH-31 could easy be fed under low feed rates (1 and 5 kg) with a high feed factor but if the feed rates increases the cohesiveness of the powder could result in electrostatic charge and thus create problems at high feed rates. The long fibers of LH-11 result in a high energy necessary to fluidize the powder and tend to reduce the feed factor due to higher mass flow fluctuation but do not influence the powder flow at high feed rates (Fig.2). NBD-021 with its optimized PSD could be feed without problems at all feed rates because of its easy flowability and non-cohesive behavior.

References: 1. Chien, Y.W. Human insulin: Basic sciences to therapeutic uses, Drug Dev. Ind. Pharm. 22, 753-789 (1996).
2. Carino, G. and Mathiowitz, E. Oral insulin delivery. Adv. Drug Del. Rev. 35, 249-257 (1999).
3. Divya. S , Dr. GNK Ganesh; Characterization of Powder Flowability Using FT4 – Powder Rheometer. J. Pharm. Sci. & Res. Vol. 11(1), 2019, 25-29.
4. https://www.freemantech.co.uk/powder-testing/ft4-powder-rheometer-powder-flow-tester/shear-testing

Table 1. L-HPC grades with their typical D50 particle sizes and shapes.

Figure 1. A. Stability and variable flow rates of LH-11, LH-31 and NBD-021; B. Flow Function of L-HPC, whereby LH-11 and NBD-021 are easy flowing and LH-31 is cohesive. (for each product 3 batches were measured).

Figure 2. Feeding trial of L-HPC at a feed rate of 20 kg/h.