The effect of material properties and process parameters on die filling at varying throughputs: A pls-model-based analysis

Abstract

When tablets are manufactured on a rotary tablet press and the throughput is increased, it leads to changes in powder dynamics during die filling due to formulation characteristics and changing powder flow in the feed frame. This may result, a.o. in increased tablet weight variability, poorer content uniformity, capping and lamination. This research focuses on explaining the die filling performance depending on material properties and process settings, including throughput for small and large tablets. It was concluded that throughput had a negative impact on die filling variability, which is related to reduced residence time and lower fill fraction of feed frame and dies. Furthermore, the die filling mechanism was inherently different for large tablets in comparison to small tablets. Higher die filling consistency was observed for dense, less porous, less compressible and better flowing powders. As a result of this work, a model was developed to predict impact of formulation properties and process settings on die filling variability and its dependency on changes in throughput. This model will benefit formulation development at an early stage when active ingredient availability may be challenging as it will avoid the need to conduct experiments at high throughputs.

Introduction

During early formulation development of tablets for pharmaceutical use, the available amount of Active Pharmaceutical Ingredient (API) may be limited. However, it is important to understand what the impact of formulation characteristics is when the tableting throughput (amount of material produced per unit of time) is increased to meet commercial manufacturing requirements.

Although the work presented in this paper is also applicable to tablet compression in batch manufacturing, it will have specific benefits for continuous manufacturing (CM) processes. Often, in CM, development and commercial manufacturing are performed on the same equipment or the transfer from a development CM line to commercial manufacturing CM line is done where the equipment is similar. In CM, initial development can be performed at a low throughput to accommodate supplies for clinical trials. During tech transfer to commercial manufacturing the throughput will be increased to the intended commercial throughput.

It is important to understand what the impact of this throughput increase is on the tablet properties prior to defining the commercial formulation composition, hence avoiding issues during tech transfer and potential failure modes (e.g., high weight variations, capping and lamination, poor content uniformity). The link between throughput increase and the risk of the aforementioned tablet quality issues, can be found in formulation characteristics, tablet dimensions, tablet process settings and associated die filling mechanisms. Studies describing the mechanism of die filling have already been covered in literature (Mateo-Ortiz and Méndez, 2015, Wu et al., 2003, Schomberg et al., 2023, Van Snick, B. et al. 2018, Baserinia and Sinka, 2019, Goh et al., 2018, Grymonpré et al., 2018) in which three mechanisms can be defined: gravity filling, suction filling and forced feeding. Gravity filling of the die occurs as powder flows into a die cavity under the influence of gravity. Secondly, suction filling is enabled by a pressure gradient caused by the downward movement of the lower punch pulling powder into the die cavity. For powders with a small particle size, large bulk density and small permeability, the suction effect has a greater impact on the mass discharged into the die (Baserinia and Sinka, 2019). Forced feeding on the other hand is achieved by feeding systems with moving paddles such that powder is forced into the die.

Shoe-die filling models have been used to examine the die fill process, where powder is delivered from a moving shoe into a die (Goh et al., 2018, Jackson et al., 2007, Schneider et al., 2007, Xie and Puri, 2006, Baserinia and Sinka, 2019). Goh et al. showed how feeder velocity, forced feeding and suction effect impacts die fill performance. In general, suction effect had greatest impact on die fill performance, especially for smaller orifices because gravity filling becomes less efficient since there is less available surface area for residual air to escape from the die prior to powder entry. The effect of suction fill is also greater for less permeable powders. For larger orifices on the other hand, the effect of paddle velocity on die fill was greater. It was also concluded that generally, forced feeding did not significantly affect die fill performance in comparison to suction and paddle velocity.

Although, shoe-die filling models allow for an in-depth investigation of passive die filling from a moving feeder, while limiting the use of costly material, it is a different process compared to what occurs in a rotary tablet press, where powder moves from a stationary feed frame into a moving die on a rotating turret. A rotary tablet press, used in commercial production, is equipped with a stationary feed frame in which one to three paddles are mounted to enable forced feeding of the dies. Grymonpré et al. showed that turret speed most significantly impacts the die filling step. Moreover, depending on the paddle design, a higher die filling uniformity as a function of tableting speed can be reached. Not only, paddle design has a major impact on tablet weight and weight homogeneity, also paddle speed is a critical process parameter. Increasing the paddle speed has a favorable impact on tablet weight (variability), particularly for poorly flowing powders (Elisabeth Peeters et al., 2015, Van Snick, B. et al. 2018). There is however, the risk of overlubrication of the blend, causing reduced tensile strengths of the tablets (Elisabeth Peeters et al. 2016, de Backere et al., 2022). Schomberg et al. developed a model equation to describe the volume flow in dependence on the paddle speed and calculate the minimum paddle rotation frequency (critical paddle speed) which leads to completely filled dies at a given turret speed. This model for die filling on a pilot scale rotary tablet press was extended to allow the scale-up to tablet presses in industrial scale and can be used to calculate the critical paddle speed to completely fill the dies (Schomberg et al., 2023). Van Snick et al. developed a partial least squares (PLS) model to gain insight in the correlation between material properties, process parameters (paddle wheel and turret speed) and die filling performance with the purpose of evaluating commercial scale compression using a limited amount of material. It was shown that lower tablet weight variability was obtained for dense and good flowing blends. Additionally, the dominant effect of turret speed on die filling variability related to a decreased feed frame residence time was shown.

While aforementioned research contributed to a better understanding of die filling on high-speed rotary tablet presses, the impact of tablet diameter (size) was not addressed. Next to that, other process parameters such as overfill and the speed ratio of the feeding and metering wheel were not considered.

The aim of this study was to investigate the link between material properties and tablet compression specifically related to die filling variability under different throughputs and process conditions addressing potential technology transfer challenges for different tablet diameters. To achieve this, different formulations were characterized and compressed into tablets according to a Design of Experiments (DoE). Additionally, the increase in die filling variability for increasing throughputs was quantified depending on formulation characteristics and modelled. This will allow for predictions to be made regarding scale flexibility of a certain blend upon blend characterization and limiting the need for large amounts of material in early stage development.