Influence of material and process parameters on the correction factor Kp in roller compaction simulation

Abstract

It is widely believed that compaction simulators can replicate the uniaxial compression process of a roller compactor. The correction factor (Kp) is a parameter used to adjust a mathematical model for compaction simulation to obtain the same product relative density, therefore accounting for specific variables in machinery and scale up. However, the Kp has often been established for a single material and within a limited design space. This study investigates the impact of material and process parameters such as roll speed, roll gap and specific compaction force (SCF) on the Kp during roller compaction simulation. MCC, Starch and a 50:50 % blend of the two materials were used as model materials for the investigation. The relative densities from ribbons and riblets were measured using pycnometry and Kp was determined using ratio calculation of the respective relative densities. The influence of roll speed on Kp was found to be statistically significant (p < 0.05) for Starch, however the same influence was not statistically significant for MCC and MCC:Starch 50 %:50 % (p > 0.05).

Furthermore, the influence of roll gap on Kp was found to be statistically significant (p < 0.05) for all three materials. The influence of the SCF on the Kp was found to be statistical significant for Starch (p < 0.05), however the same influence was not statistically significant for MCC and MCC:Starch 50 %:50 % (p > 0.05). In addition, the combined influence of the gap and material exhibits also a statistically significant (p < 0.05) effect based on Kp leading to a second-order combined effect. The interaction of SCF, roll gap, and material properties affecting Kp, indicates the need for a tailored approach when determining Kp for different formulations.

Highlights

The correction factor, Kp is significantly influenced by roll gap parameters.

Starch shows a second-order interaction with roll gap and specific compaction force (SCF), affecting Kp.

The relative densities of riblets and ribbons depend on roll gap and SCF

Introduction

Roller compaction is widely utilised within drug product manufacturing to improve blend flowability and bulk density, as well as to reduce the risk of segregation and dust generation. Although many different roller compactors exist on the market, they generally operate in the same way. The material is drawn between two rolls and compacted into ribbons, which are then milled into granules for further downstream processing. Once the powder begins to flow, particularly in the area where the powder surface movement matches that of the rolls, the thickness of the ribbon is primarily determined by the minimum roll gap distance.

The ribbon may experience a slight increase in thickness after being released from the rolls due to material elastic recovery [1]. Schiano et al. (2017) and Kleinebudde (2022) emphasise how variations in powder flow can affect the in-process alterations in roll gap and ribbon thickness due to changes in the quantity of powder passing through the rolls. Keizer et al. (2020) have also shown a significant impact of roll gap on ribbon relative density where a consistently lower relative density for microcrystalline cellulose (MCC), lactose and dicalcium phosphate, anhydrous DCPA is seen at a higher roll gap [2]. This is explained by the higher volume of material over the same specific compaction force (SCF). An increase in the roll speed may result in decreased densification of the ribbon, which can be explained by the reduced dwell time during compaction [1,[3], [4], [5]]. Souhi et al. (2015) showed no significant influence of roll speed on the ribbon relative density, but a significant impact of SCF as expected [4]. In contrast, Lück et al. (2022) also investigated the influence of roll speed on the ribbon relative density.

The study showed that for MCC, the ribbon relative density decreased from approx. 0.6 to approx. 0.5 when increasing roll speed from 2 to 6 rpm at a pressure of 41 MPa. Conversely, no influence of roll speed was seen for lactose [6]. Particle characteristics such as flow, particle size distribution and water content can also impact the relative density during compaction. Bacher et al. (2007) investigated the effects of roller compaction process parameters, calcium carbonate morphology, and sorbitol particle size on the flow, compaction, and compression properties of calcium carbonate granules. It was reported that to achieve acceptable mechanical strength of calcium carbonate tablets, the right morphological form of calcium carbonate and adding finely sized sorbitol as a binder are crucial. Particle deformation behaviours and morphology evolution may also have an impact on compaction and relative density. Zhang et al. (2022) investigated the evolution of microstructural of lithium-ion battery electrode during the calendering process with the aim to develop a predictive model for determining electrode thickness and porosity. Here, it was initially observed that compression pressure increases slowly due to pore reduction and particle rearrangement, then exponentially due to friction and extrusion, with elastic recovery first increasing and then decreasing as particles deform plastically. Furthermore, it was found that particle pulverization increases surface area and water adsorption, while secondary particle fusion at high pressure reduces electrolyte penetration and ion transport due to microporous connections. [7]

Compaction simulation has, in recent years, become more attractive for the early-phase development and scale up process due to the reduced material demand and better understanding of compression events before large scale manufacture [1,8]. A compaction simulator compresses uniaxially with specific punch tooling chosen to mimic the desired process, e.g. a flat face rectangular punch to mimic the smooth roll surface in a roller compactor. The simulation involves using a mathematical expression based on a sine function to mimic the movement of a point on the roll surface. This model helps control the compression and decompression of the powder to create the compact referred to as a riblet [1,5,8]. The ribbon densification, often denoted as the ribbon relative density, is a critical quality attribute indicator for the comparison of product from a roller compactor and compaction simulator. Hancock et al. (2003) demonstrated the importance of monitoring the relative density of roller compacted ribbons and the differences in raw materials influencing the properties of the resultant ribbons. The relative density of ribbons was also noted to influence downstream processes and product characteristics further, such as the granule size distribution and tabletability [[8], [9], [10]]. Zinchuk et al. (2004) also emphasise the importance of measuring ribbon relative density. This parameter is essential for evaluating the feasibility of compaction simulation and serves as an assessment indicator of how ribbons impact unit operations such as milling and compression. While the compaction simulator cannot address specific aspects of roller compaction, such as non-homogeneous ribbon density due to segregation phenomena and material bypass, it does allow for the prediction of the effects that critical parameters, such as roll speed, pressure, and radius, have on ribbon properties [8,11].

The ribbon densification is influenced by the SCF, roll gap width and roll speed [6,9]. During compaction simulation using a MEDELPHARM STYL’One Evo, there is a possibility for a correction factor to be used in the mathematical model to account for differences seen in relative density, e.g. between ribbons produced by the roller compactor and riblets produced by the compaction simulator. Kiezer et al. (2021) evaluated the correction factor using a MedelPharm STYL’One Evo and different roller compactors, as follows: Gerteis Mini-Pactor, LB Bohle BRC25, and Alexanderwerk WP120 and WP200. The Kp was determined by comparing the relative densities of ribbons and riblets produced at increasing SCF. It was not possible to determine a universal correction factor across all machines.

This is attributed to the differences in roll width, diameter, and surface, which cannot be accurately attributed to only one Kp factor by the MEDELPHARM STYL’One Evo [12]. In a study by Reimer and Kleinebudde (2019), MCC and lactose were roller compacted at SCFs ranging from 3 to 18 kN/cm. The researchers investigated the ribbon relative density of both materials at two different roll gaps. They found that reducing the roll gap from 4 mm to 2 mm increased the ribbon relative density for all applied SCFs. Conversely, increasing the roll gap resulted in thicker ribbons, which decreased stresses and densification when the same SCF was applied [13]. The work indicated that the compaction simulator consistently overestimated the relative density, requiring a correction factor of 0.677 to attain an equivalent solid fraction for both riblets and ribbons. Furthermore, material independency was reported in the design space investigated, but with a higher degree of error for more elastic materials [14]. Hassan et al. (2023) investigated the ribbon and riblet relative density of MCC and dicalcium phosphate dihydrate (DCPD) at five different SCF. They showed that an increase in ribbon relative density from approx. 0.6 to approx. 0.9 for both materials was observed when increasing the SCF from 1 to 12 kN/cm. Furthermore, the study concluded that, to simulate a Gerteis Mini-Polygran compactor on the MedelPharm STYL’One Evo, a correction factor Kp of 1 was used independent of the material. This conclusion is based on ribbons and riblets produced using parameters of a 2 mm roll gap, 1 rpm roll speed, and specific compaction forces (SCFs) ranging from 1 to 12 kN/cm [15].

The Kp was also investigated by Arpago and Dall’Ara. (2024) using 25 multicomponent mixtures, including active pharmaceutical ingredients (API) to improve the prediction of relative density using a compaction simulator. The Kp was determined using the ratios between the SCF of MedelPharm STYL’One Evo and SCF of Gerteis Mini-Pactor used to achieve the same relative density. Four varying correction factors were calculated that were dependent on material, SCF or a combination of the two. The study concluded that averaging the material dependant correction factors over the 25 formulations could provide a universal correction factor (0.699). However, the study concluded that the use of a universal correction factor may compromise the accuracy of achieving the desired relative density as it does not take into account material properties that are relevant for scale-up processes involving a specific roller compactor [16]. While the simulation doesn’t consider all the variables of the true roller compaction process, such as feeding and shear stresses due to the use of uniaxial compression, it is still considered a useful tool for early phase development [1]. These formulation factors are found to be more critical than modifying the roller compaction process parameters, i.e. roll gap and SCFs, which impact the determination of Kp. [24].

Gupta et al. (2005) used NIR spectroscopy to monitor the effect of moisture on the relative density of simulated ribbons and those prepared by roller compaction. It was reported that moisture significantly affects the relative density of simulated ribbons under uniaxial compression but has little impact on samples prepared by roller compaction with consistent roller compactor settings due to a constant roll gap [23]. Previous studies have shown that the Kp was constant across compaction pressures and independent of SCF, roll speed and roll gap width [9,10]. Nevertheless, the influence of roll speed on ribbon and granule properties continues to be a topic of debate, as it is often asserted that the roll speeds commonly used during roller compaction are sufficiently slow, making strain rate effects related to material residence time between the rolls and any viscoelastic properties of the powder negligible [17].

In the development of the roller compaction processes, it is important to explore the impact of roll force SCF, roll gap width, and roll speed to gain a comprehensive understanding of the connection between roller compaction parameters and ribbon properties [18]. During the development of a drug product in the clinical stages, it’s common for the size or design of equipment to change. The limited amount of material available during the early clinical stages also presents a challenge to reach a validated process. To overcome this challenge, several studies have investigated the use of a compaction simulator for roller compaction process development.

The transfer between roller compactors is often based on ribbon relative densities. Several studies have shown that over a range of SCF, the ribbons produced from a roller compactor and the riblets produced from a compaction simulator had similar relative density [8,14,19,20]. Nevertheless, a correction factor must usually be utilised to account for the variation in relative density observed between machines. With the use of hybrid modelling, it is possible to predict the relative density of materials when using compaction simulation at fixed processing parameters. However, the variance in process parameters is yet to be discussed in detail, as well as the effect of a design space on the determination of the correction factor Kp. This present study aims to investigate the materials that have different attributes and parameters that influence the relative density by varying roll speed, roll gap, and SCF and their impact on correction factor Kp.

Materials

Microcrystalline cellulose (MCC) (Avicel PH200) was obtained from FMC (Philadelphia, PA, United States) and Starch (Starch 1500) was obtained from Colorcon (Kent, United Kingdom) Magnesium Stearate was provided from Peter Greven (Bad Münstereifel, Germany) and added at 1 % to each material and blend.

Layla Hassan, René Jensen, Zahra Sodal, Frederik H. Ørtoft, Lasse I. Blaabjerg, Umair Zafar, Influence of material and process parameters on the correction factor Kp in roller compaction simulation, Powder Technology, Volume 459, 2025, 120983, ISSN 0032-5910, https://doi.org/10.1016/j.powtec.2025.120983.

Read also our introduction article on Microcrystalline Cellulose here:

excipients formulation