A novel regime map for twin-screw melt granulation: Unveiling new insights into key operating variables

Abstract

Regime maps are vital in twin-screw granulation, predicting outcomes via dimensionless numbers. This study develops a novel regime map for twin-screw melt granulation, adapting a wet granulation model. Using Design of Experiments, screw speed, screw configuration, temperature, and binder amount were optimized with lactose and PEG 6000. Results show how these variables impact on particle size and flowability. Optimal conditions (20 wt% PEG, 70 °C, 100 rpm) yielded granules with 0.360 mm median size and 6.67% Carr Index, indicating excellent flow. Increased binder and kneading elements led to larger granules, while higher screw speed enhanced mixing. Elevated temperatures boosted binder melting. The regime map accurately categorized growth, largely in the breakage-dominated region, and was validated across systems, proving its predictive potential.

Highlights

Introduction

In pharmaceutical manufacturing, granulation plays an important operation due to its ability to enhance the performance of solid dosage forms. It not only improves powder flow and compressibility but also contributes to better content uniformity and, in some formulations, accelerates dissolution rates (Cotabarren et al., 2021). Among the various granulation techniques—wet, dry, and melt—melt granulation stands out for its unique advantages. This method relies on thermal binders that, once softened or melted, facilitate the agglomeration of fine powders (Grymonpré et al., 2018). Its solvent-free nature makes it especially suitable for drugs that are sensitive to moisture or highly water-soluble, and the resulting granules often show superior tabletability (Batra et al., 2017). Traditionally, this process has been carried out in batch systems using high-shear mixers with heating capabilities (Schæfer & Mathiesen, 1996) or fluidized-bed equipment (Veliz Moraga et al., 2015). However, one of the main drawbacks of these batch setups is the lack of precise and uniform temperature control, which can hinder process consistency and granule quality (Kittikunakorn et al., 2020). In contrast to traditional batch manufacturing, twin-screw granulation (TSG) as a continuous process offers several benefits, including a flexible design, shorter residence times, lower production costs, minimized segregation, and higher throughput (Zheng et al., 2021). In TSG, the interaction between the rotating screws and the granulator barrel facilitates the conveying, mixing, and compression of the feed material (Zheng et al., 2021). Twin-screw melt granulation (TSMG) has emerged as a promising continuous manufacturing technique in the pharmaceutical industry. It offers superior mixing capabilities and uniform local heating through heat conduction from the barrel and from the frictional forces between particles and equipment surfaces (Kittikunakorn et al., 2020). This distinctive heating mechanism minimizes formulations exposure to high temperatures, while the equipment’s small volume enables efficient heat and mass transfer, resulting in consistent product quality (Lodaya & Thompson, 2018). In TSMG, the material temperature, residence time, and mixing intensity are determined by the interactions between operating variables, such as the screw configuration, screw speed, feed rate, and barrel temperature (Liu et al., 2021). Due to the absence of solvent evaporation, the mechanisms of TSMG are less complicated than TSWG. A distinctive aspect of TSMG is the role of the temperature, which controls granulation formation by affecting binder rheology. Bonds between the seeds and the molten binder convert from liquid bridges to solid bridges when the molten binder solidifies after exiting the barrel (Liu et al., 2021).

Read more here

Materials

The α-Lactose monohydrate HMS (NZ) (Chutrau S.A.C.I.F, DFE PHARMA, New Zeeland) was used as the model excipient, while PEG 6000 (Sistemas Analíticos S.A, Argentina) served as the binders. The binder was pre-conditioned by milling the commercial flakes using a laboratory hammer mill (Laboratory Mill 120, Perten, Stockholm, Sweden) fitted with a 2 mm sieve. Following milling, PEG was sieved, and the fraction ranging from 0.105 to 0.250 mm was collected for the granulation process.

Jacquelina C. Lobos de Ponga, Marcos Díaz Muñoz, Ivana M. Cotabarren, Juliana Piña, A novel regime map for twin-screw melt granulation: Unveiling new insights into key operating variables, Particuology, 2025, ISSN 1674-2001, https://doi.org/10.1016/j.partic.2025.09.012.

Read also our introduction article on Binders here: