Continuous twin-screw wet granulation without adding granulation liquid

Abstract

Granulation is a major focus of pharmaceutical R&D, as a key step in the development of solid pharmaceuticals. In parallel, the spread of continuous integrated powder-to-tablet production lines is also underway. In this research, a new wet granulation method has been investigated in terms of operation and scalability in a fully continuous powder-to-tablet line. The new wet granulation technique requires no addition of granulation liquid to the powder blend; thus, requires only minimal cooling after granulation, providing a more energy-efficient continuous integrated system for the pharmaceutical industry. This can be achieved by adding an excipient with a monograph and a high daily intake, potassium sodium tartrate tetrahydrate (PST), to the starting powder mixture. PST contains water of crystallization which is released by temperature, forming an in-situ granulation liquid during the process. This wet granulation-based technology produced granules with excellent flowability and immediate-release tablets exceeding 100 N breaking force and 1.5 MPa tensile strength. The continuous setup enabled easy scale-up from 0.5 to 10 kg/h using the same equipment and process parameters.

Highlights

Wet granulation was performed without the addition of granulation liquid.

The products were manufactured on a fully continuous powder-to-tablet line.

Only minimal cooling was needed in the integrated continuous wet granulation line.

The process reliably produced high-quality granules and tablets, including scale-up.

Introduction

Tableting is one of the most important steps in formulation technology, as more than half of the solid dosage forms on the market are tablets (Akhtar et al., 2020; Sadia et al., 2018). In order to achieve the appropriate tabletability of the active pharmaceutical ingredients (APIs), an intermediate process called granulation is often carried out. During this process, the API is mixed and processed with various excipients to increase the particle size; thereby, improving the flowability and the compressibility of the powder blend (Djuric & Kleinebudde, 2008; Suresh et al., 2017).

The most commonly used granulation method is wet granulation, in which a granulation liquid is added during the process (Gabbott et al., 2016; Singh et al., 2022). This liquid is usually a polymer solution and the residual solvent evaporates during the drying step following granulation, while the remaining polymer binds the particles together.

In most cases, fluidized bed (Aleksić et al., 2014; Burggraeve et al., 2013) or high-shear (Börner et al., 2016; B. Liu et al., 2021) granulators are used for wet granulation, which generally operate in batch mode. However, an alternative continuous technology, the twin-screw granulation (TSG), is becoming increasingly popular (Dhenge et al., 2010; Peeters et al., 2024; Portier et al., 2020; Seem et al., 2015; Vercruysse et al., 2015). Continuous manufacturing has a number of advantages over batch granulation techniques, which have been described in several publications (Bandari et al., 2020; Behjani et al., 2017; Fonteyne et al., 2015; Ko et al., 2018; Vervaet & Remon, 2005). For instance, batch-based processing often requires significant time and energy to adapt process parameters when scaling up to different equipment. In contrast, continuous manufacturing allows scale-up by simply increasing production time or material throughput on the same equipment. Continuous technologies are increasingly being developed as a production line, thus integrating multiple processes into an integrated system (Domokos et al., 2021; Fülöp et al., 2021; Záhonyi et al., 2023). In the field of continuous wet granulation, more and more publications are appearing that examine and develop processes in conjunction with the energy-consuming drying process following granulation (Domokos et al., 2021; Gabbott et al., 2016; Monaco et al., 2021).

However, there are less common granulation techniques that can be used to avoid the drying step (Shanmugam, 2015). One such technology could be dry granulation (roller compaction), where the powder mixture is passed between two high-pressure rollers and then milled. Another such technique is moisture activated dry granulation (MADG), in which granulation is achieved by adding a small amount of water (typically less than 5%) as a granulation liquid, followed by a separate step in which a moisture-absorbing material (microcrystalline cellulose, silicon dioxide, etc.) is added to the system to obtain dry granules (Moravkar et al., 2017; Takasaki et al., 2016).

Another option is wet granulation in a special device, in which the granulation process is carried out in a closed system at high temperature with a small amount of granulation liquid, known as thermal adhesion granulation (TAG) (Chen et al., 2014; Lin et al., 2008). Finally in melt granulation (MG), a binder is used to increase the particle size. The binder is often a polymer that is heated to near or above its melting point or glass transition temperature, thus that the molten binder bonds the particles together (Kittikunakorn et al., 2020; Monteyne et al., 2016). These examples show that granulation processes without drying have already begun to be investigated, as they offer great potential. However, the widely-used wet granulation has a number of known advantages over the other granulation methods: although moisture-sensitive materials cannot be used, it does not require high temperatures like melt granulation, and there is no high mechanical stress as during dry granulation. Therefore, developments to avoid drying during wet granulation can overcome the disadvantages of other techniques while make the wet granulation more energy efficient.

One such promising new method could be a new wet granulation technique with potassium sodium tartrate tetrahydrate (PST) excipient (Ries et al., 2023), that could be a potential solution for drying issues, such as high energy consumption, the risk of segregation and agglomeration, as well as inhomogeneous moisture content (Askarishahi et al., 2023). As granules require no or minimal cooling after granulation, making the entire production line energy-efficient and thus greener. PST is an excipient containing bound crystal water, which releases its crystal water during the granulation process at higher temperatures and acts as a granulation liquid, and after granulation, the residual water is taken back by the PST. Further advantages of PST are that it is a compound with a monograph, and no adverse effects are known in terms of high daily doses and long-term effects; therefore, it can also be used in the manufacture of pharmaceutical products (EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP), 2015).

The aim of this research was to be the first to manufacture and scale up the above-mentioned new wet granulation technology using an integrated continuous granulation line, which includes continuous feeding, twin-screw wet granulation (TSWG), cooling, milling and tableting. Experiments were conducted with different powder blend compositions at different granulation temperatures in order to find the appropriate product properties. Scale-up experiments were performed with the best composition without compromising product quality, at a maximum mass flow rate of 10 kg/h. Thus, the investigation of such an innovative new granulation technology in an integrated continuous powder-to-tablet production line, in line with pharmaceutical trends, may be very relevant and promising.

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Materials

The formulation included anhydrous caffeine as the model API, potassium sodium tartrate tetrahydrate (PST, Kollitab® PST) as a granulation aid, and two types of polyvinylpyrrolidone: cross-linked PVPP (Kollidon® CL) and non-cross-linked PVP (Kollidon® 30), all of them supplied by BASF (Ludwigshafen, Germany). α-lactose monohydrate (GranuLac® 230) was provided by Meggle Pharma (Wasserburg, Germany), while sodium stearyl fumarate (SSF, PRUV®) was ordered from JRS Pharma (Rosenberg, Germany). Before each experiment, 2 kg of physical mixture was pre-homogenized manually for 5 minutes in a polyethylene bag. The components were mixed without any pre-treatment or milling.

Dániel Fekete, Richárd Ferdinánd Tóth, Zsombor Kristóf Nagy, Thorsten Cech, Lukas Ries, Edina Szabó,
Continuous twin-screw wet granulation without adding granulation liquid, European Journal of Pharmaceutical Sciences, 2025, 107295, ISSN 0928-0987, https://doi.org/10.1016/j.ejps.2025.107295.

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