An iterative process and mixture design approach for dry granulated ternary blends of filler-binders
Abstract
Roller compaction/dry granulation (RC/DG) is a key process in pharmaceutical manufacturing for improving powder flowability, density, and segregation resistance. Advanced statistical modeling was used to optimize RD/DG process parameters and subsequently binder compositions by employing process and mixture design experiments. The authors used microcrystalline cellulose (MCC), silicified MCC (SMCC), and dicalcium phosphate (DCP) as filler-binder examples in RC/DG experiments. Granule and tablet properties, including flowability, bulk and tapped densities, as well as resistance to crushing, were analyzed using compendial methods. The process design experiments confirmed that RC/DG reduces manufacturability compared to direct compression. Optimal processing conditions, balancing sufficient tablet strengths and granule formation, were identified to be between 20 (SCF * ϑ) [kN/cm] and ~ 60 (SCF * ϑ) [kN/cm]. Thereby (ϑ) is defined as the screw-to-roll speed ratio and (SFC) as the specific compaction force. Mixture design experiments revealed optimal mixtures balancing SMCC, MCC, and DCP to achieve desired properties like low angle of repose, high bulk density, and strong tablets. These findings provide guidance for selecting formulations and process parameters in RC/DG applications. The derived ‘SCF * ϑ’- factor was found to effectively describe the granulation intensity. A superimposed mixture design model based on precise target values of the parameters bulk density, flow properties, and breaking force allowed identification of the best formulation.
Highlights
- An iterative design for process- mixture-design optimization is presented.
- Optimal process settings for RC/DG are identified based on the ‘SCF * ϑ’ factor.
- Following ICH Q8, a model is built based on combined target parameters.
Introduction
In many processes in the field of pharmaceutical technology, powdered raw and intermediate products are used. In the interest of uncomplicated processing, the primary particles are often initially agglomerated into granules. Thereby, material material is produced, which has a reduced tendency to segregate (Keitzer, 2021), and which exhibits improved flow characteristics. The latter is achieved via a narrow -ideally monomodal- particle size distribution and a reduced bulk volume, thus decreasing the specific surface area and the particle-particle interaction (Schiano et al., 2016).
To achieve mentioned benefits, various processes, relating to wet, melt and dry granulation, can be applied. Thereof, wet granulation is mainly used in pharmaceutical industry (Thapa et al., 2019). However, the required drying step can initiate degradation processes of heat sensitive substances, and is time, and thus, cost intensive. Now, compared to three types of wet granulators (a fluidized bed granulator, a high shear granulator and a twin screw granulator) – it was recently shown that a roller compactor used for dry granulation was the most efficient with regard to energy and time (Karunanayake et al., 2024). The underlying roller compaction/dry granulation (RC/DG) process is furthermore priorised over wet granulation by the manufacturing classification system for oral solid dosage forms, when direct compression is not feasible (Leane et al., 2015). Consequently, roll(er) compaction/dry granulation (RC/DG) has become a standard technique in pharmaceutical manufacturing (Kleinebudde, 2022). Gaining knowledge about process characteristics and material behavior is, therefore, of growing interest. In line with this, many studies have evaluated the impact of the critical process parameters, such as the specific compaction force SCF [kN/cm], the roll gap width [cm], the roll speed NR [min−1], and the feeding screw speed NS [min−1], alone or in combination, on the quality of the ribbons, granules and relating tablets.
Since ribbons with a high solid fraction lead to coarser granules (Jaminet and Hess, 1966) and improved flowability (Wagner et al., 2013), processes are designed to produce according ribbons. Researchers found that SCF has the highest impact on the ribbon’s solid fraction with an increased SCF leading to an increased solid fraction of the produced ribbons (Csordas et al., 2018), which also increased ribbon tensile strength (Reimer and Kleinebudde, 2019). It has also been shown that SCF is directly linked to the granule size distribution as an increase in SCF leads to a decreased fraction of fines (Mangal and Kleinebudde, 2018). By increasing the roll gap width at constant SCF, ribbons with increased thickness and decreased relative densities were produced (Peter et al., 2010). Also NR impacts the density and tensile strength of the ribbons (Atanaskova et al., 2020; Kleinebudde, 2022; Li et al., 2024; Rowe et al., 2017; Souihi et al., 2015). However, the impact of NR on ribbon solid fraction is controversally discussed in the literature. This is why (Lück et al., 2022) systematically investigated the influence of NR at different SCF for different materials on ribbon and granule properties. Their results indicated that the solid fraction of ribbons made from plastic materials is, compared to the solid fraction of ribbons made from brittle materials, more affected by NR. Recently also different working groups (Li et al., 2024; Muthancheri et al., 2024) developed roller compaction models accounting for the importance of NR on the product quality. (Li et al., 2024) thereby improved the model of (Johanson, 1965) and found that the ribbon solid fraction depends on both, NR and the composition of the formulation. (Muthancheri et al., 2024) introduced a modification of the model of (Sousa et al., 2020) which particularly improved the prediction accuracy, particularly at higher NR.
If tablets are to be produced based on RC/DG material, their tensile strengths are strongly influenced by the properties of the ribbons and related granules (Boersen et al., 2015). Particularly, the work hardening phenomenon (Malkowska and Khan, 1983), related to a loss in tabletability, has to be taken into consideration (Sun and Kleinebudde, 2016).
It becomes obvious that optimizing the RC/DG process is complex. Since many factors interact, their impact on the quality of the final product is often difficult to predict. Design of Experiments (DoE) (Politis et al., 2017) is a fundamental tool for systematically investigating and optimizing a roller compaction process (Atanaskova et al., 2020; Csordas et al., 2018; Soh et al., 2008; Wilms and Kleinebudde, 2020). The applied experimental designs can be assigned as process designs (Eriksson et al., 1998).
As indicated above, the quality of the ribbons and resutling products is also influenced by the applied materials and their physico-chemical attributes. Both, brittle and plastic materials are typically necessary to produce ribbons with good quality. Plastically deformable components thereby form new bonds under pressure by irreversibly deforming after exceeding the yield point, creating new contact surfaces and closer distances for new interparticle interactions, leading to mechanical interlocking. Microcrystalline cellulose (MCC) is frequently used as binder, but also hydroxypropyl cellulose grades or polyvinylpyrrolidones (Mangal et al., 2016). Such plastically deformable components are characterized by the formation of hard and mechanically resistant compacts during compaction. The relative sensitivity to specific compaction force (SSC) is for MCC thereby described by an exponential function, which accounts for a disctinct loss in tabletability (Janssen et al., 2022). Of particular interest for this work are MCC and silicified MCC (SMCC). SMCC is a type of MCC co-processed with highly dispersed silicon dioxide. The fine silicon dioxide particles are immobilized and evenly distributed on the surface of the MCC, thereby multiplying the specific surface area, improving the flow behavior and increasing the compactability (Alfa et al., 2006; van Veen et al., 2005).
Brittle materials, such as dicalcium phosphate (DCP), lactose, or mannitol are typically used as fillers (Janssen et al., 2022; Lück et al., 2022; Wagner et al., 2013; Yu et al., 2013). Such materials fragment into smaller particles under pressure, increasing the specific surface area for the formation of new interparticle interactions. Applying materials with less adequate binding properties for RC/DG can increase the residual fines, which would, in turn, negatively impact the flowability of the granules (Gamble et al., 2010). However, such materials are less impacted by the work hardening phenomenon compared to plastically deformable materials, as presented for two different lactose types by (Janssen et al., 2022). Finding the right formulation for roller compaction processes is thus also essential. Others than process designs, mixture designs help to assess product qualities based on changing mixture compositions and indicate to what extent the changes will affect the process-related properties of the mixture (Anderson-Cook et al., 2004; Snee, 1979).
The present study describes an iterative approach towards a ternary mixture design preceeded by a process design step. This is in contrast to the typical procedure in the industry, where usually the effect of process variations on the performance of a given formulation is evaluated as part of establishing the design space under Quality by Design rules (European Medicines Agency, 2017). Here, however, the aim was to identify suitable process conditions first to subsequently investigate the effect of substantial formulation changes. Specifically, the mixing ratios of the plastically deformable binders MCC and SMCC, as well as the brittle binder DCP, were systematically varied in a series of experiments. The resulting RC/DG granules were examined for their flow behavior, particle size distributions, bulk densities, and re-compressibility in a tableting step following roller compaction.
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Materials
Three materials were used for RC/DG studies: Microcrystalline cellulose (MCC, VIVAPUR® 101, JRS Pharma, predominantly plastically deforming material), silicified microcrystalline cellulose (SMCC, PROSOLV® SMCC 50, JRS Pharma, predominantly plastically deforming material), and dicalcium phosphate (DCP, Emcompress® Anhydrous Powder, JRS Pharma, brittle deforming). Due to the dependency of DG/RC granule properties on the particle size of plastically deformable binders, the raw materials MCC and SMCC were selected with comparable particle sizes. Particle size distributions of the raw materials can be found in the supporting material.
Niclas Märkle, Gernot Warnke, Miriam Pein-Hackelbusch, An iterative process and mixture design approach for dry granulated ternary blends of filler-binders, International Journal of Pharmaceutics: X, 2025, 100331, ISSN 2590-1567, https://doi.org/10.1016/j.ijpx.2025.100331.
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