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Formulation and Design of Multiunit Particulate Systems

Formulation and design of multiunit particulate systems

Introduction to the Formulation and Design of Multiunit Particulate Systems

Formulation and design of multiunit particulate systems focus on oral dosage forms that contain many small, functional subunits instead of one single unit. These systems typically consist of pellets, granules, or coated spheres that are filled into capsules or compressed into tablets. As a result, they allow precise control of drug release and improved robustness during gastrointestinal transit. Moreover, the formulation and design of multiunit particulate systems emphasize a deep understanding of materials, coating technologies, and compression behavior. Therefore, developers can protect sensitive drug layers while ensuring consistent performance. In recent years, Quality by Design approaches have further strengthened this concept by linking formulation variables directly to product quality and clinical relevance.

Functionality and Consumer Compliance Opportunities of Multiunit Particulate Systems

Multiunit particulate systems offer clear functional advantages that directly support consumer compliance. First, the multiparticulate structure distributes the drug dose along the gastrointestinal tract, which improves absorption consistency. In addition, this distribution reduces local irritation and lowers the clinical risk of dose dumping. Furthermore, these systems often improve swallowability because the individual subunits are small and well tolerated. Consequently, patient groups such as children and older adults benefit significantly. At the same time, multiunit particulate systems enable flexible dosing and advanced release profiles. Therefore, they align better with daily routines and long-term treatment needs, which ultimately enhances adherence.

Formulation and Design of Multiunit Particulate Systems

Formulation and Design of Multiunit Particulate Systems

Summary of the Pantoprazole MUPS Tablet Study

The referenced publication examines the formulation and design of multiunit particulate systems (MUPS) through the development of a pantoprazole MUPS tablet using a Quality by Design framework. The study aimed to understand how selected formulation variables affect critical tablet characteristics. To achieve this, the authors used enteric-coated pantoprazole pellets as multiparticulate units and compressed them into tablets with protective excipients. As a result, the formulation needed to balance mechanical strength with coating integrity.

The researchers applied a factorial design of experiments to evaluate three key variables: dry polymer content, matrix-forming polymer concentration, and pellet loading. Subsequently, they measured responses such as dissolution behavior, tablet hardness, friability, and disintegration time. The results showed that each variable influenced tablet quality in a measurable way. For example, higher pellet content increased the risk of coating damage during compression. However, appropriate polymer levels reduced this risk and stabilized drug release.

Based on statistical analysis, the study defined an optimized design space that delivered robust tablets with acceptable mechanical properties. In addition, the optimized formulation demonstrated dissolution behavior comparable to a marketed reference product. Therefore, the study confirmed that a well-designed multiunit particulate system can deliver pantoprazole effectively without compromising enteric protection. Overall, the work highlights how systematic formulation control improves both product performance and development efficiency.

Role of MCC Spheres in the Multiunit Particulate System

MCC spheres (such as CELLETS® 150-300) played a central role as inert starter cores in the multiparticulate formulation. First, they provided a uniform and mechanically stable substrate for drug layering. Moreover, their spherical shape supported homogeneous coating and predictable dissolution behavior. During compression, MCC spheres showed favorable plastic deformation, which helped absorb mechanical stress. As a result, they protected the enteric coating from cracking or rupture. Consequently, MCC spheres enabled the successful conversion of coated pellets into a compressed MUPS tablet while maintaining functional integrity.

Conclusion and Outlook

In conclusion, formulation and design of multiunit particulate systems offer a robust strategy for developing patient-friendly oral dosage forms. The pantoprazole study clearly demonstrates how a Quality by Design approach links formulation variables to tablet performance. Moreover, the use of MCC spheres highlights the importance of selecting suitable core materials for compression stability. Looking ahead, advances in material science and process understanding will further strengthen multiunit particulate systems. Therefore, these systems will continue to play a key role in improving therapeutic consistency and consumer compliance.

References

[1] G.S. Sonar, S. Rawat, International Journal of PharmTech Research, CODEN (USA): IJPRIF, ISSN: 0974-4304, Vol.8, No.8, pp 05-23, 2015. (link)

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MCC pellets under rheological investigation-thumbnail
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MCC pellets under rheological investigation

MCC pellets under rheological investigation

MCC pellets under rheological investigation are ideal model spheres for studying powder behavior. In this study, we revisit the work of V. Mohylyuk and R. Dattani to analyze the effect of pellet size on powder properties. Understanding how pellet size influences flow and handling is essential for optimizing powder performance. Moreover, investigating size variations helps improve material processing and formulation strategies. By focusing on these aspects, researchers can better predict and control the behavior of MCC spheres in different applications.

Rheological behavior has a deep impact

The rheological behavior of powders greatly affects pharmaceutical formulations and processing steps. In particular, when studying MCC pellets under rheological investigation, powder rheology becomes a key area of focus. Typically, powders behave as solids under static conditions; however, they can fluidize under certain circumstances. Consequently, fluidization is widely used in pharmaceutical processes because it enables controlled and uniform coating or layering of starter beads with drugs and functional excipients. Moreover, while fluid behavior in liquids depends on inter- and intra-molecular interactions, network bonds, and temperature, powder fluidization primarily relies on micro-particular properties such as particle size, surface characteristics, and flowability. In addition, the exact gas speed and volume required for powder fluidization must be carefully adjusted for each system. Therefore, a thorough analysis of the powder is essential to achieve precise control and optimal performance.

Materials: MCC pellets

CELLETS®

In this study, CELLETS® are used for the investigation. These pellets consist of Microcrystalline Cellulose, featuring a smooth surface, high sphericity, and minimal friability. Due to these properties, CELLETS® are popular as starter beads in pharmaceutical formulations and are ideal model spheres for rheological studies. Four types—CELLETS® 90, CELLETS® 100, CELLETS® 200, and CELLETS® 350—were examined, with size distributions ranging from 90 µm to 500 µm. The D50 values for these types vary between 94 µm and 424 µm. The specific size distribution of each CELLETS® type is summarized in Table 1.

Type Particle size distribution (≥ 85 %)
CELLETS® 90 60-100 µm
(250/150)
CELLETS® 100 100-200 µm
(150/80)
CELLETS® 200 200-355 µm
(80/50)
CELLETS® 350 350-500 µm
(50/35)

Table 1: Particle size distribution of selected MCC spheres.

 

MCC pellets under rheological investigation

Characterization Methods for MCC Pellets Under Rheological Investigation

First, we measured the particle size distribution of MCC pellets under rheological investigation using optical digital microscopy (Keyence VHX 600). This approach provides precise and reliable data on pellet dimensions, which is essential for understanding their flow and handling properties.

Next, we applied standard pharmacopoeia methods to determine bulk and tapped density, as well as flow rate using a gravitational funnel. In addition, we analyzed the dynamic angle of repose and dynamic cohesivity index with a rotating drum tester (GranuDrum). Furthermore, we used a powder rheometer (FT4 Powder Rheometer) to evaluate basic flowability energy, specific energy, aerated energy, permeability, and compressibility. Altogether, these measurements give a comprehensive understanding of MCC pellets under rheological investigation and offer detailed insights into their performance in pharmaceutical applications.

Results of the rheological investigations

Figure 1 presents the particle size distribution of MCC pellets under rheological investigation, as measured with an optical digital microscope.

Mohylyuk 2022 MCC pellets under rheological investigation image 1

With increasing particle size the apparent specific surface area (fig. 2) decreases obviously. Hence, a decrease in pellet size, allow an expectation in increase in mechanical interlocking.

Mohylyuk 2022 MCC pellets under rheological investigation image 2
specific surface area

With increasing particle size, the bulk and tapped density of CELLETS® increases; however, the densification kinetics remained approximately the same for all pellet sizes (Fig. 3). Moreover, a few periodic oscillations significantly influenced the density of the pellets, highlighting subtle variations in their behavior.

density

With increasing particle size the compressibility decreases (fig. 4). The applied force was identical for all pellets sizes. Worsening packing efficiency.

Mohylyuk 2022 MCC pellets under rheological investigation image 4 compressibility

With increasing particle size the permeability increases while applying the same force for all pellet types. (fig. 5). increase in voids between particles.

permeability

The gravitational funnel method suggests an absence of correlation between the mass flow rate and pellet size or specific surface area (fig. 6).

mass flow rate

Analyzing the dynamic angle of repose

We analyzed the dynamic angle of repose to evaluate the powder flow of MCC pellets under rheological investigation. All pellet sizes showed similar behavior: as the rotation speed increased, the angle of repose rose almost linearly. The measurements for all pellet types formed a funnel shape within the range of analytic errors (Fig. 7). These results clearly characterize the dynamic flow ability of the powders.

Mohylyuk 2022 MCC pellets under rheological investigation image 7 angle

With increasing particle size the specific energy decreases (fig. 8). The level of interlocking and friction between powder particles decreased, the flowability increased.

Image 8 specific energy

With increasing particle size the basic flowability energy decreases (fig. 9). the flowability in a constrained environment increased.

basic flowability

The aerated energy rises as air velocity decreases (Fig. 10). This parameter helps determine the minimum fluidization velocity, as increasing air velocity alters interparticle interactions.

aerated energy

The aerated energy increased with increasing pellet size (fig. 11). dependent on particle mass and inter-particle interactions (friction).

Mohylyuk 2022 MCC pellets under rheological investigation image 11 aerated energy size

with increasing pellet size, the cohesive index decreases (fig. 12). an indicator of the sum of inter-particle interaction forces.

12-cohesive index

Summary

Overall, researchers have now characterized MCC pellets under rheological investigation more comprehensively than ever before, providing new insights into their flow behavior and material properties. Powder rheology methods successfully revealed the bulk powder behavior, flow properties, and inter-particular interactions as a function of pellet size. CELLETS® served as robust model spheres made of Microcrystalline Cellulose, making them ideal for these detailed investigations. This study highlights the importance of pellet size in predicting and optimizing powder performance in pharmaceutical formulations.

References

[1] V. Mohylyuk and R. Dattani, “Assessment of the effect of microcrystalline cellulose (MCC) spheres size on the flow via powder rheology”, Conference: The FORGE: Hybrid Conference on Particle Characterisation (March 2022), doi:10.13140/RG.2.2.14935.75688

 

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Benefits of multilayer high drug-loaded amorphous solid dispersions

Benefits and challenges of multilayer high drug-loaded amorphous solid dispersions

Introduction on amorphous solid dispersions

What is the benefit of multilayer amorphous solid dispersions? Recently, several studies had been performed on amorphous solid dispersions working spheres or starter beads. Starter beads, such as MCC (Microcrystalline Cellulose) spheres are employed due to their high friability and chemical inertness. Some studies are even working on solventless pelletization and amorphization using high shear granulator techniques [1].

Amorphization of poorly water-soluble drugs is a promising approach to improve the solubility and dissolution rate as amorphous solids lack a crystal lattice with long-range order [2]. Unfortunately, a high chemical potential compared to crystalline forms makes amorphous forms thermodynamically unstable. Thus, amorphous drugs exhibit low physical stability and finally lack of recrystallization [3,4]. In turn, surface crystallization is to be minimized.

Multilayer amorphous solid dispersions

This is the key focus of a publication by Eline Boel and Guy Van den Mooter: They had been investigating a promising solution of multilayer high-drug load amorphous solid dispersions, as follows [5]:

Inhibiting surface crystallization is an interesting strategy to enhance the physical stability of amorphous solid dispersions (ASDs), still preserving high drug loads. The aim of this study was to investigate the potential surface crystallization inhibitory effect of an additional polymer coating onto ASDs, comprising high drug loads of a fast crystallizing drug, layered onto pellets. For this purpose, bilayer coated pellets were generated with fluid-bed coating, of which the first layer constitutes a solid dispersion of naproxen (NAP) in poly(vinylpyrrolidone-co-vinyl acetate) (PVP-VA) in a 40:60 or 35:65 (w/w) ratio, and ethyl cellulose (EC) composes the second layer. The physical stability of these double-layered pellets, in comparison to pellets with an ASD layer only, was assessed under accelerated conditions by monitoring with X-ray powder diffraction (XRPD) at regular time intervals. Bilayer coated pellets were however found to be physically less stable than pellets with an ASD layer only. Applying the supplementary EC coating layer induced crystallization and heterogeneity in the 40:60 and 35:65 (w/w) NAP-PVP-VA ASDs, respectively, attributed to the initial contact with the solvent. Caution is thus required when applying an additional coating layer on top of an ASD layer with fluid-bed coating, for instance for controlled release purposes, especially if the ASD consists of high loads of a fast crystallizing drug.

Read more on doi:10.1016/j.ijpharm.2022.122455.

How about following up studies on ASD formulation with starter beads? Simply, contact us für MCC spheres, such as CELLETS® 700 (700-1000 µm, US mesh 18/25).

Your technology and formulation partner for amorphous solid dispersions:

Glatt in amorphous solid dispersions

References

[1] K. Kondo, T. Rades, European Journal of Pharmaceutics and Biopharmaceutics 181 (2022) 183–194 doi:10.1016/j.ejpb.2022.11.011

[2] B.C. Hancock, M. Parks, Pharm. Res. 17 (2000) 397-404.

[3] L.I. Blaabjerg, E. Lindenberg, T. Rades, H. Grohganz, K. Lobmann, Int. J. Pharm. 521 (2017) 232-238.

[4] A. Singh, G. Van den Mooter, Adv. Drug Deliv. Rev. 100 (2016) 27-50.

[5] E. Boel, G. Van den Mooter, International Journal of Pharmaceutics (2022) 122455. doi:10.1016/j.ijpharm.2022.122455

 

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Amorphous solid dispersions at various aspects part 2ingredient pharm

Amorphous solid dispersions at various aspects

Amorphous solid dispersions play an essential role in modern pharmaceutical research. They improve the solubility and dissolution rate of poorly water-soluble drugs, and therefore they gain more importance in drug development. Although several approaches exist, each method shows clear benefits but also some challenges. As a result, it is necessary to examine amorphous solid dispersions in a broader scientific context. For a detailed overview, Thomas Rades and Keita Kondo [Rades_2022] present valuable insights into the fundamentals and latest findings. In addition, recent studies highlight CELLETS® 175, microcrystalline cellulose spheres, as a promising solution. These MCC spheres act as drug carriers and, due to their excellent friability, also function as milling balls. Consequently, they create new opportunities for drug formulation. Moreover, MCC starter beads expand these applications even further. Researchers who want to test this approach can request material samples before exploring the work of Rades and colleagues in more detail.

Draw-back on Amorphous solid dispersions

Amorphization is a promising way to improve solubility and dissolution of poorly water-soluble drugs. Amorphous solids lack a crystal lattice with long-range order [1]. However, amorphous forms remain thermodynamically unstable because their chemical potential is higher than in crystalline forms. As a result, amorphous drugs often show low physical stability and eventually recrystallize [2], [3]. Therefore, stabilizing strategies are crucial in the development of amorphous products. These strategies include amorphous solid dispersions (ASDs) [4], [5] and co-amorphous formulations [6], [7], [8].

ASDs are the most widely used method to prepare amorphous products. They involve glass formation by dispersing drug molecules into an amorphous polymer [4], [5]. Nevertheless, ASD systems often need a large amount of polymer to stabilize the drug, since miscibility between drug and polymer is low [9]. This requirement leads to a high bulk volume of the final product.

In contrast, co-amorphous systems have gained attention as an alternative. They create a single amorphous phase in which multiple low molecular weight compounds, including drugs, mix uniformly at the molecular level [6], [7], [8]. Moreover, co-amorphous mixtures usually provide both higher physical stability and improved dissolution [6], [7], [10].

drug-drug combinations and drug-excipient mixtures

Co-amorphous systems usually fall into two groups: drug-drug combinations and drug-excipient mixtures. In drug-drug combinations, two drug compounds form an amorphous phase. They stabilize each other through intermolecular interactions [11], [12], [13]. These systems can provide combined therapeutic effects. However, their use remains limited. Not all drug-drug pairs are suitable for combination therapy, and fixed dosing often restricts their application to co-amorphization.

In contrast, drug-excipient systems use low molecular-weight substances as co-formers. These include organic acids [14], sugars [15], and amino acids [16]. Their properties and the mixing ratio with the drug strongly influence both dissolution and physical stability [8], [10]. Recently, researchers systematically studied different combinations of drugs with amino acids [17], [18]. The results showed that well-chosen amino acids can improve dissolution and stability. For example, acidic drugs combined with basic amino acids often create strong interactions. Thus, amino acids emerge as a highly promising class of co-formers for co-amorphous formulations.

Amorphous solid dispersions: Co-amorphous mixtures

Co-amorphous mixtures have been prepared using melt quenching [13], [19], spray drying [20], [21], and ball milling [16], [22]. The resulting solids appear as cakes or powders regardless of the method. Therefore, downstream processes such as milling and granulation are usually necessary to obtain final dosage forms like capsules or tablets for oral use [23]. However, these additional steps often increase the risk of phase separation and crystallization because of moisture, thermal stress, and mechanical stress.

In amorphous solid dispersion (ASD) systems, researchers developed one-step preparation methods to avoid these issues. For example, ASD granules have been produced by amorphizing drug compounds during granulation with fluidized bed processors [24–30] or high shear granulators [31–34]. Yet, no reports exist on one-step methods for co-amorphous granules.

Feasibility of solvent-free amorphization

In the first part of this study, we explored the feasibility of solvent-free amorphization and pelletization using a high shear granulator. We successfully produced fully amorphized indomethacin-layered pellets simply by mixing indomethacin crystals with microcrystalline cellulose spheres, without applying solvent or heat. Collisions with the spheres pulverized and amorphized the crystals, which then deposited on the surface of the spheres. Based on this, we hypothesized that co-amorphous mixture-layered pellets could also be prepared through one-step amorphization and pelletization. Since earlier studies have achieved co-amorphous mixtures by mechanical activation [16], [22], this approach seems highly promising. Moreover, it provides both economical and sustainable benefits by eliminating the need for solvent and heating.

Previous studies systematically investigated different combinations of indomethacin and amino acids for co-amorphous preparations. The results showed that arginine works as an excellent co-former for indomethacin [18]. This combination produces co-amorphous mixtures with fast dissolution and high physical stability. The reason is that an amorphous salt forms due to strong interactions between acidic indomethacin and basic arginine [35], [36].

Co-amorphous layer pellets

In this study, we aimed to test whether co-amorphous layer pellets can be produced through a one-step amorphization and pelletization process. Therefore, indomethacin was chosen as the model drug and arginine as the co-former. In the first stage, indomethacin crystals were mixed with microcrystalline cellulose spheres of various diameters (140 μm, 195 μm, 275 μm, 414 μm, and 649 μm) at a 1:10 weight ratio using a high shear granulator (TMG1/6, Glatt GmbH, Binzen, Germany). Fully amorphized indomethacin-layered pellets were obtained with 414 μm carriers, while 195 μm carriers resulted in partial amorphization. This difference was most likely caused by the higher impact forces of the larger carriers, which promoted stronger mechanical activation of indomethacin crystals.

To further clarify the role of arginine in amorphization and pelletization, we used smaller cellulose spheres of 195 μm as carriers. Indomethacin and arginine crystals were mixed at different molar ratios (1:1, 2:1, and 3:1). These mixtures were then granulated with cellulose spheres at a 1:10 weight ratio using high shear mixing. The resulting composite particles were analyzed with solid-state and particle characterization methods. In addition, we examined high shear mixing under different jacket temperatures to identify effective co-amorphization conditions. Finally, the physical stability and dissolution behavior of the co-amorphous layer pellets were investigated.

References

[Rades_2022] K. Kondo, T. Rades, 181 (2022) 183-194. doi:10.1016/j.ejpb.2022.11.011

[1] B.C. Hancock, M. Parks, Pharm. Res. 17 (2000) 397-404.

[2] L. Yu, Adv. Drug Deliv. Rev. 48 (2001) 27-42.

[3] L.R. Hilden, K.R. Morris, J. Pharm. Sci. 93 (2004) 3-12.

[4] T. Vasconcelos, S. Marques, J. das Neves, B. Sarmento, Adv. Drug Deliv. Rev. 100 (2016) 85-101.

[5] S. Baghel, H. Cathcart, N.J. O’Reilly, J. Pharm. Sci. 105 (2016) 2527-2544.

[6] R. Laitinen, K. Lobmann, C.J. Strachan, H. Grohganz, T. Rades, Int. J. Pharm. 453 (2013) 65-79.

[7] R.B. Chavan, R. Thipparaboina, D. Kumar, N.R. Shastri, Int. J. Pharm. 515 (2016) 403-415.

[8] S.J. Dengale, H. Grohganz, T. Rades, K. Lobmann, Adv. Drug Deliv. Rev. 100 (2016) 116-125.

[9] S. Janssens, G. Van den Mooter, J. Pharm. Pharmacol. 61 (2009) 1571-1586.

[10] R. Laitinen, K. Lobmann, H. Grohganz, P. Priemel, C.J. Strachan, T. Rades, Int. J. Pharm. 532 (2017) 1-12.

[11] S. Yamamura, H. Gotoh, Y. Sakamoto, Y. Momose, Eur. J. Pharm. Biopharm. 49 (2000) 259-265.

[12] M. Allesø, N. Chieng, S. Rehder, J. Rantanen, T. Rades, J. Aaltonen, J. Control. Release 136 (2009) 45-53.

[13] K. Lobmann, R. Laitinen, H. Grohganz, K.C. Gordon, C. Strachan, T. Rades, Mol. Pharm. 8 (2011) 1919-1928.

[14] Q. Lu, G. Zografi, Pharm. Res. 15 (1998) 1202-1206.

[15] M. Descamps, J.F. Willart, E. Dudognon, V. Caron, J. Pharm. Sci. 96 (2007) 1398-1407.

[16] K. Lobmann, H. Grohganz, R. Laitinen, C. Strachan, T. Rades, Eur. J. Pharm. Biopharm. 85 (2013) 873-881.

[17] G. Kasten, H. Grohganz, T. Rades, K. Lobmann, Eur. J. Pharm. Sci. 95 (2016) 28-35.

[18] G. Kasten, K. Lobmann, H. Grohganz, T. Rades, Int. J. Pharm. 557 (2019) 366-373.

[19] A. Teja, P.B. Musmade, A.B. Khade, S.J. Dengale, Eur. J. Pharm. Sci. 78 (2015) 234-244.

[20] A. Beyer, L. Radi, H. Grohganz, K. Lobmann, T. Rades, C.S. Leopold, Eur. J. Pharm. Biopharm. 104 (2016) 72-81.

[21] E. Lenz, K.T. Jensen, L.I. Blaabjerg, K. Knop, H. Grohganz, K. Lobmann, T. Rades, P. Kleinebudde, Eur. J. Pharm. Biopharm. 96 (2015) 44-52.

[22] K.T. Jensen, F.H. Larsen, C. Cornett, K. Lobmann, H. Grohganz, T. Rades, Mol. Pharm. 12 (2015) 2484-2492.

[23] B. Demuth, Z.K. Nagy, A. Balogh, T. Vigh, G. Marosi, G. Verreck, I. Van Assche, M.E. Brewster, Int. J. Pharm. 486 (2015) 268-286.

[24] D.B. Beten, K. Amighi, A.J. Möes, Pharm. Res. 12 (1995) 1269-1272.

[25] H.-O. Ho, H.-L. Su, T. Tsai, M.-T. Sheu, Int. J. Pharm. 139 (1996) 223-229.

[26] N. Sun, X. Wei, B. Wu, J. Chen, Y. Lu, W. Wu, Powder Technol. 182 (2008) 72-80.

[27] A. Dereymaker, D.J. Scurr, E.D. Steer, C.J. Roberts, G. Van den Mooter, Mol. Pharm. 14 (2017) 959-973.

[28] A. Dereymaker, J. Pelgrims, F. Engelen, P. Adriaensens, G. Van den Mooter, Mol. Pharm. 14 (2017) 974-983.

[29] T. Oshima, R. Sonoda, M. Ohkuma, H. Sunada, Chem. Pharm. Bull. 55 (2007) 1557-1562.

[30] H.J. Kwon, E.J. Heo, Y.H. Kim, S. Kim, Y.H. Hwang, J.M. Byun, S.H. Cheon, S.Y. Park, D.Y. Kim, K.H. Cho, H.J. Maeng, D.J. Jang, Pharmaceutics 11(3) (2019) 136.

[31] N.S. Trasi, S. Bhujbal, Q.T. Zhou, L.S. Taylor, Int. J. Pharm. X 1 (2019) 100035.

[32] A. Seo, P. Holm, H.G. Kristensen, T. Schæfer, Int. J. Pharm. 259 (2003) 161-171.

[33] T. Vilhelmsen, H. Eliasen, T. Schaefer, Int. J. Pharm. 303 (2005) 132-142.

[34] Y.C. Chen, H.O. Ho, J.D. Chiou, M.T. Sheu, Int. J. Pharm. 473 (2014) 458-468.

[35] K.T. Jensen, L.I. Blaabjerg, E. Lenz, A. Bohr, H. Grohganz, P. Kleinebudde, T. Rades, K. Lobmann, J. Pharm. Pharmacol. 68 (2016) 615-624.

[36] K.T. Jensen, F.H. Larsen, K. Lobmann, T. Rades, H. Grohganz, Eur. J. Pharm. Biopharm. 107 (2016) 32-39.

More information on ASD

Read more about amorphous solid dispersions in our application notes.

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titelbild - Hydrodynamic behavior of MCC Spheres in a spouted bedingredientpharm
,

Hydrodynamic behavior of MCC Spheres in a spouted bed

Abstract

This case study is a short abstract on spouted bed characteristics, following closely findings in the publication by J. Vanamu and A. Sahoo [1].

Spouted bed systems are of highest importance for all powder processing industries, and more specific in pharmaceutical industry for coating and drying in pellet technologies [2]. These systems offer manufacturing particularly fine and temperature-sensitive particles from small to large scale: laboratory systems are capable of processing product volumes of very few grams, while production systems can handle capacities of several tons [3].

But how to control conditions in spouted beds for efficient process applications, like mixing, coating, or drying?

There might be certain reasons, that the hydrodynamic behavior of the spouted bed in the pharmaceutical industries is less investigated. The referred publication shed some light on the hydrodynamic characteristics of a spouted bed where the MCC Spheres (CELLETS®) are adopted as the bed material. These starter cores are ideal model systems due to their perfect sphericity and zero-level friability. At the same time, smooth and defined surface structure initiate perfect modelling conditions in the spouted bed dynamics.

Material

CELLETS®, made of 100% Microcrystalline Cellulose, have been used as bed material. The physical properties of the CELLETS® are shown in Table 1. The CELLETS® particle morphology is represented in Figure 1.

Parameter Value
CELLETS® 700 and CELLETS® 1000
Size distribution 700-1000 µm (CELLETS® 700)

1000-1400 µm (CELLETS® 1000)
Bulk density 800 kg/m3
Particle sphericity > 0.9
Void fraction 0.42
Geldart classification B

Table 1: Physical properties of the CELLETS®.

SEM micrographs of CELLETS® 700

Figure 1: SEM micrographs of CELLETS® 700, found in [1].

Spouted bed: experiment setup

There are some international players on the market of spouted bed technologies, such as Glatt which seems to be the major one (Figure 2). In this framework, a self-made setup is used for experiments. The experiments that have been carried out in a column, which is fabricated from a Perspex sheet. This column consists of a cylindrical section of height 0.53 m and a diameter of the cylinder of 0.135 m. The column further converged the diameter of the cylinder to 0.05 m as a conical bottom having a length of 0.47 m. The spouting air is supplied by a compressed air line is controlled by a gas regulator. The airflow is controlled by a gate valve and a mesh plate having a mesh size less than the size of the bed material is employed as a separator preventing the backflow of the bed material. Images are captured using a high-speed video camera to gain more details of the hydrodynamic characteristics of the flow pattern inside the spouted bed geometry.

Spouted bed

Figure 2: Scheme of a spouted bed (Glatt, Germany).

Experiments & spouted bed results

Experiments are carried out with three different static bed heights of shallow depth wherein the bed height is in the range of factor 2-3 of the Inlet diameter using two different particle distribution classes at 500-710 µm and 700-1000 µm, respectively. Analyzed parameters are the pressure drop across the bed, the bed expansion ratio, and the clusters concerning the superficial gas velocity are focused in the following.

J. Vanamu et al. found that the “bed expansion ratio increases with increasing superficial gas velocity until the onset of external spouting, further increase in the superficial gas velocity, the bed expansion ratio decreases. With increasing the volume of bed, the bed expansion ratio decreases. In a larger volume of bed, the particles tend to spout into the freeboard region rather than expanding with higher superficial gas velocity”. Initial spouting is symmetric, but with increasing superficial gas velocity spouting becomes asymmetric, and asymmetry is more pronounced or starts at lower superficial gas velocities for smaller particles. This agrees with existing theories of hydrodynamic behavior in a fluidized environment. Respecting the necessarity of a proper flow behavior for mixing, coating or drying applications in drug processing, symmetric spouting is essential. In turn, the superficial gas velocity may be kept low.

In case that high superficial gas velocity regimes are required for the operations a draft tube may be installed within the column to achieve the symmetric spout formation.

Summary

This case study highlights the Hydrodynamic behavior of MCC spheres in a spouted bed using image processing method. MCC spheres in the range between 500-710 µm and 700-1000 µm had been employed. All spheres showed a symmetric and asymmetric spouting in the spouted bed. With increasing superficial gas velocity, the fully suspended particles are limited to a certain height in the freeboard region due to the gas-solid crossflow. A change from symmetric to asymmetric spouting is observed with increasing superficial gas velocity.

Keeping the conditions efficient for the mixing, coating or drying applications requires finally to suppress high superficial gas velocities, or changing the setup in such way, that symmetric spouting conditions are kept upright even at higher superficial gas velocities.

References

[1] J. Vanamu and A. Sahoo, Particuology 76 (2023) 101

[2] L. A. P. de Freitas, Particuology 42 (2019) 126

[3] Glatt GmbH, Binzen, Germany. Online on Nov 8, 2022: Spouted bed systems – Glatt – Integrated Process Solutions

Great thanks to Arihant Innochem Pvt. Ltd. who supplied and donated CELLETS® for this study.

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