CELLETS® 350

(350-500 µm)

CELLETS® 350 is a subtype of pellets made of microcrystalline cellulose. The size ranges from 350 µm to 500 µm. Find more product information and technical specifications.

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Impact of the particle size on powder behavior in a Wurster fluid-bed process

Abstract

Cellets are inert starter cores made of microcrystalline cellulose (MCC). They play an important role in new formulations of solid dosage forms. As a carrier system for actives, the chemical inertness and surface smoothness are crucial parameters. Additionally, high level of robustness and sphericity simplify formulations and technical processes, such as fluidized bed technologies for coating and layering. In a joint study between the University of Hertfordshire and Freeman Technology (a Micromeritics company), the effect of pellets’ size on the behavior in a Wurster process is explained. Wurster fluid bed coating of Cellets with particle size larger than 400 µm is unproblematic. However, decreasing the particle size begins to complicate the coating process. So, powder rheology was used to compare Cellets with different particle sizes in terms of their effect on the powder flow in the Wurster fluid bed coater. For deeper knowledge, we strongly recommend reading investigations by V. Mohylyuk et al. [1]

Materials

Cellets® 90, 100, 200 and 350 (D50-size from 94 µm to 424 μm, Ingredientpharm, Switzerland). MCC powder Avicel® PH-102 (supplied by IMCD UK Ltd., UK) is included in the investigations, as it is widely used in industry and can be used by readers for comparison with other studies.

Wurster fluid-bed

Wurster process is a bottom-spray method, employed as a coating technology, for layering powder-like particles in a fluidized bed system (Figure 1). The process can be separated in different zones of mass flow, such as the down-flow zone or the horizontal transport zone. The flowability in these zones is crucial for homogeneous and efficient coating of the particles.

wurster_500x500

Figure 1: Wurster process is a bottom-spray method for layering powder-like particles in a fluidized bed system.

Hereby, the size of particles might play an important role. The narrow size distribution of MCC pellets is shown in Figure 2 and Figure 3. Measured data is presented in Table 1.

Figure-2

Volume weightened size distribution of Cellets 90 (red, diamonds), Cellets 100 (orange, triangles), Cellets 200 (blue, circles), Cellets 350 (green, squares).

The compact Cellets with fair sphericity, zero friability and a high level of surface smoothness show a fair mass flow rate which is almost independent of particle size at given experimental conditions and was determined by the gravitational funnel method. The reference MCC powder did not flow through the orifice.

Excipient PSD
[µm]		 Span
[µm]		 Flow rate
[g/s]
Avicel PH-102 115a 1.85 No flow
Cellets 90 94b 0.44 1.76
Cellets 100 163b 0.27 2.06
Cellets 200 270b 0.34 1.89
Cellets 350 424b 0.22 1.83

Table 1: Particle size distribution (D50) value and span by laser diffraction (a) and digital microscopy (b), and the mass flow rate by gravitational funnel method (5 mm diameter orifice) for the investigated excipients.

Impact of the Cellets’ size

The impact of the Cellets’ size on bulk powder behavior can only be estimated by screening additional parameters. In addition to the mass flow rate, standard pharmacopoeia methods such as bulk/tapped density were initially employed for the characterization of the powder’s properties. This was extended to rotating drum measurements providing the dynamic angle of repose and dynamic cohesivity index. Via powder rheology the conditioned bulk density, basic flowability energy, specific energy, pressure drop, permeability and compressibility (Figure 4) were obtained [1].

By picking the compressibility of Cellets at an applied force of 10 kPa normal stress, two key points need to be mentioned: (a) smaller particle size induces a higher rate of compressibility; (b) Cellets are less compressible than the reference MCC powder.

These findings are part of the open question on powder flow in a Wurster process. It is expected, that Cellets with a lower compressibility will result in better flow behavior in the fluidized bed.

Figure-3

Microscopic imaging of Cellets 100 (top left), 200 (top right), 350 (bottom left) with 1 mm scale bar and 100x magnification. Bottom right: surface of Cellets 350 in 1000x magnification.

Figure-4

Compressibility at 10 kPa normal stress on Cellets with varying particle size (D50) and Avicel® PH-102.

Summary

The flow of Cellets’ through a Wurster fluid-bed coater is likely to show improved performance as the Cellets’ particle size increases. Among others, a lower compressibility demonstrates a rheological behavior which is superior to MCC.

References

[1] Mohylyuk V, Styliari ID, Novykov D, Pikett R, Dattani R. Assessment of the effect of Cellets’ particle size on the flow in a Wurster fluid-bed coater via powder rheology. J D Deliv Sci Tec. 2019; 54: 101320, doi: 10.1016/j.jddst.2019.101320.

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Pellets and micropellets can be further processed into a wide rangeglatt.com
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The path to the perfect sphere

The renaissance of micropellets is promoting innovative technologies

In recent years, formulations based on pellets and micropellets have been the trend. New technologies make it possible to circumvent property rights for active ingredients and are therefore very popular with pharmaceutical customers. But which technologies are the most important?

Pellets are the jack-of-alltrades of solid dosage forms. Positioned somewhere between powder and granulate, they make bitter medicine more palatable and can even awaken a child’s instinct to play when the dosage forms are imaginative enough. One well-known example is the Xstraw, a plastic tube shaped like a drinking straw which is filled with pellets of active ingredient, through which children or elderly people can take in the medicine with water. Pellets in tablets are also making a splash – hybrids which combine all the advantages of both dosage forms. The pioneers in the development of these formulations, known as Multiple Unit Pellet Systems (or MUPS for short), was Astra Zeneca in 1999. Their move to embed the proton pump inhibitor Omeprazole in micropellets and then compress these pellets into immediate release tablets was an award-winning one at the time. The development of MUPS and Xstraw symbolizes the impetus pellets have fueled in recent years.

Klaus N. Möller, Head of Business Development at Glatt in Binzen / Germany, explains: “New excipients, coating materials and sophisticated processes allow us to extend the patent protection period and to make the dosage form more attractive.“

The number of patents registered yearly for pellet-based formulations has increased exponentially and is set to continue. According to research performed by IMS Health, the market for OSD (Oral Solid Dosage Forms) is growing by 6 to 8 percent every year. The number of drugs approved by the FDA also reflect this trend: in 2015, more than half were solid products.

Pellets, as defined by pharmacy guru Prof. Peter Kleinebudde are “an isometric agglomerate of powder particles in an approximate spherical or cylindrical form”, and are a task for perfectionists. The smoother and rounder the pellets, the better they are at fulfilling their purpose. The equipment manufacturer Glatt and their specialists from Pharmaceutical Services have been actively ursuing the subject for years.

There are two fundamental ways of making active ingredient pellets: direct pelletization, in which the powdered active ingredient and excipient combine in a matrix, and active ingredient layering, in which uses side spray or Wurster technology to apply the active ingredient to a starter core of sugar or microcrystalline cellulose.

A case for the specialists

One interesting process variant for matrix pellets is the extrusion of wet granulate in a basket extruder and subsequent rounding in a spheronizer. Möller elucidates: “Continuous wet granulation, followed by extrusion, spheronization and drying now make it possible to perform continuous processes”. Active ingredient pellets made like this can then be covered with a functional coating, be continuously mixed with excipients and be directly compressed into a MUPS tablet. The challenge is to avoid separation of the ingredients and destruction of the tablets during pressing.

Glatt, whose portfolio comprises all granulation and pellet manufacturing techniques, has spent recent years developing additional ways of “fine tuning” the pellet process and has opened up a range of new, interesting possibilities for the lifecycle management of active ingredients.

Pellets and micropellets can be further processed into a wide range

Pellets and micropellets can be further processed into a wide range

Applying the final touches

But what differentiates the manufacturing of granulates from the manufacturing of pellets? From a pharmaceutical point of view, both processes are closely related and are only separated by the form of the particle, since the ideal shape for pellets is a sphere. There are also definite commonalities in procedure. As Möller explains: “The fluidized bed can be used for both granulation and pelletization. This is why we configure fluidized bed machines on request to be multipurpose installations which then allow the continuous manufacturing of pellets. The individual process modules for direct pelletization with rotor technology, for layering active ingredient and for pellet coating with Wurster technology or the simple drying of wet granulates can be added as necessary. Wurster technology has been used in practice for many years: it is a fluidized bed technique in which starter cores or active ingredient pellets are sprayed with a insists. Möller says: “This method is robust and, because the process is so stable, it’s generally the most popular way to process pellets.”

Depending on the composition of the tablets, processing can last anywhere between eight and ten hours. The knack is knowing how to optimize the efficiency and times of the production process. Additionally, Möller recommends timely expert assistance during the development of the pellet formulation and the production process: “Right from the beginning, it will help to avoid mistakes and to keep an eye on process times and manufacturing costs”.

Micropellets and more

Glatt’s development team demonstrated how to refine an established process with the fluidized bed agglomeration technique known as MicroPx. The trick is to use the Conti process, which was conceived in Pharmaceutical Services’ laboratories in Binzen: first, the active ingredient/excipient liquid is spray-dried to a very fine product dust in a fluidized bed and agglomerated into tiny primary particles. The micropellets then build up, layer by layer, until the desired size is reached. The heart of this technology is a zigzag classifier which continuously ejects particles of sufficient size from the process, while simultaneously allowing smaller particles to reenter the process chamber where they continue to grow. Möller explains that the result of this method are high dosage active ingredient pellets in the size range of 100 to 400 μm with a narrow particle size distribution and content uniformity of a consistent 90 to 95 percent. This means that one significant limitation of former times is now no longer an issue: for many years, the volume of a pellet- filled capsule was larger — and therefore much harder to swallow — than the equivalent tablet with the same dose and composition. The use of microencapsulation, which changes bitter-tasting active ingredients into tasteless microparticles, means the taste is much improved now, too. Micropellets can be also pressed into tablets or MUPS tablets which already begin disintegration in the mouth. But the reason pharmaceutical companies find the MicroPx process so exciting is that it makes completely new formulations possible and therefore allows the legal circumvention of property rights. The technology experts have long known the secret to the perfect pellet, too, an answer provided by Complex Perfect Spheres Technology (CPS). CPS is a souped-up rotor process for fluidized bed machines that uses direct pelletization to yield functionalized pellets and micropellets which are perfectly round and smooth. Unlike classic rotor technology, the modified technique uses a tapered rotating disc which allows the movement of particles to be directed and pelletization to be performed to a defined endpoint. The results are perfectly spherical pellets of exactly defined sizes of between 100 and 1500 μm and extremely narrow size distribution. This is how Glatt’s own Cellets of microcrystalline cellulose are created, which are used as starter cores for pellets and in the Wurster process, for example — thus completing the formulation cycle.

Author

Klaus Möller, Head of Business Development Glatt Process Technology Pharma

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Cellets_350-1-3ingredientpharm
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Some light on sugar and microcrystalline cellulose pellets

Abstract

Microcrystalline cellulose pellets (MCC) and sugar are well-known materials in pellet technology. Pellet technology describes the drug load onto starter pellets for controlled release formulations by Wurster process or others. Inert pellets are made of microcrystalline cellulose, while water soluble pellets are composed of sugar. Both material classes show desirable characteristics, such as a narrow particle size distribution, sphericity, surface smoothness. Also the batch-to-batch reproducibility and robustness of starter cores is high. A comparison does not seem to be that easy …

Starter cores in the micron range

Respecting the final application, the initial size of starter pellets defines the final size of the drug loaded pellet. In case of several layers of API and excipients, the initial size is factorized by the layering process. Pellet sizes in a range from 200 µm to 700 µm are frequently used (Table 1). We will focus on three size classes within this range and compare MCC pellets with those made of sugar.

Cellets_200-1-3

Figure 1: MCC pellets (here: Cellets® 200) are shown with good sphericity and striking surface smoothness.

Small-sized pellets starting at 200 µm

Small-sized pellets with sizes starting at 200 µm and larger, exhibit a comparably large surface-to-volume ratio. This can be beneficial in some applications. For example, taste-masking of bitter API is accessible.

Cellets_200-1-4

Figure 2: Sugar pellets (here: 50/70 mesh) are shown with moderate sphericity and reduced surface smoothness.

Figure 1 displays a microscopic image of MCC Cellets® 200 and Figure 2 displays the image of sugar pellets in 50/70 mesh, respectively. It is obvious, that for small-sized pellets, the sphericity and surface smoothness of MCC pellets is superior.

Size MCC Sugar
small Cellets® 200 50/70 mesh
Medium Cellets® 350 40/50 mesh
large Cellets® 500 25/30 mesh

Table 1: Size definition of MCC and sugar pellets.

Mid-sized pellets up to 500 µm

This class of pellets is frequently used for multi-layer coating technologies. Easy processing and reliable batch-to-batch control are positive aspects. Exemplary application is a hydrocortisone formulation for peadiatrics. Again, Figure 3 (MCC pellets) and Figure 4 (sugar pellets) show advantages in surface properties for the MCC material.

Cellets_350-1-3

Figure 3: MCC pellets (Cellets® 350) are shown.

Cellets_350-1-4

Figure 4: Sugar pellets (40/50 mesh) are shown

Large-sized pellets above 500 µm

In some applications, larger pellet sizes are requested. Let’s have short excurse into straws which can contain larger pellets in dry state. Upon use by sucking liquid through the straw, the API coating dissolves immediately while the pellet remains in the straw by simple filters.

In this size range the striking advantages of MCC pellets are not of immediate importance, but still visible.

Cellets_500-1-3

Figure 5: MCC pellet above 500 µm (Cellets® 500).

Cellets_500-1-4

Figure 6: Sugar pellet above 500 µm (25/30 mesh).

Summary

Microcrystalline cellulose pellets (Cellets®) show superior surface and sphericity properties compared to sugar pellets. In case of non-dissolving applications, MCC pellets are first choice. As sugar pellets exhibit strong dissolution in water, there is still a fair application range for them.

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CS_sphericity_image_1
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Sphericity and size distribution of µm-sized microcrystalline pellets

Abstract

Microcrystalline Cellulose (MCC) pellets represent a chemically inert class of active pharmaceutical ingredients (API) carriers. A narrow particle size distribution (PSD) maximizes control over content uniformity. In this case study, we will focus on measuring the particle size distribution and on sphericity.

Pellets for oral drug forms

MCC pellets are used as starter beads for API loading. Low or high drug dose loading is technically feasible. These pellets are made of pure MCC and provide a robust platform for delivery of one or multiple APIs. Certain processing technologies for pellet coating allow these starter beads to be compatible with soluble or insoluble APIs, e.g. by Wurster bottom spray [1,2] or Rotor dry powder layering technology [3]. Coated pellets can be filled into capsules, or compacted into multiple-unit pellet system (MUPS) tablets [4], where a tight PSD maximizes control over content uniformity.

Particle size distribution maximizes the control over content uniformity in applications of complex oral dosing forms. Speaking about uniform or monodisperse particles, these information always point to general information of the particular system, not of the individual particle itself. Therefore, PSD is a globular measure allowing simple, easy and fast analysis of the particulate matter. Major key information from a PSD measure are the so called D-values. A Dx value represents a dimension, where a ratio of X particles is smaller. For reasons of simplicity weighted functions, such as number, radius or volume, are not. Extending these metrics to D10 and D90 additionally informs about the width of the entire size distribution (Figure 1).

CS_sphericity_image_1

Particle size distribution of two different particle systems with identical median dimension D50. Blue: wide PSD, green: narrow PSD. Dotted lines are guides to the eyes.

Figure 1: Particle size distribution of two different particle systems with identical median dimension D50. Blue: wide PSD, green: narrow PSD. Dotted lines are guides to the eyes.

Dimensions of pellets

In this study, imaging technology (Horiba, Camsizer) was employed for the size analysis. Representatively, more than 50 charges of Cellets® 100 and Cellets® 500  (Figures 2-3) have been analyzed for the D10, D50 and D90 values.

CS_sphericity_image_2

D10 (red), D50 (green) and D90 (blue) value for several Cellets® 100 charges. Solid lines are measures, dashed lines represent the averaged value of all charges. The standard deviation is below 10 %.

Figure 2: D­10 (red), D50 (green) and D90 (blue) value for several Cellets® 100 charges. Solid lines are measures, dashed lines represent the averaged value of all charges. The standard deviation is below 10 %.

CS_sphericity_image_3

D10 (red), D50 (green) and D90 (blue) value for several Cellets® 500 charges. Solid lines are measures, dashed lines represent the averaged value of all charges. The standard deviation is below 4 %.

Figure 3: D10 (red), D50 (green) and D90 (blue) value for several Cellets® 500 charges. Solid lines are measures, dashed lines represent the averaged value of all charges. The standard deviation is below 4 %.

The results show only slight variations in the PSD between the charges. The standard deviation is smaller than 4 % (Cellets® 500) and smaller than 10 % (Cellets® 100) which confirms a high reproducibility in production (Table 1). Both values are remarkably good for technical spheres. Furthermore, none of the charges was out of specifications and fit into the desired size distribution between 500 µm and 710 µm easily. The close gap between D­10 and D90 clearly identify an excellent monodispersity.

Standard deviation Cellets 100 Cellets 500
of D­10 8.28 % 3.97 %
of D50 7.12 % 3.52 %
of D90 4.68 % 3.11 %

Table 1: Standard deviation for D­10, D­50 and D­90 values Cellets® 100 and Cellets® 500 charges.

CS_sphericity_image_4

Electron microscopy yield perfect imaging data of the MCC pellets’ surfaces. Magnification: 250x, working distance 8.0 mm, voltage: 10 keV.

Figure 4: Electron microscopy yield perfect imaging data of the MCC pellets’ surfaces. Magnification: 250x, working distance 8.0 mm, voltage: 10 keV.

Perfect sphericity? – Yes!

For a more detailed shape analysis, electron microscopy yield perfect imaging data of the MCC pellets’ surfaces (Figure 4). Additionally, MCC pellets have a distinguishing friability.

Summary

Microcrystalline Cellulose (MCC) pellets show excellent chemically inertness, high degree of sphericity, narrow size distribution and high reproducibility in production. These properties make Cellets® becoming one of the first choice for inert API carriers. We have proven these excellent properties for Cellets® 100 and Cellets® 500. The obtained results are representative for other size classes ranging from 100 µm to 1400 µm.

Acknowledgement

We acknowledge IPC Process-Center (Dresden, Germany) for the analytics, and Fraunhofer IFAM (Dresden, Germany) for recording the electron microscopic pictures.

References

[1] H. R. Norouzi, International Journal of Pharmaceutics, Volume 590 (2020) 119931

[2] D. Jones, Developing Solid Oral Dosage Forms, Pharmaceutical Theory And Practice (2009) 807-825

[3] M. Ahtola, Dry powder layering of high viscosity polymers using a fluidized bed rotor granulator, Master thesis, U of Helsinki (2014)

[4] S. Abdul, A. Chandewar, S. Jaiswal, Journal of Controlled Release, Volume 147(1) (2010) 2-16

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