CELLETS® 100

(100-200 µm)

CELLETS® 100 is a subtype of pellets made of microcrystalline cellulose. The size ranges from 100 µm to 200 µm. Find more product information and technical specifications.

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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).

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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.

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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 %.

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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.

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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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Better MUPS tablets: Aspects of MCC starter beads

Abstract

Starter beads such as pellets made of microcrystalline cellulose (MCC) are frequently used in the formulation of oral drug delivery systems, e.g. multiparticulates [1] or multi-unit pellet system (MUPS) tablets [2]. Certain properties are requested to MCC pellets. We shed some light on sphericity size and friability in this note.

Starter beads for MUPS tablets

MUPS tablets consist of pellets which are compressed – assisted by excipients such as disintegrants and fillers. The pellets used are usually functional coated to achieve desired drug release profiles.

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Top: Inert Cellets® 100 (100-200 µm, left) in comparison with another MCC sphere (75-212 µm, right). Bottom: Inert Cellets® 200 (200-350 µm, left) in comparison with another MCC sphere (150-300 µm).

Figure 1: Top: Inert Cellets® 100 (100-200 µm, left) in comparison with another MCC sphere (75-212 µm, right). Bottom: Inert Cellets® 200 (200-350 µm, left) in comparison with another MCC sphere (150-300 µm).

The characteristics of the starter bead as a neutral carrier should therefore include high sphericity (Figure 1), constant particle size distribution and smooth surface. These aspects count especially for the formulation of low dosed highly active APIs.

For the application in MUPS tablets small size and high mechanical stability (low friability) are of interest to achieve desired drug loading and avoid film damage during compression.

Size

Any question relating to optimized drug load and coating layers of pellets is a question of size and sphericity of the starter beads.

So, what is the main influence of size? Size needs to be considered for achieving desired drug load in relation to a total dimension of the pellet. While the total dimension of the pellet is mainly defined by the application – e.g. processing as a capsule, tablet or sachet –, the initial pellet size defines the maximum thickness of coating levels (Figure 2). Size might also be a matter of content uniformity with low dosed API and also needs to be mentioned by means of processability, which is in particular electrostatic loading or sticking. Particle size distribution influences the dissolution profile.

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Figure 2: Sketch of a functionally coated pellet. The size of the initial pellet (green) defines the maximum thickness of all coating layers (blue) which may contain API and excipients, as well.

Figure 2: Sketch of a functionally coated pellet. The size of the initial pellet (green) defines the maximum thickness of all coating layers (blue) which may contain API and excipients, as well.

Sphericity

Sphericity is a strong parameter which influence depends on drug loading and coating levels. Also for the control of dissolution profile where specific surface area and content uniformity play important roles, the influence of sphericity needs to be understood (Figure 3). Please do not forget, that with decreasing sphericity, the flow probabilities of powders are decreasing (powder rheology), which might affect process properties such as powder transport.

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Figure 3: Sketch of non-spherical starter beads (green) with coating layers (blue). Coating layer thickness and dissolution profiles are hard to control in this case.

Figure 3: Sketch of non-spherical starter beads (green) with coating layers (blue). Coating layer thickness and dissolution profiles are hard to control in this case.

Thus, starter beads of uniform size (distribution) and sphericity are the better solution for overcoming these issues by simplifying drug formulation and processing. Such starter beads can be pellets of MCC, sugar or tartaric acid. MCC pellets surely show perfect initial conditions as they exhibit chemical inertness and therefore can be combined with several APIs. In case of weakly basic APIs, tartaric acid pellets are advantageous.

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Figure 4: A pellet inside a compressed MUPS tablet. The starter bead is surrounded by a coating layer of exemplarily excipient or API. A powdery excipients matrix surrounds the coated pellet. Friability is absolutely low.

Figure 4: A pellet inside a compressed MUPS tablet. The starter bead is surrounded by a coating layer of exemplarily excipient or API. A powdery excipients matrix surrounds the coated pellet. Friability is absolutely low.

Figure 4 shows a cross-section of a pellet in the matrix of a compressed MUPS tablet. It is mentionable, that due to low friability a high degree of sphericity as well as surface smoothness are kept after compression and film damage of coating layers is not identified.

Summary

Cellets® offer a perfect combination of chemical inertness towards the selection of the API and physical properties that allow optimized and stable processing in a fluid bed process for layering and coating of the starter beads. Main advantages are the low friability, smooth surface, sphericity and narrow size distributions.

Cellets® starter beads therefore provide excellent conditions for controlled drug dissolution profiles.

Acknowledgement

We acknowledge Fraunhofer IFAM (Dresden, Germany) for providing electron microscopic images.

References

[1] Pöllinger N, Drug Product Development for Older Adults—Multiparticulate Formulations. In: Stegemann S. (eds) Developing Drug Products in an Aging Society. AAPS Advances in the Pharmaceutical Sciences Series, vol 26 (2016). Springer, Cham. https://doi.org/10.1007/978-3-319-43099-7_16

[2] Bhad ME, Abdul S, Jaiswal SB, Chandewar AV, Jain JM, Sakarkar DM. MUPS tablets—a brief review. Int J Pharm Tech Res. 2010;2:847–55

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Theophylline size distribution

Case Study: Layering of Theophylline

Abstract

Theophylline is a powerful active used for the acute treatment of respiratory distress. Its bioavailability and uptake rates are high. Drug carrier systems are pellets made of sugar or microcrystalline cellulose (MCC). This case study will point on the specific advantages of MCC pellets.

Layering on starter pellets

Basically, theophylline is an alkaloid that occurs in nature together with other purine alkaloids such as caffeine and theobromine, but it occurs in comparably small fractions up to 0.25 %. Anyhow, it can be synthetically composed. In application, theophylline is used for the acute treatment of respiratory distress due to airway constriction in bronchial asthma and other obstructive airway diseases.

After oral administration theophylline is rapidly and completely absorbed in the gastrointestinal tract (GIT). Retard preparations are used for long-term treatment, reaching their maximum effect after around six to eight hours [1].

Typical carrier systems are sugar and MCC pellets (Cellets®). By subsequent layering, retard and individual release profiles can be achieved. For both types of starter pellets, a drug solution for 200 g pellets (batch size) was formulated in the following way as listed in Table 1.

Parameter weighted mass
theophylline 8.32 g
PVP K30 0.67 g
distilled water 80.0 g
ammonia 25 % 4.0 g

Table 1: Substances for a drug solution for 200 g batch size.

Process Technology

The formulation results in a drug load of 4.2 %. A Wurster tube at 0.8 cm was used with a processing temperature at 50 °C. In contrast to MCC pellets, sugar pellets are soluble in water. Therefore, process parameters are slightly different, since the process for sugar spheres requires a slower start to avoid sticky particles (Table 2). Obviously, the slower process start required for the sugar pellets results in an additional time consumption of +50 % compared to the Cellets® process.

Parameter Sugar pellets Cellets®
Batch size 200.0 g
Wurster tube 0.8 cm
Fluid bed temperature 50 °C
Inlet air volume (pressure) 0.4 bar 0.35 bar
Atomizing air pressure 2.3 bar 1.8 bar
Spray rate 0.41 g/min 0.73 g/min
Process time 218 min 145 min
Drying period 30 min

Table 2: Process parameter for the formulation with sugar pellets and Cellets®.

Finalized pellets

The processed drug layered pellets show a size distribution as shown in Figure 1. Here, the variation between the batches of the sugar pellets are more pronounced (18.6 %) than for the batches of Cellets® (2.8 %).

The formulation results in a drug load of 4.2 %. A Wurster tube at 0.8 cm was used with a processing temperature at 50 °C. In contrast to MCC pellets, sugar pellets are soluble in water. Therefore, process parameters are slightly different, since the process for sugar spheres requires a slower start to avoid sticky particles (Table 2). Obviously, the slower process start required for the sugar pellets results in an additional time consumption of +50 % compared to the Cellets® process.

Parameter Sugar pellets Cellets®
Batch size 200.0 g
Wurster tube 0.8 cm
Fluid bed temperature 50 °C
Inlet air volume (pressure) 0.4 bar 0.35 bar
Atomizing air pressure 2.3 bar 1.8 bar
Spray rate 0.41 g/min 0.73 g/min
Process time 218 min 145 min
Drying period 30 min

Table 2: Process parameter for the formulation with sugar pellets and Cellets®.

The processed drug layered pellets show a size distribution as shown in Figure 1. Here, the variation between the batches of the sugar pellets are more pronounced (18.6 %) than for the batches of Cellets® (2.8 %).

Theophylline size distribution

Theophylline size distribution

Figure 1: Analysis of batches. From left to right: (1) best batch sugar pellets, (2) worst batch sugar pellets, (3) best batch Cellets®, (4) worst batch Cellets®.

Summary

In this case study, the coating of pellets with theophylline was investigated. A targeted drug load of 4.2 % was reached. By sophisticated formulation, further improvements towards optimized release profiles of the active in the GIT can be performed. Here, MCC pellets are superior to sugar pellets in terms of reproducibility, process time and quality rating after coating.

Acknowledgement

We acknowledge Dr. Riedel (Bayer) for assisting this case study.

References

[1] B. Lemmer, R. Wettengel: Erkrankungen der Atemwege. In: B. Lemmer, K. Brune: Pharmakotherapie – Klinische Pharmakologie. 13. Auflage. Heidelberg 2007, ISBN 978-3-540-34180-2, S. 343–344, S. 349–350.

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