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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.

Authors

Dr. Bastian Arlt

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.

Authors

Authors: Dr. Bastian Arlt

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.