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.
ingredientpharm
Abstract
Patients with dysphagia may have obstacles to swallow tablets or large multiparticulates. The former dosage form can even not be crushed in case that the tablet exhibits a modified release or taste-masking profile through outer layering. As a solution, so called jelly formulations may be a valuable attempt. Jellies are delivery vehicles incorporating sustained release microparticles for patients with dysphagia. This case study investigates a modified release formulation based on Gliclazide. Gliclazide is used to treat diabetes mellitus type 2. In combination with selected excipients, a jelly-like appearance is composed. Micropellets made of microcrystalline cellulose (Cellets®) are used as API carrier systems.
Goals and Formulation of a Gliclazide drug
The goal is to investigate a revolutionary method for geriatrics with dysphagia or potentially for paediatrics based on jelly-like formulations. The formulation should carry an API such as Gliclazide and show a modified release profile.
Free-standing jellies are formulated by mixing sodium alginate (0.5 % w/v with another polymer, and 1 % w/v w/o polymer), with an aqueous solution of dicalcium phosphate dihydrate (0.1-1 % w/v).
Soft granular jellies are formulated by preparing an aqueous sodium alginate (0.5-2 % w/v) solution with or without the presence of another polymer and by later adding an aqueous calcium chloride solution (0.1-0.3 % w/v).
Figure 1: Image of MCC micropellets (Cellets® 100).
MCC micropellets (Cellets® 100, Figure 1) are used as drug carriers. Gliclazide is layered onto the starter beads using a Wurster fluidized bed coater (Mini-Glatt, Glatt GmbH, Germany), so that a 50 % drug loading weight gain was reached. The overall final drug load including the functional layer is 21 % w/w. The composition of the layering suspension is given in Table 1.
| Material | QTY |
| Starter pellet: Cellets® 100 | 100 g |
| API: Gliclazide | 10 % w/w |
| Aqueous vehicle for API: | |
| Hypromellose | 1 % w/w |
| Talc | 1.9 % w/w |
| Coating of API layered pellets: | |
| Water | |
| Eudragit® NM 30 D | |
| Talc | |
| Functional coating: | |
| Magnesium stearate | |
| Silicon dioxide | |
Table 1: Formulation for Gliclazide layered starter pellets: starter pellets, aqueous API layering, release profile coating, functional coating.
Although the formulation contains several coating and layering processes, the processed micropellets stay smooth in surface, show a high sphericity and narrow size distribution.
Size distribution and dissolution profiles of Gliclazide microparticles
Polymer coated micropellets with CL25 (coating level 25 %) are shown in Figure 2. The yield of polymer coating and the final D50 values of the micropellets are displayed in Table 2.
Figure 2: SEM image of layered Gliclazide sustained release micropellets with a weight gain at 25 % (CL25).
Depending on the polymer coating, micropellets show a different Gliclazide release profile as shown in Figure 3: With increasing weight gain, the dynamics of Gliclazide release are slowed down. A comparison to Diamicron SR tablets in a pH 7.4 phosphate buffer, the CL25 formulation results in an adequate release profile.
| Micropellet | Size D50 [µm] | Yield [%] |
| Starter pellet (Cellets® 100) | 160 ± 2.1 | |
| Micropellet at CL16 | 173 ± 3.6 | 98.4 |
| Micropellet at CL20 | 185 ± 2.4 | 99.3 |
| Micropellet at CL25 | 198 ± 4.3 | 99.0 |
| Micropellet at CL60 | 208 ± 6.7 | 98.7 |
Table 2: Particle size of the micropellets with and without layering. CL = coating level / weight gain in [%]. The yield for the polymer coatings at respective weight gains.
Figure 3: Gliclazide release from layered micropellets at coating levels 16 % (filled diamond), 20 % (open circles), 25 % (filled squares) and 60 % (filled circles) and the commercial Diamicron SR tablets (open squares) in phosphate buffer pH 7.4.
Incorporation of the Gliclazide microparticles into jellies
The incorporation of sustained release Gliclazide microparticles into the Jellies is realized through mixing the required quantity of microparticles with polymers (sodium alginate or polymer mixture).
Sodium alginate is known to form gels in the presence of calcium ions at room temperature. Depending on the formulation, granular jellies (soft and easy to flow) or free-standing jellies (“ready-to-eat”) are formed. Formulations of jellies with and without API layered micropellets are shown in Figure 4. Incorporating the micropellets into the jellies did not cause a visual change in color or appearance. The API was kept inside the jellies. Also physical-chemical properties such as the gel strength, the texture, and the oral transit time in an in-vitro swallowing simulator are remained unchanged.
Figure 4: Images of a Jelly without (left) and with incorporation of sustained release micropellets (right).
Figure 4: Images of a Jelly without (left) and with incorporation of sustained release micropellets (right).
A release profile of Gliclazide with a coating level of 25 % in a jelly formation is shown in Figure 5. In comparison to a reference release profile of a Diamicron 30 mg SR tablet, the coated micropellets show a competitive behavior as already discussed in Figure 3. After incorporating into the jelly formation, the release profile is decaying. Obviously, the intact and also the fragmented jelly formulation show comparable dynamics. In order to obtain a comparable release profile than with the non-formulated micropellets, a coating level of down to 20 % is required.
Figure 5: Gliclazide release from coated microparticles and in combination with Jellies in a pH 7.4 phosphate buffer. Diamicron 30 mg SR tablet (open triangle), no jelly at CL25 (closed triangle), jelly formulation (intact) incorporated with CL25 (closed circle), jelly formulation (fragmented) incorporated with CL25 (open circle), jelly formulation (intact) with CL20 (open square).
Summary
Sustained release Gliclazide micropellets with a final particle size D50 of less than 200 µm are successfully formulated with a 99 % production yield and adjustable drug release profiles.
The micropellets are based on Cellets® 100 and present an excellent surface smoothness, high sphericity and narrow size distribution. They were successfully incorporated in jelly formulations. This novel drug delivery platform is a suitable vehicle for the administration of sustained release microparticles. It is a valuable attempt to replace the commonly used thickened fluids for dysphagia patients.
Acknowledgement
Dr. Fang Liu and her team are gratefully acknowledged for serving content for this note.
Fluid Pharma Ltd
Contact: Dr. Fang LIU
College Lane, Hatfield, AL10 9AB, UK
Tel: +44 1707 28 4273
+44 796 3230 628
References
[1] S. Patel et al., Journal of Pharmaceutical 109 (2020) 2474-2484.
Abstract
Modified drug release formulations for suspensions are a perfect solution for children and patients with swallowing difficulties. In many cases, these formulations are based on pellets serving as starter beads. In this report, an attempt on microparticle coating by Mohylyuk et al. [1] is described. Herein, small scaled microcrystalline cellulose pellets (Cellets® 90 and Cellets® 100, Table 1) in the size range smaller than 150 µm are used. Through a modified Wurster fluidized bed process, a yield of 99 % was reached.
| Starter materials | PSD (> 85 %) |
| Cellets® 90 | 63-125 μm |
| Cellets® 100 | 100-200 µm |
Table 1: Size distribution of Cellets® as starter beads in this formulation.
Goals and Formulation
The goal is to investigate a revolutionary platform for sustained-release microencapsulation using the industrial fluidized bed coating technology. Significant challenges of particle cohesion in the process shall be avoided by applying a small quantity of dry powder glidant periodically during the coating process. A highly water-soluble drug, which is metoprolol succinate, is reproducibly microencapsulated on pellet technologies with total pellet sizes of less than 200 µm and a drug release time of 20 hours.
Excipients for extended release profiles
For obtaining a sustained release profile, polymethacrylate-based copolymers, Eudragit RS/RL® 30 D and Eudragit® NM 30 D, were used in combination with a range of anti-tacking agents. The coating onto placebo Cellets® 100 starter beads was performed in a fluidized bed coater with a Wurster insert (Mini-Glatt, Glatt GmbH, Germany) in order to analyze the release profile. Process parameters are shown in Table 2. A small quantity of dry powder glidant was periodically added during processing, so that particle cohesion was eliminated. The optimized excipient composition for the desired release profile is achieved by testing 10 different compositions.
| Parameter | Value |
| Inlet air temperature | |
| Eudragit RS/RL® 30 D | 35-40 °C |
| Eudragit® NM 30 D | 30-35 °C |
| Product temperature | |
| Eudragit RS/RL® 30 D | 25-30 °C |
| Eudragit® NM 30 D | 18-20 °C |
| air flow rate | 18 m3/h |
| Atomization pressure | 1.5 bar |
| Spray rate | 1.1-2.4 g/min |
Table 2: Process parameter for a fluidized bed coater with a Wurster insert. A sustained release drug layer is coated onto placebo Cellets® 100 starter beads.
Drug coating
For drug coating, Cellets® 90 were layered with a suspension of metoprolol succinate in a composition as shown in Table 3.
| Material | Concentration (w/w) |
| Metoprolol succinate | 22.8 % |
| Hypromellose | 0.6 % |
| talc (Pharma M) | 4.0 % |
| Deionized water | 72.6 % |
Table 3: Composition of metoprolol succinate suspension for drug layering onto Cellets® 90.
The metoprolol succinate-loaded Cellets® 90 microparticles were successfully coated with the Eudragit® NM 30 D based aqueous dispersion, achieving a high product yield of 99 % and a final particle size of less than 200 µm (D50 value).
Figure 1: Size distribution of Cellets® 90 as uncoated (empty squares), drug loaded (filled diamonds) and drug loaded and coated (filled circles) particles.
The API loaded and coated starter beads are of high sphericity and show a homogeneous and narrow size distribution, which is shown as a SEM (scanning electron microscope) image in Figure 2.
In dissolution tests, an extended release time of up to 20 hours is obtained and can still be varied by the composition of excipients (Figure 3).
Figure 2: SEM image of drug loaded and coated starter beads. Microparticles show a high level of homogeneity in size distribution.
Figure 3: Drug release profiles of three batches of metoprolol succinate loaded and coated Cellets. An extended release of 20 hours is obtained.
Summary
This case study is a short abstract of the publication on microparticle coating by Mohylyuk et al. [1], highlighting the proof of concept for reproducible microencapsulation of a highly water-soluble drug by applying a small quantity of dry powder glidant periodically during Wurster fluidized bed coating. The challenge of particle cohesion in the “down flow” zone was eliminated and a high product yields up to 99% was achieved.
Coated microparticles are in size of less than 200 μm and show a 20 hours sustained drug release profile. These conditions allow the usage in liquid suspensions. Furthermore, the applied technology is scalable. In conclusion, this displays a sustained-release dosage solution, which is suitable for paediatrics and geriatrics with swallowing difficulties.
Acknowledgement
Dr. Fang Liu and her team are gratefully acknowledged for serving content and data for this note.
Fluid Pharma Ltd
Contact: Dr. Fang LIU
College Lane, Hatfield, AL10 9AB, UK
Tel: +44 1707 28 4273
+44 796 3230 628
References
IngredientpharmAbstract
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.
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.
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.
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.
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.
glatt.comThe 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
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
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).
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.
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 %.
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.
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
[4] S. Abdul, A. Chandewar, S. Jaiswal, Journal of Controlled Release, Volume 147(1) (2010) 2-16
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.
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.
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.
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.
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
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
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.