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Pharmaceutical Manufacturing and Packing Sourcer

Pellet Power

In contrast to classic single-unit dosage forms such as tablets, the dosage of the drug substance in multi-particulate systems is divided on a plurality of subunits – typically consisting of thousands of spherical pellet particles with a diameter of between 100 and 2,000 μm. This means that non-disintegrating, monolithic single-unit forms retain their structure in the digestive tract, whereas the multi-particular preparations consist of numerous sub-units which disperse after administration. Each single sub-unit then acts as an individual modified release entity. As a consequence of this property, the multiple-unit approach offers certain advantages as a modified release dosage form over preparations such as tablets, including:
  • Reduced variability of gastric emptying
  • Reduced dependency on the nutrition state
  • Minimised risk of high local drug concentrations within the gastrointestinal (GI) tract
  • Reduced risk of sudden dose-dumping
  • Lower intra- and inter-individual variability
  • Controlled onset time of drug release
  • Delivery of the active ingredient to distal sites within the GI tract
In addition, with multi-particular pharmaceutical drugs, optimised pharmacokinetic behaviour can improve patient compliance.

Several creative options can be explored that result in intelligent, sophisticated and reliably acting pharmaceutical dosage forms.The question is: do we have feasible technologies that can establish reproducible product and process quality?

The multi-particulate pellet units described here can be formulated into different drug application forms (see Figure 1), of which the capsule is the most conventional form. Pellets may be further compressed into tablets, and after disintegration of the tablet in the stomach the pellets are set free, acting as multi-particulates. Pellets with a small particle size (less than 500 μm) can be applied as oral suspensions without providing a sandy mouthfeel. In order to achieve such small pellet sizes, particular technologies are required – therefore, the extrusion technique is not applicable.

With classic fluid bed drug layering and coating technologies, such as Wurster or rotor technology, such pellet particle sizes are essentially achievable, taking into account that the Wurster process is limited to drug layering approaches. However, an optimised rotor technology could lead to an even better performance than the existing one.

In addition to the existing and established pelletising technologies, innovative technologies allowing new formulation options and product qualities have been developed. In particular, unique benefits and opportunities such as a small pellet size range of 100 to 500 μm, uniformity of particle size distribution, smooth particle surface, high density and high drug loading are achievable.



CPS Technology

An optimised fluid bed rotor technology, CPS is a direct pelletising process resulting in matrix-type pellets. Release characteristics of API from these pellets depend on both the pellet formulation as well as the pelletising process. CPS technology is an advanced fluid bed rotor technology which allows the preparation of matrix pellets with particular properties in a batch process. Extremely low-dosed and highly potent drugs can be formulated into matrix pellets, as well as high dosed APIs; the drug concentration can vary from less than one per cent up to 90 per cent.

Due to its modifications compared with the established rotor fluid bed system, the optimised rotor technology works with a conical rotating disc and additional devices ensuring a directed particle movement (see Figure 2). Inert starting beads are not required for this technology; typically, microcrystalline cellulose powder is used as a basic excipient. Moreover, other functional excipients, such as polymers, disintegrants, solubilisers and so on can be part of the formulations in combination with the API.

The starting powder (blend) is wet with the pelletising liquid until a defined stage of moisture is achieved; at this time, spherical pellets begin to form.The pelletising liquid can be water and/or organic solvents which may also contain functional compounds. One option to consider is feeding dry powder into the process.With the help of torque measurement at the rotor, the endpoint of the pelletising process can be defined. By means of a characteristic rolling particle movement – and thereby the application of different forces, in particular of centrifugal forces on the arising pellet cores – a defined densification of the particles can be reached. Finally, the pellets are dried in the rotor or in a classical fluid bed dryer configuration.

Figures 3 and 4 compare the characteristics of pellets containing 75 per cent of an API with the same formulation manufactured by extrusion. The pellets obtained by the optimised rotor fluid bed process provide a higher density due to the particular spheronisation process; their surfaces are smoother than those of the extruded pellets, and therefore provides ideal pre-requisites for coating applications.

Outstanding the characteristics of the pellets obtained from the optimised rotor process include:
  • Spherical and smooth pellet surfaces; these are ideal for coating applications
  • High density/low porosity of pellets
  • Broad potency range for APIs
  • Low attrition and friability
  • Dust-free surfaces
  • Mean particle size range of 100 to 1,500 μm
  • Narrow particle size distribution
  • Controlled drug release from the matrix




Fluid Bed Micropelletisation Technology (MicroPx)

The technology described is a fluid bed agglomeration process resulting in matrix type pellets. Particle size could be rather small, for example less than 400 μm, together with a high drug loading (typically 95 per cent). Functional pharmaceutical excipients, such as those used for bioavailability enhancement or controlled drug release, can be integrated in the pellet matrix.

The fluid bed micropelletisation technology (MicroPx) is a continuous process; again, for the pelletisation, no starting cores are required.Typically, all formulation components, such as the API, pharmaceutical binder(s) and other functional ingredients, are contained in a liquid which is fed into the agglomeration process via spray guns; the spraying liquid can either be a solution, suspension or emulsion.The design of the fluid bed micropelletisation technology is shown in Figure 5.



In both the pilot studies and on a commercial scale, a rectangular-shaped processing chamber provides an ideal product flow. The fluidising air is led through a Konidur inlet air distribution plate into the processing area; by this means a directed air stream is provided, allowing a directed product transport over the inlet air distribution plate towards the classifying unit. One or more spray guns are mounted in the air distribution plate. A set of cartridge filters will blow dust back into the processing area in a controlled manner. At the front of the processing chamber, a zig-zag sifter – an on-line classification unit – is mounted in order to continuously discharge well-sized product from the continuous process and retain products that are still too small in the process. By adjusting the classification of the airflow, the particle size of the ‘good’ product that is to be discharged is defined. As a number of channels – each of them having a number of edges – are used for the classification, a narrow particle size distribution is achieved (see Figure 5).

The direct pelletisation process starts with spraying the APIcontaining liquid into the empty fluid bed unit. Initially, powder is generated by spray drying; the powder is stepwise agglomerated to seeds. The seeds provided online are continuously layered with droplets from the bottom spray nozzles ending up in onion-like structured micropellets.

The process is characterised by a permanently balanced ratio of spray drying and layering of already existing seeds.Well-sized pellets are continuously discharged out of the process through a rotary valve after classification by the zig-zag sifter. In order to allow spray drying besides the layering of existing pellets the product bed in the process must not be too high. This requirement is also true when the directed product flow towards the sifter is put into effect.

Besides the classical fluid bed operating parameters such as inlet air volume and temperature, atomisation air pressure and liquid feed rate, the classification air volume defining the particle size of the discharged product is characteristic for the agglomeration process. As a certain degree of spray drying is important for the performance of the continuous pelletising process, it is understandable that the product temperature is typically higher than in a Wurster layering or coating

process, where losses of product by spray drying must be avoided at all costs.

The characteristics of pellets obtained by this agglomeration technology include:
  • Spherical and smooth pellet surfaces, ideal for coating applications such as taste-masking, controlled release coating and so on
  • High density/low porosity of pellets
  • High drug loading (typically 95 per cent)
  • Low attrition and friability
  • Dust free surfaces
  • Mean particle size range (100 to 500 μm)
  • Narrow particle size distribution (more than 90 per cent between 100 to 300 μm without sieving)
  • Inclusion of bioavailability enhancers, controlled release polymers and so on
Fluid bed micropelletisation technology can ideally be applied when taste-masked micropellets need to be manufactured – for use in oral suspensions and sachets, among other applications.

For example, imagine that an extremely bitter-tasting API needs to be formulated in an oral suspension to be given to children. The high-dosed drug substance must be taste-masked in order to give a water-based suspension, after which the preparation must be perfectly taste-masked for a two-week period at room temperature. Nevertheless, the in vitro dissolution of the API from the taste-masked form should be fast (more than 75 per cent after 15 minutes). To fulfil these requirements, the API must be formulated into micropellets using the special agglomeration technology. In the end, the taste-masked coated pellets should be smaller than 500 μm; avoiding an unpleasant sandy mouthfeel. Figure 6 shows the crosssectional view of the micropellets with the two-layer coating.



Comparison of Pellets

A comparison of pellets from the optimised fluid bed rotor process (CPS) and pellets from the fluid bed micropelletisation process (MicroPx) provides some interesting observations. The described innovative fluid bed technologies should be applied for different applications:
  • The MicroPx technology is the most feasible technology when particles with drug loading more than 90 per cent must be provided in a particle size range of 100 to 400 μm; such small pellets are needed frequently for tastemasking applications, but also for the compression of pellets into tablets
  • Pellets provided by the CPS technology have a particle size range of 100 to 1,500 μm – typically lower API loads are intended and reached; a regular API load range is from 0.01 to 75 per cent.As the densification can be well controlled by adjusting the processing parameters – in particular by the form and speed of the rotating disc – the matrix pellets from the optimised fluid bed rotor process are most appropriate for a modified drug release from the matrix.Any functional coating can be applied additionally onto these matrix pellets in order to achieve a particular in vitro dissolution profile
Both processes are appropriate to provide high valuable pharmaceutical products with unique properties.

Conclusion

The innovative fluid bed pelletising technologies described complement the actual capabilities of fluid bed technology. In addition to established pelletising approaches, new options are continually being made available, although it should not replace the classical standard technologies.New possibilities for drug product development are demonstrated as having potential for line-extensions for NCEs, but also has the potential of bypassing the existing specific patent landscape in the generic business. The technologies have already been established in commercial pharmaceutical productions.

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Norbert Pöllinger studied Pharmacy at the University of Nürnberg-Erlangen, Germany, where he obtained his PhD in pharmaceutical technology in 1986. From 1987 until 1995 he worked at Bayer AG Leverkusen in the pharmaceutical development and headed the clinical supplies manufacturing group. In 1995 he joined Glatt GmbH where he is responsible for the Glatt Technology Center in Binzen, Germany. Email: norbert.poellinger@glatt.com
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Norbert Pöllinger
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