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INNOVATIVE GLATT FLUID BED PELLETISING TECHNOLOGIES

by Dr. Norbert Pöllinger, Glatt Pharmaceutical Services, Technology Center Binzen

In multi-particulate systems the dosage of the drug substance is – in contrast to classic single-unit dosage forms like tablets – divided on a plurality of sub-units, consisting of thousands of spherical pellet particles with a diameter of typically 100 – 2000 µm.

Although their manufacture and design is more complex in comparison to classic single-unit dosage forms, multi-particulate dosage forms offer a magnitude of different interesting options and advantages to accomplish unique product characteristics and in particular specific drug release patterns. In contrast to nondisintegrating monolithic single-unit forms which retain their structure in the digestive tract, the multiparticular preparations consist of numerous sub-units which disperse after administration. Each single sub-unit acts as an individual modified release entity. As a consequence of this property, the multiple-unit approach offers certain advantages for a modified release dosage form over monolithic preparations like tablets:

- reduced variability of the gastric emptying
- reduced dependency on the nutrition state
- minimised risk of high local drug concentrations within the 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

With multiparticular pharmaceutical drugs an optimised pharmacokinetic behaviour can go together with good patient compliance.

Many creative options in order to end up with intelligent, sophisticated and reliably acting pharmaceutical dosage forms are technically available. The question is: do we have feasible technologies in order to establish reproducible product and process quality?

The described multiparticulate pellet units can be formulated to different drug application forms (fig. 1): the most conventional form is the capsule. Pellets may further be compressed to tablets – after disintegration of the tablet in the stomach the pellets are set free acting as multiparticulates.

Fig. 1: Final drug application forms with pellets

Pellets having a particle size < 500 µm can be applied as oral suspensions without providing a sandy mouthfeel. To achieve such small pellet sizes particular technologies providing micropellets are required – the extrusion technique is not applicable therefore (fig. 2).

Fig. 2: Product Characteristics with different pelletization technologies

With classic fluid bed drug layering and coating technologies like the Wurster and the Rotor technology such pellet particle sizes are basically achievable taking into account that the Wurster process is limited to drug layering approaches; an optimised Rotor technology could lead to an even better performance than the existing one.

In addition to said existing and established pelletising technologies GLATT has developed new pelletising technologies (fig. 3) allowing new formulation options and product qualities. In particular, unique benefits and opportunities such as a small pellet size range of 100 – 500 µm, uniformity of particle size distribution, smooth particle surface, high density and high drug loading are achievable.

Fig. 3: Innovative GLATT pelletization technologies

1. CPS™ Technology (Controlled Release Pelletising Technology)

CPS™ Technology is a direct pelletisation process resulting in matrix type pellets. Release characteristics of API from CPS™ pellets depend both on the pellet formulation and on the pelletising process.

The CPS™ technology is an advanced fluid bed rotor technology allowing the preparation of matrix pellets with particular properties in a batch process; extremely low dosed and high potent drug can be formulated to CPS™ matrix pellets as well as high dosed APIs (fig. 2); the drug concentration can vary from < 1% up to 90%.

Due to its modifications compared to the established GLATT Rotor system the CPS™ Technology works with a conical shaped rotating disc and additional devices ensuring a directed particle movement (fig. 4).

Fig. 4: Rotor Technology and CPS™ Technology

Inert starting beads are not required for the CPS™ Technology; typically, microcrystalline cellulose powder is used as a basic excipient; moreover, other functional excipients like polymers, disintegrants, solubilizers and the like can be part of the CPS™ formulations in combination with the API.
The starting powder (blend) is wetted with the pelletising liquid until a defined stage of moisture will have been achieved; at this time, spherical pellets begin to form (fig. 5). The pelletising liquid can be water and / or organic solvents which may also contain functional compounds. As an option, dry powder may be fed into the process.

Fig. 5: CPS™ Pelletising process in progress

With the help of torque measurement at the CPS™ rotor the endpoint of the pelletisation 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 CPS™ or in a classical fluid bed dryer configuration.

Fig. 6 shows the characteristics of CPS™ pellets containing 75% of an API in comparison with the same pellet formulation manufactured by extrusion (fig. 7): the CPS™ pellets provide a higher density due to the particular spheronisation process; their surface is smoother than the one of the extruded pellets and therefore provides ideal prerequisites for coating applications.

Fig. 6: CPS™ Matrix Pellets

Outstanding product characteristics of CPS™ pellets:
- spherical and smooth pellet surfaces = 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: 100 – 1500 µm
- narrow particle size distribution (fig. 8)
- controlled drug release from the CPS matrix (fig. 9)

Fig. 7: Pellets from an Extrusion / Spheronisation process

Fig. 8: Particle size distribution of extended release CPS™ pellets

Fig. 9: Effect of particle size distribution on the in vitro dissolution of extended release CPS™ pellets (phosphate buffer pH 6.8, 37°C)

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