Esomeprazole Pellet Production for MUPS Applications – High-Precision Fluid Bed Coating
MUPS formulations are a widely used pharmaceutical dosage form for esomeprazole, a proton pump inhibitor. For this purpose, micropellets are coated with the active ingredient and administered in the form of tablets or capsules. An appropriate solution for the coating of micropellets is the use of fluid bed processors which utilise air flow bed technology
Bastian Käding at Romaco Innojet
Efficient, high-quality production of MUPS micropellets with fluid bed processors
Esomeprazole blocks the production of stomach acid and is therefore used, amongst other things, to treat gastric and intestinal ulcers and prevent reflux symptoms. The acid-labile proton pump inhibitor is absorbed in the intestine and either administered parenterally or taken orally as an enteric-coated preparation. The drug is accordingly available as an injection solution or in the form of tablets or capsules; for example so-called multiple unit pellet systems (MUPS). For these preparations, micropellets containing active ingredients are either mixed with powdery excipients and then compressed into tablets or alternatively filled into capsules.
One big advantage of MUPS tablets is that they dissolve easily, so that the pellets with the active pharmaceutical ingredients (APIs) pass through the stomach quickly due to their small diameter, regardless of whether or not it is full. The medication is consequently characterised by a highly controlled release profile and high bioavailability.
Since the active ingredient of MUPS tablets is distributed between a large number of pellets, the tablets can also be halved. By contrast, dividing coated sustained-release tablets in two would have negative effects for consumers: the active ingredient would be released immediately after swallowing, which would be tantamount to dose dumping. MUPS formulations, on the other hand, facilitate compliance.
Three-Stage Micropellet Coating
Esomeprazole pellets for MUPS applications are often produced in a fluid bed coating process comprised of three stages. First of all, neutral starter pellets made from glucose are sprayed with the aqueous API suspension. A protective insulating layer is applied next, followed by the enteric sustained-release coating, which ensures controlled release of the drug in the intestinal tract. Depending on the formulation, the diameter of the micropellets increases from approximately 300µm (microns) to 1300µm during the coating process. Parallel to this, their weight is roughly trebled from about 1.5g to 4.7g per pellet. Several days are usually scheduled for this method in the pharmaceutical industry. Fluid bed processors based on air fluid bed process technology can meet all the requirements of this demanding production process.
A booster with overlapping circular plates ensures controlled process air movement without any mechanical stress on the esomeprazole pellets
Three Functional Units Make It Possible
The interaction of three functional units for air inlet, spraying nozzle and particle filtration in these air fluid bed processors lays the foundation to produce esomeprazole pellets that comply with the needs of users in terms of quality and efficiency. In the described process, the process air is introduced into a cylindrical product container through a booster plate, resulting in a spiral product movement. The spray liquid is applied with a central spraying nozzle by the bottom spray method and the process air is subsequently discharged again via a particle recirculating filter system.
The booster plate in this setup consists of overlapping circular plates which ensure homogeneous process air flow inside the container. The speed of the micropellets and their path through the container can thereby be precisely controlled, preventing the particles from colliding and agglomerating. The risk of this happening is particularly great when spraying on the very sticky enteric suspensions. Esomeprazole coatings, on the other hand, tend to be highly abrasive, which is why gentle intermixing of the batch without any mechanical stresses is so immensely important.
Efficient Injection System
Due to the controlled movement of the process air, the coating liquid can be applied very precisely with one central spray nozzle. Ideally, the liquid spray is directed upwards at the product bed (bottom spray), so that spray loss is significantly reduced. In addition, a rotating nozzle head can effectively prevent blocked spray nozzles. This is especially vital when the sustained-release coating is applied to the esomeprazole pellets, because the enteric coating liquid polymerises easily. To optimise the coating process even further, the air temperature – and hence the product temperature – around the nozzle can be controlled differently from the rest of the process container. This ensures particularly efficient drying and enables very short processes. The particle droplet size is defined by the spray air introduced above and below the circular spraying gap, so that no over-wetting of the product occurs during the MUPS coating process, which takes several hours to complete. The pellets are built up homogeneously, which results in maximum moisture extraction. This shortens the drying time by up to 25% and reduces the system’s energy consumption dramatically. If, additionally, the nozzle can be easily replaced during the actual process without having to stop production and empty the product container, far shorter batch processing times are the outcome.
Sustainable Particle Filter
Process air is discharged via a filter system, which enables particles to be constantly returned to the process. Conditioned process air cleans the individual filter bags continuously throughout the production cycle. This hot, conditioned cleaning air prevents condensation and helps extend the filter system’s service life. At the same time, the geometry of the filters can permit a compact machine design. The space saved in the cleanroom is another advantage on the sustainability side, first and foremost because only one machine is needed to produce esomeprazole pellets. And its cylindrical product container provides another benefit: a large batch variability, in some machines from 10 – 100%. This means that there is no need to empty the batch and divide it into sub-batches in the event of a process-inherent increase in pellet weight, which in turn leads to a smaller carbon footprint for the process and time, money and storage capacity are saved.
Scale-Ups Made Easy
Production-scale fluid bed processors are often in charge for a batch size range from 60 to 1500l. When the geometry of both the cylindrical product container and the spray nozzle is scalable, scale-up processes are greatly simplified. For process validation, trials should be carried out in a laboratory environment. Here, process parameters for new formulations can be determined quickly and easily using DoE (Design of Experiment), the lab software. For instance, once the spray rate, product temperature and process air volume are optimally matched, maximum leverage can be obtained from the fluid bed processor’s capacity in terms of performance and quality, making it the ideal starting point for developing new esomeprazole products.
Bastian Käding has been at the helm of Romaco Innojet as managing director since 2019. After joining Innojet as a project manager in 2015, he soon transitioned to the position of area sales manager with a focus on customer service activities. In 2017, Mr. Käding was appointed deputy managing director, responsible for project management, operations and quality. He started his professional career as a laboratory technician at Süd-Chemie AG in 2003. After a three-year assignment for Süd-Chemie in Italy, he was promoted to project manager. During his management career, Bastian Käding never lost touch with research and development activities.
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