Extrusion & Sphenronization

Extrusion / Spheronization is a commonly used manufacturing process in the pharmaceutical industry whereby small drug-containing spheres/pellets are produced. The pellets produced in the spheronization process are then typically encapsulated. The steps involved in the spheronization manufacturing process include dry blending, wet massing, extrusion, spheronization and drying/coating. Screening may be performed to optimize the particle size distribution range prior to encapsulation.

The active and excipients are initially mixed together in a granulator followed by the addition of a granulation liquid. The resulting wet mass is passed through a screen forming soft, pliable extrudate. The size of the final pellets (spheres) is principally determined by the hole diameter of the screen used in the extrusion step.

The extrudate is charged to the spheronizer which consists of a plate/disc, spinning at speeds of approximately 400–500 rpm, inside a spheronization bowl. The extrudate is broken down into cylindrical shaped pieces of approximately equal length, which is directly related to the diameter of the extrudate. These cylindrical segments are gradually rounded by the collisions with the bowl wall, the plate and each other. When the particles have reached the desired level of sphericity, they are then discharged from the spheronizer. The wet pellets are collected and dried, typically, in a fluid bed drier (FBD). The FBD can also be used to coat the pellets if required.

Spheronization Process Challenges

Although spheronization is an established manufacturing operation in the pharmaceutical industry, the actual formation of the pellets from the extrudate is not always fully understood for all manufacturing processes. Also the impact of raw material variability is not always fully understood and this variability may cause product quality issues. Uniform particle size distribution, good sphericity, shape and surface characteristics, have been identified as critical to quality attributes (CQA) of pellets. These critical quality attributes are particularly important if the pellets are to be coated for controlled release purposes. Understanding how pellets are formed and the impact of raw material variability for each of your spheronization processes may be critical to the success and consistency of your products. Therefore, measuring particle size distributions and particle shape can be critical to the success of your businesses.

Particle Size Analysis: Sieve Analysis

Although all particles are three dimensional, sieve analysis results are based on one dimension only. Because of the mechanical vibrations applied during sieve analysis testing, particles may orientate in such a way that they will pass through sieves based on their second smallest dimension. Therefore, sieve analysis tests can generate low results biased towards the low end if not controlled properly. Some materials (such as hygroscopic or electrostatic materials), can be difficult to analyze by sieve analysis, especially at small sieve sizes. Sieve analysis testing may only be done at line as it is not suitable for in line analysis.

Particle Size Analysis: Eyecon 3D Particle Characterizer

The Eyecon interfaced with GEA Nica Systems monitor the pellet formation process and particle size distribution in real-time. Real-time direct images are provided to aid process understanding. The process knowledge/understanding gained will help manufacturers to fully understand their spheronization processes, enable them to identify the critical process parameters in these processes and also to understand the impact of input variability within their processes.

Advanced software functions allow product particle size limits to be set based on deviation from a defined ideal state/standard of the spheronization process. As measurements happen in real-time, this unique alarm feature enables manufacturing issues/deviations/variation to be identified in real-time. This allows the manufacturer to take action to correct the issues as soon as the issue arises, thus minimizing waste, maintaining overall product quality and ensuring patient safety.

The Eyecon is unique in that it does not come into direct contact with the product (no contamination risks), there is no sample preparation required (reduces variability of resulting from sample preparation variation) and it uses direct sample measurement technology (less complexity of calculation algorithms). The same unit can be used as a bench-top analyzer and as an in-line process analyzer.

Case Study 1

The Eyecon has been used to measure spheroid particle size and the shape of sustained release spheroids (Figure X). Use of the Eyecon was instrumental in identifying and thus reducing common cause variation within the manufacturing process. This customer realized savings of €1 million per annum through process optimisation on this spheroid manufacturing process.

Case Study 2

The Eyecon can be used both on-line and in benchtop format to measure particle size and shape. In addition to control of routine spheronization processes, an alternative example involves a customer intending to benchmark the same process across a number of manufacturing sites. It has proved to be very beneficial in monitoring product quality, improving manufacturing yields and overall process robustness.