The choice of possible mixing and blending equipment for the preparation of solid and semisolid dosage formulations is extensive. Therefore, the first step in a successful mixing process is to select the most appropriate equipment. “The choice of mixing equipment is greatly dependent on the products/materials being mixed. Therefore, good blending and mixing equipment will be determined by how suitable the configuration of the blender is for the powders being mixed,” says Wilf Sangüesa, product manager for Quadro Engineering’s IDEX Material Processing Technologies Group.,
Specifically, good blending equipment for solid dosage formulations offers a large filling span at constant blending performance and provides homogeneous distribution of the API within the formulation using gentle blending conditions that do not lead to destruction of the particles or granules, according to Tobias Borgers, head of marketing for L.B. Bohle. Adds Pär Almhem, president of ModWave: “The mixer or blender must achieve the specified quality of the final product in a very short time using a very stable and repeatable process and with minimal residual product in the machine and good cleanability.”
Some of the different types of mixing equipment used for the preparation of solid and semisolid dosage formulations include ribbon and tumble blenders for dry-powder blends, multishaft mixers for transdermal drug/adhesive mixtures, and double planetary mixers for the processing of wet granulations and viscous gels. “Performance characteristics, such as the shear input, cleanability, ease of discharge, flexibility in terms of batch size and viscosity, vacuum capability, temperature control, and scalability, vary from one mixer design to another and depend on the properties of the particular application as well as the mixing objective itself,” explains Christine Banaszek, an application engineer at Charles Ross & Son Company.
Flexibility is becoming increasingly important as well, notes Sangüesa “The better blending systems are the ones that are able to mix a wide number of powders so that fewer blenders are required in a given facility. Because blending can be a costly and labor-intensive step, equipment also must be efficient and provide the maximum yield possible with few trap points and proper surface finishes that allow the maximum amount of powder to flow out upon completion of the mixing process. Systems also need to readily integrate with upstream/downstream equipment.”
Recent advances matter
Sangüesa has observed that the drive to reduce the number of components needed to perform a task has been greatly influenced by rising costs for not just capital investment, but also by increasing processing costs, such as cleaning, maintenance, space constraints, safety, product losses, and so on. One solution has been the introduction of blending systems that utilize the same holding recipient (i.e., intermediate bulk container, or IBC) to do both blending and at its completion, product transfer. “In the past,” he says, “powders had to be loaded from an IBC or Supersack to a blender and then, once the mixing was completed , transferred back. Each step adds the potential for powder losses, segregation, operator exposure, higher space needs, and more pieces to clean and maintain. By having the powders inside the IBC, blending them without further handling and then taking the IBC to its next process, many of these concerns and costs are greatly reduced. Companies, such as Matcon have innovative approaches in this area.”
New mixer designs have also been introduced that have also had an impact. For semisolid formulations, for instance, Banaszek points to double planetary mixers with improved mixing efficiency and diminished contamination risk. “We have developed a custom-fabricated and sealed gearbox that protects the drive assembly from all product contact, including solvent vapors. Newer design helical blades also prevent the ‘climbing’ issue commonly experienced with traditional rectangular planetary stirrers. These blades generate a unique mixing action; each sweeping curve firmly pushes batch material forward and downward, keeping it within the mixing zone at all times,” she notes.
Ekato Corp. has also introduced new technology for highly viscous materials, such as those used for the production of softgel and hard shell capsules. “Softgel capsule formulations often undergo several physical property changes during mixing, such as from a liquid to a paste or even a solid-like material and then back to a paste again. Such systems require very powerful mixers,” observes process systems sales engineer Rainer Engenhart. The company has adapted its high-torque, high-viscosity mixers to meet the specific sanitary requirements of the pharmaceutical industry and developed customized solutions that include ergonomic loading of solids materials with a low melting point into a hot vessel, elevated designs that allow for gravity transfer of the finished bulk into transfer tanks, and in-place cleaning systems for quick changeovers from one formulation to another.
Most importantly, the systems address the critical needs for high shear mixing combined with excellent de-aeration in both the shell and fill materials, according to Engenhart. For capsules, if air bubbles remain in the shell material, they can create pinholes that can be sources of potential leaks, while entrapped air in the fill materials can cause fill weight issues. In oral strip products, even a tiny amount of trapped air can lead to the generation of large pores during the drying process. In addition, in capsules, if moisture remains in the fill material, it can migrate from the interior and cause degradation of the water-soluble shell, leading to a loss of integrity.
“We have found that the solution for good de-aeration is to bring the bubbles to the surface while pulling a vacuum on the system to remove the air. Because air bubbles can’t move in the very viscous materials used for the production of softgels, we developed a shear laminar flow impeller that gently moves them to the surface (without breaking them into smaller bubbles), where they are removed under a strong vacuum.”
Other developments have also had an impact on the mixing and blending equipment used for solids and semi-solid formulations. For Borgers, the ability to conduct online analysis of blend homogeneity has helped manufacturers better understand blending behavior and made it possible to detect properly the required blending time. Ekato has found that determination of the end point of mixing using inline techniques such as viscosity, pH, and particle size analysis, but on a bypass loop, enables increased automation.
Meanwhile, for Almhem and Reiner Lemperle, director of sales with Lödige Process Technology, the shift to continuous processing has been a notable development. “This approach allows the use of smaller equipment, which translates to less expensive production space, reduced product losses, and fewer material surfaces to clean, and eliminates scale-up issues, because the only factor is running time.” Lödige has developed a solution for continuous mixing, granulation, and drying that can be used for continuous mixing with a throughput of up to 200 kg/h, and for granulation and drying from 5 to 30 kg/h.
More work to do
Despite these advances, there are still numerous ways in which blending and mixing of solid and semisolid formulations can be improved. Engenhart believes that even higher batch size flexibility is needed to increase efficiency and productivity in the mixing and blending of both solid and semisolid dosage forms. Currently, some Ekato mixing systems can efficiently mix batch sizes that are in the range of 10–25% of the maximum batch size that can be processed in a specific size of equipment. Engenhart is confident that these limitations can be pushed further.
For Sangüesa, the main issue is segregation. “Blenders can do a great job to ensure that all the powders, even those with varying densities, particle shapes, flow characteristics, etc., are thoroughly mixed inside the blender. But the moment those powders are either discharged or transferred out, segregation can occur,” he explains. “Depending on the surface finish, for example, some powders will flow better than others, thus negating the very benefits the blender had achieved. As powders flow out, there is always the concern that some of the ingredients will no longer be represented in the same percentage throughout the batch.”
To address issues such as segregation, Borgers would like to see more simulations of blending processes. He believes the ability to effectively simulate different mixing and blending processes will lead to the development of more effective approaches to scale-up of processes and help address equipment transfer questions. “Fortunately, advances are being made in simulation software, and I am thus hopeful that useful software tools will be available in the near future.”
At the same time, there are a growing number of specialty products and “individual drugs” that are produced in much smaller quantities. “Scaling down production throughput to these small volumes is a challenge. The mixing and blending equipment needed for these niche products looks a lot different than the existing units in use today,” Lemperle notes. To help its customers, Lödige has introduced a mixer designed for batch sizes down to 0.5 kg/batch. Engenhart adds that many of these specialty semisolid formulations, including softgels and oral strip products, involve exceptionally high viscosity materials that require special mixing conditions.
Furthermore, there is a trend toward the use of non-animal-based shell materials for softgel capsules, and these materials are more challenging to work with, according to Engenhart. In addition to having higher melting temperatures that require an even tighter allowable process parameters during mixing and transfer, these newer shell materials are often of even higher viscosity than conventional materials, and thus higher shear mixing is necessary to adequately disperse some of the solids raw materials.
Re-evaluation and partnering
There are also general challenges related to the selection of appropriate mixing and blending equipment. Because many mixing technologies today overlap in use and function such that certain formulations can be produced in more than one distinct type of mixer, making sure that the mechanical and physical aspects of the equipment enable safe, repeatable, and sanitary mixing is very important, according to Banaszek. “More often than not, there is no all-purpose, off-the-shelf solution,” she says.
In addition, manufacturers that are using inherited equipment or procedures because they have worked in the past may actually be at a disadvantage and limiting their production capabilities. “With the greater understanding of mixing and blending processes that we have today, combined with the advances in mixing technology and new equipment, it is generally beneficial in such cases to reevaluate the existing mixing strategy to determine if it is efficient,” Banaszek observes. She concludes that, to identify the best mixer or blender for a particular formulation, it helps to partner with a reliable mixer supplier that offers long-term experience, rental, and testing resources.