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Paul Sheskey of Dow Chemical provides an update on foam granulation technology.
Granulation is one of most important unit operations involved in solid dosage form manufacturing and several granulation technologies have been developed. Traditionally, an aqueous solution of a binder is sprayed on the powder during mixing in a granulator. In 2003, The Dow Chemical Company (Midland, MI) introduced foam technology for delivering aqueous binder systems in high-shear and fluid-bed wet granulation applications (1) (see Figure 1). A foam generator can be set up with a binder solution tank and high-sheer granulator to introduce the binder as a foam rather than spraying or pouring in binder onto a moving powder bed. Last year, Pharmaceutical Technology published an article discussing the scale-up of foam granulation technology in a high-shear process (2) (see Figures 2, 3). As a follow-up to that discussion, Paul Sheskey, research and development leader at Dow, provides an update on foam granulation, including process challenges the company has encountered from industry and future applications of the technology.
Q. What was the motivation to develop a new granulation technology versus conventional granulation techniques?
A: We became aware of the granulation needs of the industry through the sale of our functional polymers, whether it was for granulating a matrix controlled-release system using METHOCEL cellulose ethers polymers or immediate-release granulation using our low molecular-weight polymer family. A significant issue experienced throughout the industry, as represented by a large number of research papers published throughout the years, is the uniform distribution of the liquid/binder combination evenly throughout a moving powder bed. It may appear to be uniform when spraying, but it doesn't always happen. We've referenced papers by Litster and Hapgood that showed this is not a very easy thing to accomplish. In their studies they proved it at the very basic level.
Manufacturers of pharmaceutical granulations would call us saying that they were having trouble either during their formulation development work or in a production setting. We determined that a significant proportion of their issues directly related to the even distribution of the granulating liquid. They have hydrophilic polymers in their formulations that tend to preferentially grab the water in the granulating liquid and sometimes this would interfere with its uniform distribution. So we investigated various atomizing techniques when spraying the binder solutions. We did a lot of work to better understand the issues so that we could provide the pharmaceutical formulators specific, hands-on type of advice. However, even that was not doing as good a job as was needed for the pharmaceutical industry. Then we discovered foam technology for granulation applications in our laboratory. My colleague and co-inventor, Colin Keary has a lot of expertise in the area of foams when he was a scientist in the oil well industry. Working in combination, we serendipitously came up with this for pharmaceutical granulating. That satisfied the need of evenly distributing the liquid binder phase much better than a spray could do. That is a recognized need of the industry and that is what foam helps with tremendously.
Q. What are some of the unique challenges and applications of using foam granulation?
A: The pharmaceutical industry is very conservative when it comes to new applications and new technologies. Our job has been to educate people on the use of this technology globally. This has become better, but it always takes time. We've seen that once it gets into a company, they'll also use it for the everyday-type granulations.
We have found that most people are using it for new applications and some are looking at it as replacement for current methods, especially because of potential cost savings. For example, the technology does not use nozzle systems. The technology also has been helpful in some cases where there may be difficulty in scaling up a process because of over-wetting and the number of nozzle systems that may need to be used. Foam technology has been proven to scale very easily for both immediate release and matrix controlled-release products. The technology also uses less water per granulation, which means less drying time and less impact on the environment.
This technology appears to help solve the issues that people have been having with wet granulation of highly water-soluble and even very poorly water soluble drugs. These issues include areas of concentrated over wetting and over granulated products. The technology seems to provide a better and a wider endpoint in which to granulate to even with some very difficult actives that we work with, including natural ingredients in the nutritional supplement industry.
People have approached us who may initially have had an issue with a particular active ingredient that is water sensitive but they still want to go with an aqueous system because of EPA (Environmental Protection Agency) concerns. Or they have issues with distributing a very low concentration drug level—milligram or microgram per tablet—in a powder bed, which has been an issue for years in the industry. People have used many techniques to solve the low-dose distribution issue. Foam does a good job of solving this problem because it is a good carrier of components, not just the liquid itself and the polymer, but it also can carry active ingredients at very low concentrations.
Q. There is interest in converting some unit operations from batch processing to continuous processing. Has continuous application of foam granulation been explored?
A: One of the application areas we are looking into is continuous granulation using foam. Some manufacturers of continuous granulation equipment have approached us regarding possibly working with them to use foam to deliver the liquid binder system to a continuous manufacturing system. If you have a continuous granulation, definitely one of your key questions is whether you are getting uniform distribution of a binder under short residence times during the process. This is one area where foam technology might be able to provide some advantage.
Q. Are there any remaining regulatory issues or concerns with foam granulation technology?
A: We have met with and have presented this technology to the US Food and Drug Administration's Center for Drug Evaluation and Research. They were very excited and approved the concept because they could see how this technology could resolve issues in getting better reproducibility of granulations. They are very supportive of the technology, and they have told us that if people come in using this technology, it would not slow down any approvals.
Q. What are the future plans for this technology? Will its applications be extended?
A: One of the things that we are continuing to develop and that we have patents for is to fine-tune the technology for coating of tablets using foam rather than conventional spraying. We are working with equipment vendors on that. On the granulation side, we are continuing work on using foam to distribute low-dose drugs uniformly within a powder bed or to improve content uniformity of low-dose active pharmaceutical ingredients. We are also working with fluid-bed applications.
1. P. Sheskey et al., "Foam Technology: The Development of a Novel Technique for the Delivery of Aqueous Binder Systems in High-Shear and Fluid-Bed Wet-Granulation Applications," poster presented at AAPS Annual Meeting and Exposition, Salt Lake City, UT, Oct. 26-30, 2003.
2. P. Sheskey et al., "Scale-Up Trials of Foam Granulation Technology—High Shear," Pharm. Technol. 31 (4), 94–108 (2007).