Elsevier

Chemical Engineering Science

Volume 66, Issue 21, 1 November 2011, Pages 5204-5211
Chemical Engineering Science

Foam granulation: Liquid penetration or mechanical dispersion?

https://doi.org/10.1016/j.ces.2011.07.012Get rights and content

Abstract

There have been significant advances in the understanding of wet granulation processes. Foam granulation is the latest development and an emerging area of interest for pharmaceutical manufacturing.

Single foam penetration experiments were carried out on static powder beds, followed by short-nucleation experiments (where nuclei are formed by a nucleation-only mechanism) and full foam granulation experiments (where nucleation, growth and breakage are occurring simultaneously). All experiments were performed with lactose monohydrate powder using a 5 L high shear mixer–granulator. The foam penetration/dispersion behaviour was examined and the granule size distributions were investigated as a function of foam quality (83–97% FQ), impeller speed (105–515 rpm) and wet massing period (0–4 min).

Nucleation in foam granulation is postulated to undergo either “foam drainage” or “mechanical dispersion” controlled mechanisms. For “foam drainage” mechanism, the foam penetrates the powder bed to form coarse and broad granule size distributions. For “mechanical dispersion” mechanism, the wetting and nucleation conditions are governed by the powder mixing conditions and similar granule size distributions are produced. Regardless of the mechanism, the initial wetting and nucleation behaviour controls the initial nuclei size distribution, and this initial distribution is retained in the final granule size distribution. This work demonstrated the critical importance of the nucleation and binder distribution in determining the granule size distributions for foam granulation process.

Highlights

► Foam granulation involves “foam drainage” and “mechanical dispersion” mechanisms. ► The mechanisms control the initial nuclei size distribution. ► The effects are retained in the final granule size distributions. ► “Foam drainage” mechanism produced coarse and broad granule size distributions. ► “Mechanical dispersion” mechanism produced similar granule size distributions.

Introduction

The use of foam has increasingly emerged in many technological processes, with so many advantages to be gained by processing with foam systems that potentially foam technology may gradually replace water systems. In particular, foams attract more attention in the pharmaceutical research as new alternative delivery method (Arzhavitina and Steckel, 2010, Kealy et al., 2008). A new foam delivery method for liquid binder during granulation processes has recently been developed for the manufacture of pharmaceutical tablets (Keary and Sheskey, 2004). Foam is made by mixing the binder solution with air via a foam generator, and the foamed binder is then delivered to the granulator through a pipe while the powder is agitated. Keary and Sheskey (2004) and Sheskey et al. (2007) demonstrated that foam granulation uses less liquid to achieve the same extent of size enlargement, and reduces drying and manufacturing time in the granulation stage due to lower liquid requirements, faster addition rates, and improved process control. They pointed out that common problems with selecting the nozzle could be eliminated, and claimed that since the foam is simply added onto the top of the powder bed, either as part of the granulator charging process, or during operation. As a result, a simplified scale-up can be achieved by reducing the number of variables (Keary and Sheskey, 2004, Sheskey et al., 2007). This method also increases manufacturing flexibility for water-sensitive drugs and low-dose drugs (Keary and Sheskey, 2004, Sheskey et al., 2007, Sheskey et al.,, Sheskey et al.,) and can be used in mixers or fluidised beds (Sheskey et al., 2003).

More recently, Cantor et al. (2009) compared the physical and mechanical properties of granules and tablets made by foam granulation and traditional spray granulation for three high drug load formulation. They found no major difference in the granule surface area or granule pore size when using foam or spray granulation, but there were differences in the mechanical properties of the tablets. When the granules contained a high loading of a brittle drug, the plasticity of the granules was higher when foam granulation was used, possibly due to the improved surface coverage of the liquid binder on the brittle drug particles. Different mechanical properties and deformation characteristics were found for each drug formulation, and this affected whether the foam or spray granulation process performed better. Cantor et al. (2009) concluded that knowledge of the mechanical properties of the drug and formulation is required before selecting the best granulation process (spray or foam) for manufacturing.

The wetting and nucleation process, where the liquid first come into contact with the powder to form the initial “nuclei”, has been well studied for spray granulation. The behaviour of spray droplets landing on both static (Ax et al., 2008, Hapgood et al., 2002, Marston et al., 2010, Nguyen et al., 2009) and dynamic (Chouk et al., 2009) powder beds has been investigated. However, studies on foam–powder interactions are quite rare. In our previous work (Tan et al., 2009), we investigated the time required for a given volume of foam to penetrate into a static powder bed, and compared this to the time required for a droplet of the same fluid to penetrate into the same powder bed. Foam penetration is generally slower to penetrate into the powder bed compared to a drop, particularly if the foam drainage rate is slow. Slow draining foams are made from high viscosity fluids and/or foams with high “foam quality”, which is defined as the ratio of the volume of air compared to the total volume of the foam. The nuclei formed from foam were larger than the nuclei formed from drops, even after accounting for the larger mass of fluid initially added in the foam (Tan et al., 2009).

These observations of foam–powder interactions and the importance of the foam quality were confirmed by studies of small quantities of foam added onto the top of a moving powder bed inside a lab scale mixer granulator (Tan and Hapgood, 2011). After analysis of the factors that affect foam wetting and nuclei formation, two wetting and nucleation mechanisms were defined, depending on the interacting effect of foam quality and impeller speed. Foam nucleation is postulated to undergo either a “foam drainage” controlled or a “mechanical dispersion” controlled mechanism (Tan and Hapgood, 2011). “Foam drainage” controlled nucleation occurs at low foam quality and leads to formation of coarse nuclei due to the relatively rapid drainage of foam. At high foam quality, the foam is very stable and it wets into the powder slowly. The wetting will require high intensity mixing to efficiently disperse the foam, and the nucleation will be “mechanical dispersion” controlled. Increasing the impeller speed increases the shear forces developed within the granulator, leading to a shear controlled wetting and nucleation. These investigations were performed using a small amount of foamed binder solution, where nucleation occurred with limited granule growth and breakage.

This paper continues to evaluate the two proposed foam wetting and nucleation mechanisms by first performing short-nucleation experiments in a moving powder bed in a high shear mixer–granulator at two impeller speeds to study the initial foam dispersion and nucleation. A predetermined small amount of foamed binder solution was added, which was sufficient to induce nucleation but no growth or breakage by keeping the saturation low (Iveson and Litster, 1998). Foam penetration tests were also conducted for the specific formulation used here to link the foam stability and penetration time with the foam nucleation mechanisms. The experiments were then extended to deliver a larger quantity of foamed binder solution to granulate the entire batch and investigate the role of granule growth and breakage effects on foam dispersion, granule formation and granule growth.

Section snippets

Materials

Lactose monohydrate 100 mesh (Wyndale, New Zealand) was granulated with a liquid binder of 4% hydroxylpropyl methyl cellulose, denoted as HPMC (Methocel E5PLV, Dow Wolff Cellulosics). A small quantity of food dye (Queens Fine Food Ltd.) was dissolved in the binder solution for visual observations during the experiments. The liquid binder was made into aqueous foam at a controlled foam quality (FQ) by mixing the binder solution with compressed air using a foam generator (Dow Wolff Cellulosics,

Foam penetration experiments

Fig. 1 shows the relationship between the foam quality and the specific foam penetration time (defined as the penetration time per unit mass of foam) for the lactose and 4% HPMC formulation. The error bars show the standard error of the mean for 5 replicates.

The foam penetration time is highly influenced by the foam stability, which is determined by foam quality. Increasing the foam quality produces a more stable foam, which takes longer to drain and penetrate into the powder bed due to the

Foam wetting and nucleation mechanisms

Previous work on short-nucleation experiments, where the powders were nucleated using low amount of foamed binder and a very short granulation time demonstrated the importance of the two foam wetting and nucleation mechanisms—“foam drainage” controlled and “mechanical dispersion” controlled mechanisms (Tan and Hapgood, 2011). The two foam wetting and nucleation mechanisms describe the binder dispersion and nucleation by foam on based on the drainage behaviour of foam and the powder flowing

Conclusions

In this study, foam penetration time was found to be proportional to foam quality. At powder roping flow conditions, the foam has minimal time to drain and the majority of wetting and nucleation occurs beneath the powder surface by mechanical mixing. At powder bumping flow conditions, foam drains to form coarse nuclei. Decreasing foam quality caused an increase in the average granule size and the spread of the granule size distribution, but increasing the impeller speed offsets the foam quality

Acknowledgements

This project was financially supported by Dow Wolff Cellulosics, Midland, USA, and by an Australian Postgraduate Award and a Monash Research Graduate School Publications Award. Dow Wolff Cellulosics reviewed the manuscript before submission, but did not have input into the experimental design, data analysis or interpretation.

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