Particle design using fluidized hot melt granulation

June 1, 2007
Michelle A. Vann, David S. Jones, Gavin M. Walker, Dr Steven Bell, Gavin P. Andrews
Pharmaceutical Technology Europe
Volume 19, Issue 6

Fluidized hot melt granulation (FHMG) is an emerging technique combining the advantages of both dry and wet granulation methods, and represents an innovative continuous granulation process capable of mixing and agglomerating excipients and active pharmaceutical ingredients (APIs) to produce uniform blends of particles suitable for use in the manufacture of pharmaceutically elegant solid dosage forms.


Fluidized hot melt granulation (FHMG) is an emerging technique combining the advantages of both dry and wet granulation methods, and represents an innovative continuous granulation process capable of mixing and agglomerating excipients and active pharmaceutical ingredients (APIs) to produce uniform blends of particles suitable for use in the manufacture of pharmaceutically elegant solid dosage forms.

This study investigates the influence of process parameters and formulation variables on the FHMG of two model pharmaceutical systems using either polyethylene glycol (PEG) or a copolymer of polyoxyethylene/polyoxypropylene (Lutrol F68, BASF; Ludwigshafen, Germany). Granule growth within the FHMG process reached equilibration after a defined period for both model systems. The Lutrol F68 system reached equilibration after 2.5 min, whereas PEG required at least 5 min. The equilibration time significantly decreased as the molecular weight (Mw) of PEG increased from 6000 to 10000.

Granule growth for these systems proceeded via a coalescence mechanism, which decreased significantly as the molecular weight of the binder increased.

Increasing the binder content within the systems increased the mean particle diameter until a threshold value was reached (20% w/w PEG and 10% w/w Lutrol F68), after which the system defluidized and an overwetted mass was produced. Interestingly, the regularity of the granules was shown to be dependent upon the binder concentration within the fluidized system. Increased binder content resulted in irregular granules, whereas lower binder contents produced highly spherical granules.


Orally administered drug delivery platforms, such as tablets and capsules, are considered the preferred and most patient-convenient dosage forms available today.1 This is primarily because of the ease of administration, convenience of handling and increased stability compared with their liquid counterparts.2 Typically, solid dosage forms administered orally are an intricate blend of excipients (diluents, binders, disintegrants, glidants, lubricants and flavours) and APIs. To successfully manufacture acceptable pharmaceutical products, these materials must be adequately mixed and/or granulated to ensure that the resultant agglomerates possess the required fluidity and compressibility, and avoid demixing during postgranulation processes.3

Currently, the techniques in existence for the agglomeration and mixing of pharmaceutical powders involve either wet or dry methods.4 Although dry techniques lead to associated decreases in process time and the avoidance of wetting and drying processes, the inherent difficulties in compressing crystalline solids, the uneven and erratic flow properties of APIs, and the development costs associated with dry methods, culminates in wet granulation remaining the preferred and most widely accepted method for powder agglomeration. However, it is well accepted that there is an increasing need for alternative processes to dramatically improve particle processing to ensure acceptable and reproducible solid dosage forms.

One such emerging technique is FHMG, a nonambient temperature process conducted at elevated temperatures to change the physical nature of one or more of the components. FHMG is an innovative process involving meltable binders to agglomerate fluidized dry powders.5 FHMG avoids using solvents — negating the problems associated with in-process hydrolysis and solvent removal. FHMG is a simple and rapid technique that does not require powder blends to possess high levels of fluidity and compressibility, and reflects the simplicity of dry techniques in that it may be performed in one step. This is in contrast to conventional wet techniques whereby transfer from the granulator to the drying equipment is usually necessary — commonly involving losses in transfer, contamination of manufacturing equipment, increased processing and operator time, and increased dust levels: issues that are particularly pertinent when manufacturing dosage forms containing potent drugs.

Although FHMG is being highlighted as a next generation method for producing pharmaceutical granules, very little research in this area has been reported in scientific literature. The majority of work that has been described involves processes whereby molten binder is sprayed onto a bed of fluidized particles. While not identical to FHMG, investigations in this respect have identified key parameters affecting granule growth within the fluid bed. Abberger et al. have previously shown that granule growth mechanisms are dependent upon the ratio of binder/powder particle size, whereas Kidokoro et al. have shown that the molecular weight of the binder is significant in controlling the physical properties of compressed tablets.7,8 Furthermore, Walker et al. have previously reported the influence of process parameters on FHMG and the characteristics of resultant tablets pressed from pharmaceutical powders.6

This investigation reports the use of FHMG for the agglomeration of model pharmaceutical powders and discusses the effect of binder type, molecular weight, concentration and granulation time on both granule growth mechanisms and granule characteristics. Moreover, we identify the significant potential of the process and provide a fundamental understanding of the growth mechanisms within the fluidized bed using both a model pharmaceutical excipient (lactose) and standard Ballotini (glass) beads as inert fillers. We also highlight the diversity of the process in relation to the choice of meltable binder using two different examples, PEG and Lutrol F68.


Lactose (alpha-D-lactose monohydrate), polyvinylpyrrolidone (PVP) (Mw 29000) was supplied by Sigma-Aldrich Chemical Company (Gillingham, UK). Standard Ballotini beads (100–250 μm) were supplied by Ulster Anaesthetics (County Down, UK). PEG (Mw 6000, 10000 and 20000) were supplied by Fluka Chemie AG (Buchs, Switzerland) and Lutrol F68 (Mw ~7000, mean average particle size [Dp] 430 μm), a copolymer of polyoxyethylene-polyoxypropylene was supplied by BASF plc (Cheadle, UK). In this study, the PEG flakes were finely ground and sieved between 250 μm and 106 μm mesh to give a mass mean particle size of 178 μm.


Pharmaceutical powders were granulated in a Sherwood Scientific (Mark II) fluidized bed dryer (Cambridge, UK) consisting of a 5 L container with a fine mesh nylon gauze air distributor, stainless steel support gauze and a filter bag at the top of the unit. FHMG was performed at a temperature of 100 °C ±1 °C using a constant air velocity of either 1.0 (PEG/lactose blends) or 0.5 ms-1 (Lutrol/PEG/Ballotini blends) for predetermined time periods (5–20 min).

Given that all FMHG processes were in excess of the melt temperature of the binders, consolidation of the agglomerated particles was achieved by fluidizing the granulate using ambient air for 30 s at the end of each granulation run.6 The granules that were produced were sized using standard sieving techniques to determine the effect binder viscosity, concentration, molecular weight and filler type had on the particle size distribution of the powder bed. The viscosity of the binders (PEG and Lutrol) were determined at 100 °C using an AR2000 rotational rheometer (TA Instruments; Crawley, UK) in continuous shear mode. Granule shape, uniformity and dimensions were determined using a Nikon Eclipse ME600 microscope using ×50 magnification and Lucia G software (both Nikon Instruments; Badhoevedorp, The Netherlands).

Results and discussion

Typically, the characteristics of granulated powder blends (particle size, particle shape, uniformity of powder blend and powder compressibility) are major contributors to the performance of orally administered dosage forms post-manufacture and, therefore, the ability to control such factors is pertinent to their successful manufacture. Despite the vast array of current granulation methods, they all inherently have problems. The process described in this article is a highly novel and exciting combination of both wet and dry techniques.

FHMG is an innovative method of preparing pharmaceutical granules of a suitable size and compression profile for subsequent processing into high-performance solid dosage forms. In FHMG, a molten binder, API and other functional excipients are heated together in a fluidized bed system; when the granules are cooled to the solid state (also within the fluidized bed) it is found that the molten binder acts to form solid bridges resulting in a consolidated granule.

FHMG has significant potential for the preparation of granules for tablet pressing, but it has not been widely applied because the detailed mechanism of granule growth and the relationship between the growth parameters and the properties of the granules that will ultimately determine the performance of the product are poorly understood.

The effect of binder viscosity on granule growth within melt granulation processes has been reported by many authors,8–10 and it has been suggested by Iveson and Lister that variation in the binder viscosity may change the dominant granule growth mechanism within the powder bed.11 Figure 1 illustrates the effect of PEG molecular weight (6000, 10000 and 20000) on the mass mean diameter at various granulation times (5–15 min) using lactose as an inert filler. The extent of granulation was significantly higher for PEG 6000 compared with 10000 and 20000 at granulation times exceeding 5 min (10 and 15 min).

Figure 1

Notably, the mass mean diameter of PEG 6000 increased significantly (P<0.05) as a function of granulation time, whereas granule growth did not significantly change (P>0.05) as a function of granulation time for 10000 and 20000, suggesting that agglomerates within these systems had reached an equilibrium mass after 5 min. PEG 6000 has a viscosity of 500 mPa.s, whereas 10000 and 20000 have significantly higher molten viscosities (3500 and 19000 mPa.s, respectively). The increased molecular weight, and hence, chain length within PEG 10000 and 20000 significantly reduces polymer chain mobility and deformation.12 Given the shear forces operating within the fluidized bed are significantly lower than alternative granulating systems, the extremely low granule deformation within this process and the extent of polymer chain mobility for PEG 10000 and 20000 is insufficient to force the high viscosity binders to the outer layers of agglomerating particles during granule–granule collision within the fluidized bed, and, therefore, granules fail to grow in mass after initial powder layering and coalescence has occurred.13

Pharmaceutical granulation encompasses a large number of processes designed to agglomerate a powder mass together and is a classical example of particle design, whereby the characteristics of the resultant agglomerates are carefully tailored using a unique combination of formulation design and process design.14 One of the most important processes during the granulation of suspended solid particles, is the formation of new primary particles (wetting and nucleation). Therefore, an adequate quantity of binder is required to ensure that this process continues; however, excessive binder may result in a slurry as a result of an overwetted powder mass.15 Thus, the concentration of binder within the powder bed is fundamental to the growth and stability of the granulation process.

The concentration of meltable binder within the fluidized bed is extremely important to the successful manufacture of particles possessing the required characteristics. In this investigation, granule growth was examined as a function of binder concentration (10%, 12% and 14% w/w) and granulation time (5, 10, 15 and 20 min). There was shown to be no significant granule growth occurring after a period of 10 min (mass mean Dp ~0.70). Additionally, granule growth also appeared to be largely independent of binder content after initial nucleation and coalescence had occurred. When granulation was attempted with a PEG content of 20% (w/w), an overwetted slurry was produced and granulation moved to the overwet massing regime (i.e., the system was overwetted and defluidized). The oversaturation at 20% w/w PEG content induced a liquid-like agglomerate that was unable to maintain its identity under the shearing forces acting within the FHMG process.15

The second system investigated in this study involved the use of glass beads as a model pharmaceutical filler and Lutrol F68 as a model meltable binder. The effect of varying binder concentration on the particle size distribution of the powder bed is shown in Figure 2. Lutrol F68 has a relatively low viscosity and, therefore, when in the molten state has a high degree of mobility resulting in diffusion to the outer surface of the growing agglomerates.16

Figure 2

Consequently, the Ballotini/Lutrol F68 system overwetted at a much lower concentration (8–10% w/w) than any previous PEG systems that have been investigated.6 Analysis of the granule shape (×50 magnification) illustrated a distinct difference in granule shape as a function of binder concentration (Figure 3). As the concentration of binder increased within the powder bed, the resultant agglomerate was more irregular in shape, whereas those agglomerates formed with lower concentrations of binder were more uniform. The shape of the granules supports the visual observation of overwetting occurring during the 10% and 12% w/w binder content. At such high concentrations of binder, the binder diffuses to the outer surface of the agglomerates. During granulation, two colliding agglomerates fuse together, a coalescence granule growth mechanism dominates and the resultant particle is highly irregular. Conversely, at low binder concentrations (3%, 5% and 8% w/w) the mechanism of granule growth is that of layering, where the binder is able to distribute freely through out the bed to form spherical granules.17

Figure 3

The effect of granulation time on the mean particle diameter is shown in Figure 4. The mean particle diameter does not change significantly after 2.5 min suggesting that granule growth has reached equilibrium after this time period. As previously discussed, Lutrol F68 is a low molecular weight binder with a high degree of mobility. After 2.5 min the binder has diffused throughout the entire fluidized bed of Ballotini and formed liquid–liquid bridges. These liquid-bridged ballotini form a flocculated system, which continues to grow, thus forming defined agglomerates.

The viscosity of Lutrol F68 is such that it supports the rapid diffusion of the binder, and consequently the process is effectively complete within a short time period (2.5 min). However, increasing the binder concentration from 3% to 5% w/w significantly increased the mean particle diameter. Granule growth will only continue to occur when binder is available at the granule surface to form pendular bonds between colliding granules.15 Therefore, the system containing 5% w/w Lutrol F68 has a higher mass of binder available and hence, more pendular bonds maybe formed, increasing the probability of granular growth during collisions, explaining the observed difference in mean particle diameter between powders blends containing 3% and 5% w/w Lutrol F68.

Figure 4


Continuous granulation within the pharmaceutical industry is very much in its infancy, with it being more typical for pharmaceutical solid dosage forms to be batch-processed. However, more recently, many factors have led to an increased interest in continuous processes such as fluidized bed agglomeration, spray-drying, extrusion, instant agglomeration and roller compaction.1 The technique described in this article (FHMG) is an innovative example of continuous granulation, combining the advantages of both conventional wet and dry processes.

While FHMG has significant potential, the process has been bottlenecked by the lack of understanding in relation to granule growth within the fluidized system when employing a meltable binder and the relationship between process parameters and granule properties. The research described in this paper addresses this deficit through the use of two model pharmaceutical systems. The first consisted of PEG as a meltable binder and lactose as a model inert diluent. The experimental data obtained for this system suggested that binder content, molecular weight and granulation time were significant factors in controlling the granule growth during processing. After initial nucleation and coalescence, binder content was shown to have no effect on granule growth until 20% w/w, at which point an overwetted slurry was produced and the powder bed defluidized. Binder viscosity was shown to significantly influence granule growth, and it may be concluded that low viscosity, highly mobile molten polymers will produce a system that grows via coalescence and layering, whereas higher viscosity binders will result in a system that fails to grow after powder layering has occurred because of the inability of the binder to migrate to the outer surface of the colliding granules.

Key points

In the second system containing glass Ballotini and Lutrol F68, granule growth was significantly influenced by binder concentration and granulation time. Within this system, the process produced an overwetted powder mass at binder concentrations greater than 8% w/w. This may be a result of the nondeformable, nonpermeable nature of the Ballotini compared with the lactose that results in a much lower tolerability of binder within the powder bed (8% versus 20% w/w). Moreover, the granule shape was shown to be more irregular at higher binder concentrations, evident of granule fusion and coalescence; at lower binder concentrations (3% and 5% w/w), granules were highly regular, typical of a layering process in which the binder can distribute freely throughout the fluidized system. For both systems, granulation time was shown to be extremely important with both exhibiting a threshold value, after which no further granule growth occurred.

While this study describes the use of two model pharmaceutical systems, both have shown that the properties and growth of granules within FHMG may be carefully controlled through the manipulation of formulation variables (binder type, concentration and molecular weight) and process variables (granulation time).

Dr Gavin Andrews

is a lecturer in pharmaceutics and academic member of the MPRI. More recently, he has worked as a visiting scientist within Professor McGinity's research group at the University of Texas at Austin.

Professor David Jones

holds the Chair of Biomaterial Science, School of Pharmacy, Queen's University Belfast (UK). Professor Jones is a director of the Drug Delivery and Biomaterials Group and team leader of the Biomaterials Group within the Medical Polymers research Institute (MPRI). His particular interests are in the design, synthesis and physicochemical characterization of biomaterials as medical devices and drug delivery systems.

Dr Gavin Walker

is a senior lecturer in the School of Chemistry & Chemical Engineering at Queen's University Belfast (UK). Dr Walker's particular interests involve mathematical aspects of materials technology and granulation processing.

Dr Steven Bell

is a senior lecturer in the School of Chemistry & Chemical Engineering at Queen's University Belfast (UK). His research group are working on the development and use of laser-based spectroscopic methods to study problems of fundamental interest, such the nature of structural changes that occur in ultra fast chemical reactions, and on the nondestructive characterization of complex real-life chemical systems, ranging from foodstuffs to forensic evidence.

Michelle A. Vann

is an MEng student at the School of Chemistry & Chemical Engineering, Queen's University Belfast (UK).


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