Melt Granulation Technique : A Review

P. D. Chaudhari

Melt granulation is one of the most widely applied processing technique in
the array of pharmaceutical manufacturing operations. Melt granulation process
is currently applied in the pharmaceutical for the manufacture of variety of
dosage forms and formulation such as immediate release and sustained release
pellets, granules and tablets.

This article intends to address the influence
of meltable material on the processes of  melt granulation and melt tumbling
granulation. Approaches to meet the processing attributes of the meltable materials
for these melt agglomeration processes via spray congealing are discussed

Introduction:

Industrial application of the extrusion process dates back to 1930’s.
Hot-melt extrusion is one of the most widely applied processing technologies
in the plastic, rubber and food industry. Currently, more than half of all plastic
products, including plastic bags, sheets and pipes are manufactured by this
process. Recently melt extrusion has found its place in the array of the pharmaceutical
manufacturing operations. Several research groups have evaluated this technology
to achieve enhancement in dissolution rates for poorly water soluble drugs,
to modify drug release and transdermal passage of the drug. Extrusion is the
process of converting a raw material into a product of uniform shape and density
by forcing it through a die under pressure^1,2.

Advantages:

· Neither solvent nor water used in this process.

· Fewer processing steps needed thus time consuming drying steps eliminated.

· There are no requirements on the compressibility of active ingredients and the entire procedure simple, continuous and efficient.

· Uniform dispersion of fine particle occurs.

· Good stability at varying pH and moisture levels.

· Safe application in humans due to their non-swellable and water insoluble nature^1,3.

Disadvantages:

 · Requires high energy input.

· The melt technique is that the process cannot be applied to heat-sensitive materials owing to the elevated temperatures involved.

· lower-melting-point binder risks situations where melting or softening of the binder occurs during handling and storage of the agglomerates

· Higher-melting-point binders require high melting temperatures and can contribute
to instability problems especially for heat-labile materials.

Applications in the pharmaceutical industry:

In pharmaceutical industry the melt extrusion has been used for various
purposes, such as

1.     Improving the dissolution rate and bioavailability
of the drug by forming a solid  dispersion or solid solution.

2.    Controlling or modifying the release of the drug.

3.    Masking the bitter taste of an active drug^1,3,4.

Materials Used In Lipid Matrix Systems:

Lipids are considered as an alternative to polymer in the design of
sustained drug delivery systems due to their advantages such as the low melt
viscosity (thus avoiding the need of organic solvents for solubilization) absence
of toxic impurities such as residual monomer catalysis and initiators, potential
biocompatibility and biodegradability. The various meltable binders used for
the sustained drug delivery systems are mentioned in the table no. 1 and 2.

 Table no. 1

Hydrophilic Meltable Binders in the Melt Granulation Technique⁵. 

Table no.2

Hydrophobic Meltable Binders in the Melt Granulation Technique⁵. 

Melt Extrusion Technology:

Melt extrusion technology has proven to be a suitable method for the
production of controlled release reservoir systems consisting of polyethylene
vinyl acetate (EVA) co-polymers. Based on this technology, two controlled release
systems Implanon® and Nuvaring® have been developed. Mank et al., reported in
1989 and 1990 the extrusion of a number of thermoplastic polymers to produce
sustain-release pellets. A melt extrusion process for manufacturing matrix drug
delivery system was reported by Sprockel and co-workers. In 1994 Follonier and
co-workers investigated hot-melt extrusion technology to produce sustained-release
pellets. Diltiazem hydrochloride, a relatively stable, freely soluble drug was
incorporated into polymer-based pellets for sustained-release capsules. Four
polymers were considered for extrusion trials, namely ethylcellulose, cellulose
acetate butyrate (CAB), poly (ethylene-co-vinyl acetate) (EVAC) and polymethacrylate
derivative (Eudragit® RSPM)⁶. The plasticizers included triacetin
and diethyl phthalate. The porosity of the formulations was assessed using mercury
porosimetry. The pellets produced, exhibited a smooth surface and low porosity.
The in-vitro release of the drug was biphasic, with the CAB and EVAC pellets
giving the lowest release rate.

In a later study, Follonier et al. examined different parameters influencing the release of diltiazem hydrochloride from hot melt extruded pellets. These parameters included polymer type, drug/polymer ratio, and pellet size. The authors incorporated various polymer excipients such as croscarmellose sodium (Ac-Di-Sol) and sodium starch glycolate (Explotab) into the formulations to vary the drug-release rate¹. These pellets could be applicable for incorporation into hard gelatin capsules. With optimization techniques and formulation, it is apparent that hot-melt extrusion of these and other sustained-release pellets is a viable drug delivery technology.

Another application of hot-melt extrusion was described by Miyagawa, Sato, and coworkers in 1996 and 1997^7,8. They studied the controlled release and mechanism of release of diclofenac. These researchers utilized a twin-screw compounding extruder to prepare wax matrix granules composed of carnauba wax, the model drug, and other rate controlling agents. Their first investigation showed that a wax matrix with high mechanical strength could be obtained even at temperatures below the melting point of the wax. Dissolution release profiles of diclofenac from wax matrix granules were strongly influenced by the formulation of the granules. The rate controlling additives that were varied in the formulations included hydroxypropyl cellulose, methacrylic acid copolymer (Eudragit L-100), and sodium chloride. The authors emphasized the advantages of using twin-screw extruder for wax matrix tablets, such as low temperatures, high kneading and dispersing ability and low residence time of the material in extruder. The investigators concluded in a second study that selection of rate-controlling agents based on physicochemical properties (solubility and Swelling characteristics) had significant impact on the properties of wax matrix granules prepared by this extrusion process. Similar study was conducted by Zhang and McGinity in 2000. The objective of this study was to investigate the properties of poly vinyl acetate (PVA) as a retardant polymer and to study the drug release mechanism of theophylline from matrix tablets prepared by hot-melt extrusion. The release rate of the drug was shown to be dependent on the granule size, drug particle size, and drug loading in the tablets. As the size of hot-melt extruded theophyllline/PVAc granules was increased, there was a significant decrease in the release rate of the drug. Higher drug loading in the hot-melt granules also showed higher release rates of drug⁹.

Melt Agglomeration:

Melt agglomeration is a process by which the solid fine particles are
bound together into agglomerates, by agitation, kneading, and layering, in the
presence of a molten binding liquid. Dry agglomerates are obtained as the molten
binding liquid solidifies by cooling. Typical examples of melt agglomeration
processes are melt pelletization and melt granulation. During the agglomeration
process, a gradual change in the size and shape of the agglomerates would take
place. It is usually not possible to clearly distinguish between granulation
and pelletization. Thus granulation is considered a pelletization process when
highly spherical agglomerates of narrow size distribution are produced. Conversely,
an unsuccessful pelletization process may be classified as granulation¹⁰.

The equipment for melt agglomeration include rotating drums or pans, fluid-bed granulators, low-shear mixers such as Z-blade and planetary mixers, and high-shear mixers. Presently, the more popular agglomeration equipment for industrial-scale production are high-shear mixers and fluid-bed granulators. In both methods, a gradual buildup of agglomerates occurs during the process. The marked difference between the methods is the absence of shearing forces in the fluid-bed process, whereas very high shearing forces are generated in high-shear mixing.

During a melt agglomeration process, the meltable binder may be added as molten liquid, or as dry powder or flakes. In the latter, the binder may be heated by hot air or by a heating jacket to above the melting point of the binder. Alternatively, the melt agglomeration process exploits an extremely high shear input, of a high-shear mixer, where the heat of friction alone raises the temperature of the binder and effects melting. Typically, the melting points of meltable binders range from 50 to 80°C. A lower-melting-point binder risks situations where melting or softening of the binder occurs during handling and storage of the agglomerates.

In assessing the influence of meltable materials on the formative and growth processes of melt agglomerates, it is imperative to have a thorough understanding of the melt agglomeration process. The mechanism of melt agglomeration is similar to that of wet agglomeration³.

Modes of melt agglomeration:

Fig 1: Modes of melt agglomeration: (a) Distribution and (b) Immersion

These are based on the elementary mechanisms have been proposed—distribution
and immersion. In agglomeration by the distribution mode, a distribution of
molten binding liquid on the surfaces of primary particles will occur, and agglomerates
are formed via coalescence between the wetted nuclei (Fig. 1). In agglomeration
by the immersion mode, nuclei are formed by immersion of the primary particles
onto the surface of a droplet of molten binding liquid (Fig. 1). The distribution
of molten binding liquid to surfaces of nuclei has to be effected by densification
prior to coalescence between the nuclei. Depending on the relative size between
the solid particles and the molten binding liquid droplets, the distribution
will be a dominant mode when the molten binding liquid droplets are smaller
than the solid particles or of a similar size. On the other hand, the immersion
mode will dominate when the molten binding liquid droplets are larger than the
solid particles. The distribution mode is promoted by a low molten binding liquid
viscosity. In the case of immersion, it is more favorable for molten binding
liquid of high viscosity, which could resist breakup by dispersive forces.

Techniques for Melt Granulation:

Spray Congealing:

Spray congealing is a melt technique of high versatility. In addition
to manufacture multiparticulate delivery system¹¹, it can be applied
to process the raw meltable materials into particles of defined size and viscosity
values for the melt agglomeration process. Processing of meltable materials
by spray congealing involves spraying a hot melt of wax, fatty acid, or glyceride
into an air chamber below the melting point of the meltable materials or at
cryogenic temperature. Spray-congealed particles (10–3000 µm in diameter) are
obtained upon cooling. The congealed particles are strong and nonporous as there
is an absence of solvent evaporation. Ideally, the meltable materials should
have defined melting points or narrow melting ranges. Viscosity modifier, either
meltable or non-meltable at the processing temperature, may be incorporated
into the meltable matrix to change the consistency of the molten droplets.

Tumbling Melt Granulation:

A newer melt agglomeration technique, i.e., tumbling melt granulation,
for preparing spherical beads has been reported¹². A powdered mixture
of meltable and non-meltable materials is fed onto the seeds in a fluid-bed
granulator (Fig. 2). The mixture adheres onto the seeds with the binding forces
of a melting solid to form the spherical beads. In preparing the spherical beads,
both viscosity and particle size of the meltable materials should be kept at
an optimum value. The particle size of a meltable material should be 1/6 or
lower than the diameter of the seeds. High-viscosity meltable materials should
not be employed to avoid agglomeration of seeds and producing beads of low sphericity.

Both particle size and viscosity of the meltable materials play a significant role in the melt agglomeration process. The control of the melt agglomeration process is best initiated by using meltable materials of controlled properties. For the melt pelletization and melt granulation processes, it is desirable that meltable materials have a high viscosity to improve the mechanical strength of the agglomerates, but a reduced particle size to prevent uncontrollable agglomerate growth. In tumbling melt granulation, small meltable particles with sufficient viscous binding forces are obligatory for the production of spherical beads¹³.

Fig 2: Process of Tumbling Melt Granulation

Conclusions and outlook:

Today melt extrusion technology represents an efficient pathway for
manufacture of drug delivery systems. Resulting products are mainly found among
semi-solid and solid preparations. The potential of the technology is reflected
in the wide scope of different dosage forms including oral dosage forms, implants,
bioadhesive ophthalmic inserts, topical films, and effervescent tablets. In
addition, the physical state of the drug in an extrudate can be modified with
help of process engineering and the use of various polymers. The drug can be
present in crystalline form for sustain release applications or dissolved in
a polymer to improve dissolution of poorly water-soluble drugs. The possible
use of a broad selection of polymers starting from high molecular weight polymers
to low molecular weight polymers and various plasticizers has opened a wide
field of numerous combinations for formulation research.

Drawbacks of the technology are often related to high energy input mainly related
to shear forces and temperature. This is where process engineering becomes significant.
The design of screw assemblies and extruder dies are two major areas, which
have significant impact on product quality and degradation of drug and polymers.
Drugs which are sensitive to elevated temperatures can be processed successfully
when the residence time is short compared to conventional processes like sterilization.
Work in this field is increasing and the literature published reveals many novel
and interesting aspects of this technology such as in-situ salt formation, fast
dispersing systems with foam like structures, complex formation in the melt,
and naoparticles released from molecular dispersions manufactured by melt extrusion.

References:

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2.  Schafer T, Holm P, Kristensen HG. Melt granulation in a laboratory
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3.  Heng WS, Wong TW., Melt processes for oral solid dosage forms, Pharm
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4.  Evrard B, Delattre L. In vitro evaluation of lipid matrices for the
development of a sustained–release sulfamethazine bolus for lambs, Drug Devl
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5.   Eliasen H, Kristensen HG, Schafer T. Growth mechanism in melt
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6.  Brabander C. D., Vervaet C., Remon J. P., Development and evaluation
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7.   Miyagawa Y, Okabe T, Yamaguchi Y. Controlled release of diclofenac
sodium from wax matrix granules, J Pharm Sci. 1996; 138: 215-224.

8.  Sato H, Miyagawa Y, Okabe T. Dissolution mechanism of diclofenac sodium  from wax matrix granules, J Pharm Sci. 1997; 86: 929-934.

9.  Breitenbach J., Melt extrusion: from process to drug delivery technology,
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11. Passerini N, Perissutti B, Monoghini M, Voinovich D, Albertini B, Cavallari
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12. Maejima T, Osawa T, Nakjima K, Kobayashi M. Application of tumbling melt
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13. Kidokoro M, Sasaki K, Haramiishi Y, Matahira N. Effect of crystallization
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493.

{mospagebreak title=About Authors}

About Authors

P. D. Chaudhari*, Mrs. S. P. Chaudhari, G. S. Yeola, N. S. Barhate.

 *Author for correspondence

P. D. Chaudhari

Asst. Prof. of Pharmaceutics,

Dept. of Pharmaceutics,

Pad. Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research,

Pimpri, Pune-18,

Maharasthra, India.

Email: pdchaudhari_21@yahoo.com

Telephone No: +91-020-27420026, 27420261.

Fax          - +91-020-27420261.

Mrs. S. P. Chaudhari

Lect. of Pharmaceutics,Pad. Dr. D. Y. Patil Institute of Pharmacy,Pimpri, Pune-18.

G. S. Yeola,M.Pharm.

Dept. of Pharmaceutics, Pad. Dr. D. Y. Patil Institute of Pharmaceutical Sciences
and Research

N. S. Barhate, M.Pharm.

Dept. of Pharmaceutics,Pad. Dr. D. Y. Patil Institute of Pharmaceutical Sciences
and Research