Iranian Journal of Pharmaceutical Research (2004) 3: 3-16

Received: December 2003

Accepted: February 2004

Review Article

Hot-Melt Extrusion Technique: A Review

Rina Chokshi, Hossein Zia

College of Pharmacy, University of Rhode Island, Rhode Island, USA.

Abstract

Hot-melt extrusion is one of the most widely applied processing technologies in the plastic,
rubber and food industry. Today this technology has found its place in the array of
pharmaceutical manufacturing operations. Melt extrusion process are currently applied in the
pharmaceutical field for the manufacture of a variety of dosage forms and formulations such as
granules, pellets, tablets, suppositories, implants, stents, transdermal systems and ophthalmic
inserts. This review article in detail describes the melt extrusion equipment and process.
Industrial application of this process along with specific areas on pharmaceutical industry is
illustrated. This article concludes with the overview of published examples of the melt extrusion
process.

Keywords: Hot-melt extrusion; Manufacturing operations; Extrusion geometry.

Introduction high throughput rates. An extruder consists of

two distinct parts: the conveying system which
Industrial application of the extrusion transports the material and imparts a degree of
process dates back to 1930’s (1). Hot-melt distributive and dispersive mixing, and the die
extrusion is one of the most widely applied system which forms the material into the
processing technologies in the plastic, rubber required shape. Extrusion may be broadly
and food industry. Currently, more than half of classified into a molten system under
all plastic products, including plastic bags, temperature control or a semisolid viscous
sheets and pipes are manufactured by this system. In molten extrusion, heat is applied to
process (2). the material in order to control its viscosity and
Recently melt extrusion has found its place enable it to flow through the die. Whereas,
in the array of the pharmaceutical semisolid systems are multiphase concentrated
manufacturing operations. Several research dispersions containing a high proportion of
groups have evaluated this technology to solid mixed with liquid phase (3).
achieve enhancement in dissolution rates for
poorly water soluble drugs, to modify drug Process and Equipment
release and transdermal passage of the drug.
Extrusion is the process of converting a raw Hot-melt extrusion equipment consists of an
material into a product of uniform shape and extruder, auxiliary equipment for the extruder,
density by forcing it through a die under down stream processing equipment, and other
controlled conditions (1). Extrusion can be monitoring tools used for performance and
operated as a continuous process, which is product quality evaluation (2). The extruder is
capable of consistent product flow at relatively typically composed of a feeding hopper, barrels,
* Corresponding author: single or twin screws, and the die and screw–
E-mail: [email protected] driving unit (Figure 1). The auxiliary equipment
R Chokshi, H Zia / IJPR 2004, 3: 3-16

Input for Barrel

temperature
Feeding
hopper
Heating barrels

Die system
Screw driving unit

Figure 1. Micro-18 Twin screw co-rotating Leistritz extruder

for the extruder mainly consists of a 2) Conveying of mass (mixing and

heating/cooling device for the barrels, a reduction of particle size).
conveyer belt to cool down the product and a 3) Flow through the die.
solvent delivery pump. The monitoring devices 4) Exit from the die and down-stream
on the equipment include temperature gauges, a processing.
screw-speed controller, an extrusion torque Generally, the extruder consists of one or
monitor and pressure gauges. two rotating screw inside a stationary
The theoretical approach to understanding cylindrical barrel. The barrel is often
the melt extrusion process is therefore, manufactured in sections, which are bolted or
generally presented by dividing the process of clamped together. An end-plate die, connected
flow into four sections (4): to the end of the barrel, determines the shape of
1) Feeding of the extruder. the extruded product. (Figure 1 and Figure 2)

Heating barrels

Co-rotating screws

Figure 2. Heating barrels and co-rotating screws for hot-melt extruder

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 Hot-melt extrution technique

Figure 3. Screw and kneading elements

The heat required to melt or fuse the material is requirements, for example, from standard to
supplied by the heat generated by friction as the high shear extrusion or addition of solvent and
material is sheared between the rotating screws evaporating the solvent form material.
and the wall of the barrel in combination with Modifying screw designs allow the extruder to
electric or liquid heaters mounted on the barrels perform a mixing and reduction of particle size
(5). in addition to extrusion, so that material can be
Most commercial extruders have a modular blended into the extrudate or even dissolved
design, providing a choice of screws or (Figure 3). The various screw and die design
interchangeable sections which alter the available and practical considerations of
configuration of the feed, transition, and thermoplastic extrusion are reviewed by
metering zones. This makes it possible to Whelan and Dunning (6).
modify the process to meet particular The extrusion channel is conventionally

Figure 4. Component parts of single –screw extruder

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Figure 5. Extrusion screw geometry

divided into three sections: feed zone, transition rate through the die cavity (4).
zone, and metering zone (Figure 4). The The twin-screw extruder has two agitator
starting material is fed from a hopper directly in assemblies mounted on parallel shafts These
to the feed section, which has deeper flights or shafts are driven through a splitter/reducer gear
flights of greater pitch (Figure 5). This box and rotate together with the same direction
geometry enables the feed material to fall easily of rotation (co-rotating) or in the opposite
into the screw for conveying along the barrel. direction (counter rotating) and are often fully
The pitch and helix angle determine the intermeshing. In such case, the agitator element
throughput at a constant rotation speed of the wipes both the surface of the corresponding
screws. The material is transported as a solid element on the adjacent shaft, and the internal
plug to the transition zone where it is mixed, surfaces of the mixing chamber and ensures a
compressed, melted and plasticized. narrow and well-defined residence time
Compression is developed by decreasing the distribution. In general, co-rotating shafts have
thread pitch but maintaining a constant flight better mixing capabilities as the surfaces of the
depth or by decreasing flight depth while screws move towards each other. This leads to a
maintaining a constant thread pitch (7). Both sharp change in mass flow between the screw
methods result in increased pressure as the surfaces (4, 5). As the screws rotate, the flight
material moves along the barrel. The melt of one screw element wipes the flank of the
moves by circulation in a helical path by means adjacent screw, causing material to transfer
of transverse flow, drag flow, pressure flow and from one screw to the other. In this manner the
leakage; the latter two mechanisms reverse the material is transported along the extruder barrel.
flow of material along the barrel. The space The twin-screw extruder is characterized by
between screw diameter and width of the barrel the following descriptive features (5):
is normally in the range of 0.1-0.2 mm (5). 1) Short residence time: The residence time
The material reaches the metering zone in in the twin-screw extruder in a typical extrusion
the form of a homogeneous plastic melt suitable processes ranges from 5-10 minutes depending
for extrusion. For an extrudate of uniform on the feed rate and screw speed.
thickness, flow must be consistent and without 2) Self wiping screw profile: The self
stagnant zones right up to the die entrance. The wiping screw profile i.e. the flight of the one
function of the metering zone is to reduce screw wipes the root of the screw on the shaft
pulsating flow and ensure a uniform delivery next to it, ensures near complete emptying of

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 Hot-melt extrution technique

the equipment and minimizes product wastage and controlling parameters are barrel
on shutdown. temperatures, feed rate, screw speed, motor
3) Minimum inventory: Continuous load and melt pressure. Barrel temperature, feed
operation of the equipment coupled with the rate and screw speed are controlling parameters
continuous feeding of the material helps in and motor load and melt pressure are
reducing inventories of work in progress. This monitoring parameters.
is important when processing valuable or i) Barrel temperatures: The glass
potentially hazardous materials. transition or melting temperatures of polymers
4) Versatility: Operating parameters can be and drug usually determines the barrel
changed easily and continuously to change temperature
extrusion rate or mixing action. The segmented ii) Feed rate and screw speed:. The
screw elements allow agitator designs to be constant feeding rate and screw speed
easily optimized to suit a particular application. throughout the process is important as the
Die plates can also be easily exchanged to alter combination of these two factors establishes the
the extrudate diameter. This allows processing level of fill in extruder. This is critical to the
of many different formulations on a single process, because it governs the balance between
machine, leading to good equipment utilization. the weak and strong mass transfer mode (5).
Polymers with a wide range of viscoelastic and Due to constant feed rate and screw speed, there
melt viscosities may be processed and even fine will be a constant amount of material in the
powders may be directly fed into the system. extruder and thus the shear stress and residence
5) Superior mixing: The screws have time applied to material remains constant.
various mixing elements which impart two iii) The motor load and melt pressure:
types of mixing, distributive mixing and These parameters depend on feed rate and
dispersive mixing. The distributive mixing screw speed. With constant feed rate and screw
ideally maximizes the division and recombining speed these parameters depend upon the
of the material while minimizing energy. The molecular weight of polymer and drug as well
dispersive mixing ideally breaks droplet or as polymer miscibility in binary mixtures (4).
solid domains to fine morphologies using
energy at or slightly above the threshold level Industrial applications
needed. This mixing aids in efficient
compounding of two or more materials in the General
twin-screw extruder. Extrusion technology is extensively applied
Typical twin-screw laboratory scale in the plastic and rubber industries, where it is
machines have a diameter of 16-18 mm and one of the most important fabrication processes.
length of four to ten times the diameter. A Examples of products made from extruded
typical throughput for this type of equipment is polymers include pipes, hoses, insulated wires
0.5- 5 gm/min. As the residence time in the and cables, plastic and rubber sheeting, and
extruder is rather short and the temperature of polystyrene tiles. Plastics that are commonly
all the barrels are independent and can be processed by extrusion include acrylics
accurately controlled from low temperatures (polymethacrylates, polyacrylates) and
(30oC) to high temperatures (300oC) cellulosics (cellulose acetate, propionate, and
degradation by heat can be minimized (5). acetate butyrate), polyethylene (low and high
Extrusion processing requires close density), poly propylene, polystyrene, vinyl
monitoring and understanding the various plastics, polycarbonates, and nylons (9). This
parameters: viscosity and variation of viscosity process is often referred to as profile or line
with shear rate and temperature, elasticity and extrusion in which the shape of the extrudate,
extensional flow over hot metal surfaces. Today, such as a tube, is determined by the die. The
extruders allow in-process monitoring and extrudate profile proceeds horizontally to the
control of parameters, such as the temperature cutoff equipment, which controls its length.
in the extruder, head and die as well as pressure Profiles may be further processed, for example,
in extruder and die (8). The main monitoring

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as in film extrusion, blow molding, or injection permeability. Due to advent of high throughput
molding (9). screening (HTS) in the drug discovery process
In film extrusion, the polymer melt is the resultant compounds are often high
extruded through a long slit die onto highly molecular weight and highly lipophilic and
polished cooled rolls which form and wind the exhibits poor solubility (12). Scientists have
finished sheet. This is known as cast film. tried to address solubility issues by various
Plastic packaging film is also formed by blow pharmaceutical interventions. Today among the
extrusion, where tubular film is produced by many methods available to improve solubility
melt, usually vertically, through an annular- and dissolution rate, preparation of solid
shaped slit die. The extruded tube is inflated by dispersions and solid solutions has gained vast
air to form a large cylinder. Blow molding attention.
refers to a process where the plastic is heated to The most relevant technologies for the
a melted or viscous state and section of molten manufacture of solid dispersions are melting of
polymer tubing is extruded usually downward excipients or fusion method (13), embedding of
from the die head in to an open mold. The mold drug by means of spray drying (14), co-
is closed around it, sealing it at one and. evaporation, co-precipitation (15), freeze-
Compressed air is blown into the open end of drying (16), and roll-mixing or co-milling (17,
the tube, expanding the viscous plastic to the 18).
walls of the cavity, thus forming the desired Lately the melt extrusion technology has
shape of the container. During injection evolved as an efficient manufacturing technique,
molding the molten plastic is not extruded but to disperse or dissolves the drug in molten
rather injected into a cavity and then solidifies. polymer, forming a solid dispersion or solid
The mold is then opened and the article is solution. It is the convenience of the technology
removed. that gives new hope to the solid dispersion and
In the food industry extrusion has been solid solution approach as a delivery system for
utilized since 1930 for pasta production. A poorly water soluble drugs. The essential
widely used versatile technique combines advantage of the melt process in this domain is
cooking and extrusion in a so-called extrusion its solvent free formation of solid dispersions
cooker (10). (19).
In the animal feed industry, extrusion is Sekiguchi and Obi were first to report the
most commonly applied as a means of melting or fusion method (20). In 1974 solid
producing palletized feeds (11). The dispersions of drugs were described as: “… a
manufacture of implants by extrusion or relatively new field of pharmaceutical
injection molding is another field of application technique and its principles play an important
in the veterinary field. role in increasing dissolution, absorption and
therapeutic efficacy of the drug” (21).
Applications in the pharmaceutical By definition, solid dispersions and solid
industry solutions can be differentiated based on the
molecular state of the drug in the carrier matrix.
Drug delivery technology If the drug is dissolved at molecular level i.e.
In pharmaceutical industry the melt the drug forms one phase system with polymer,
extrusion has been used for various purposes, it is referred as a solid solution; whereas, if the
such as drug is in a two phase system with polymer and
i) Improving the dissolution rate and forms a microcrystalline dispersion, it is
bioavailability of the drug by forming a solid generally referred to as a solid dispersion (20,
dispersion or solid solution 22). Improvement in bioavailability with these
ii) Controlling or modifying the release of systems is primarily based on improving
the drug dissolution rates (23, 24). In the case of a solid
iii) Masking the bitter taste of an active drug dispersion, this is achieved by improvement in
The bioavailability of an orally administered the wetting behavior of the hydrophobic drug as
drug mainly depends on solubility and well as deagglomeration and micellization of

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 Hot-melt extrution technique

the drug with hydrophillic polymers. In case of Application of melt extrusion as a drug
solid solutions, improvement in dissolution rate delivery technology
is due to the high energy amorphous nature of
the drug. Thermodynamically, solid solutions Overview of the literature
are more unstable compared to solid dispersions For over two decades, the value of
because in the solid solution the drug exists in a “continuous processing” in the pharmaceutical
high energy amorphous form, (25) which is industry has been recognized. The potential of
prone to precipitation or crystallization under automation and the reduction of capital
environmental stress such as moisture and heat, investment and labor costs have made hot-melt
especially during processing and storage of the extrusion worthy of consideration (37).
drug products. Two major factors that stabilize Until recently, hot-melt extrusion had not
solid solutions are intermolecular interactions received much attention in the pharmaceutical
between the drug and the carrier (26-28) and the literature. Pellets comprising cellulose acetate
viscosity of the carrier (29). Glass transition phthalate were prepared using a rudimentary
temperature has long been seen as the ram extruder in 1969 and studied for dissolution
predominant factor governing the physical rates in relation to pellet geometry (38). More
stability of the solid solution. The higher the recently, production of matrices based on
glass transition temperature of system the better polyethylene and polycaprolactone were
the thermodynamic stability (30). The investigated using laboratory scale extruders
solubilizing and stabilizing effects of the (39, 40). Mank et al., reported in 1989 and 1990
polymer and interactions with the drug are often the extrusion of a number of thermoplastic
far greater importance for the physicochemical polymers to produce sustain-release pellets (41).
stability of solid solutions (31-34) A melt extrusion process for manufacturing
Since solid dispersions were introduced in matrix drug delivery system was reported by
1961 (20), an immense amount of research has Sprockel and co-workers (42).
been done in this area. However, very few solid In 1994 Follonier and co-workers
dispersion systems have been marketed. These investigated hot-melt extrusion technology to
include a griseofulvin-polyethyleneglycol produce sustained-release pellets (43).
dispersion (Gris-PEG® marketed by Wander), Diltiazem hydrochloride, a relatively stable,
Cesamet® a nabilone-PVP (polyvinyl- freely soluble drug was incorporated into
pyrrolidone) preparation (marketed by Lilly) as polymer-based pellets for sustained-release
well as a formulation of toglitazone (Rezulin® capsules. Four polymers were considered for
marketed by Parke-Davis) which was extrusion trials, namely ethylcellulose, cellulose
withdrawn from the market for toxicology acetate butyrate (CAB), poly (ethylene-co-vinyl
related issues to the drug. Several implants acetate) (EVAC) and polymethacrylate
containing a LHRH agonist for parentral use derivative (Eudragit® RSPM). The plasticizers
have become commercially available, such as included triacetin and diethyl phthalate. The
geoserelin (Zoladex®) or buserelin (Depot- porosity of the formulations was assessed using
profact®) embeddings in poly(lactide- mercury porosimetry. The pellets produced,
coglycolide) (PLGA) (35) exhibited a smooth surface and low porosity.
The troglitazone formulation in PVP was The in-vitro release of the drug was biphasic,
actually manufactured by melt extrusion (ref.). with the CAB and EVAC pellets giving the
Melt extrusion technology has proven to be a lowest release rate. In a later study, Follonier et
suitable method for the production of controlled al. examined different parameters influencing
release reservoir systems consisting of the release of diltiazem hydrochloride from hot-
polyethylene vinylacetate (EVA) co-polymers. melt extruded pellets (44). These parameters
Based on this technology, two controlled included polymer type, drug/polymer ratio, and
release systems Implanon® and Nuvaring® pellet size. The authors incorporated various
have been developed (36). polymer excipients such as croscarmellose
sodium (Ac-Di-Sol) and sodium starch
glycolate (Explotab) into the formulations to

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vary the drug-release rate. These pellets could properties of the films such as tensile strength,
be applicable for incorporation into hard gelatin percentage elongation, and young’s modulus
capsules. With optimization techniques and were investigated. The authors observed that a
formulation, it is apparent that hot-melt pure HPC film could not be produced without
extrusion of these and other sustained-release incorporation of a plasticizer due to high stress
pellets is a viable drug delivery technology. exhibited in the extruder. With exception of
Aitken-Nichol and co-workers investigated PEG 400, all the plasticizers investigated
the viability of hot-melt extrusion technology in demonstrated adequate stability throughout the
1996 for the production of thin, flexible acrylic duration of the study. Although PEG 400
films for topical drug delivery (45). One of the initially exhibited excellent plasticizer qualities
advantages they pointed out was that the for HPC films, it was found to be unstable in all
delivery manufacturing process is not restricted parameters tested. Chlopheniramine maleate
by solvent concerns. The investigation proved to be an excellent plasticizer for HPC,
compared cast films with various extruded providing mechanical stability for the hot-melt
films. They also studied the effect of types and extruded film, and was chemically stable for up
levels of plasticizers using the model drug to 12 months. Hydrocortisone was shown to be
lidocaine HCL; on the glass transition a good plasticizer comparable to the
temperature (Tg) and the mechanical properties conventional plasticizers studied. However, the
of high density polyethylene (HDPE) and chemical stability of drug incorporated into
Eudragit E-100 extruded films. Eudragit E-100 HPC films was shown to be a function of
was the primary thermoplastic polymer processing temperature and residence time in
extruded. The authors found that hot-melt the extruder.
extrusion was viable technology for the Another application of hot-melt extrusion
production of free films of this acrylic resin. was described by Miyagawa, Sato, and co-
Triethyl citrate (TEC) was an acceptable workers in 1996 and 1997 (47, 48). They
plasticizer for Eudragit E-100. The authors studied the controlled release and mechanism of
concluded that the differences in the dissolution release of diclofenac. These researchers utilized
and ductile properties between cast films and a twin-screw compounding extruder to prepare
extruded films were due to amount of drug wax matrix granules composed of carnauba wax,
dissolved in the polymer. The dissolution rate the model drug, and other rate controlling
of lidocaine HCL was affected by the drug agents. Their first investigation (47) showed
loading, in contrast to the solvent–cast films that a wax matrix with high mechanical strength
tested. could be obtained even at temperatures below
Transdermal and transmucosal drug delivery the melting point of the wax. Dissolution
systems are frequently produced by films cast release profiles of diclofenac from wax matrix
from organic or aqueous solvents. Repka and granules were strongly influenced by the
co-workers discussed the numerous dis- formulation of the granules. The rate-
advantages accompanying these techniques, controlling additives that were varied in the
including long processing times, environmental formulations included hydroxypropyl cellulose,
concerns and excessive costs (46). In 1999 they methacrylic acid copolymer (Eudragit L-100),
used Killion melt extruder to produce and sodium chloride. The authors emphasized
hydroxypropyl cellulose (HPC) films the advantages of using twin-screw extruder for
employing a. Polyethylene glycol 8000 (PEG wax matrix tablets, such as low temperatures,
8000) 2%, triethyl citrate (TEC) 2%, high kneading and dispersing ability, and low
acetyltributyl citrate (ATBC) 2%, and residence time of the material in extruder. The
polyethylene glycol 400 (PEG 400) 1% were investigators concluded in a second study (48)
the plasticizing agents studied. In addition, that selection of rate-controlling agents based
either hydrocortisone 1% or chlorpheniramine on physicochemical properties (solubility and
maleate 1% was incorporated into the films as a swelling characteristics) had significant impact
model drug. The influence of these plasticizers on the properties of wax matrix granules
and drugs on the physical-mechanical prepared by this extrusion process.

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 Hot-melt extrution technique

Zhang and McGinity (49) in 1999 granules and tablets were compared containing
investigated the properties of polyethylene 15 to 25% polyethylene glycole 6000. The drug
oxide (PEO) as a drug carrier and studied the release from granules was improved over that
release mechanism of chlopheniramine maleate from tablets. Tablets containing 15%
(CPM) from matrix tablets. In these extruded polyethylene glycol released more than 80% of
tablets, PEG 3350 was included as a plasticizer the drug after 30 min as required for
to facilitate processing. The molecular weight acetoaminophen tablets in the USP 23.
of the PEO, the drug loading percentage, and In similar study Perissutti and co-workers
the inclusion of PEG were all found to (2002) applied hot-melt extrusion technology to
influence the processing conditions and the improve dissolution of carbamazepine (52). The
drug release properties of the extruded tablets. aim of this research was to use a ram extruder
An increase in the percentage of PEG 3350 to directly prepare a fast release dosage form
increased the release rate of the drug. PEG 3350 with uniform shape and density, containing
is composed of the same structural unit as PEO. poorly water soluble model drug and
The hydration and dissolution rate of the entire polyethylene glycol 4000 (PEG 4000) as a
matrix system were thus accelerated due to the hydrophilic carrier and low melting binder. The
presence of the plasticizer. When CPM loading investigation revealed that the extruded
was increased from 6 to 12%, no change in the mixtures of an equivalent composition
percentage of drug release with respect to time exhibited more rapid release than simple
was observed. There was a slight increase when physical mixtures.
the drug loading reached 20%. This study Hülsmann and co-workers worked on hot-
conveyed the reproducibly of dissolution data melt extrusion to improve solubility and
from tablets manufactured by hot-melt dissolution of 17-Estradiol hemihydrate, a
extrusion. poorly water soluble drug (53). Different
Similar study was conducted by Zhang and compositions of excipients such as PEG 6000,
McGinity in 2000 (50). The objective of this polyvinylpyrrolidone or a vinylpyrrolidone-
study was to investigate the properties of poly vinyl acetate-copolymer were used as polymers
vinyl acetate (PVA) as a retardant polymer and and Sucroester® WE 15 or Gelucire® 44/14 as
to study the drug release mechanism of additives. The solid dispersions resulted in a
theophyline from matrix tablets prepared by significant increase in dissolution rate when
hot-melt extrusion. The release rate of the drug compared to the pure drug or to the physical
was shown to be dependent on the granule size, mixture. A 30-fold increase in dissolution rate
drug particle size, and drug loading in the was obtained for a formulation containing 10%
tablets. As the size of hot-melt extruded drug, 15% PVP and 40% Gelucire TM tablets.
theophyllline/PVAc granules was increased, Nakamichi and co-workers prepared a
there was a significant decrease in the release floating sustained release dosage form
rate of the drug. Higher drug loading in the composed of nicardipine hydrochloride and
hot-melt granules also showed higher release hydroxypropylmethylcellulose actate succinate,
rates of drug. Water-soluble materials such as using twin-screw extruder (54). By adjusting
PEG 400 and lactose were demonstrated to be the position of the high-pressure screw
efficient release rate modifiers for this system. elements in the immediate vicinity of the die
McGinity and Koleng in 1997, employed outlet, and by controlling the barrel temperature,
hot-melt extrusion technology for the a puffed dosage form with very small and
preparation of rapid-release granules (51). In uniform pores was obtained. It was shown that
this investigation, a hot-melt extrusion process the puffed dosage form prepared by twin-screw
was used to granulate acetaminophen and filler extruder, consisting enteric polymer was very
excipients with low molecular weight helpful as a floating dosage form that was
polyethylene glycols. The resultant granules retained for long period in the stomach.
were combined with additional excipients In a later study Nakamichi and co-workers
(disintegrant and lubricant) and compressed also investigated the role of the kneading
into tablet compacts. Drug release from bulk paddle and the effect of screw revolution on the

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preparation of a solid dispersion using twin- extrusion, a relatively new technology to the
screw extruder (55). The authors concluded pharmaceutical industry, offers many benefits
that the kneading paddle element of the screws over traditional processing techniques. The melt
play an important role in changing the extrusion process is anhydrous, avoiding any
crystallinity and dissolution properties of a potential drug degradation due to hydrolysis
solid dispersion of nifedipine and following the addition of aqueous or
hydroxypropylmethylcellulose phthalate. hydroalcoholic granulating media. In addition,
Along with literature describing the in vitro poorly compactable materials can be
performance of solid dispersions a number of incorporated into tablets produced by cutting an
melt extruded solid dispersions have been extruded rod, eliminating any potential
examined in human clinical studies. tableting problems seen in traditional
The antiretroviral agent, loviride when melt compressed dosage forms (58). The active
extruded to a solid molecular dispersion in ingredient should be thermally stable to be
HPMC showed remarkable, lower food effect melt-extruded and thus an initial assessment of
compared to capsules (56). thermal, chemical and physical properties of the
Antifungal compositions of intraconazole drug substance is very essential. Depending on
were prepared as solid dispersions using the the unique properties of the drug substance and
melt extrusion process. In a limited number of the other excipients in the formulation, the drug
volunteers these tablets gave an area under the may be present as undissolved i.e. solid
curve (AUC) in the fasted state that was 2.3 dispersion or completely dissolved in polymer
times the AUC of the marketed reference i.e. solid solution in the final dosage form. The
capsules. (57) state of the drug in the dosage form may have
Materials used in hot-melt extrusion profound impact on the processibility and
technology stability of the product (59).
The materials used in the production of hot- In addition to thermal degradation, the active
melt extruded dosage forms must meet the same compound may interfere with the functionality
level of purity and safety as those used in of the other components in the formulation.
traditional dosage forms. Most of the Oxprenolol hydrochloride was shown to melt
compounds used in production of hot-melt under melt extrusion processing conditions,
extruded pharmaceuticals have been use in which lowered the viscosity of the extrudate to
production of other solid dosage forms such as yield material with poor handling properties
tablets, pellets, and transdermals. The materials (44). In similar work preparing dosage forms by
must possess some degree of thermal stability injection molding, Cuff and Raouf (60) reported
in addition to acceptable physical and chemical that the fenoprofen calcium inhibited hardening
stability. The thermal stability of each of a PEG-MCC matrix, resulting in an unusable
individual compound and of the composite product. Lidocaine was also shown to
mixture should be sufficient to withstand the effectively lower the Tg of Eudragit E/HDPE
production process. Hot-melt extruded dosage flms (61), and hydrocortisone demonstrated a
forms are complex mixtures of active drug and time-dependent lowering of the glass transition
functional excipients. The functional excipients temperature of hydroxypropyl cellulose (HPC)
may be broadly classified as matrix carriers, films (62).
release–modifying agents, bulking agents, and Polymer systems: The selection of polymer
various additives (58). The excipients can for hot-melt extrusion process mainly depends
impart specific properties to melt extruded on drug–polymer miscibility, polymer stability
pharmaceuticals in manner similar to those in and function of final dosage form. A variety of
traditional dosage form. carrier systems have been studied or used in
Active ingredient: The properties of the hot-melt extrusion dosage forms. Such carrier
active drug substance often limit the systems include polyvinylpyrrolidone (PVP)
formulation and preparation option available to (63) or its co-polymer such as poly
the pharmaceutical scientist in the development vinylpyrrolidone-vinyl acetate (64),
of an acceptable dosage form. Hot-melt poly(ethylene-co-vinyl acetate) (44), various

12
 Hot-melt extrution technique

grades of polyethylene glycols (52), cellulose functional excipients. The dissolution rate of
ethers (65) and acrylates (66), various the active compound can be increased or
molecular weight of polyethylene oxides (49), decreased, depending on the properties of the
poly methacrylate derivatives and poloxamers. rate-modifying agent. For systems that display
Amongst the different classes of biodegradable oxidative or free-radical degradation during
polymers, the thermoplastic aliphatic processing or storage, the addition of
poly(esters) such as poly (lactide) (PLA) , poly antioxidants, acid acceptors, and/or light
(glycolide) (PGA) and copolymer of lactide and absorbers may be advised (59).
glycolide, poly(lactide-co-glycolide) (PLGA)
have been used in extrusion. Starch and starch Conclusions and outlook
derivatives have been applied along with low
molecular weight excipients like sugars and Today melt extrusion technology represents
sugar alcohols and waxes (67, 68). The basic an efficient pathway for manufacture of drug
prerequisite for the use in melt extrusion is the delivery systems. Resulting products are mainly
thermo plasticity of the polymers or that of the found among semi-solid and solid preparations.
respective formulation. The potential of the technology is reflected in
Plasticizers: The choice of suitable the wide scope of different dosage forms
plasticizer depends on many factors, such as including oral dosage forms, implants,
plasticizer-polymer compatibility and bioadhesive ophthalmic inserts, topical films,
plasticizer stability. Triacetin (44), citrate esters and effervescent tablets. In addition, the
(45, 46), and low molecular weight physical state of the drug in an extrudate can be
polyethylene glycols (44, 46, 49) have been modified with help of process engineering and
investigated as plasticizers in hot-melt extruded the use of various polymers. The drug can be
systems. The plasticizer lowers the glass present in crystalline form for sustain release
transition temperature (Tg) of the polymer as applications or dissolved in a polymer to
well as the processing temperature necessary improve dissolution of poorly water soluble
for production. A reduction in polymer Tg drugs. The possible use of a broad selection of
depends upon the plasticizer type and level (59). polymers starting from high molecular weight
A reduction in processing temperatures may polymers to low molecular weight polymers
improve the stability profile of the active and various plasticizers has opened a wide field
compound (62) and/or of the polymer carrier of numerous combinations for formulation
(44, 49). Plasticizers also lower the shear forces research.
needed to extrude a polymer, thereby improving Drawbacks of the technology are often
the processing of certain high molecular weight related to high energy input mainly related to
polymers (49, 62). The thermo-chemical shear forces and temperature. This is where
stability and volatility of the plasticizer during process engineering becomes significant. The
processing and storage must also be taken into design of screw assemblies and extruder dies
consideration (62, 69, 70). are two major areas, which have significant
The materials used in the production of hot- impact on product quality and degradation of
melt extruded forms are the same drug and polymers. Drugs which are sensitive
pharmaceutical compounds used in the to elevated temperatures can be processed
production of more traditional systems. successfully when the residence time is short
Thermal stability of the individual compounds compared to conventional processes like
is a prerequisite for the process, although sterilization.
because of the short processing times not all Work in this field is increasing and the
thermolabile compounds are excluded. The literature published reveals many novel and
incorporation of plasticizers may lower the interesting aspects of this technology such as
processing temperatures required in hot-melt in-situ salt formation, fast dispersing systems
extrusion, thereby reducing drug and carrier with foam like structures, complex formation in
degradation. Drug release from these systems the melt, and naoparticles released from
can be modified by the addition of various

13
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