Review articles

By Mr. Sandeep Singhal , Mr. Vikram K Lohar , Mr. Vimal Arora
Corresponding Author Mr. Sandeep Singhal
Faculty of pharmaceutical sciences, Jodhpur National University, 284-A, Jwala vihar,opp-2nd pulia, C.H.B. - India 342001
Submitting Author Mr. Sandeep Singhal
Other Authors Mr. Vikram K Lohar
Faculty of Pharmaceutical Sciences, Jodhpur National University, 284-A, Jwala Vihar, Jodhpur (Raj.) - India 342001

Mr. Vimal Arora
Faculty of Pharmaceutical sciences,Jodhpur National University, Ashapurna Nagar - India 342001


Extrusion, Melt, Extruder, Polymer, Twin Extruder, Solid Solution

Singhal S, Lohar VK, Arora V. Hot Melt Extrusion Technique. WebmedCentral PHARMACEUTICAL SCIENCES 2011;2(1):WMC001459
doi: 10.9754/journal.wmc.2011.001459
Submitted on: 14 Jan 2011 04:45:12 AM GMT
Published on: 16 Jan 2011 03:38:27 AM GMT


Various approaches have been adopted to address this including preparation of solid dispersions and solid solutions. Hot-melt extrusion is an efficient technology for producing solid molecular dispersions with considerable advantages over solvent-based processes such as spray drying and co-precipitation. Hot-melt extrusion has been demonstrated to provide sustained, modified, and targeted drug delivery. Hot-melt extrusion (HME) is an established process that has been used since the early 1930s, predominately in the plastics manufacturing industry, but also in the food processing industry. Currently, more than half of all plastic products, including bags, sheets, and pipes, are manufactured using HME. Since the advent of plastics production, polymers have been melted and formed to different shapes for a variety of industrial and domestic applications. HME is the process of embedding drug in a polymeric carrier. Specifically, HME dosage forms are complex mixtures of API, functional excipients, and processing aids which are blended using industry-standard equipment. The mixture is processed at elevated temperature and pressure, which disperses the drug in the matrix at a molecular level through the formation of a solid solution. Extruded material can be further processed into a variety of dosage forms, including capsules, tablets and transmucosal systems. 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 is relevant for poorly-soluble pharmaceutically active substances, frequently encountered among novel drugs.

Introduction, Method , Discussion

1.1 History
The advent of high through-put screening in the drug discovery process has resulted in compounds with high lipophilicity and poor solubility. Increasing the solubility of such compounds is a major challenge to formulation scientists. Various approaches have been adopted to address this including preparation of solid dispersions and solid solutions. (1)
Then after Joseph Brama invented the extrusion process for the manufacturing of lead pipes at the end of the eighteenth century. However, hot-melt extrusion was not applied in the plastics’ industry until the mid-nineteenth century, when it was first introduced into a wire insulation polymer coating process. (2)
Since the early 1930s, Hot-melt extrusion (HME) was established and has been used predominately in the plastics manufacturing industry, but also in the food processing industry. Currently, more than half of all plastic products, including bags, sheets, and pipes, are manufactured using HME. Since the advent of plastics production, polymers have been melted and formed to different shapes for a variety of industrial and domestic applications. (3)
Hot-melt extrusion is an efficient technology for producing solid molecular dispersions with considerable advantages over solvent-based processes such as spray drying and co-precipitation. Hot-melt extrusion has been demonstrated to provide sustained, modified, and targeted drug delivery. (1)
In recent years, the continuous extrusion process has been applied successfully to pharmaceutical formulations by downsizing sound, established continuous manufacturing techniques.
In addition to being a proven manufacturing process, continuous extrusion meets the goal of the US Food and Drug Administration's process analytical technology (PAT) initiative for designing, analyzing, and controlling the manufacturing process through quality control measurements during processing.(4)
Hot-Melt Extrusion (HME) technology is currently being explored and used in the pharmaceutical field because it offers several advantages over traditional processing methods.
HME may be used to disperse drugs in a given matrix at the molecular level, thus forming solid solutions. It is well documented that the solid solution approach is commonly used for delivery of poorly soluble drugs because of its role in increasing the dissolution, absorption, and therapeutic efficacy of drugs. Also, in the case of transdermal drug delivery systems, at least part of the incorporated drug must be in solution since only drug in solution diffuses from the polymeric patch and is available for absorption.(5)
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.(10)
This is relevant for poorly-soluble pharmaceutically active substances, frequently encountered among novel drugs. However, reliable scale-up of HME technology is still a major challenge and a breakthrough has not been achieved yet. This is mainly due to a limited insight into the process. (6)
Melt extrusion is considered to be an efficient technology in this field with particular advantages over solvent processes like co-precipitation. (7)
Finally, extrusion technology is a continuous process which helps to provide the possibility to make certain drug forms directly in one process with not only pharmaceutical advantages but also providing economical advantages. (8)
ØHot Melt Extrusion is the process of embedding drug in a polymeric carrier.(9)
Hot Melt Extrusion is the process of converting a raw material into a product of uniform shape and density by forcing it through a die under controlled conditions.(10)
Hot Melt Extrusion can be simply defined as the process of forming a new material (the extrudate) by forcing it through an orifice or die under controlled conditions, such as temperature, mixing, feed-rate and pressure.(3)
1.2. Advantages (11, 12, 13, 14)
HME offers several advantages over traditional pharmaceutical processing techniques including:
Enhanced bioavailability of poorly soluble compounds.
Processing in the absence of solvents and water.
Economical process with reduced production time, fewer processing steps, and a continuous operation.
Clinically advantaged dosage forms, such as drug abuse and dose dumping deterrent technology.
Sustained, modified and targeted release capabilities.
Better content uniformity was obtained from the HME process among granules of different size ranges.
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.
Reduced number of unit operations.
Production of a wide range of performance dosage forms.
Production of a range of geometries.
1.3. Disadvantages (11, 13)
Thermal process (drug/polymer stability).
Flow properties of the polymer are essential to processing.
Limited number of available polymer
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.
The materials used in the production of hot melt extruded dosage forms must meet the same level of purity and safety as those used in traditional dosage forms. Most of the compounds used in production of hot-melt extruded pharmaceuticals have been use in production of other solid dosage forms such as tablets, pellets, and transdermals. The materials used in hot melt extruded products must possess some degree of thermal stability in addition to acceptable physical and chemical stability. The thermal stability of each individual compound and of the composite mixture should be sufficient to withstand the production process. (2)
Hot-melt extruded dosage forms are complex mixtures of active drug and functional excipients. The functional excipients may be broadly classified as matrix carriers, release–modifying agents, bulking agents, and various additives (16). The excipients can impart specific properties to melt extruded pharmaceuticals in manner similar to those in traditional dosage form. (10)
2.1 Active Ingredient
The properties of the active drug substance often limit the formulation and preparation options available, in the development of an acceptable dosage form. Hot-melt extrusion offers many benefits over traditional processing techniques. This is a relatively new technique to the pharmaceutical industry. The process is anhydrous, thus avoiding any potential drug degradation from hydrolysis following the addition of aqueous or hydro alcoholic granulating media. In addition, poorly compactable materials can be incorporated into tablets produced by cutting an extruded rod, thus eliminating any potential tableting problems seen in traditional compressed dosage forms. As an initial assessment, the thermal, chemical, and physical properties of the drug substance must be characterized. Depending on the unique properties of the drug substance and the other excipients in the formulation, the drug may be present as undissolved particles, a solid solution, or a combination in the final dosage form. The state of the drug in the dosage form may have a profound impact on the processability and stability of the product. (2)
In addition to thermal degradation, the active compound may interfere with the functionality of the other components in the formulation. Oxprenolol hydrochloride was shown to melt under melt extrusion processing conditions, which lowered the viscosity of the extrudate to yield material with poor handling properties (16). In similar work preparing dosage forms by injection molding, Cuff and Raouf (17) reported that the fenoprofen calcium inhibited hardening of a PEG-MCC matrix, resulting in an unusable product. Lidocaine was also shown to effectively lower the Tg of Eudragit E/HDPE flms (18), and hydrocortisone demonstrated a time-dependent lowering of the glass transition temperature of hydroxypropyl cellulose (HPC) films.
2.2 Polymer Systems
In hot-melt extruded drug delivery systems, the active compound is embedded in a carrier formulation comprised of one or more meltable substances and other functional excipients. The meltable substances may be polymeric materials (19, 20) or low melting point waxes. (21, 22)
The selection of polymer for hot-melt extrusion process mainly depends on drug–polymer miscibility, polymer stability and function of final dosage form. A variety of carrier systems have been studied or used in hot-melt extrusion dosage forms.
Such carrier systems include polyvinylpyrrolidone (PVP) (23) or its co-polymer such as polyvinylpyrrolidone-vinyl acetate(24), poly(ethylene-co-vinyl acetate) (16), various grades of polyethylene glycols , cellulose ethers (25) and acrylates (26), various molecular weight of polyethylene oxides (20), poly methacrylate derivatives and poloxamers. Amongst the different classes of biodegradable polymers, the thermoplastic aliphatic poly (esters) such as poly (lactide) (PLA), poly (glycolide) (PGA) and copolymer of lactide and glycolide, poly (lactide-co-glycolide) (PLGA) have been used in extrusion. Starch and starch derivatives have been applied along with low molecular weight excipients like sugars and sugar alcohols and waxes (27, 28). The basic prerequisite for the use in melt extrusion is the thermo plasticity of the polymers or that of the respective formulation.
The various meltable binders used for the sustained drug delivery systems are mentioned in the Illustration - 2.1 and 2.2. (11)
2.3 Plasticizers
The use of polymeric carriers usually requires the incorporation of a plasticizer into the formulation in order to improve the processing conditions during the manufacturing of the extruded dosage form or to improve the physical and mechanical properties of the final product. (2) Plasticizers are added to HME formulations to facilitate the extrusion of the material and to increase the flexibility of the extrudate. This approach may reduce the likelihood of degradation problems that are associated with temperature-sensitive drugs or polymers. (29)
The choice of suitable plasticizer depends on many factors, such as plasticizer-polymer compatibility and plasticizer stability. Triacetin (16), citrate esters (18, 30), and low molecular weight polyethylene glycols (16, 20, 30) have been investigated as plasticizers in hot-melt extruded systems. The plasticizer lowers the glass transition temperature (Tg) of the polymer as for production. A reduction in polymer Tg depends upon the plasticizer type and level (2). A reduction in processing temperatures may improve the stability profile of the active compound (30) and/or of the polymer carrier (16, 20). Plasticizers also lower the shear forces needed to extrude a polymer, thereby improving the processing of certain high molecular weight polymers (20, 30). The thermo-chemical stability and volatility of the plasticizer during processing and storage must also be taken into consideration (30, 31, 32). The materials used in the production of hot melt extruded forms are the same pharmaceutical compounds used in the production of more traditional systems. Thermal stability of the individual compounds is a prerequisite for the process, although because of the short processing times not all thermolabile compounds are excluded. The incorporation of plasticizers may lower the processing temperatures required in hot-melt extrusion, thereby reducing drug and carrier degradation. Drug release from these systems can be modified by the addition of various functional excipients. The dissolution rate of the active compound can be increased or decreased, depending on the properties of the rate-modifying agent. For systems that display oxidative or free-radical degradation during processing or storage, the addition of antioxidants, acid acceptors, and/or light absorbers may be advised (2).
2.4 Other Processing Aids (33)
The excessive temperatures needed to process unplasticized or under plasticized polymers may lead to polymer degradation. The stability of polymers that are susceptible to degradation can be improved with the addition of antioxidants, acid receptors and or light absorbers during hot melt extrusion.
Antioxidants are classified as preventive antioxidants or chain breaking antioxidants based upon their mechanism. Preventive antioxidants include materials that act to prevent initiation of free radical chain reactions. Reducing agents, such as ascorbic acid, are able to interfere with autoxidation in a preventive manner since they preferentially undergo oxidation. The preferential oxidation of reducing agents protects drugs, polymers and other excipients from attack by oxygen molecules. These antioxidants are sometimes called oxygen scavengers. They are most effective when used in a closed system where oxygen cannot be replaced once it is consumed. Chelating agents such as edetate disodium (EDTA) and citric acid are another type of preventive antioxidant that decrease the rate of free radical formation by forming a stable complex with metal ions that catalyze these reduction reactions.
Other materials have been used to facilitate hot-melt extrusion processing. Waxy materials like glyceryl monostearate have been reported to function as a thermal lubricant during hot-melt processing. Vitamin E TPGS has been reported to plasticize polymers and enhance drug absorption (Illustration no 2.5).
3.1 Equipment
Hot-melt extrusion equipment consists of an extruder, auxiliary equipment for the extruder, down stream processing equipment, and other monitoring tools used for performance and product quality evaluation (34). The extruder is typically composed of a feeding hopper, barrels, single or twin screws, and the die and screw– driving unit (Illustration 3.1). The auxiliary equipment for the extruder mainly consists of a heating/cooling device for the barrels, a conveyer belt to cool down the product and a solvent delivery pump. (10)
Generally, the extruder consists of one or two rotating screw inside a stationary cylindrical barrel. The barrel is often manufactured in sections, which are bolted or clamped together. An end-plate die, connected to the end of the barrel, determines the shape of the extruded product (Illustration 3.2).
Simple single screw arrangements consist of only a single rotating screw inside a stationary extruder barrel, whereas more advanced machines involve twin-screw systems utilizing either a corotating or counter-rotating screw configuration. It is common for the extrusion screw to be characterized by the length/diameter (L/D) ratio, which typically ranges from 20 to 40:1. Typical pilot plant extruders have diameters ranging 18–30 mm, whereas production machines are much larger with diameters typically exceeding 50 mm. Irrespective of the complexity of the machine, the extruder must be capable of rotating the screw(s) at a selected speed while compensating for the torque generated from the material being extruded.
A simple single screw extrusion system comprises one rotating screw inside a stationary barrel that may be conveniently subdivided into three distinct zones: feed zone, compression zone and metering zone. The depth and/or pitch of the screw flights differ within each zone, generating variable pressure along the screw length (zone dependent). Because of the large screw flight depth and pitch, the pressure within the feed zone is very low, allowing for consistent feeding from the hopper and gentle mixing of API and excipients (Figure 3.1). The primary function of the subsequent compression zone is to melt, homogenize and compress the extrudate so that it reaches the metering zone in a form suitable for extrusion. Consequently, the compression zone must impart a high degree of mixing and compression to the material. This is achieved by decreasing the screw pitch and/or the flight depth, resulting in a gradual increase in pressure along the length of the compression zone. The final section, the metering zone stabilizes the pulsating flow of the matrix, thus ensuring the extruded product has a uniform thickness. Constant screw flight depth and pitch helps maintain continuous high pressure to ensure a uniform delivery rate of molten material through the extrusion die and, hence, a uniform product.
At a minimum, a screw extruder consists of three distinct parts:
A conveying system for material transport and mixing
A die system for forming
Downstream auxiliary equipment for cooling, cutting and/or collecting the finished product.
Individual components within the extruder are the feed hopper, temperature controlled barrel, rotating screw, a die and heating/cooling elements. Additional systems include mass flow feeders to accurately meter materials into the feed hopper, PAT to measure extrudate properties (near infra red systems and laser systems), liquid and solid side stuffers, vacuum pumps for degassing, pelletizers and calendaring equipment. Standard process control and monitoring devices include zone temperature and screw speed with optional monitoring of torque, drive amperage, melt pressure and melt viscosity. Temperatures are normally controlled by electrical heating bands and monitored by thermocouples. (3)
During the hot-melt extrusion process, different zones of the barrel are preset to specific temperatures before the extrusion process. A blend of the thermoplastic polymers and other processing aids is then fed into the barrel of the extruder through the hopper. The materials are transferred inside the heated barrel by a rotating screw. Temperatures at different sections of the barrel are normally controlled by electrical heating bands, and the temperature is monitored by thermocouples. The materials inside the barrel are heated mainly by the heat generated due to the shearing effect of the rotating screw and the heat conducted from the heated barrel. The molten mass is eventually pumped through the die, which is attached to the end of the barrel. The extrudates are then subject to further processing by auxiliary downstream devices.
During a continuous extrusion process, the feed stock is required to have good flow properties inside the hopper. For the material to demonstrate good flow, the angle between the side wall of the feeding hopper and a horizontal line needs to be larger than the angle of repose of the feed stock. In the case of cohesive materials or for very fine powders, the feed stock tends to form a solid bridge at the throat of the hopper, resulting in erratic powder flow. For these situations, a force-feeding device is sometime used.
The design of the extrusion screw has a significant influence on the efficiency of the hot-melt extrusion process. The function of the screw is to transfer the material inside the barrel and then to mix, to compress, and to melt the polymeric materials and to pump the moltenmass through the die. Several parameters are used to define the geometrical features of the screw.
Most screws are made from stainless steel that is surface-coated to withstand friction and potential surface erosion and decay that may occur during the extrusion process. Based on the geometrical design and the function of the screw at each section, an extruder is generally divided into three zones: feeding section, melting or compression section, and metering section. Only single-screw extruders were used during the early days of this technology. Twin-screw extruders were invented in the late 1930s. The two screws can either rotate in the same direction (co-rotating extruder) or in the opposite direction (counter-rotating screw). Twin-screw extruders possess many advantages when compared to single-screw extruders, such as easier material feed, more intensive mixing, less tendency to overheat the materials, and a shorter residence time.
The purpose of the feeding section is to compact and to transfer the feed stock into the barrel of the machine. The channel depth (Illustration 3.3) is normally greatest in this section. The performance of the feeding section depends on the external friction coefficient of the feed stock at the surface of the screw and barrel.
The friction at the inner surface of the barrel is the driving force for the material feed, whereas the friction at the surface of the screw restricts the forward motion of the material. A high friction coefficient in the barrel and a low friction coefficient at the screw surface would contribute to a more efficient transfer of the materials in the feed section. Other properties of the feed stock, such as bulk density, particle size, particle shape, and material compactability, can also have an impact on the performance of the feeding section. The transfer of the material should be efficient in order to maintain an increase in pressure in the compression zone and the metering zone. The pressure rise in these zones should be high enough to provide an efficient output rate of the extrudate. It is also possible to fine tune the barrel temperature at the feeding section in order to optimize the friction at the surface of the barrel. Inconsistent material feed may result in a ‘‘surge’’ phenomenon that will cause cyclical variations in the output rate, head pressure, and product quality. (2)
The monitoring devices on the equipment include:
Temperature gauges,
A screw-speed controller,
An extrusion torque monitor,
And pressure gauges.(7)
3.2 Single-Screw Extrusion
Single-screw extrusion is a fundamental operation for polymer processing. It is used to increase pressure within a polymer melt, allowing extrusion through a die or injection into a mould. Although a relatively simple process, single screw extrusion does not possess the mixing capability of a twin-screw machine and is, therefore, not the preferred approach for the production of pharmaceutical formulations. Moreover, the versatility of a twin-screw extruder (process manipulation and optimization) and the ability to accommodate various pharmaceutical formulations makes this set-up much more favorable. In relation to machine design, rotation of the screws inside the extruder barrel may either corotate (same direction) or counter-rotate (opposite direction); both directions being equivalent from a processing perspective. Another significant design variable is whether the two screws are intermeshing or no intermeshing, the former being preferred because of the greater degree of conveying achievable and the shorter residence times. Additionally, the configuration of the screws themselves may be varied using forward conveying elements, reverse conveying elements, kneading blocks and other designs to achieve particular mixing characteristics.(3)
3.3 Twin-Screw Extrusion
Twin-screw extrusion offers the pharmaceutical formulator a rapid, continuous process that has much better mixing capability than single screw extrusion. Moreover, twin screw extrusion provides a more stable melting process, shorter residence times and significantly greater output. Industrially, twin screw extrusion has become extremely favorable because of process practicality and the ability to combine separate batch operations into a single continuous process, thus increasing manufacturing efficiency. Twin-screw extruders were used in the plastics industry to mix polymers with additives and fillers for nearly every plastics product we encounter, including plastic pipes, garbage bags, and carpet fibers.(4) Now day’s Twin-screw extruders are extensively used in pharmaceutical industry for preparation of variety of products. The twin-screw extruder has two agitator assemblies mounted on parallel shafts These shafts are driven through a splitter/reducer gear box and rotate together with the same direction of rotation (co-rotating) or in the opposite direction (counter rotating) and are often fully intermeshing. In such case, the agitator element wipes both the surface of the corresponding element on the adjacent shaft, and the internal surfaces of the mixing chamber and ensures a narrow and well-defined residence time distribution. In general, co-rotating shafts have better mixing capabilities as the surfaces of the screws move towards each other. This leads to a sharp change in mass flow between the screw surfaces (7, 35). As the screws rotate, the flight of one screw element wipes the flank of the adjacent screw, causing material to transfer from one screw to the other. In this manner the material is transported along the extruder barrel.
The twin-screw extruder is characterized by the following descriptive features (35):
1) Short residence time: The residence time in the twin-screw extruder in a typical extrusion processes ranges from 5-10 minutes depending on the feed rate and screw speed.
2) Self wiping screw profile: The self wiping screw profile i.e. the flight of the one
Screw wipes the root of the screw on the shaft next to it, ensures near complete emptying of the equipment and minimizes product wastage on shutdown.
3) Minimum inventory: Continuous operation of the equipment coupled with the continuous feeding of the material helps in reducing inventories of work in progress. This is important when processing valuable or potentially hazardous materials.
4) Versatility: Operating parameters can be changed easily and continuously to change extrusion rate or mixing action. The segmented screw elements allow agitator designs to be easily optimized to suit a particular application. Die plates can also be easily exchanged to alter the extrudate diameter. This allows processing of many different formulations on a single machine, leading to good equipment utilization. Polymers with a wide range of visco elastic and melt viscosities may be processed and even fine powders may be directly fed into the system.
5) Superior mixing: The screws have various mixing elements which impart two types of mixing, distributive mixing and dispersive mixing. The distributive mixing ideally maximizes the division and recombining of the material while minimizing energy. The dispersive mixing ideally breaks droplet or solid domains to fine morphologies using energy at or slightly above the threshold level needed. This mixing aids in efficient compounding of two or more materials in the twin-screw extruder.
Typical twin-screw laboratory scale machines have a diameter of 16-18 mm and length of four to ten times the diameter. A typical throughput for this type of equipment is 0.5- 5 gm/min. As the residence time in the extruder is rather short and the temperature of all the barrels are independent and can be accurately controlled from low temperatures (30oC) to high temperatures (300oC) degradation by heat can be minimized (35).
3.4 Process
The theoretical approach to understanding the melt extrusion process is therefore, generally presented by dividing the process of flow into four sections (7):
1) Feeding of the extruder.
2) Conveying of mass (mixing and reduction of particle size).
3) Flow through the die.
4) Exit from the die and down-stream processing.
The starting material is fed from a hopper directly in to the feed section, which has deeper flights or flights of greater pitch .This geometry enables the feed material to fall easily into the screw for conveying along the barrel. The pitch and helix angle determine the throughput at a constant rotation speed of the screws. The material is transported as a solid plug to the transition zone where it is mixed, compressed, melted and plasticized. (7) The polymer will begin to melt once the material enters the compression section of the extruder. The temperature of the melting section is normally set at 30–60OC above the glass transition temperature of amorphous polymers or the melting point of a semi crystalline polymer. (2)
Compression is developed by decreasing the thread pitch but maintaining a constant flight depth or by decreasing flight depth while maintaining a constant thread pitch (36). Both methods result in increased pressure as the material moves along the barrel. The melt moves by circulation in a helical path by means of transverse flow, drag flow, pressure flow and leakage; the latter two mechanisms reverse the flow of material along the barrel. The space between screw diameter and width of the barrel is normally in the range of 0.1-0.2 mm (35). The material reaches the metering zone in the form of a homogeneous plastic melt suitable for extrusion. For an extrudate of uniform thickness, flow must be consistent and without stagnant zones right up to the die entrance. The function of the metering zone is to reduce pulsating flow and ensure a uniform delivery rate through the die cavity (7).
3.5 Monitoring parameters
Extrusion processing requires close monitoring and understanding the various parameters: viscosity and variation of viscosity with shear rate and temperature, elasticity and extensional flow over hot metal surfaces. Today, extruders allow in-process monitoring and control of parameters, such as the temperature in the extruder, head and die as well as pressure in extruder and die (18). The main monitoring and controlling parameters are barrel temperatures, feed rate, screw speed, motor load and melt pressure. Barrel temperature, feed rate and screw speed are controlling parameters and motor load and melt pressure are monitoring parameters.
i) Barrel temperatures: The glass transition or melting temperatures of polymers and drug usually determines the barrel temperature.
ii) Feed rate and screw speed: The constant feeding rate and screw speed throughout the process is important as the combination of these two factors establishes the level of fill in extruder. This is critical to the process, because it governs the balance between the weak and strong mass transfer mode (35). Due to constant feed rate and screw speed, there will be a constant amount of material in the extruder and thus the shear stress and residence time applied to material remains constant.
iii) The motor load and melt pressure: These parameters depend on feed rate and Screw speed. With constant feed rate and screw speed these parameters depend upon the Molecular weight of polymer and drug as well as polymer miscibility in binary mixtures (7).
4. EVALUATION (5,33,38,39,40):
Evaluation of Formulations Produced via Hot Melt Extrusion that Contain High API Loading is done using several methods, depending upon type of dosage form developed. The evaluation methods can be used to differentiate between solid solutions (molecularly dispersed drug), solid dispersions in which drug is only partly molecularly dispersed and physical mixtures of drug and carrier.
It is difficult to precisely characterize systems which are molecularly dispersed from those that are not due to the complexity of the systems, and different analytical methods may yield contrasting results.
In general, dispersions in which no crystallinity can be detected are molecularly dispersed and the absence of crystallinity is used as a criterion to differentiate between solid solutions and solid dispersions.
4.1 Differential Scanning Calorimetry (DSC)
Thermoanalytical methods include those that examine the system as a function of temperature. Differential scanning calorimetry (DSC) has been widely used to study the thermal properties of materials used in hot melt extrusion. DSC can be used for the quantitative detection of transitions (melting point, glass transition) in which energy is required or liberated (i.e. endothermic and exothermic phase transformations). Generally, the hot-melt extrudate is scanned and compared to a physical mixture of the drug, polymeric carrier and other excipients. The lack of a melting transition in the DSC scan of the hot-melt extrudate indicates that the drug is present in an amorphous rather than crystalline form.
4.2 Thermo Gravimetric Analysis (TGA)
TGA is a measure of thermally induced weight loss of a material as a function of applied temperature. TGA is limited to studies involving either a weight gain or loss, and is commonly used to study desolvation and decomposition. TGA can be used as a screening tool for the thermal stability of materials used in hot-melt extrusion.
4.3 X-Ray Diffraction (XRD)
XRD is also used to characterize the crystalline properties of hot-melt extruded dosage forms. The principle of XRD is based on Bragg’s law, in which parallel incident X-rays strike the crystal planes and are then diffracted at angles related to the spacing between the planes of molecules in the lattice. Crystallinity is reflected by a characteristic fingerprint region in the diffraction pattern. If the fingerprints of the drug and carrier do not overlay one another, the crystallinity of the drug and polymer following hot-melt extrusion can be determined. Thus, X-ray diffraction can be used to differentiate between solid solutions, in which the drug is amorphous, and solid dispersions, in which it is at least partly present in the crystalline form, regardless of whether the carrier is amorphous or crystalline. However, the sensitivity of the XRD technique is limited and cannot generally detect crystallinity of less than 10%.
4.4 Infrared Spectroscopy (IR)
IR can be used to detect changes in bonding between functional groups due to structural changes or a lack of crystal structure. IR can be used to differentiate between peaks that are sensitive to changes in crystallinity from those that are not.
4.5 Nuclear Magnetic Resonance (NMR)
Solid state nuclear magnetic resonance (NMR) has been used to probe the crystallinity of materials. Although any NMR-active nucleus can be studied, most efforts have focused on 13C investigations.
4.6 Microscopy
Microscopy is one of the best methods to study the crystalline properties of hot-melt extrudates. Both optical and electron methods are suitable to examine the surface morphology of samples to probe for the presence of crystalline particles or amorphous domains. It is also possible to obtain reliable particle size information using these techniques.
For over two decades, the value of ‘‘Hot Melt Extrusion’’ in the pharmaceutical industry has been recognized. The potential of automation, reduction of capital investment, and the reduction in labor costs has given hot-melt extrusion an importance for consideration. (2)
5.1 General Application
Extrusion technology is extensively applied in the plastic and rubber industries, where it is one of the most important fabrication processes. Examples of products made from extruded polymers include pipes, hoses, insulated wires and cables, plastic and rubber sheeting, and polystyrene tiles. Plastics that are commonly processed by extrusion include acrylics (polymethacrylates, polyacrylates) and cellulosics (cellulose acetate, propionate, and acetate butyrate), polyethylene (low and high density), poly propylene, polystyrene, vinyl plastics, polycarbonates, and nylons.
In the food industry extrusion has been utilized since 1930 for pasta production. A widely used versatile technique combines cooking and extrusion in a so-called extrusion cooker.
In the animal feed industry, extrusion is most commonly applied as a means of producing palletized feeds. The manufacture of implants by extrusion or
Injection molding is another field of application in the veterinary field. (10)
5.2 Applications in the Pharmaceutical Industry
HME is considered to be an efficient technique in developing solid molecular dispersions and has been demonstrated to provide sustained, modified and targeted drug delivery resulting in improved bioavailability.(p) Hot Melt extrusion process is 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, as well as other routes of admnistration.(6)
In pharmaceutical industry the melt extrusion has been used for various
purposes, such as :( 10, 12, 13, 41)
1)Masking the bitter taste of an active drug.
2)Formation of polymer-drug solutions/dispersions:
Increased drug solubility
Increased drug dissolution rate
3) Formulation of controlled release dosage forms (including implants).
4) Formulation of targeted release dosage forms.
Until recently, hot-melt extrusion had not received much attention in the pharmaceutical literature the Pellets comprising cellulose acetate phthalate were prepared using a rudimentary ram extruder in 1969 and studied for dissolution rates in relation to pellet geometry.
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. (10)
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). 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. (2)
In 1996 Aitken-Nichol and co-workers investigated the viability of hot-melt extrusion technology for the production of thin, flexible acrylic films for topical drug delivery. One of the advantages they pointed out was that the delivery manufacturing process is not restricted by solvent concerns. They also studied the effect of types and levels of plasticizers using the model drug lidocaine HCL; on the glass transition temperature (Tg) and the mechanical properties of high density polyethylene (HDPE) and Eudragit E-100 extruded films. The authors found that hot-melt extrusion was viable technology for the production of free films of this acrylic resin. (2)
Another application of hot-melt extrusion was described by Miyagawa, Sato, and coworkers in 1996 and 1997. 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.
Zhang and McGinity (20) in 1999 investigated the properties of polyethylene oxide (PEO) as a drug carrier and studied the release mechanism of chlopheniramine maleate (CPM) from matrix tablets. In these extruded tablets, PEG 3350 was included as a plasticizer to facilitate processing. The molecular weight of the PEO, the drug loading percentage, and the inclusion of PEG were all found to influence the processing conditions and the drug release properties of the extruded tablets. An increase in the percentage of PEG 3350 increased the release rate of the drug. PEG 3350 is composed of the same structural unit as PEO. The hydration and dissolution rate of the entire matrix system were thus accelerated due to the Presence of the plasticizer.
Perissutti and co-workers (2002) applied hot-melt extrusion technology to improve dissolution of carbamazepine.
Hülsmann and co-workers worked on hot melt extrusion to improve solubility and dissolution of 17-Estradiol hemihydrate, a poorly water soluble drug.
Nakamichi and co-workers prepared a floating sustained release dosage form composed of nicardipine hydrochloride and hydroxypropylmethylcellulose actate succinate, using twin-screw extruder. It was shown that the puffed dosage form prepared by twin-screw extruder, consisting enteric polymer was very helpful as a floating dosage form that was retained for long period in the stomach.
Along with literature describing the in vitro performance of solid dispersions a number of melt extruded solid dispersions have been examined in human clinical studies.
The antiretroviral agent, loviride when melt extruded to a solid molecular dispersion in HPMC showed remarkable, lower food effect compared to capsules.
Antifungal compositions of intraconazole were prepared as solid dispersions using the melt extrusion process. In a limited number of volunteers these tablets gave an area under the curve (AUC) in the fasted state that was 2.3 times the AUC of the marketed reference capsules. (10)
The interest in HME is growing rapidly. The US and Germany hold approximately more than half (56%) of all issued patents. In spite of this increased interest, there are few commercialized HME pharmaceutical products currently marketed.
There is no. of companies using HME as a drug delivery technology including Pharma Form (TX, USA) and SOLIQS (Germany). SOLIQS has developed a proprietary Meltrex formulation and redeveloped a protease inhibitor combination product, Kaletra, for the treatment of human immunodeficiency virus (HIV). Moreover, HME Kaletra tablets were shown to have significant advantages for the patient compared with the previous soft gel capsule formulation, such as reduced dosing frequency and improved stability.
SOLIQS has also developed a fast-onset ibuprofen system and a sustained release formulation of verapamil (Isoptin SRE) that was the first directly shaped HME product on the market. (3)
In the same instance there is no. of products which has been developed by no. of companies using HME as drug delivery technology and this technology is becoming a robust in the field of pharmaceuticals.
The application of HME technology in the pharmaceutical industry has tended to focus on the development of bio-enhanced formulations to increase the efficacy of poorly water soluble compounds. There has also been an increase in the application of HME for the development of controlled release formulations, in the form of pellets, beads or minimatrices, and as a means to facilitate the continuous processing of products to reduce the number of manufacturing unit operations. (3)
Moreover, there have been several articles investigating the application of HME technology for the production of Bio adhesive hot-melt extruded film for topical and mucosal adhesion applications and drug delivery. (42)
Recent studies have also demonstrated the production of biocompatible shape-memory polymers for use in biomedical applications, using HME as a manufacturing process. The production of multiparticulate dosage forms using HME has been investigated using hot melt pelletization and, lately, the use of die, face-cutting the polymer extrudate to produce HME pellets shows the continuing utilization of technology from the plastics industry for pharmaceutical manufacturing.
The scope of the technology has also been broadened to expand the range of polymers and APIs that can be processed through application of HME.
The growing market in medical devices, including those that incorporate drugs such as biodegradable stents and drug loaded catheters, will require HME manufacturing processes to be commercialized, and may lead to new areas of collaboration across pharmaceutical, medical device and biotechnology research.
The HME is a versatile processing technology for pharmaceutical industry and has broad prospectus for future. (3)
Hot Melt Extrusion is an efficient technology for manufacture of drug delivery systems. The products prepared by Hot Melt Extrusion are mainly found in form of semi-solid and solid preparations. The potential of this technology in pharmaceutical industry is reflected through its wide scope in producing different dosage forms including oral dosage forms, implants bioadhesive ophthalmic inserts, topical films, effervescent tablets, controlled released dosage forms etc.
Formulations with high API loading, extended release properties and excellent content uniformity can be successfully prepared via HME. HME-prepared tablets exhibited exceptional tablet hardness and friability results over control samples produced via direct compression.
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. 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.
Success of this technique is dependent on the processibility (and stability) of the drug and/or polymers and optimization of this technique requires fundamental knowledge of the physicochemical properties of the drugs and polymers.
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 nano particles released from molecular dispersions manufactured by melt extrusion.
Hot Melt Extrusion appears to be a viable approach to produce dosage forms that contain high API loadings and exhibit controlled release behavior. It is a valuable technique for poorly soluble APIs


1. Repka MA, Battu SK, Upadhye SB, Tumma S, Crowley MM, Zhang F, et al. Pharmaceutical Application of Hot-Melt Extrusion: Part-II. Drug Dev Ind Pharm 2007; 33(10):1043-57.
2.Swarbrick James, editor. Encyclopedia of Pharmaceutical Technology. 3rd Ed (3); P.2004-20.
3.Andrews, Gavin P.J, David S, Osama AM, Daniel NM, Mark.S. Hot Melt Extrusion: An Emerging Drug Delivery Technology.Pharmaceutical Technology Europe 2009; 21(1):24-27.
4.M Charlie. Continuous mixing of solid dosage forms via Hot-Melt Extrusion.    Pharmaceutical Technology 2008; 32(10):76-86.
5.Prodduturi s, Urman KL, Otaigbe JU, Repka MA. Stabilization of Hot-Melt Extrusion Formulations Containing Solid Solutions Using Polymer Blends. AAPS PharmSciTech 2007; 8 (2):E1-E10.
6.Radl S, Tritthart T, Khinast JG. Modeling Hot-Melt Extrusion Pelletizers. Extended Upload Report 2008 Annual Meeting.Abstract-178e, ID no.130125.
7.Breitenbach J, Soliqs, GmbH A, Co KG.  Melt Extrusion: From Process to Drug Delivery Technology. European Journal of Pharmaceutics and Biopharmaceutics 2002; 54(2): 107-117.
10. Choksi R, Zia H. Hot-Melt Extrusion Technique: A Review. Iranian Journal of Pharmaceutical Research 2004; (3):3-16.
11. granulation techniques/reviews.
12. McGnity JW, KOleng JJ. Preparation and Evaluation of Rapid Release Granules Using Novel Melt Extrusion Technique. 2004; 1997: 153-54.
13. David S. Jones. Engineering Drug Delivery Using Polymer Extrusion/Injection Moulding Technologies. School of Pharmacy, Queen’s University, Belfast: 4-9, 18, 25, 27.
14. Grunhagen HH, Muller O. Melt extrusion technology. Pharm. Manu. Int. 1995, 1, 167–170.
15. Mcginity JW, Zhang F, Repka M and Koleng JJ. Hot Melt Extrusion Process as a Pharmaceutical Process. Am. Pharm. Rev.2001: 25-36.
16. Follonier N, Doelker E, Cole ET. Various Ways of Modulating the Release of Diltiazem Hydrochloride from Hot-Melt Extruded Sustained-Release Pellets Prepared using Polymeric Material. J. Controlled Release 1995. (36): 342 250.
17. Cuff G, Raouf F. A preliminary Evaluation of Injection Molding as a Technology to Produce Tablets. Pharm. Tech.1998: 97-106.
18. Aitken-Nichol C, Zhang F, Mcginity JW. Hot Melt Extrusion of Acrylic Films. Pharm. Res.1996; 13: 804-808.
19. Follonier N, Doelker E, Cole E.T. Evaluation of Hot Melt Extrusion as a New Technique for the Production of Polymer-Based Pellets for Sustained Release Capsules Containing High Loading of Freely Soluble Drugs. Drug Dev. Ind. Pharm. 1994; 20 (8): 1323–1339.
20. Zhang F, Mcginity JW. Properties of Sustained Release Tablets Prepared By Hot-Melt Extrusion. Pharm. Develop. Tech.1998; 14: 242-250.
21. Miyagawa Y, Okabe T, Yamaguchi Y, Miyajima M, Sunada H. Controlled Release of Diclofenac Sodium from Wax Matrix Granule. Int. J. Pharm. 1996; 138: 215–254.
22. Sato H, Miyagawa Y, Okabe T. Dissolution Mechanism of Diclofenac Sodium from Wax Matrix Granules. J. Pharm. Sci. 1997; 86: 929–934.
23. Tantishaiyakul V, Kaewnopparat N, Ingkatawornwong S. Properties of Solid Dispersions of Piroxicam in Polyvinylpyrrolidone. Int. J. Pharm.1999; 181: 143-151.
24. Zingone G, Moneghini M, Rupena P, Vojnovic D. Chracterization and Dissolution Study of Solid Dispersions of Theophylline and Indomethacin with PVP/VA Copolymers. STP Pharm. Sci.1992; 2: 186- 192.
25. Yano K, Kajiyama Y, Hamada M, Yamamoto K. Constitution of Colloidal Particles Formed from Solid Dispersion System. Chem. Pharm. Bull.1997; 45:1339-1344.
26. Abd A, El-Bary A, Geneidi AS, Amin SY, Elainan AA. Preparation and Pharmacokinetic Evaluation of Carbamazepinr Controlled Release Solid Dispersion Granules. J. drug Res. Egypt 1998; 22: 15- 31.
27. Henrist D, Remon JP. Influence of the Process Parameters on the Characteristics of Starch Based Hot Stage Exrudates. Int. J. Pharm.1999; 189: 7-17.
28. Ndindayino F, Vervaet C, Van den Mooter G , Remon JP. Direct Compression and Moulding Properties of Co-Extruded Iso-Melt/Drug Mixtures. Int. J. Pharm.2002; 235: 159-168.
29. Karen AC, Mark JH, et al. Hypermellose, Ethylcellulose, Polyethylene Oxide Use in Hot Melt Extrusion. Pharmaceutical Technology.2006:26-33.
30. Repka MA, Gerding TG, Repka SL , Mcginity JW. Influence of Plasticizers and Drugs on the Physical Mechanical Properties of Hydroxypropyl Cellulose Films Prepared by Hot-Melt Extrusion. Drug Develop.Ind. Pharm.1999; 25: 625- 633.
31. Price JC. Polyethylene Glycol. In: Wade A, Weller PJ, editors. Handbook of Pharmaceutical Excipients. 2nd ed. American Pharmaceutical Association, Washington; 1994: 355-361.
32. Gutierrz-Rocca JC and Mcginity JW. Influence of Aging on the Physical-   Mechanical Properties of Acrylic Resin Films Cast from Aqueous Dispersions and Organic Solutions. Drug Develop. Ind. Pharm.1993; 19: 315- 332.
33. Crowley MM, Physicochemical and Mechanical Characterization of Hot-Melt   Extruded Dosage Forms, The University of Texas at Austin 2003:  31-33, 40- 44.
34. Kruder GA. Extrusion. In: Encyclopedia of Polymer Science and Engineering  Vol. 1, 2nd ed. John Wiley & Sons Inc, New York. 1985: 571-631.
35. Martin C. Guidelines for Operation of Leistritz Twin screw Extruder, American Leistritz Corporation, Somerville 2001:21-25.
36. Johnson PS. Development in Extrusion Science and Technology, Polysar   technical publication, Ontario, 1982: 42-46.
37. Ghebre-Sellassie I, Martin C. Pharmaceutical Extrusion Technology. Marcel  Dekker, Inc. 2003: 197-200,370,374,395.
38. Coppens K, Hall M, Vicky H,  Koblinski B,  Larsen P,  Mandare P, et al.  Evaluation of Formulations Produced via Hot Melt Extrusion That Contain High API Loading and Exhibit Controlled Release, American Association of Pharmaceutical Scientists 2007:2-4.
39. Chokshi RJ, Sandhu HK, Iyer RM, Shah NH, Malick AW, Zia H. Evaluation of  Hot Melt Extrusion Technology For Delivering A Poorly Water Soluble Drug. University of Rhode Island, Hoffmann-La Roche Inc.
40. Andrews Gavin P, Jones David S, Diak Osama A, McCoy Colin P, Watts Alan  B, McGinity James W. The Manufacture and Characterisation of Hot-Melt Extruded Enteric Tablets. European journal of pharmaceutics and Biopharmaceutics 2008;69(1):264-73.
41. Zhang F ‌, McGinity JW, Properties of Sustained-Release Tablets Prepared by   Hot-Melt Extrusion. Pharmaceutical Development and Technology 1999; 4(2): 241-50.
42. Repka MA, Repka SL, Mcginity JW. Bioadhesive hot-melt extruded film for topical  and mucosal adhesion applications and drug delivery and process for  preparation thereof. United States Patent 2002: no. 6375963.

Source(s) of Funding


Competing Interests



This article has been downloaded from WebmedCentral. With our unique author driven post publication peer review, contents posted on this web portal do not undergo any prepublication peer or editorial review. It is completely the responsibility of the authors to ensure not only scientific and ethical standards of the manuscript but also its grammatical accuracy. Authors must ensure that they obtain all the necessary permissions before submitting any information that requires obtaining a consent or approval from a third party. Authors should also ensure not to submit any information which they do not have the copyright of or of which they have transferred the copyrights to a third party.
Contents on WebmedCentral are purely for biomedical researchers and scientists. They are not meant to cater to the needs of an individual patient. The web portal or any content(s) therein is neither designed to support, nor replace, the relationship that exists between a patient/site visitor and his/her physician. Your use of the WebmedCentral site and its contents is entirely at your own risk. We do not take any responsibility for any harm that you may suffer or inflict on a third person by following the contents of this website.

1 review posted so far

Review on Hot Melt Extrusion Technique for EGR 599
Posted by Mr. Benjamin Burdette on 19 Nov 2016 04:15:48 AM GMT Reviewed by Interested Peers

0 comments posted so far

Please use this functionality to flag objectionable, inappropriate, inaccurate, and offensive content to WebmedCentral Team and the authors.


Author Comments
0 comments posted so far


WebmedCentral Article: Hot Melt Extrusion Technique

What is article Popularity?

Article popularity is calculated by considering the scores: age of the article
Popularity = (P - 1) / (T + 2)^1.5
P : points is the sum of individual scores, which includes article Views, Downloads, Reviews, Comments and their weightage

Scores   Weightage
Views Points X 1
Download Points X 2
Comment Points X 5
Review Points X 10
Points= sum(Views Points + Download Points + Comment Points + Review Points)
T : time since submission in hours.
P is subtracted by 1 to negate submitter's vote.
Age factor is (time since submission in hours plus two) to the power of 1.5.factor.

How Article Quality Works?

For each article Authors/Readers, Reviewers and WMC Editors can review/rate the articles. These ratings are used to determine Feedback Scores.

In most cases, article receive ratings in the range of 0 to 10. We calculate average of all the ratings and consider it as article quality.

Quality=Average(Authors/Readers Ratings + Reviewers Ratings + WMC Editor Ratings)