Introduction:

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

Extrusion can be operated as a continuous process, which is capable of consistent product flow at relatively high throughput rates. An extruder consists of two distinct parts: the conveying system which transports the material and imparts a degree of distributive and dispersive mixing, and the die system which forms the material into the required shape. Extrusion may be broadly classified into a molten system under temperature control or a semisolid viscous system. In molten extrusion, heat is applied to the material in order to control its viscosity and enable it to flow through the die. Whereas, semisolid systems are multiphase concentrated dispersions containing a high proportion of solid mixed with liquid phase.

Hot-melt extrusion is an efficient technology for producing solid molecular dispersions with considerable advantages over solvent-based processes such as spray drying and coprecipitation. Hot-melt extrusion has been demonstrated to provide sustained, modified, and targeted drug delivery. 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. Hot-Melt Extrusion (HME) technology is currently being explored and used in the pharmaceutical field because it offers several advantages over traditional processing methods.

1. DEFINITION^4,5:

Hot Melt Extrusion is the process of embedding drug in a polymeric carrier.

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. 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.

1.1. THE EXTRUSION PROCESS^6,7

Extruders for pharmaceutical use have been designed and adopted for mixing drugs with carriers in various dosage forms. The significant difference between extruders for thermoplastics and pharmaceutical applications is the equipment used and hence the contact surface, which must meet regulatory requirements. The contact parts of the extruders used in pharmaceuticals must not be reactive nor may they release components into the products. The extruder equipment is specially configured to fulfill all cleaning and validation standards applicable to the pharmaceutical industry. The utilization of extruders in the pharmaceutical industry cannot be seen as a niche application; this is clearly shown in below fig.1.

Application		Dosage form
· Bioavailability enhancement · Controlled release · Sustained release · Safer medication · Reduced side effect		· Direct shaping · Powders · Granules, Spheres · Films & Patches · Injection moiding

Formulation		Process
· Broad excipient range available · Reduced no. of ingredients for formulation		· High throughput flexible with respect to time & scale · Continous quality monitoring · Continous, low cost · Small footprint

Fig.1.The 4 Filed of versatility of hot-melt extrusion technology in the pharmaceutical Industry

Demonstrating four field of versatility of the technology. Not all of the benefits have been actively adopted to date.

In principle, an extruder consist of barrels enclosing single or twin screws which transport and subsequently force the melt through a die, giving it a particular shape. The barrel can be heated to the desired temperature. Due to the external heat and shear provided by the screw, the polymer is plasticized and hence its viscosity reduced. Since the extruder is fed at one side and the extruded material exits from the other side, it is a typical continuous process; this makes it even more attractive for pharmaceuticals. The hot-melt extrusion process comprises the steps melting, mixing and shaping. The purpose of the feeding section is to transfer the materials from the feeder to the barrel. The polymer mixture typically begins to soften in the melting zone. The melt moves by circulation in a helical patch by means of transverse flow, drug flow, pressure flow and leakages. Thermoplastic polymers primarily exist in a molten state when entering the shaping section. The function of this zone is to reduce the pulsation flow and ensure a uniform delivery rate through the die. At the end of the barrels, the attached die dictates the shape of the extrudates.

The complete extrusion set-up consists of four distinct parts is shown in above fig.2.

1. An opening through which material enters the barrel, that may have a hopper that is filled with the materials to be extruded, or that may be continuously supplied to in a controlled manner by one or more external feeders.

2. A conveying section, which comprises the barrel and the screw that transport, and where applicable, mix the material.

3. An orifice for shaping the material as it leaves the extruder.

4. Downstream auxillary equipment for cooling, cutting and/or collecting the

finished product.

2. Materials used in hme formulation^8,9,10,11

The use of HME in pharmaceutical applications requires the inclusion of a number of functional excipients and a complex mixture of active ingredients in the formulation, which should possess the following characteristics:

1. They must meet the same levels of purity and safety as those used in traditional dosage forms.

2. They must be able to deform easily inside the extruder and solidify on exiting it.

3. They must be thermostable and maintain an acceptable physical and chemical stability during the HME process and afterward during long-term storage. Thermal stability of the individual compounds is a prerequisite for the process, although the short processing time used in the HME process does not limit the use of all thermolabile compounds.

4. The desired in vitro release and in vivo performance should be achieved by the final dosage form. These functional excipients can be broadly classified as matrix carriers, release-modifying agents, fillers, thermal lubricants, stabilizing agents, plasticizers, antioxidants, and miscellaneous additives. The selection and use of the various excipients can impart specific properties to hot-melt extruded pharmaceuticals in a manner similar to those obtained with traditional dosage forms.

Fig.2. HME process

1.2 Advantages of HME

Table 1.Advantage of HME

Sr.No.	Traditional process of organic and aqueous Solvent Extrusion	Hot Melt Extrusion
1	Require Solvent and drying step	An anhydrous process and no solvent is required.
2	May be a concern for moisture sensitive drugs	Suitable for moisture sensitive drugs.
3	Aqueous extrusion mostly involves the use of microcrystalline cellulose (MCC) which yields no disintegrating pellets and lowering of drug load may be required to increase the API release	No Such Limitation
4	Large amount of water is required for granulation and hence long drying times, leading to shrinkage and densification of pellets during drying which may also impact the stability. Additionally, oversized particles after drying are very difficult to reprocess	No such Concern
5	Organic solvent extrusion is suitable for moisture sensitive drugs, but the non-volatile organic solvents and oils result in sticky products and the large amount of volatile solvents required for granulation leads to safety hazards needing explosion proof equipment	No Such Concern
6	Multi-step, non continuous process: at least for spheronization	A fast continuous manufacturing process without the requirement of drying and a short thermal exposure of active allows processing of heat sensitive drugs

1.3. Disadvantages of HME

Table 2.Disadvantages of HME

Sr.No.	Hot melt Extrusion	Traditional process of aqueous and organic solvent extrusion
1	High process Temperature	No requirement of high temperature
2	High Process Knowledge required.	No special skill require for operation
3	Type and amount of Plasticizer may affect the dissolution	No Such Concern
4	Reprocessing of material is difficult	Reprocessing is not difficult
5	Cleaning is difficult and the material requirement for extruder often conflict with good manufacturing practices (GMP) issues	No Such Concern

2.1. Active ingredient:

Active ingredients selected must be stable at the processing temperature and be capable of mixing in the molten state. It should be compatible with the polymer and other excipients used in the process.

2.2. Carriers:

In hot melt extrude dosage form, the active drug is embedded in the carrier which must be able to deform easily and remains stable during processing. The molten carriers functioned as thermal binder and drug release retardants. The choice of the carrier selection is based on the Process ability and thermal stability as well as drug-polymer compatibility, drug release kinetics and route of administration.

The carriers used in hot melt extruded dosage forms can be grouped into two categories including polymeric and non-polymeric carriers. The selection of an appropriate carrier for the HME process mainly depends on the drug–polymer miscibility, polymer stability, and function of the final dosage form. Because numerous drugs are heat-sensitive, HME requires the selection of polymers that can be processed at low temperatures. Commonly used polymeric carriers include polyvinyl pyrrolidone (PVP) or its copolymers such as polyvinyl pyrrolidone-vinyl acetate (PVP-VA), poly (ethylene-co-vinyl acetate), various grades of polyethylene glycol (PEG), cellulose-esters and cellulose acrylates, polyethylene oxides (PEOs) of varying molecular weights, poly-methacrylate derivatives, and poloxamers. Repka et al. showed that a thermo labile drug such as hydrocortisone could be incorporated into hydroxyl propyl cellulose (HPC) films produced by melt extrusion.

2.3. Plasticizers¹²:

Plasticizer is used to reduce the glass transition temperature and thus melt viscosity of a polymer leading to facilitate the hot melt extrusion process.

Plasticizers can be divided into different classes such as traditional, non-traditional, and special plasticizers. The most commonly used traditional plasticizers are triacetin, citrate ester, vitamin E D-alpha tocopheryl PEG 1000 succinate (TPGS), surfactants, and low molecular-weight polyethylene glycols. Non-traditional plasticizers are included in formulations to serve other critical functions and are often low-molecular-weight materials such as the active substance itself. Special plasticizers are low-molecular-weight materials, which also act as plasticizers for polymeric carriers depending on their physical state. This category includes pressurized CO2, which when injected during the HME process, reduces the temperature of various polymers in addition to acting as a foaming agent.

2.4 Thermal Lubricant:

Thermal lubricant is defined as materials which are added into the formulation to improve its Processability. Thermal lubricants decrease the melt viscosity of the molten materials and reduce the friction of molten materials in the extruder during processing. Unlike plasticizers thermal lubricants have just little effect on the solid state properties. Thermal lubricant is also affecting the final product properties. Glycerol monostearate, wax material, are two examples of the thermal lubricant.

2.5 Antioxidants:

The degradation of materials may occur under the thermal process. Incorporation of antioxidants can prevent the thermal oxidation thus improve the stability of materials. Some substances used for prevention of oxidation are ascorbic acid and citric acid.

3. Hot-melt extrusion: equipmentand process^13,14:

Extrusion is the process of changing the physical properties of the substance by forcing it through an orifice or die under controlled conditions. The extrusion equipment is classified into three main categories: ram, radial screen, and roll and screw extruders . Among these, the screw extruders are the most important in the pharmaceutical industry because they continuously convert feed material to the finished form such as a rod, tube, or film. The rotating screws force the feed material forward towards the die, and the material is softened by the frictional heat developed through the barrel wall. The feed reaches the end of the screw in a viscous state that can then be forced through an orifice (or die) and molded into the desired shape.

Figure 3: Ram Extruder

3.1. Ram extrusion¹⁵:

Ram extrusion is simple in design and discontinuity in the mode of operation. It operates with the positive displacement ram which generates high pressure to push materials through the die is shown in below fig.3. Materials are heated in the cylinder until soften materials are obtained thus extruding through a desired shape die is pushed by a ram. The drawback of ram extrusion is the limited melting capacity and poor temperature uniformity thus leading to the poor temperature uniformity. In addition the extruded products have poor homogeneity than the products from screw extrusion.

3.2.Types of screw extruders^16,17,18:

Pharmaceutical screw extruders are designed based on the desired extrudate and are required to meet the current regulatory standards for the manufacture of dosage forms. A screw extruder provides higher shear stress and intense mixing. Screw extruder consists of at least three parts: (i) a conveying system for material transport and mixing, ii) a die for forming, and (iii) equipment for cooling, cutting and collecting. The components in the extruder are a feed hopper, a barrel with heating system, a rotating screw and die.

Screw extruder is classified into two categories;

(i) Single Screw Extruder

(ii) Twin Screw Extruder.

(iii) Multi Screw Extruder

3.2.1.Single Screw Extruder(SSE)¹⁹:

SSEs are the most widely used extruders because they are mechanically simple devices that have only had slight modifications to their operational principles since their invention around 1897. The SSE consists of one continuously rotating screw in a barrel that results in good quality molten material (melt) and generates a high stable pressure for a consistent output (Fig. 4). In general, the screw design may consist of 20 or more turns with a pitch similar to the screw diameter, thereby creating a long slender machine in which substantial longitudinal temperature gradients can be maintained and controlled. It also provides considerable residence time, thereby permitting an adequate degree of end-to-end mixing. Different operations can be performed in the SSE such as feeding of raw materials, conveying, melting, devolatilizing, pumping, and shaping. Mixing can also accomplished for less demanding applications. The SSE receives the raw material in the feeding area and then conveys it along a flighted screw enclosed in the barrel. The SSE is flood fed via the feed hopper, and the screw rpm determines the output rate. However, they may occasionally be starve fed, where the feed system sets the mass flow rate and is independent of the screw rpm. The flights of the screw and the inner surface of the barrel form a flow channel due to the rotation of the screw. As a function of the frictional forces in the flow channel, the SSE propels the raw material towards the proximal portion of the screw. The heated barrel surface and the mechanical energy input supplied by the screws induce the material to form a melt pool, which is inversely proportional to the solid bed size, and therefore, the melt pool increases as the solid bed decreases. Finally, the molten extrudate is pumped through a die that imparts a definite shape for further downstream processing. These essential features combined with low maintenance and low cost make the HME the equipment of choice for the production of almost all extruded products.

3.2.2.Twin Screw Extruder(TSE)^20:

Twin screw extruder uses two screws arranged side by side. The use of two screws allows a number of different configurations to be obtained. The two screws can either rotate in the same direction (co-rotation), or the screws can rotate in opposite directions (counter-rotation) shown in below fig.5.Co-rotational screws can rotate either clockwise or counterclockwise, and both directions are equivalent from a processing standpoint. If the two screws rotate in different directions (either rotate toward the center, or rotate away from the center).

Figure5: Co-rotating(left) and Counter rotating(right)

They are known as counter-rotating extruders. Co-rotation extruder is further classified into (i) fully intermeshing co-rotation extruder and (ii) non-intermeshing co-rotation extruder. The fully intermeshing extrude is self-wiping where it minimizes the non-motion and prevents localized overheating of materials in the extruder. The extruder operates by first in/ first out principle since the materials does not rotate along with the screw. The non-intermeshing extruder are often used for processing when large amounts of volatiles need to be removed from a material due to the large vent opening that can be accommodated as the screws are positioned apart from each other. They are also used when processing highly viscous materials, where the intermeshing extruder can cause problematical torque buildups. The hot melt extrusion process is divided the process into four sections: (i) feeding of the extruder, (ii) conveying of mass (mixing and reduction of particle size), (iii) flowing through the die and (iv) exiting from the die and down-stream processing. The screw is divided into three sections along the length of the barrel: (i) feeding, (ii) melting or compression, and (iii) metering. Feeding section is to transfer the materials from the hopper to the barrel. The polymer typically begins to soften and melt in the compression zone mainly by the heat generated from the frictional force between materials and screws and also the heated barrel. The melt moves circularly in a helical path by means of transverse flow, drag flow, pressure flow, and leakage. Thermoplastic polymers primarily exist in a molten state when entering the metering section. Metering zone reduces the pulsating flow and ensures a uniform delivery rate through the die.

Fig. 6. Cross-section of single- and twin-screw extruders

Table 6.Comparison between Single screw and Twin screw extruder²¹:

Single Screw Extruder	Twin Screw Extruder
Use in simple profile extrusion and co-extrusion	Used in compounding profile and reactive extrusion
Modular design of Screw and barrel is rarely used, less flexibility	Often used with modular design of screw and barrel, great flexibility
Prediction of Extruder performance less difficult than for TSE	Prediction of extruder performance is often difficult
Fair Feeding, Slippery additives tend to cause problems	Good feeding, can handle pellets, powder, liquids
Fair melting, continuous solid melting mechanism	Good melting, dispersed solid melting mechanism
Good distributive mixing with effective mixing elements	Good distributive mixing with effective mixing elements
Good dispersive mixing with effective mixing elements	Good dispersive mixing with effect mixing elements
Fair degassing	Good degassing
Not self –wiping, barrel is wiped but screw root and flight flanks are not	Intermeshing can have completely self wiping characteristics
Relatively inexpensive	Modular is very Expensive
Usually run between 10-50 rpm; high screw speed possible but not often used	Co-rotating can run at very high screw speed, up to 1400rpm

3.2.3. Multiple Screw Extruder (MSE):²²

The extruders that incorporate more than two screws are generally referred to as MSE. Depending upon the number of screws used in the extruder, the assembly may vary. For example, if the extruder has six or eight screws, then they are organized in a circumferential manner. On the other hand, if the extruder has three or five screws, then they are set up in a linear fashion, and in the case of the four screws, the extruder has a control screw and three spurs. These arrangements of the screws in the MSE are in no unique sense and may vary depending upon the requirements of the food and pharmaceutical industries. MSE are preferred over SSE as a highly shear-dominated flow of the melted material in SSE results in a large amount of heat generation, which thermally degrades the material (thermal labile material). However, in MSE, due to positive displacement flow in the intermeshing region between the screws, prevention of degradation of thermal labile materials is attained.

APPLICATIONS²³:

· The applications of hot stage extrusion has gained much attention in advanced drug delivery systems due to its potential to manufacture dosage forms with improved physicochemical properties like tablets, capsules, granules, pellets, powders, films, implants, inserts etc.

· It can provide sustained, modified, targeted and local drug delivery with the use of suitable formulation and process parameters.

· HME is an efficient technology and is used today for the preparation of solid molecular dispersions with considerable advantages over solvent based processes such as spray drying and co-precipitation. It helps in the scale-up of solid dispersions for solubility enhancements of poorly soluble drugs.

· It can also be used for the development and scale up of drug-in-adhesive type transdermal drug delivery system.

· It is a viable technology to produce thin stable and homogenous drug incorporated polymeric film matrices. These matrices have potential for immediate or sustained release dosage forms, e.g. Lidocaine solid solution in the form of films for local delivery.

· This technique of melt extrusion is used in the fabrication of ocular inserts as solid polymeric rods to be placed in the cul-de-sac of the eyes.

· Preparation of the enteric capsules by HME is a suitable alternative to film coating for preparing delayed release matrix tablet systems and enteric capsules.

· This technology is used in the preparation of floating tablets for gastro retentive controlled drug release system and gastro resistant matrix tablets.

· Taste masked products can also be prepared by choosing the drug and polymer having opposite charges for ionic interaction to take place between them.

· It is used to prepare tablets for targeted delivery and the controlled release, for e.g.5-amino salicylic acid (ASA) tablets for colonic drug delivery of 5-

ASA.

· Hot melt extruded pellets are unique dosage forms because they can be used for immediate release or controlled release applications depending on the properties of matrix polymers.

· Production of minitablets and mini matrices is preferred over the production of pellets, as the scale-up of pelletisation process is a problem. They are generally prepared by using waxes, starch derivatives and matrices.

· The extrudates are milled and sieved in order to obtain granules, which can be compressed into mini tablets. Sustained release mini matrices can also be prepared by HME for obtaining zero order release.

· Matrix-in-cylinder system consisting of a barrier in the form of hot melt extruded pipes (e.g. ethyl cellulose pipe) surrounding a core (HPMC-Gelucire 44/4 core) can be formulated. Drug release characteristics of the matrix-in cylinder system can be modified by changing the length of the system.

CONCLUSIONS:

HME has proven to be a robust method of producing numerous drug delivery systems and therefore it has been found to be useful in the pharmaceutical industry enlarging the scope to include a range of polymers and APIs that can be processed with or without plasticizers. It has also been documented that HME is a solvent-free, robust, quick, and economy-favored manufacturing process for the production of a large variety of pharmaceutical dosage forms.

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Received on 16.05.2016 Modified on 17.07.2016

Research J. Science and Tech. 2016; 8(3):155-162.

DOI: 10.5958/2349-2988.2016.00022.X