Melt Extrusion Presentation

Melt extrusionPresented by:Rana Hashlamoun Supervised by :Dr Ashok Komar

Extrusion Extrusion is a process that involves forcing a raw material or

blend through a die or orifice under set conditions such as temperature, pressure, rate of mixing and feed-rate, for the purpose of producing a stable product of uniform shape and density The two main advantages of this process over other manufacturing processes are 1-its ability to create very complex cross-sections and work materials that are brittle, because the material only encounters compressive and shear stresses. 2- It also forms finished parts with an excellent surface finish. Extrusion may be : -continuous (theoretically producing indefinitely long material) or - semi-continuous (producing many pieces).

The extrusion process can be done with the material hot or

cold. Commonly extruded materials include metals, polymers, ceramics, concrete foodstuffs . The technology has now found application in the pharmaceutical industry in the area of drug deliver

Hot extrusion Hot extrusion is a hot working process which means it is done above the

material's recrystallization temperature to : 1-keep the material from work hardening and 2-to make it easier to push the material through the die. Most hot extrusions are done on horizontal hydraulic presses that range from 230 to 11,000 metric tons. Pressures range (4,400 to 100,000 psi), lubrication is required, - oil or graphite for lower temperature extrusions, - glass powder for higher temperature extrusions.

The extrusion process Extruders for pharmaceutical use have been designed and

adapted for mixing drugs with carriers in various dosage forms. The complete extrusion set-up consists of three distinct parts: A conveying system for material transport and kneading system for material mixing A die system for forming the extrudates Downstream auxiliary equipment (cooling, pelletizing and collecting) The components of the extruder are: The feed hopper (gravimetric or volumetric feeding) Temperature-controlled barrels (heating and / or cooling) Die (different die congurations are available)

The hot-melt extrusion process comprises the steps :

melting, mixing and shaping (see Figure 1-1).

In principle, an extruder consists 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 screws, 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 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 path by means of transverse ow, drag ow, pressure ow 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 ow and ensure a uniform delivery rate through the die. At the end of the barrels, the attached die dictates the shape of the extrudates

Additional equipment: Process analytical technology (e.g. spectroscopic systems) Vacuum pumps for degassing extrudates Pelletizer equipment Calendering equipment In-process control parameter can be : Zone and die temperature Screw speed Torque or powder consumption Pressure Melt viscosilty Feed rate

Extruders are available as: single- or multi-screw versions. Twin-screw extruders utilize two screws usually arranged

side by side. The use of two screws allows a number of different congurations to be obtained and imposes different conditions on all zones of the extruder. In the twin-screw extruder, the screws can either rotate in the same (co-rotating) or in the opposite (counter-rotating) direction

Advantages of twin-screw compared to single-screw

extruders : Easier material feeding High kneading potential High dispersing capacities Less tendency to overheat (important for sensitive APIs) Shorter and constant residence times Advantages of single-screw compared to twin-screw extruders: Mechanical simplicity Low cost of investment

Dosage forms prepared using HME technology This technology has proven useful in the design of a number of

drug delivery systems such as: immediate and modified release tablets, granules, pellets, implants, matrix systems, transdermal drug delivery systems and ocular inserts, and targeted delivery such as enteric matrix tablets and Capsules - matrix mini-tablets it minimise the risk of dose dumping, reduce inter- and intra-subject variability and provide highly dispersive formulations within the gastrointestinal tract. -the coating of hot-melt extruded tablets with suitable polymers has been shown to significantly delay the onset of crystallization during dissolution and Storage

Hot-melt extrusion use to formulate poorly soluble drugs : Hot-melt extrusion is mainly used to formulate poorly soluble

actives as solid dispersions. . Of the various types of solid dispersions, 3 are relevant for pharmaceutical applications since the applied polymers are usually amorphous. Principally, the drug can be either dissolved or dispersed whilst in an amorphous or crystalline state. A thermodynamically stable formulation (Figure 1-7) is achieved when the drug is completely dissolved below its saturation solubility in the polymer, resulting in a solid solution.

When the drug concentration exceeds the saturation solubility,

the whole system is only kinetically controlled since the drug may crystallize or precipitate out of the polymer during storage. Formulation in the middle is also kinetically controlled. This is because the amorphous drug is dispersed in an amorphous polymer and as the drug may crystallize, denitely changing the dissolution and biopharmaceutical properties. The system on the left is quite stable in this case the polymer contains crystalline drug . However, this is not very pronounced due to the low diffusivity of the drug in a solid polymer. Based on the pH-dependant solubility of the polymer, instantrelease (IR), enteric or sustained-release (SR) drug delivery systems can be developed. The selection of the polymer strongly determines the release rate of the drug (Figure 1-8). In most cases, instant-release systems have been developed and commercialized so far.

Advantages of hot-melt extrusion Within the pharmaceutical industry hot-melt extrusion has been

used for various purposes, such as: 1-Enhancement of the dissolution rate and bioavailability of a drug 2-Controlling or modifying drug release 3-Taste masking 4-Stabilizing the API 5-Parenteral depots and topical delivery systems 6-Increasing dissolution rate and bioavailability of APIs that are poorly soluble in water are important challenges in dosage form development (Figures 1-11

disadvantages.:

There might be unwanted reactions that may result from the exposure of the drug to the atmosphere of the surroundings. The biggest disadvantage of this process is its cost for machinery and its upkeep.

Polymers for hot-melt extrusion

Polymers for hot-melt extrusion -Polymers with a high solubilization capacity are particularly

suitable because large quantities of drugs can be dissolved. Some features like lipophilicity, hydrogen bonding acceptors or donors [32] and amide groups are basic prerequisites for a high solubilization capacity; the same applies to organic solvents (Figure 1-10). This explains why povidone, copovidone and Soluplus are highly suitable for hot-melt extrusion. Copovidone and Soluplus in particular are much more lipophilic than many other water-soluble polymers containing hydroxyl groups and, therefore, is best suited to the lipophilicity of poorly soluble drugs. In addition, the solubility parameter can be used to determine whether actives and polymers are compatible.

The polymers used in the extrusion process may function as

: 1-thermal binders, 2-drug stabilisers, 3-drug solubilisers and/or drug release controlling excipients with no compressibility requirements.

1 Kollidon VA 64 / VA 64 Fine The Kollidon VA 64 grades are manufactured by free-

radical polymerization of 6 parts of N-vinylpyrrolidone and 4 parts of vinyl acetate. Vinylpyrrolidone is a hydrophilic, water-soluble monomer whereas vinyl acetate is lipophilic and water-insoluble. The ratio of both monomers is balanced in such a way that the polymer is still freely water soluble. Intended release prole of extrudates: Since Kollidon VA 64 is quite soluble in aqueous media, the release prole of these formulations is mostly instant release; however, it can also be used in modied release drug delivery systems

2 Soluplus Soluplus is a polyvinyl caprolactam-polyvinyl acetate

polyethylene glycol graft copolymer. It has an amphiphilic structure and can be regarded as a polymeric solubilizer. was designed to be used in hot-melt extrusion and to solubilize poorly soluble actives. Intended release prole of extrudates: Soluplus is expected to show an instant release prole

3-Kollidon 12 PF, Kollidon 17 PF, Kollidon 30 and Kollidon 90 F The soluble Kollidon grades are obtained by free-radical

polymerization of vinylpyrrolidone. The current range of soluble Kollidon grades consists of pharmaceutical grade products with different nominal Kvalues. Intended release prole of extrudates: All PVP powders are quite water-soluble and therefore intended to be used for instant release dosage forms

4 Kollidon SR Kollidon SR is a spray-formulated mixture of polyvinyl

acetate and polyvinylpyrrolidone (povidone) in the ratio 8:2. Intended release prole of extrudates: Kollidon SR is insoluble in water and is expected to deliver the active in a sustained release manner

5 Kollicoat MAE 100P This copolymer consists of methacrylic acid and ethyl

acrylate in a ratio of 1:1. It is an anionic copolymer that can be neutralised by bases such as sodium hydroxide Intended release prole of extrudates: Kollicoat MAE 100P is intended to be used as an enteric

matrix in hot-melt extrusion formulations, the drug being released mainly in the intestine

6 Kollicoat IR and Kollicoat Protect Kollicoat IR powder (Polyvinyl alcohol polyethylene

glycol graft copolymer) comprises polyethylene glycol and polyvinyl alcohol in the ratio of 25:75 (w / w %). The polyethylene glycol chain forms a backbone onto which side chains of polyvinyl alcohol are grafted. Kollicoat Protect is a formulated mixture of Kollicoat IR and polyvinyl alcohol. Intended release prole of extrudates: Due to the good water solubility of Kollicoat IR and Kollicoat Protect, an instant release prole can be expected

Lutrol F 127, Ltrol micro 127 (Poloxamer 407) and Lutrol F 68, Ltrol micro 68 (Poloxamer 188) The Lutrol F grades F 68 / F 127 and Ltrol micro 68 /

micro 127 are synthetic copolymers of ethylene oxide (a) and propylene oxide (b) where a = approx. 80 and b = approx. 27 for Lutrol F 68 / Ltrol micro 68 and a = approx. 101 and b = approx. 56 for Lutrol F 127 / Ltrol micro 127. Principally, the Lutrol grades are amphiphilic molecules where polyoxypropylene represents the lipophilic and polyethylene glycol the hydrophilic part. Typically, Lutrol F gels show increased viscosities when the temperature increases from room temperature to 40 C

Intended use in HME: Poloxamers are intended to be used as plasticizers and as

wetting and dissolution enhancers. Ltrol micro grades can be preblended with other components and also mix more homogeneously in the extruder.

8 Cremophor RH 40 Cremophor RH 40 (macrogolglycerol hydroxystearate 40) is a non-ionic solubilizer and emulsifying agent Intended use in HME: The various PEGs are intended to be used as plasticizers.

9 Polyethylene Glycols Polyethylene glycols (PEGs) are liquids or low-melting

solids depending on their molecular weights. They are prepared by the polymerization of ethylene oxide and are commercially available with a wide range of molecular weights. The numbers that are often included in the names of PEGs indicate their average molecular weights, e.g. a PEG with n=9 would have an average molecular weight of approximately 400 g /mol and would be labeled PEG 400 (Lutrol E 400). Intended use in HME: Cremophor RH 40 is intended to be used as plasticizer

or solubility enhancer for actives that are poorly soluble

Current marketed products

Several companies specialize in the use of HME as a drug

delivery technology including PharmaForm (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) (Figure 2). HME Kaletra tablets were shown to have significant advantages for the patient compared with the previous soft gel capsule formulation, such as 1- reduced dosing frequency and 2- improved stability, as evidenced by FDA's decision to fast track approval. 3-The formulated HME product significantly enhanced the bioavailability of both APIs.35 In addition, SOLIQS has also developed : -a fast-onset ibuprofen system -a sustained release formulation of verapamil (Isoptin SRE) that was the first directly shaped HME product on the market.

One proprietary melt extrusion based technology,

PharmaForm Abuse Deterrent Technology (PADT), has been developed to deter and prevent drug abuse. 1-This technology utilizes HME to produce a drug delivery platform that helps prevent rapid drug absorption and the desired euphoric effect. 2-The drug delivery technology offered by the company provides a solution to this problem as the dosage forms are very difficult to chew and/or crush. 3-Additionally, PADT systems prevent alcohol induced dose-dumping and alcohol extraction by maintaining sustained release characteristics in 40% alcohol, comparable to the release in water or normal dissolution media, for more than 3 h.

The use of HME to improve oral bioavailability has been

detailed in numerous scientific articles and patents. A recent study examined the performance of itraconazole melt extrudates prepared using HPMC (hydroxypropyl methylcellulose) and PVP-VA/Eudragit E polymeric platforms. In this specific example, HPMC was shown to significantly increase the area under the plasma concentration time curve compared with the other extrudates, despite having a slower dissolution rate. One conclusion drawn from this work is that dissolution rate may not always be the most important factor when screening such formulations; inhibition of precipitation from a supersaturated state may be more important. More recently, HPMCAS hypromellose acetate succinate)has been shown to be of particular benefit in the preparation of solid dispersions and for the production of enteric dosage forms. Industrially, Pfizer has used HPMCAS solid dispersions prepared by a spray drying method to significantly enhance AUC for a number of their poorly soluble drugs compared with conventional formulations The acetyl and succinate groups present within HPMCAS

References http://www.pharmtech.com/pharmtech/Manufacturing+

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