Hot Melt Extrusion - An emerging drug delivery technology

Hot-melt Extrusion An emerging drug delivery technology: 

Hot-melt Extrusion An emerging drug delivery technology 01 Aug 2011 1 D. N. Ajay Kumar ( M.Pharm ) Under the supervision of Dr.Vijaya Ratna A.U . College of Pharmaceutical Sciences

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Contents Introduction Pros & Corns Materials used Description of extruder Types of Extrusion process Hot melt extrusion process Applications Marketed products 01 Aug 2011 2

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Introduction: The advent of synthetiv chemistry in the drug discovery process has resulted in compounds with lipophilicity and poor solubility. Hot melt extrusion is an efficient technology for producing solid molecular dispersions with considerable advantages over solvent based processes 01 Aug 2011 3

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Hot melt extrusion can be broadly defined as the process of embedding drug in a polymeric carrier under controlled conditions of temperature, shear & pressure to generate a wide variety of finished products. Extrusion involves conversion of raw materials into a product of uniform shape and density by forcing through a die under controlled conditions. 01 Aug 2011 4 Source: Technical brief 2011 volume 3, Particle Science Drug Delivery Services

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Historical Overview of Extrusion Technology Extrusion is a well known processing technology that has been developed over the last century and spans many diverse industrial fields. It was Joseph Brama who designed the first extruder to manufacture lead pipes. El- Egakey and co-worker reported the first hot-melt extrusion of a polymeric matrix for pharmaceutical application in 1970. 01 Aug 2011 5

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Pharmaceutical interest In HME 01 Aug 2011 6

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Introduction Pros & Corns Materials used Description of extruder Types of Extrusion process Hot melt extrusion process Applications Marketed products 01 Aug 2011 7

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PROS Solvent free, Short processing time Easily controlled process parameter Robust, economic and continuous process Closed process unit to prevent cross contamination Reduced number of unit operations Poorly compactable material can be easily compressed. 01 Aug 2011 8

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CORNS Thermal process (drug/polymer stability) Limited number of polymers Flow properties of the polymers are essential to processing Requires high energy input Non- traditional equipment, requires training & education . 01 Aug 2011 9

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Introduction Pros & Corns Materials used Description of extruder Types of Extrusion process Hot melt extrusion process Applications Marketed products 01 Aug 2011 10

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Materials used in HME: Active Ingredient Polymers Plasticizers Anti-oxidants API: Thermal Physical Chemical 01 Aug 2011 11

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Polymers: Thermo-plasticity Drug polymer miscibility (solubility parameter) Polymer stability Purpose of the final dosage form 01 Aug 2011 12

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01 Aug 2011 13 Chemical name Trade name Use Polyethylene glycol Carbowax Plasticizier , immediate and controlled release Polyethylene oxide PolyOx Plasticizier , immediate and controlled release Hydroxypropyl cellulose Klucel Controlled release Methacrylate co-polymers Eudragit Immediate and controlled release Poly(vinyl pyrrolidone ) Kollidon Immediate and controlled release Ethyl cellulose Ethocel Sustained release Soluplus Immediate release Polymers for HME

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Plasticizers: To improve processing conditions, physical and mechanical properties of final product. To facilitate the extrusion and increase flexibility. Plasticizers reduces the T g of the polymer processing temperature and increases the stability shear forces Examples: triacetin , citrate esters and low molecular weight polyethylene glycols 01 Aug 2011 14

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Anti-oxidants: Anti-oxidants are added to prevent the degradation of active ingredients during extrusion. Example: Ascorbic acid EDTA Citric acid 01 Aug 2011 15

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Introduction Pros & Corns Materials used Description of extruder Types of Extrusion process Hot melt extrusion process Applications Marketed products 01 Aug 2011 16

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Description of an Extruder: In the pharmaceutical field, hot-melt extrusion equipment consists of an extruder, downstream auxiliary equipment and other monitoring tools used for performance and product quality evaluation. The extruder is typically composed of a feeding hopper, barrel, single or twin screws , die, screw-driving unit heating and cooling device 01 Aug 2011 17

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Feeder/ hopper: Feed streams are introduced into the extruder either in a “starve-fed” manner “flood feeding” manner. Source: www.webmedcentral.com Twin screw extruders are generally starved fed and single screw extruders are normally flood fed. 01 Aug 2011 18

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Barrel: The extruder barrel is a heavy steel cylinder that houses the screw of extruder. The barrel is made of highly wear-resistant materials. The inner surface of the barrel is reinforced with an iron- nitriding or bimetallic alloying technique. The barrel is often manufactured in sections, which are bolted or clamped together. 01 Aug 2011 19

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Screws 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. 01 Aug 2011 20

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Auxiliary equipment: The auxiliary equipment for the extruder consists of a heating/cooling device for the barrels, downstream equipment to collect the extrudates prior to further processing (such as chill rolls, take-up rolls and flaker ). Monitoring devices on the equipment include temperature gauges, a screw speed controller, pressure gauges, and an extrusion torque monitor. 01 Aug 2011 21

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Introduction Pros & Corns Materials used Description of extruder Types of Extrusion process Hot melt extrusion process Applications Marketed products 01 Aug 2011 22

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Types of Extrusion Processes Ram extrusion Screw extrusion Ram Extrusion: A ram extruder is basically positive displacement equipment that is capable of generating high pressure in order to push the material through a die which actually gives the shape of the desired product. Ram extrusion is used for materials having extremely high melting range and strange flow properties which makes it unsuitable for screw extrusion. 01 Aug 2011 23

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Disadvantages: Poor temperature control of the extrudates, Limited melting capacity. Extrudates prepared by ram extrusion are less homogeneous, in comparison with extrudates that are processed by screw extrusion. 01 Aug 2011 24

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Screw Extrusion: A screw extruder consists of a screw rotating inside a barrel in which the temperature of the different sections is controlled. Materials are subjected to more intense mixing and higher shear stress in a screw extruder versus a ram extruder. And extrudates prepared by screw extrusion are more homogeneous. Screw extruders include single-screw and twin-screw extruders. 01 Aug 2011 25

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01 Aug 2011 26 Source: Technical brief 2011 volume 3, Particle Science Drug Delivery Services

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Single Screw Extrusion: It is a simple, continuous, high pressure generating pumps for viscous materials that can generate thousands of pounds of pressure while melting and mixing. It work under the principle of flood feeding, in that the hopper is filled, and the screw takes what it wants. Hence, the output level can be controlled by the screw speed. Advantages : Mechanical simplicity Low cost of investment. 01 Aug 2011 27

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01 Aug 2011 28 Twin- screw extruders, as the name implies, use two screws usually arranged side by side. The two screws can either rotate in the same (co-rotation) or the opposite direction (counter-rotation).

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Based on the design of the screw the primary types then can be further separated into: Intermeshing: self-wiping, and prevents the material from rotating with the screw. Non-intermeshing: cannot form closed or semi- closed compartments, a lower degree of positive conveying characteristics. 01 Aug 2011 29

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Characteristics of screw extruder Short residence time: 5-10 minutes depending on the feed rate and screw speed. Self wiping screw profile: the flight of the one screw wipes the root of the screw on the shaft next to it, ensures near complete emptying of equipment and minimizes product wastage. Minimum inventory Versatility Superior mixing 01 Aug 2011 30

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Advantages of twin screw: Easier material feeding High kneading potential High dispersing capacities Less tendency to overheat, stable melting process Shorter and constant residence times Significant greater output 01 Aug 2011 31

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Introduction Pros & Corns Materials used Description of extruder Types of Extrusion process Hot melt extrusion process Applications Marketed products 01 Aug 2011 32

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01 Aug 2011 33 Hot Melt Extrusion Process Source: Technical brief 2011 volume 3, Particle Science Drug Delivery Services

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The theoretical approach to understand the melt extrusion process is generally presented by dividing the process into four sections: Feeding of the extruder. Conveying of mass (mixing, shearing and reduction of particle size). Flow through the die. Exit from the die and down-stream processing. 01 Aug 2011 34

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Feeding: The purpose of the feeding section is to compact and to transfer the feedstock into the barrel of the machine. Feeders are used in conjunction with extruders to accurately meter solids. Materials are either continuously metered directly into the extruder or alternatively into a vessel to facilitate a premix. 01 Aug 2011 35

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Conveying of mass Based on the geometrical design and the function of the screw at each section the extrusion channel is conventionally divided into three sections: feed zone, transition zone, and metering zone. conveying elements kneading elements metering elements Source: Technical brief 2011 volume 3, Particle Science Drug Delivery Services 01 Aug 2011 36

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Flow through the die: The die is attached at the end of the barrel. The geometrical design of the die will control the physical shape and size of the molten extrudate. 01 Aug 2011 37

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Down-stream processing: Certain types of downstream equipment are necessary for the hot-melt extrusion of particular applications. Chill rolls, vacuum pump, flaker , calendars. Chill rolls:- used to cool down and control the film temperature, thickness of the film, surface morphology & mechanical properties. Flakers :- used to chop the film to required sizes. Calendars:- used to obtain the product of desired shape. 01 Aug 2011 38

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Introduction Pros & Corns Materials used Description of extruder Types of Extrusion process Hot melt extrusion process Applications Marketed products 01 Aug 2011 39

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Applications Hot melt extrusion process is currently applied in the pharmaceutical field for the production of a variety of dosage forms such as granules, pellets, tablets, implants, transdermal systems. In pharmaceutical industry the melt-extrusion has been used for various purposes: Masking the bitter taste of an active drug Formation of polymer-drug solutions or dispersions Controlling or modifying the release of the drug 01 Aug 2011 40

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Introduction Pros & Corns Materials used Description of extruder Types of Extrusion process Hot melt extrusion process Applications Marketed products 01 Aug 2011 41

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Hot melt extruded products: In spite of the increased interest, there are only few commercialized HME pharmaceutical products currently marketed. Several companies specialize in the use of HME as a drug delivery technology including Pharma Form and SOLIQS. 01 Aug 2011 42 Manufacturer Product Active Ingredient Use Soliqs Kaletra Lopinavir / ritonavir HIV Isoptin ® SRE Verapamil Hypertension

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Conclusion : 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. Hot melt extrusion appears to be viable approach to produce dosage forms that contain high API loading and exhibit controlled release behavior. 01 Aug 2011 43

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01 Aug 2011 44 Queries

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References: Rina Chokshi , Hossein Zia, Hot –Melt Extrusion: A Review; Iranian Journal of Pharmaceutical Research (2004) 3:3-16 Mr.Sandeep Singhal , Mr.Vikram K Lohar , Mr.Vimal Arora ; Hot Melt Extrusion Technique: Webmedcentral . 01 Aug 2011 45

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01 Aug 2011 46 Thank you