tical applications of hot-melt extrusion part1

Drug Development and Industrial Pharmacy, 33:909–926, 2007 Copyright © Informa Healthcare USA, Inc. ISSN: 0363-9045 print / 1520-5762 online DOI: 10.1080/03639040701498759 909 LDDI0363-90451520-5762Drug Development and Industrial Pharmacy, Vol. 33, No. 9, July 2007: pp. 1–71Drug Development and Industrial PharmacyReview Article Pharmaceutical Applications of Hot-Melt Extrusion: Part I Hot-melt ExtrusionMichael M. Crowley and Feng Zhang PharmaForm LLC, Austin, Texas Michael A. Repka, Sridhar Thumma, Sampada B. Upadhye, and Sunil Kumar Battu Department of Pharmaceutics, School of Pharmacy, The University of Mississippi, University, MS, USA James W. McGinity Division of Pharmaceutics, College of Pharmacy, The University of Texas at Austin, Austin, Texas, USA Charles Martin American Leistritz Extruder Corporation, Somerville, NJ, USA Interest in hot-melt extrusion techniques for pharmaceutical applications is growing rapidly with well over 100 papers pub- lished in the pharmaceutical scientific literature in the last 12 years. Hot-melt extrusion (HME) has been a widely applied tech- nique in the plastics industry and has been demonstrated recently to be a viable method to prepare several types of dosage forms and drug delivery systems. Hot-melt extruded dosage forms are complex mixtures of active medicaments, functional excipients, and processing aids. HME also offers several advantages over tra- ditional pharmaceutical processing techniques including the absence of solvents, few processing steps, continuous operation, and the possibility of the formation of solid dispersions and improved bioavailability. This article, Part I, reviews the pharma- ceutical applications of hot-melt extrusion, including equipment, principles of operation, and process technology. The raw materi- als processed using this technique are also detailed and the physi- cochemical properties of the resultant dosage forms are described. Part II of this review will focus on various applications of HME in drug delivery such as granules, pellets, immediate and modified release tablets, transmucosal and transdermal systems, and implants. Keywords melt extrusion; thermal processing; solid dispersion; solid molecular dispersion; extruder; bioavailability; sustained release; immediate release; drug delivery systems INTRODUCTION Hot-melt extrusion (HME) is one of the most widely used processing techniques within the plastics industry. Hot-melt extrusion is the process of pumping raw materials with a rotat- ing screw under elevated temperature through a die into a prod- uct of uniform shape. Currently, more than half of all plastic products, including plastic bags, sheets, and pipes, are manu- factured by this process (Kaufman et al., 1977). HME was first introduced in the plastics industry in the mid-nineteenth cen- tury to prepare polymeric insulation coatings to wires. Today, interest in HME techniques for pharmaceutical applications is growing rapidly with well over 100 papers published in the sci- entific literature in the last 12 years. The number of HME patents issued for pharmaceutical systems has steadily increased since the early 1980’s (Figure 1) with international scope (Figure 2). Several research groups have demonstrated HME processes as a viable method to prepare pharmaceutical drug delivery systems, including granules (Follonier et al., 1995), pellets (Follonier et al., 1994; Young et al., 2002), sustained release tablets (Crowley et al., 2004b; Crowley et al., 2002; McGinity et al., 1997; Zhang, 1999; Zhang et al., 2000), transdermal and transmucosal drug delivery systems (Aitken-Nichol et al., 1996; Munjal et al., 2006; Prodduturi et al., 2005; Repka et al., 1999a, 2000b, 2001a, 2001b, 2002b, 2002d) and implants (Bhardwaj et al., 1997, 1998; Rothen-Weinhold et al., 2000; Sam, 1992). The HME technique is an attractive alternative to traditional processing methods. HME offers many advantages to other pharmaceutical pro- cessing techniques. Molten polymers during the extrusion pro- cess can function as thermal binders and act as drug depots Address correspondence to Michael A. Repka, Department of Pharmaceutics, School of Pharmacy, The University of Mississippi, University, MS 38677, USA. E-mail: marepka@olemiss.edu D ru g D ev el op m en t a nd In du str ia l P ha rm ac y D ow nl oa de d fro m in fo rm ah ea lth ca re .c om b y 21 8. 93 .1 20 .2 20 o n 11 /2 9/ 11 Fo r p er so na l u se o nl y. 910 M. M. CROWLEY ET AL. and/or drug release retardants upon cooling and solidification. Solvents and water are not necessary thereby reducing the number of processing steps and eliminating time-consuming drying steps. A matrix can be massed into a larger unit inde- pendent of compression properties. The intense mixing and agitation imposed by the rotating screw cause de-aggregation of suspended particles in the molten polymer resulting in a more uniform dispersion and the process is continuous and efficient. It has been estimated that as many as 40% of all new molec- ular entities have poor bioavailability because of low aqueous solubility. This percentage is likely increasing due to the advent of combinatorial chemistry and the importance of lipo- philic receptors (Kerns, 2001). Formulation of such com- pounds for oral delivery presents one of the most frequent and formidable challenges to formulation scientists. HME has been used to improve the bioavailability of drug substances espe- cially those having low water solubility by formation of molec- ular dispersions (Breitenbach et al., 2003; Forster et al., 2001a; Kinoshita et al., 2002; Ndindayino et al., 2002c). HME requires a pharmaceutical grade polymer that can be processed at relatively low temperatures due to the thermal sensitivity of many drugs. All components must be thermally stable at the processing temperature during the short duration of the heating process. Although this requirement may some- times limit a pharmaceutical compound from HME processing, input of new techniques and equipment specifications over the last decade have expanded the list of actives not previously thought to be applicable for this emerging technology. EQUIPMENT, PRINCIPLES OF EXTRUSION, AND PROCESS TECHNOLOGY Hot-Melt Extrusion Equipment Pharmaceutical-class extruders have evolved and adapted to mix drugs with carriers for various solid dosage forms as well as for the production of wet granulations. The major differences between a plastics extruder and a pharmaceutical-class extruder are the contact parts, which must meet regulatory requirements. Typically, the metallurgy of the contact parts must not to be reactive, additive or absorptive with the product. In addition, the equipment is configured for the cleaning and validation requirements associated with a pharmaceutical environment. Otherwise, the unit operations performed for a pharmaceutical product is virtually identical to a polymer extrusion process. Extrusion processes can be categorized as either ram extru- sion or screw extrusion. Screw extrusion consists of a rotating screw inside a heated barrel, while ram extrusion operates with a positive displacement ram capable of generating high pres- sures to push materials through the die. During ram extrusion, materials are introduced into a heated cylinder. After an induc- tion period to soften the materials, a ram (or a piston) pressur- izes the soft materials through the die and transforms them into the desired shape (Perdikoulias et al., 2003). High-pressure is the operating principle of ram extrusion. This technique is well suited for the precision extrusion of highly valuable materials. The ram exerts modest and repeatable pressure as well as a very consistent extrudate diameter. The major drawback of ram extrusion is limited melting capacity that causes poor tempera- ture uniformity in the extrudate. Also, extrudates prepared by ram extrusion have lower homogeneity, in comparison with extrudates processed by screw extrusion. Unlike ram extrusion, a screw extruder provides more shear stress and intense mixing. At a minimum, a screw extruder FIGURE 1. The number of hot-melt extrusion patents issued for pharmaceutical applications from 1983 to 2006. 0 5 10 15 20 25 30 N um be r o f P at en ts Is su ed Year 1983 2004200119981995199219891986 FIGURE 2. The number and percentage of hot-melt extrusion patents issued by country since 1983 for pharmaceutical applications. Germany 28% US 28% France 5% Japan 19% UK 5% Other Asian 4% Other European 11% D ru g D ev el op m en t a nd In du str ia l P ha rm ac y D ow nl oa de d fro m in fo rm ah ea lth ca re .c om b y 21 8. 93 .1 20 .2 20 o n 11 /2 9/ 11 Fo r p er so na l u se o nl y. HOT-MELT EXTRUSION 911 consists of three distinct parts: a conveying system for material transport and mixing, a die system for forming, and down- stream auxiliary equipment for cooling, cutting or collecting the finished goods. Individual components within the extruder are the feed hopper, a temperature controlled barrel, a rotating screw, die and heating and cooling systems (Griff, 1968). Additional systems include mass flow feeders to accurately meter materials into the feed hopper, process analytical tech- nology to measure extrudate properties (near infra red systems and laser systems), liquid and solid side stuffers, vacuum pumps to devolitize extrudates, pelletizers, and calendaring equipment. Standard process control and monitoring devices include zone temperature and screw speed with optional moni- toring of torque, drive amperage, and pressure and melt viscos- ity. Temperatures are normally controlled by electrical heating bands and monitored by thermocouples. Single Screw Extruder The single screw extruder is the most widely used extrusion system in the world. One screw rotates inside the barrel and is used for feeding, melting, devolatilizing, and pumping. Mixing is also accomplished for less demanding applications. Single screw extruders can be either flood or starve fed, depending upon the intended manufacturing process (Luker, 2003). Single screw extruders are continuous, high-pressure pumps for viscous materials that can generate thousands of pounds of pressure while melting and mixing. Most extruder screws are driven from the hopper end. However, once screws are reduced to less than 18 mm, the screw becomes weak and solids trans- portation is far less reliable. To overcome these shortcomings, a vertical screw, driven from the discharge end, may be used. The discharge of such screws is two to four times stronger increasing solids transport (Luker, 2003). Single screw extruders accept material into the feed section and convey materials along a flighted screw enclosed in a bar- rel. Single screws are typically flood fed, where the hopper sits over the feed throat and the screw RPM determines the output rate. Sometimes these devices are operated under starve fed conditions, where a feed system sets the mass flow rate and is independent of screw RPM. There are three basic functions of a single screw extruder: solids conveying, melting and pumping. The forwarding of the solid particles in the early portion of the screw is a result of friction between the material and the feed section’s bore. After solids conveying the flight depth begins to taper down and the heated barrel causes a melt to form. The energy from the heaters and shearing contribute to melting. Ideally, the melt pool will increase as the solid bed reduces in size until all is molten at the end of the compression zone. Finally, the molten materials are pumped against the die resistance to form the extrudate (Luker, 2003). Twin-Screw Extruders The first twin-screw extruders were developed in the late 1930’s in Italy, with the concept of combining the machine actions of several available devices into a single unit. As the name implies, twin-screw extruders utilize two screws usually arranged side by side (Figure 3). The use of two screws allows a number of different configurations to be obtained and imposes different conditions on all zones of the extruder, from the transfer of material from the hopper to the screw, all the way to the metered pumping zone (Mollan, 2003). In a twin-screw extruder, the screws can either rotate in the same (co-rotating extruder) or the opposite (counter-rotating extruder) direction. The counter-rotating designs are utilized when very high shear regions are needed as they subject mate- rials to very high shear forces as the material is squeezed through the gap between the two screws as they come together. Also, the extruder layout is good for dispersing particles in a FIGURE 3. Twin screw prism USALAB digital 16 mm extruder (top), twin screw extruder (Courtesy of American Leistritz Co., Somerville, NJ) (bottom). D ru g D ev el op m en t a nd In du str ia l P ha rm ac y D ow nl oa de d fro m in fo rm ah ea lth ca re .c om b y 21 8. 93 .1 20 .2 20 o n 11 /2 9/ 11 Fo r p er so na l u se o nl y. 912 M. M. CROWLEY ET AL. blend. Generally, counter-rotating twin-screw extruders suffer from disadvantages of potential air entrapment, high-pressure generation, and low maximum screw speeds and output. Co- rotating twin-screw extruders on the other hand are generally of the intermeshing design, and are thus self-wiping (Breiten- bach, 2002). They are industrially the most important type of extruders and can be operated at high screw speeds and achieve high outputs, while maintaining good mixing and conveying characteristics. Unlike counter-rotating extruders, they gener- ally experience lower screw and barrel wear as they do not experience the outward “pushing” effect due to screw rotation. These two primary types can be further classified as non- intermeshing and fully intermeshing. The fully intermeshing type of screw design is the most popular type used for twin- screw extruders (Figure 4) (Thiele, 2003). This design itself is self-wiping, where it minimizes the nonmotion and prevents localized overheating of materials within the extruder. The extruder operates by a first in/first out principle since the mate- rial does not rotate along with the screw. Non-intermeshing extruders, on the other hand, are often used for processing when large amounts of volatiles need to be removed and when processing highly viscous materials. Non-intermeshing extrud- ers allow large volume de-volatization via a vent opening since the screws are positioned apart from one another. Non-inter- meshing extruders are not susceptible to high torques gener- ated while processing highly viscous materials for the same reasons (Mollan, 2003). Twin-screw extruders have several advantages over single screw extruders, such as easier material feeding, high knead- ing, and dispersing capacities, less tendency to over-heat and FIGURE 4. Twin screw design examples: intermeshing co-rotating twin-screw (top), and intermeshing counter-rotating twin-screw (Burns et al.). (Courtesy of American Leistritz Co., Somerville, NJ) (bottom). D ru g D ev el op m en t a nd In du str ia l P ha rm ac y D ow nl oa de d fro m in fo rm ah ea lth ca re .c om b y 21 8. 93 .1 20 .2 20 o n 11 /2 9/ 11 Fo r p er so na l u se o nl y. HOT-MELT EXTRUSION 913 shorter transit time. However, single-screw extruders do have the advantage over twin-screw extruders in terms of their mechanical simplicity and more reasonable cost (Repka et al., 2002a). Most commercial extruders have a modular design to facili- tate changing screws. The design of the screw has a significant impact on the process and can be selected to meet particular requirements such as high or low shear. Whelan and Dunning have reviewed the various screw designs available (Whelan et al., 1996). Specific screw features are displayed in Figure 5. In an extrusion process, the dimensions of the screws are given in terms of L/D ratio, which is the length of the screw divided by the diameter (Steiner, 2003). For example, an extruder screw that is 1000 mm long and has a 25 mm diameter exhibits a 40:1 L/D. Typical extrusion process lengths are in the 20 to 40:1 L/D range, or longer. Extruder residence times are gener- ally between 5 sec and 10 min, depending upon the L/D ratio, type of extruder, screw design, and how it is operated. The size of an extruder is generally described based on the diameter of the screw used in the system, i.e., 18–27 mm extruder (pilot scale) as compared with 60 mm extruder (production scale) (Steiner, 2003). Although the screw size difference appears small (∼2 fold) in the preceding example, the extruder output that results from doubling the screw size may be 10-fold, i.e., from 10 to 100 kg/h. This is due to the much larger volume available for processing as the screw size is increased. Screws are designed with several sections, with the function of each section ranging from feeding, mixing, compression, and metering. Most screws are made from surface coated stain- less steel to reduce friction and the possibility of chemical reactions. The screw is typically divided into three sections along the length of the barrel: feeding, melting or compression, and metering as shown in Figure 6. The purpose of the feeding sec- tion is to transfer the materials from the hopper to the barrel. The channel depth is usually widest in this section to facilitate mass flow. A decrease in channel depth in the compression zone increases the pressure, which removes entrapped air (Chokshi et al., 2004). The polymer typically begins to soften and melt in the compression zone. The melt moves by circula- tion 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. The function of the metering zone is to reduce the pulsating flow and ensure a uniform delivery rate through the die cavity. The mass flow rate of the extrudate is highly dependent upon the channel depth and the length of the metering section. FIGURE 5. Diagram of an extruder screw (repka et al., 2002a). 1) the channel depth is the distance from the screw roots to the inner barrel surface; 2) the flight clearance is the distance between the screw flight and the inner barrel surface; 3) the channel width is the distance between two neighboring flights; 4) the helix angle is the angle between the flight and the direction perpendicular to the screw axis. FIGURE 6. Schematic diagram of a single screw extruder. D ru g D ev el op m en t a nd In du str ia l P ha rm ac y D ow nl oa de d fro m in fo rm ah ea lth ca re .c om b y 21 8. 93 .1 20 .2 20 o n 11 /2 9/ 11 Fo r p er so na l u se o nl y. 914 M. M. CROWLEY ET AL. The die is attached at the end of the barrel. The shape of the die dictates the physical form or shape of the extrudate. Gener- ally, the cross section of the extrudate will increase upon leav- ing the die, a phenomenon known as “die swell” depending on the viscoelastic properties of the polymers. This entropy driven event occurs when individual polymer chains recover from deformation imposed by the rotating screw by “relaxing” and increasing their radius of gyration. Downstream Processing Equipment Providing a usable melt to the die and downstream system is only part of an extruded pharmaceutical product. A wide vari- ety of downstream systems are available following the extru- sion process. Cooling the extrudate may be in the form of air, nitrogen, on stainless steel conveyors or rolls, or in water. Pel- lets or shapes may be extruded and wound or cut-to-length (Figure 7). Co-extrusion allows the possibility of complex properties from a single structure, which can be beneficial for time-release products (Ghebre-Sel