European Journal of Pharmaceutics and Biopharmaceutics 54 (2002) 107–117
`
`www.elsevier.com/locate/ejphabio
`
`Review article
`
`Melt extrusion: from process to drug delivery technology
`
`Jo¨rg Breitenbach*
`
`Soliqs, Abbott GmbH and Co. KG, Ludwigshafen, Germany
`
`Received 14 February 2002; accepted in revised form 26 April 2002
`
`Abstract
`
`Starting from the plastic industry, today melt extrusion has found its place in the array of pharmaceutical manufacturing operations. This
`article reviews the process technology with regard to the set up and specific elements of the extruder as well as its application. Melt extrusion
`processes 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. As a specific area the manufacture of
`solid dispersions, in particular, solid molecular dispersions using the melt extrusion process is reviewed. Melt extrusion is considered to be an
`efficient technology in this field with particular advantages over solvent processes like co-precipitation. Potential drawbacks like the
`influence of heat stress and shear forces on the drug active have been overcome in a number of examples with drugs of different chemical
`structure. Examples of suitable excipients and recent findings like self-emulsifying preparations are presented. The article concludes with a
`number of published examples of melt extrudates applying the principle of solid molecular dispersions. Improved bioavailability was
`achieved again demonstrating the value of the technology as a drug delivery tool. q 2002 Published by Elsevier Science B.V.
`
`Keywords: Melt extrusion; Solid dispersion; Solid molecular dispersion; Extruder; Bioavailability; Solubility
`
`1. Introduction
`
`Industrial application of the extrusion process dates back
`to the 1930’s [1]. One can therefore consider the extrusion
`process as being a well elaborated manufacturing technol-
`ogy with a plethora of different technical solutions already
`available in other fields. Extrusion is a process of converting
`a raw material into a product of uniform shape and density
`by forcing it through die under controlled conditions [2].
`Extrusion may be operated as a continuous process, which
`affords a consistent product flow ideally at relatively high
`throughput rates.
`An extruder consists of two distinct parts: a conveying
`system which transports the material and sometimes imparts
`a degree of distributive mixing, and a die system which
`forms the materials into the required shape. Extrusion may
`be broadly classified into molten systems under temperature
`control or semisolid viscous systems. In molten extrusion,
`heat is applied to the material in order to control its viscos-
`ity, to enable it to flow through the die. Semisolid systems
`are multiphase concentrated dispersions containing a high
`proportion of solid mixed with a liquid phase [3].
`Solid molecular dispersions of drugs in a matrix fit the
`
`* Soliqs Abbott GmbH and Co. KG Knollstrasse 50, D 67061 Ludwig-
`shafen, Germany. Tel. : 1 49-621-589-3555; fax: 149-621-589-3666.
`E-mail address: joerg.breitenbach@abbot.com (J. Breitenbach).
`
`0939-6411/02/$ - see front matter q 2002 Published by Elsevier Science B.V.
`PII: S 0 9 3 9 - 6 4 1 1 ( 0 2 ) 0 0 0 6 1 - 9
`
`molten systems especially as the fusion method in poly-
`meric matrices has been applied to achieve such specific
`distributions of drugs. Generally, solid dispersions of
`drugs with poor solubility revealed remarkably higher bioa-
`vailability [4,5]. Less drug material may be applied and
`potentially a lower degree of variability in bioavailability
`are obvious advantages [6]. With the recent advent of high
`throughput screening and the growing specificity for given
`receptors poorly soluble drugs present a frequent and grow-
`ing challenge to formulation scientists [7,8].
`Solid dispersions of drugs therefore fulfill the prerequi-
`sites of drug delivery systems being designed to:
`
`increase the active agent bioavailability,
`reduce side effects,
`increase the duration of the drug action in the body.
`
`At the same time, extrusion represents an efficient manu-
`facturing technology required to disperse drugs in a melt up
`to a true molecular solution of the active agent in the matrix.
`It is a striking example of a technology transfer establishing
`a new technology life cycle curve.
`The most relevant technologies for the manufacture of
`solid dispersions are hot spin mixing [9], embeddings by
`means of spray drying [10], co-evaporation, co-precipitation
`[11], freeze-drying [12] and roll-mixing or co-milling
`[13,14].
`
`Purdue 2016
`Collegium v. Purdue, PGR2018-00048
`
`

`

`108
`
`J. Breitenbach / European Journal of Pharmaceutics and Biopharmaceutics 54 (2002) 107–117
`
`An indication that life cycle management is a key driver
`for the melt extrusion technology is the remarkable amount
`of publications in the patent literature.
`
`2. Melt extrusion: the process technology
`
`2.1. General remarks
`
`With regard to pharmaceuticals, most systems extruded
`today consist of particles dispersed in a matrix. Although
`consideration is given to the manufacture of pure thermo-
`plastics, the main emphasis is still on paste extrusions [15].
`These differ in the fact that a connective matrix is present
`between solid particles. The relative position of solid and
`liquid can change during the various stages of the extrusion
`process, and hence produce effects different from those
`associated with single-phase systems like a molecular distri-
`bution of a drug in a polymeric matrix. In the latter, the
`matrix acts as a real solvent for the drug. Ideally, such
`systems are supposed to have a single-phase over a wide
`range of solubility of the drug in the polymeric matrix.
`The various types of extruders have a common feature of
`forcing the extrudate from a wider cross-section through the
`restriction of the die. The theoretical approach to understand
`the system, is therefore, generally associated with dividing
`the process of flow into four sections:
`
`feeding of the extruder,
`conveying of mass and entry into the die,
`flow through the die,
`exit from the die and down-stream processing.
`
`These four sections drive considerations of different
`aspects like flow of powder, shear force, residence time
`and pressure, cooling rate and shaping.
`Generally, the extruder consists of at least one 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 (see
`Fig. 4).
`Sometimes as much as 80% of the heat required to melt or
`fuse the material is supplied by the heat generated by friction
`as the material is sheared between the rotating screws and the
`wall of the barrel. Additional heat may be supplied by electric
`or liquid heaters mounted on the barrel. It is important to
`realize that residence time and pressure in the die area
`might have a significant impact on the impurity profile of
`the product [16].
`Most commercial extruders have a modular design,
`providing a choice of screws or interchangeable sections
`which alter the configuration of the feed, transition, and
`metering zones. This makes it possible to modify the
`process to meet particular requirements, for example, from
`a standard to a high shear extrusion. Modified screw designs
`allow the extruder to perform a mixing role in addition to
`
`extrusion, so that the material can be blended into the extru-
`date or even dissolved (Fig. 1). The various screw and die
`designs available and practical considerations of thermo-
`plastic extrusion are reviewed by Whelan and Dunning [17].
`The extrusion channel
`is conventionally divided into
`three sections: feed zone, transition zone, and metering
`zone (Fig. 4). The starting material is fed from a hopper
`directly into the feed section, which has deeper flights or
`flights of greater pitch (Fig 2). This geometry enables the
`feed material to fall easily into the screw for conveying
`along the barrel. Pitch and helix angle determine the
`throughput at 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.
`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
`[18]. Both methods result in increased pressure as the mate-
`rial 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.
`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 func-
`tion of the metering zone is to reduce pulsating flow and
`ensure a uniform delivery rate through the die cavity.
`The twin-screw extruder has two agitator assemblies
`mounted on parallel shafts (Fig. 3). These shafts are driven
`through a splitter/reducer gearbox and rotate together with
`the same direction of rotation (co-rotating) or in the opposite
`sense and are often fully intermeshing. In such case, each
`agitator element wipes both the surface of the corresponding
`element on the adjacent shaft, and the internal surfaces of
`the mixing chamber. The agitators are said to be self-
`wiping, an arrangement that eliminates stagnation areas
`within the mixing chamber and ensures a narrow and
`well-defined residence time distribution. If the agitators
`are chosen not to intermesh, the arrangement comes close
`to a single-screw set up. 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 [19]. As the screws rotate,
`the flight of one screw element wipes the flank of the adja-
`cent 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:
`
`Short residence time: The residence time in the twin-
`screw extruder in a typical extrusion process is of the
`order of up to 2 min.
`
`Purdue 2016
`Collegium v. Purdue, PGR2018-00048
`
`

`

`J. Breitenbach / European Journal of Pharmaceutics and Biopharmaceutics 54 (2002) 107–117
`
`109
`
`Fig. 1. Screw and kneading elements.
`
`Self wiping screw profile: The self wiping screw profile
`i.e. the flight of one screw wipes the root of the screw on
`the shaft next to it, ensures near complete emptying of the
`equipment and minimises product wastage on shutdown.
`Minimum inventory: Continuous operation of the equip-
`ment coupled with the low volume of the mixing chamber
`load to reduced inventories of work in progress. This is
`important when processing valuable or potentially hazar-
`dous materials.
`Versatility: Operating parameters can be changed easily
`
`Fig. 3. Schematic presentation of a twin-screw extruder set-up.
`
`and continuously to change extrusion rate or mixing
`action. The segmented screw elements allow agitator
`designs to be easily optimized to suit a particular applica-
`tion. Die plates can also be easily exchanged to alter the
`extrudate diameter and hence the spheroid diameter. This
`allows processing of many different formulations on a
`single machine, leading to good equipment utilization.
`Polymers with a wide range of viscoelastic and melt visc-
`osities can be processed and even fine powders can be
`directly fed into the system (Fig. 3).
`
`Typical twin-screw laboratory scale machines have a
`diameter of 16–18 mm and a length of four to ten times
`
`Fig. 2. Extrusion screw geometry.
`
`Purdue 2016
`Collegium v. Purdue, PGR2018-00048
`
`

`

`110
`
`J. Breitenbach / European Journal of Pharmaceutics and Biopharmaceutics 54 (2002) 107–117
`
`the diameter. A typical throughput for such type of equip-
`ment is 0.5–3 kg/h.
`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 (308C) to high
`temperatures (2508C) degradation by heat can be mini-
`mized. In addition oxygen and moisture may be excluded
`almost completely – an advantage for components sensitive
`towards oxidation and hydrolysis.
`Extrusion processing requires close monitoring and
`understanding of the various parameters: viscosity, varia-
`tion of viscosity with shear rate and temperature, elasticity,
`extensional flow, and slippage of the material over hot metal
`surfaces. Today extruders allow in process monitoring and
`control of parameters, such as the temperature in the extru-
`der, head and die as well as pressures in extruder and die
`(Fig. 4) [20].
`In particular, the molecular weight of polymeric matrices,
`their respective glass transition temperature and the sensi-
`tivity of the matrix or the drug towards heat and shear force
`create a basic set of data that qualify materials for the extru-
`sion process. Additionally, miscibility can experimentally
`be determined with differential scanning calorimetry (DSC)
`and hot stage microscopy (HSM). In order to determine the
`miscibility of drug and excipient to predict if glass solutions
`are likely to form when drug and excipient are melt
`extruded, estimation of drug/excipient miscibility has been
`investigated. Melt extrusion of miscible components
`resulted in solid solution formation, whereas extrusion of
`an ‘immiscible’ component
`led to amorphous drug
`dispersed in crystalline excipient. In conclusion, combining
`calculation of solubility parameters with thermal analysis of
`drug/excipient miscibility has been successfully applied to
`predict formation of glass solutions with melt extrusion
`[21]. The challenge to determine the solubility of a drug
`in a polymeric matrix still needs to be addressed more
`adequately. A screening system based on a dimeric moiety
`
`of polyvinylpyrrolidone (PVP) has been presented which is
`capable of comparing the solubility in the liquid to that in
`the solid, in this case the polymer [22].
`
`2.2. Industrial applications
`
`2.2.1. General
`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
`copolymers of acronitrile, cellulosics (cellulose acetate,
`propionate, and acetate butyrate), polyethylene (low and
`high density), polypropylene, polystyrene, vinyl plastics,
`polycarbonates, and nylons.
`The process often is referred to as profile or line extrusion
`in which the shape of the extrudate like a tube is determined
`by the die. The extruded profile proceeds horizontally to the
`cutoff equipment, which controls its length. Profiles may be
`further processed, for example, as in film extrusion, blow
`molding, or injection molding [23].
`In film extrusion, the polymer melt is extruded through a
`long slit die onto highly polished cooled rolls which form
`and wind the finished sheet. This is known as cast film.
`Plastic packaging film is also formed by blow extrusion,
`where tubular film is produced by the melt, usually verti-
`cally, through an annular-shaped slit die. The extruded tube
`is inflated by air to form a large cylinder. Blow molding
`refers to a process where the plastic is heated to a melted or
`viscous state and a section of molten polymer tubing is
`extruded usually downward from the die head into an
`open mold. The mold is closed around it, sealing it at one
`end. Compressed air is blown into the open end of the tube,
`expanding the viscous plastic to the walls of the cavity, thus
`
`Fig. 4. Component parts of a single-screw extruder.
`
`Purdue 2016
`Collegium v. Purdue, PGR2018-00048
`
`

`

`J. Breitenbach / European Journal of Pharmaceutics and Biopharmaceutics 54 (2002) 107–117
`
`111
`
`forming the desired shape of the container. During injection
`molding the molten plastic is not extruded but rather
`injected into a cavity mold at high pressure. The material
`cools in the cavity and solidifies. The mold is then opened
`and the article is removed.
`Injection molding, has been used to manufacture tablets
`[24] and sustained release preparations [25]. In terms of
`feasibility, fast drug release, and economics, injection mold-
`ing was considered suitable for drug solid dispersion or
`solution manufacture [26]. Injection molding has been
`exploited for its potential to manufacture sophisticated bi-
`layer tubular systems for customized release profiles [27].
`In the food industry extrusion has been utilized since
`1930s for pasta production. A widely used versatile techni-
`que combines cooking and extrusion in a so-called extrusion
`cooker [28].
`In the animal feed industry, extrusion is most commonly
`applied as a means of producing pelletized feeds [29]. The
`manufacture of implants by extrusion or injection molding
`is another field of application in the veterinary field.
`The need to formulate drugs with poor solubility is not
`only limited to the pharmaceutical field. Fast dispersing
`PVP melt extrudates of poorly soluble active agents as
`molecular dispersions are marketed in the crop protection
`field [30].
`
`2.2.2. Application in the pharmaceutical industry
`The most important application of extrusion in the phar-
`maceutical industry is in the preparation of granules or
`pellets of uniform size, shape, and density, containing one
`or more drugs [31]. The process involves a preliminary
`stage in which dry powders, drug, and excipients are
`mixed by conventional blenders, followed by addition of a
`liquid phase and further mixing to ensure homogeneous
`distribution. The wet powder mass is extruded through
`cylindrical dies or perforated screens with circular holes,
`of typically 0.5–2.0 mm diameter, to form cylindrical extru-
`dates [32]. In the large-scale manufacture of suppositories
`and pessaries extrusion rather refers to forcing the material
`through a capillary die [33,34].
`Melt extrusion for the manufacture of pellets [35] had
`revealed the potential for controlled release of polymer-
`embedded drugs and limitations. Pioneering work in the
`field employing the melt extrusion process as a manufactur-
`ing tool was performed by Doelker [36]. Typically, a co-
`rotating twin-screw configuration is used in most of the
`published studies. The equipment for the manufacture of
`solid dispersions has been described more precisely by
`Nakamichi [37,38].
`The second core element of the integrated technological
`system is the device to shape on-line the thermoplastic
`strand leaving the extruder [39]:
`
`(a) Calendering, in which the molten strand is forced
`between two calender rollers, thus producing films, flakes
`or sheets which may already contain single tablet cores.
`
`(b) Pellet-forming, which may, for example, be a rotating
`knife cutting spaghetti-like extruded strands.
`
`2.2.3. Regulatory aspects
`Oral pharmaceutical products from the melt extrusion
`process have been approved in the USA, European and
`Asian countries. The process technology lends itself to
`comprehensive documentation, thus satisfying regulatory
`authorities. It is a major advantage that extrusion is a mature
`engineering technology. As a process it provides many para-
`meters, such as feeding rate, segmental temperatures and
`pressure or applied vacuum, which can be monitored on-
`line with local meters and sensors. Such data contribute to
`the comprehensive documentation and the quality of
`production lots and may finally simplify quality control.
`
`3. The drug delivery technology
`
`3.1. Introduction
`
`Melt extrusion may be applied to disperse drugs in a
`given matrix down to the molecular level, e.g. to form a
`true solution. It is the convenience of the technology that
`gives new hope to the glass or solid solution approach as a
`delivery system for poorly soluble drugs. The use of melts in
`order to obtain solid molecular dispersions, e.g. glass or
`solid solutions, is well known to the expert and the essential
`advantage of a melt process in this domain is its solvent-free
`formation of such dispersions [40]. Since with solvent
`processes there are various problems relating to their use
`(environmental pollution, explosion-proofing and residual
`organic solvent) and measures to counteract these problems
`are desirable [41].
`The melt extrusion process is capable of handling active
`agents of different particle sizes as well as amorphous solids
`or other polymorphic forms leading to the same product.
`Basically, solid dispersion systems can be divided into six
`different categories (Fig. 5) [42].
`Sekiguchi and Obi were first to report the melting or
`fusion method [43]. In 1974 solid dispersions of drugs
`were described as: “… a relatively new field of pharmaceu-
`tical technique and its principles play an important role in
`increasing dissolution, absorption and therapeutic efficacy
`of drugs” [44].
`When we look at the market of pharmaceutical products
`today solid dispersion systems, in particular, solid molecu-
`lar dispersions are still found to be neglected. Only a few
`ever made it to the market including a griseofulvin–poly-
`(Gris-PEGw marketed
`by
`ethyleneglycol-dispersion
`Wander), Cesametw a nabilone-PVP (polyvinyl pyrroli-
`done) preparation (marketed by Lilly) [45] as well as a
`formulation of troglitazone (Rezulinw) marketed by Parke-
`Davis which had to be withdrawn from market for toxicol-
`ogy related issues of the drug. Several implants containing
`
`Purdue 2016
`Collegium v. Purdue, PGR2018-00048
`
`

`

`112
`
`J. Breitenbach / European Journal of Pharmaceutics and Biopharmaceutics 54 (2002) 107–117
`
`Fig. 5. Categories of solid dispersions.
`
`LHRH agonists for parenteral use have become commer-
`cially available, such as goserelin (Zoladexw) or buserelin
`(Depot–Profactw) embeddings in poly(lactide-co-glycolide)
`(PLGA) [46].
`The troglitazone formulation in PVP was actually manu-
`factured by melt extrusion [47]. Melt extrusion technology
`has proven to be a suitable method for the production of
`controlled release reservoir systems consisting of polyethy-
`lene vinylacetate (EVA) co-polymers. Based on this tech-
`two controlled release systems Implanonw and
`nology,
`NuvaRingw; have been developed [48].
`Problems limiting the commercial application of solid
`dispersions involve mainly the method of preparation, repro-
`ducibility of physicochemical properties, formulation into
`dosage forms, the scale up of manufacturing processes, and
`the physical and chemical stability of drug and vehicle [49].
`A matter of uncertainty rarely addressed is the analytical
`differentiation of amorphous embeddings in crystalline
`carriers compared to a true solid solution, where the drug
`is molecularly dispersed in the carrier. The same holds true
`for the amorphous embedding in a glassy carrier compared
`to a glass solution. The term solid molecular dispersion
`differentiates from amorphous embeddings [50]. Solid
`molecular dispersion summarizes solid and glass solution
`irrespective of the nature, e.g. the molecular weight, of the
`solvent or solute.
`Two major factors that stabilize solid molecular disper-
`sions are intermolecular interactions [51–53] between the
`drug and the carrier and the viscosity of the carrier [54].
`Glass transition temperature has long been seen as the
`predominant factor governing the physical stability of
`solid dispersions. However, this concept only holds for
`true solid molecular dispersions above their saturation
`limit. Within solid amorphous dispersions, the mobility of
`the active molecule is already given in the amorphous phase
`of the active itself possibly leading to recrystallization
`processes [55]. In the meantime investigations have shown
`that direct
`linear correlations between glass transition
`temperature and recrystallization tendency are rarely
`given. The solubilizing and stabilizing effects of the carrier
`systems’ intermolecular interactions are often of far greater
`importance for physicochemical stability [56–59].
`
`The mechanisms of drug release from solid dispersions in
`water-soluble polymers has been reviewed recently [60].
`Because of surface activity of carriers used, complete disso-
`lution of drug from melt extruded solid dispersions can be
`obtained without the need for further pulverization, sieving
`and mixing with excipients [61]. The effect of the molecular
`weight of the matrix polymers on the dissolution profile has
`been described with special respect to solid dispersions and
`solid molecular dispersions [62].
`These findings contribute to the field of melt extrusion as
`the molecular weight and other characteristics of a poly-
`meric carrier such as crystallinity and hydrogen bonding,
`vice versa pre-determine the manufacturing conditions in
`the extrusion process.
`
`3.2. Application of melt extrusion as drug delivery
`technology
`
`The breakthrough was achieved by the availability of a
`great variety of pharmaceutically approved carrier systems
`[63]. Such carrier systems include PVP [64] or its co-poly-
`mers [65], poly(ethylene-co-vinylacetate) [66], polyethy-
`lene glycol
`(PEG)
`[67],
`cellulose-ethers
`[68],
`and
`acrylates
`[69]. The properties of polyethylene oxide
`(PEO) as a drug carrier in melt extrusion with the aim to
`obtain chlorpheniramine maleate matrix tablets was exam-
`ined by McGinity [70]. Amongst the different classes of
`biodegradable polymers, the thermoplastic aliphatic poly(e-
`sters) like poly(lactide) (PLA), poly(glycolide) (PGA), and
`the copolymer of lactide and glycolide, poly(lactide-co-
`glycolide) (PLGA) have been used in extrusion. Starch
`and starch derivatives have been applied along with [71]
`low molecular weight excipients like sugars and sugar alco-
`hols and waxes [72]. The basic prerequisite for the use in
`melt extrusion is the thermoplasticity of the polymers or that
`of the respective formulations.
`Long residence time and high glass transition temperature
`(Tg) resulting in high process temperatures have often been
`described as potential drawbacks of the melt extrusion
`process. The comparison of the influence of two different
`implant manufacturing techniques, extrusion and injection
`molding, on the in vitro degradation of the polymeric matrix
`
`Purdue 2016
`Collegium v. Purdue, PGR2018-00048
`
`

`

`J. Breitenbach / European Journal of Pharmaceutics and Biopharmaceutics 54 (2002) 107–117
`
`113
`
`of polylactic acid (PLA) was studied. Both kinds of implants
`were loaded with a somatostatin analogue. It was shown that
`both molecular weight and polydispersity decreased after
`extrusion or injection molding. This decrease was more
`pronounced with the latter technique possibly due to an
`increased residence time [73]. Repka et al showed that a
`thermally labile drug, hydrocortisone, could be successfully
`incorporated into hydroxypropylcellulose (HPC) films
`produced by melt extrusion [74].
`Apart from distinct dosage forms or tailored release
`profiles melt extrusion offers the chance to circumvent the
`problem of polymorphic forms with different solubilities,
`the possibility to start from different particle sizes and a
`possible reduction of tablet size. Examples have shown
`that more favorable polymorphic forms may be stabilized
`on incorporation into PVP [75,76]. Melt extrusion with
`pharmaceutical actives having a low melting point has
`also been described. Under such conditions the extrusion
`process may serve as an agglomeration step [77]. An exam-
`ple for a change in morphology, continuously introduced in
`the melt extrusion process, applied to alter the release char-
`acteristics has been presented by Gurny et al. [78]. In order
`to influence the release of an extrudate a 200 mm thick layer
`on the extrudate surface was introduced while extruding.
`In addition, implants [79,80], stents [81], oral dosage
`forms [82], bioadhesive ophthalmic inserts [83], topical
`films [84], and effervescent tablets [85] have been devel-
`oped using the melt extrusion process.
`
`3.3. Solid dispersions with melt extrusion technology
`
`Melt extrusion is a significant step forward to cover the
`technology related issues and makes the solid molecular
`dispersion approach a viable option. The viability of melt
`extrusion technology for the production of thin, flexible,
`acrylic films for topical drug delivery has been investigated
`by Aitken-Nichol et al. ([86]). Lidocaine HCl was able to
`plasticize the acrylic polymer and the drug was completely
`dispersed at the molecular level in the extruded films. Solu-
`bilized drug molecules were shown to plasticize the polymer
`by increasing the average polymer chain spacing [86].
`A contraceptive vaginal ring containing etonogestrel and
`ethinyl estradiol has been prepared by melt extrusion. Coax-
`ial fibers have been produced with varying steroid concen-
`trations in the polymer and the release has been studied. The
`powder mixtures were blended in a twin-screw extruder.
`The polymer melted and the steroids completely dissolved
`in the polymer. After leaving the extruder, the strands were
`cooled to room temperature and granulated using a strand
`granulator. For the preparation of the coaxial fibers, a co-
`extrusion installation was used. The installation consisted of
`two single-screw extruders that are connected to a spinning
`block. The two extruders were used to melt the core and
`temperatures above 1108C. The
`membrane polymer at
`molten polymers were delivered to two gear pumps,
`which assure an accurate flow of both polymers to the spin-
`
`neret. Subsequently, the membrane and core polymers were
`combined in a spinneret, thereby forming the coaxial fiber
`[87].
`A floating sustained release dosage form composed of
`nicardipine hydrochloride and hydroxypropylmethylcellu-
`lose acetate succinate was prepared using a twin-screw
`extruder. By adjusting the position of the high-pressure
`screw elements in the immediate vicinity of the die outlet,
`and by controlling the barrel temperature, a puffed dosage
`form with very small and uniform pores were obtained. It
`was shown that the puffed dosage form, consisting of enteric
`polymer prepared using the twin-screw extruder, was very
`useful as a floating dosage form that was retained for a long
`period in the stomach [88].
`Sustained release formulations of isosorbide nitrates with
`polyvinylacetate have been developed using melt extrusion
`as manufacturing process. The in vitro release profiles indi-
`cate that even at low amounts (w/w) of the polymer the
`sustaining action of the polymer is sufficient to delay the
`release [89]. Formulations and dosage forms for poorly
`soluble drugs applying melt extrusion technology have
`been evaluated in a number of cases.
`Underlining the economic importance of the melt extru-
`sion process Ghebre-Sellassie[90] examined the use of
`different polymers revealing that hydroxypropyl cellulose
`may be a better water-soluble polymer compared to PVP
`for poorly soluble drugs. X-ray powder diffraction studies
`suggested that the drug substance mostly existed in the
`crystalline state truly representing a crystalline solid disper-
`sion. Extrusion as a way of manufacture is mentioned and a
`variety of examples using melt processes are given[90].
`A number of glass solutions of poorly soluble drugs have
`been developed using the melt extrusion process with a drug
`load ranging from 30 to 60% with real time stability up to 9
`years. During this time period no crystallization could be
`detected by means of X-ray powder diffraction or differen-
`tial scanning calorimetry [91]. It seems obvious, that stabi-
`lity of solid molecular dispersions is achieved when the
`solubility of a given drug in the carrier is not exceeded.
`By definition such systems are thermodynamically stable
`as their stability is related to the solubility of the active
`and not to the viscosity of the matrix as in supersaturated
`systems which are kinetically stabilized.
`Glass solutions of a lipophilic drug substance by melt
`extrusion technology which on dissolution forms nanopar-
`ticles and thereby increases the dissolution kinetics have
`been presented recently [92]. PVP or a vinylpyrrolidone–
`vinylacetate copolymer have been studied together with
`different surfactants.
`17-Estradiol hemihydrate as a poorly water-soluble drug
`was improved with respect to its solubility and dissolution
`rate by melt extrusion. Different compositions of excipients
`such as PEG 6000, PVP or a vinylpyrrolidone–vinylacetate-
`copolymer were used as polymers and SucroesterwWE15 or
`Gelucir