HOT-MELT EXTRUSION TECHNOLOGY: OPTIMIZING DRUG DELIVERY by Marcia Williams, Yiwei Tian, David S Jones and Gavin P Andrews
H
ot-melt extrusion (HME) technology was first utilized predominantly in the plastic industry and to a lesser extent in the food industry since the 1930’s. The many advantages of HME over conventional solid dosage form manufacturing have piqued the interest of the pharmaceutical industry and academia as a novel drug delivery technology. This innovative technology has been shown to be extremely robust and a viable method of producing many different drug delivery systems, including implantable reservoirs, pellets, films, capsules and tablets. Moreover, the possibility of forming solid dispersions offering improved bioavailability renders HME an excellent alternative to other conventionally employed techniques.
Dr Gavin P Andrews is a Senior Lecturer in Pharmaceutics at the School of Pharmacy, Queen’s University Belfast, UK. Professor David S Jones is the chair of biomaterial science at the School of Pharmacy, Queen’s University Belfast, UK. Mr Yiwei Tian and Ms. Marcia Williams are PhD students at the School of Pharmacy, Queen’s University Belfast, UK. Correspondence: DR GAVIN P ANDREWS, Lecturer in Pharmaceutics School of Pharmacy, Queens University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast BT9 7BL, UK Tel: +44 (0) 28 90 97 2646 Fax: +44 (0) 28 90 247794 Email:
[email protected]
This article aims to provide an overview of the technique, a basic guide to extrusion equipment and process technology, the fundamental principles of operation and to discuss the most recent applications of HME within the field of drug delivery. Introduction
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 density1. Since the 1930’s, hot-melt extrusion has mainly been utilized in the plastic industry in the production of plastic products such as bags, sheets, and pipes2. The process is also utilized to a limited extent in the food industry in for example, extrusion cooking for the manufacture of cereals3. The technology has now found application in the pharmaceutical industry in the area of drug delivery.
The Hot-Melt Extrusion Process
At the most fundamental level, an extruder consists of a platform that
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supports a drive system, an extrusion barrel, a rotating screw arranged on a screw shaft and an extrusion die for defining product shape. Irrespective of the complexity of the machine, the extruder must be capable of rotating the screw(s) at a selected speed, while compensating for the torque generated from the material being extruded. The extudate may be shaped into tablets, rods, pellets, or milled and mixed with other extra-granular excipients for different purposes. The single screw extruder is the most widely used extrusion system. It can be either flood or starve fed, high-pressure pumped and finally the molten materials are pumped to the die to form the extrudate4. The extrusion barrel may be conveniently divided into three distinct zones: feed zone, compression zone and metering zone. The depth and/or pitch of the screw flights differ within each zone generating variable pressure along the screw length (zone dependent). Due to the large screw flight depth and pitch, the pressure within the feed zone is very low allowing for consistent feeding from the hopper and gentle mixing of API and excipient. The primary function of the subsequent compression zone is to melt, homogenize and compress the extrudate so that it reaches the metering zone in a suitable form for extrusion. Consequently, products are formed through the die continuously (Figure 1). The single screw extrusion, however, does not provide the high mixing capability of a twin-screw machine, and therefore is not the preferred approach for the production of pharmaceutical formulations. Moreover, dispersing and mixing of drugs with other ingredients involve breaking the aggregates of the minor drug particles. In order to achieve this, a critical amount of force must be applied during the process5. This force cannot be achieved with the single-screw, but the twin-screw extruder with its corotating or counter-rotating screws would provide the high energy necessary. In addition, the versatility of a twin-screw extruder (process manipulation and optimisation) and the ability to accommodate various pharmaceutical formulations makes it much more
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HOT-MELT EXTRUSI ON T ECHNOLOGY (Con t.)
Figure 1. Typical hot-melt extruder.
favourable and is the preferred choice for pharmaceuticals. Another significant design variable is whether the two screws are intermeshing or non-intermeshing, the former being preferred due to the greater degree of conveying achievable and the shorter residence times. Industrially, due to process practicality and the ability to combine separate batch operations into a single continuous process, twin-screw extrusion significantly increases manufacturing efficiency. Recent FDA guidelines (FDA Pharmaceutical cGMP for the 21st Century, 2004) for the enhancement and modernization of the pharmaceutical industry has facilitated the move towards continuous manufacturing processes and the implementation of process analytical technologies (PAT) to monitor, control and understand manufacturing processes. These are achievable with HME technology. The continuous nature of HME has most recently been extended through the use of a cylindrical die and an inner rotating knife6. This design has helped to further enhance the continuity of the process through the generation of melt extruded pellets without the need for a separate spheronization step.
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Pharmaceutical applications of hot-melt extrusion: Background
Solid dosage forms in the form of tablets and capsules are by far the most popular dosage forms in use today, due to the enhanced stability and ease of use. Although comparatively more stable than liquid dosage forms, solid dosage forms do present bioavailability, stability and manufacturing challenges. Due to the significant limitations in unit operations involved in the production of these
dosage forms, as well as the need to remain competitive and maintain constant growth, pharmaceutical manufacturers are constantly seeking innovative processes to increase the efficiency of manufacturing operations whilst improving therapeutic efficacy. HME technology is one such technology that has captured the interest of the pharmaceutical industry particularly in the area of solid dispersions7. Several advantages over traditional processing methods have been identified, and some are listed in Table 17-10.
Table 1. Advantages of hot-melt extrusion. Features and benefits of hot-melt extrusion Feature
Benefit
Solvents not required
Environmentally friendly, economical; No residual solvent in final product.
Continuous process
Fewer unit batches required; Efficient scale-up from laboratory to large-scale production
Intense mixing and agitation achieved
Improved content uniformity
Compressibility not required
Useful for powders with low compressibility index
Polymers serve multiple purposes
Less number of excipients required; Cost effective.
Greater thermodynamic stability than that produced by other hot-melt methods
Less tendency towards recrystallization
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HOT-MELT EXTRUSI ON T ECHNOLOGY (Con t.)
Figure 2. Schematic presentation of the extrusion process.
Formation of solid dispersions
Not only is HME an efficient manufacturing process, additionally it may enhance the quality and efficacy of manufactured products4. Of particular interest is the use of HME to disperse active pharmaceutical ingredients (APIs) in a matrix at the molecular level, thus forming solid solutions (see Figure 2). HME is an approach commonly utilised in the delivery of poorly water-soluble, class II compounds due to the increased dissolution achievable, and hence improved absorption and therapeutic efficacy12. Whilst the formation of solid solutions may significantly enhance drug dissolution rate of class II compounds in vivo, the presence of a metastable state, high internal energy and specific volume of the amorphous state leads to a tendency during storage (thermal and/or humidity stress) towards recrystallization. Interestingly, extruded solid solutions offer greater thermodynamic stability than those prepared by alternative processes such as spray drying, solvent evaporation and other hot-melt methods11. The polymers used in the extrusion process may function as thermal binders, drug stabilisers, drug solubilisers and/or drug release controlling excipients with no compressibility requirements. Typical examples of pharmaceutically approved polymeric materials include vinyl polymers (polyvinylpyrrolidone (PVP), PVPvinyl acetate (PVP-VA)), polyethylene oxide (PEO), Eudragit® (acrylates), PE glycol (PEG) and cellulose derivatives. While residence time within the extruder and high
processing temperatures (required to melt the polymeric carrier) were initially projected as significant disadvantages of this technology, the ability to modify screw configuration and the high-shear forces generated within the extruder allow for processing at lower temperatures. Additionally, the use of plasticizing agents and the introduction of twin-screw extruders, removed such concerns. Typical plasticizing agents for HME include PEGs, triacetin, citrate esters, citric acid, and the API’s themselves in some cases12. A recent development is the use of surfactants to improve the release profile of solid dispersions14. The surface activity improves the solubility and aids in preventing precipitation and also protects the fine crystalline particles from agglomeration. High levels of solubility improvement have been achieved using this approach. The ability to predict the suitability of a polymer for the process should be viewed as another favourable advantage. Using small quantities of drug and polymer, thermal, spectroscopic and rheological methods may be used to determine drug/polymer miscibility thus providing information on the probability of forming a suitable dispersed (down to the molecular level) drug polymer platform8. 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,
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pellets, implants, matrix systems, transdermal drug delivery systems and ocular inserts, and targeted delivery such as enteric matrix tablets and capsules1,15,16. De Brabander et al.17 described the use of HME in the preparation of matrix mini-tablets that minimise the risk of dose dumping, reduce inter- and intra-subject variability and provide highly dispersive formulations within the gastrointestinal tract. Miller et al.18 have demonstrated the ability of HME to act as an efficient process for the wettability and hence improve drug release properties of engineered particles. Additionally, the coating of hot-melt extruded tablets with suitable polymers has been shown to significantly delay the onset of crystallization during dissolution and storage19. Future developments
The pharmaceutical industry is going through a period of unparalleled change that has been brought about by a number of factors. In particular, globalization of the industry, increased risk/cost associated with the development of new drug compounds and patent expiry on numerous high revenue drugs are the most compelling factors. As a result of such dramatic changes, the demand for new drug compounds to bridge the gap in lost revenue within shorter timeframes is increasing significantly. This undoubtedly means that the industry can no longer focus on projects that do not provide early promise. Furthermore, it is well accepted that the major changes being implemented within the pharmaceutical industry will result in focus on areas that will offer significantly high growth potential. This will involve the development of
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HOT-MELT EXTRUSI ON T ECHNOLOGY (Con t.) dormant pharmaceutical compounds that have been abandoned prior to FDA approval or approved but never commercialized. Due to the implementation of high throughput screening over the last decade these compounds have been designed for the treatment of conditions that have more difficult and complex targets. Although this may provide enhanced clinical outcomes and reduce adverse effects, these drugs commonly exhibit poor solubility in gastrointestinal fluids and hence are often not absorbed after oral ingestion. Hot-melt extrusion (HME) is an emerging drug delivery technology that is currently being investigated by the industry as a suitable method for the production of solid drug dispersions exhibiting enhanced solubility in gastrointestinal fluids. To date, the development of solid dispersions using HME has been empirical and the rationale for the selection of polymers is unclear and the prediction of the stability of the resultant drug delivery platform has not been addressed sufficiently. Therefore in order for the industry to reduce the time required to develop and release new products on to the market a greater understanding of the formulation and engineering
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aspects of this process is required to ensure that stable solid dispersions may be both predicted and prepared. This will undoubtedly be the focus of both industrial and academic research in the foreseeable future so that bio-enhanced formulations with improved efficacy may be developed. References 1. Breitenbach J. Melt extrusion: from process to drug delivery technology, European J of Pharmaceutics and Biopharmaceutics, 2002; 54: 107–117. 2. Kaufman HS, Falcetta JJ. Introduction to Polymer Science and Technology: An SPE Textbook, 1977; John Wiley & Sons, New York. 3. Guy R. Extrusion Cooking – Technologies and Applications 2001; Woodhead Publishing. 4. Ghebre-Sellassie I, Martin C. Pharmaceutical Extrusion Technology 2003; Marcel Dekker, New York. 5. Douglas P, Andrews GP, Jones DS, Walker G. Chemical Engineering Journal, 2010, doi: 10.1016/j.cej.2010.03.077. 6. Radl S, Tritthart T, Khinast J. Science Direct – Chemical Engineering Science 2010; 65(6): 1976–1988. 7. Forster AH, Rades T, Hempenstall J. Selection of Suitable Drug and Excipient Candidates to prepare Glass Solutions by Melt Extrusion for Immediate Release Oral Formulations. Pharmaceutical Technology, Europe 2002; 14(10): 27–37. 8. Chokshi RJ, Sandhu HK, Iyer RM et al. Characterization of Physico-Mechanical Properties of Indomethacin and Polymers to Assess their Suitability for Hot-Melt Extrusion Process as a Means to Manufacture Solid Dispersion/Solution. J Pharmaceutical Sciences 2005; 94(11): 2463–2474.
9. Andrews GP, Jones DS, Abu Diak O, et al. Hot-Melt extrusion: an emerging drug delivery technology. Pharmaceutical Technology, Europe 2009; 21(1). 10. Forster A, Hempenstall J, Tucker I, Rades T. The potential of small-scale fusion experiments and the Gordon-Taylor equation to predict the suitability of drug/polymer blends for melt extrusion. Drug Development and Industrial Pharmacy, 2001; 27: 549–560. 11. Rades T, Patterson JE, James MB, et al. Preparation of glass solutions of three poorly water soluble drugs by spray drying, melt extrusion and ball milling. Int J Pharmaceutics. 2007; 336: 22–34. 12. Ford JL. The current status of solid dispersions, Pharmaceutica Acta Helvetiae 1986; 61(3): 69–88. 13. McGinity JW, Zhang F, Repka M, Koleng JJ. American Pharmaceutical Review 2001; 4: 25–36. 14. Bley H, Fussnegger B, Bodmeier R. International Journal of Pharmaceutics 2010; 390: 165–173. 15. Mehuys E, Remon JP, Vervaet C. Production of enteric capsules by means of hot-melt extrusion. European J Pharmaceutical Sciences 2005; 24: 207–212. 16. Andrews GP, Jones DS, Abu Diak O, et al. The manufacture and characterisation of hotmelt extruded enteric tablets, Eur J Pharmaceutics and Biopharmaceutics. 2008; 69(1): 264–273. 17. De Brabander C, Vervaet C, Remon JP. Development and evaluation of sustained release mini-matrices prepared via hot-melt extrusion, J Controlled Release 2003; 89: 235–247. 18. Miller DA, Jason TM, Yang W, et al. Hot-Melt Extrusion for Enhanced Delivery of Drug Particles, J Pharmaceutical Sciences 2007; 96(2): 361–376. 19. Bruce D, Fegely KA, Rajabi-Siahboomi AR, McGinity W. Drug Development and Industrial Pharmacy 2010; 36(2): 218–226.
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