Advances in solid dosage form manufacturing technology.

7/29/2019 Advances in solid dosage form manufacturing technology.

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doi: 10.1098/rsta.2007.0014, 2935-29493652007Phil. Trans. R. Soc. A

Gavin P AndrewstechnologyAdvances in solid dosage form manufacturing

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Advances in solid dosage formmanufacturing technology

BY GAVIN P. ANDREWS*

School of Pharmacy, Queens University Belfast, Belfast BT9 7BL,Northern Ireland, UK

Currently, the pharmaceutical and healthcare industries are moving through a period ofunparalleled change. Major multinational pharmaceutical companies are restructuring,consolidating, merging and more importantly critically assessing their competitiveness to

ensure constant growth in an ever-more demanding market where the cost of developingnovel products is continuously increasing. The pharmaceutical manufacturing processescurrently in existence for the production of solid oral dosage forms are associated withsignificant disadvantages and in many instances provide many processing problems.Therefore, it is well accepted that there is an increasing need for alternative processes todramatically improve powder processing, and more importantly to ensure that acceptable,reproducible solid dosage forms can be manufactured. Consequently, pharmaceuticalcompanies are beginning to invest in innovative processes capable of producing solid dosageforms that better meet the needs of the patient while providing efficient manufacturingoperations. This article discusses two emerging solid dosage form manufacturing

technologies, namely hot-melt extrusion and fluidized hot-melt granulation.Keywords: hot-melt extrusion; melt granulation; drug delivery

1. Introduction

Oral dosage forms such as tablets and capsules are considered the most patient-acceptable dosage forms available today. Not only do they offer convenience andease of handling, but also they are extremely stable (chemical and physical),have a high throughput and are relatively inexpensive to produce. Orallyadministered dosage forms are an intricate blend of pharmaceutical excipientsand active pharmaceutical ingredients (APIs) that must be adequately mixedand/or granulated to ensure the manufacture of acceptable pharmaceuticalproducts. Pharmaceutical granulation is often necessary to overcome thesignificant compression difficulties and erratic flow properties of many APIs;characteristics that often limit the successful production of acceptable dosageforms (Kaerger et al. 2004). Although pharmaceutical granulation is oftennecessary, it is a batch process that provides a bottleneck for the implementationof continuous manufacturing for orally administered solid dosage forms. Whilethe pharmaceutical industry has historically used batch and not continuous

Phil. Trans. R. Soc. A (2007) 365, 29352949

doi:10.1098/rsta.2007.0014

Published online 13 September 2007

One contribution of 20 to a Triennial Issue Chemistry and engineering.

*[email protected]

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processes, the significant decrease in profit margins and the need to maintainhigh competitiveness and constant growth has driven pharmaceutical companiesto invest in new and innovative processes that better meet the needs of thepatient while providing efficient manufacturing operations ( Vervaet & Remon2005). In summary, this article will provide an overview of two key technologies

(hot-melt extrusion (HME) and fluidized hot-melt granulation (FHMG)) thatare emerging within pharmaceutical technology.

2. Current solid dosage form manufacturing technology

Orally administered solid dosage forms are a blend of pharmaceutical excipients,such as diluents, binders, disintegrants, glidants, lubricants and APIs. Thesuccessful manufacture of pharmaceutically acceptable products is dependentupon the ability to adequately mix and/or granulate these materials to ensure

that the resultant solid agglomerates possess high fluidity, compressibility and inaddition avoid de-mixing during post-granulation processes, most notably duringcompression (tablets) or filling (capsules). Moreover, the final characteristics ofthe dosage form such as drug dissolution, disintegration, porosity, friability andhardness are all significantly influenced by the properties of the powder blendsused during their manufacture (Lieberman & Lachman 1981). During productmanufacture, large volumes of powder are fed through production equipment/processes and it is essential to be able to accurately determine, define and controlpowder properties to ensure reproducible manufacture and consistent productperformance. The agglomeration processes most typically used to ensure powderblends possess adequate fluidity, cohesiveness and compressibility involve eitherwet or dry methods.

Wet granulation, encompassing low- and high-shear mixing, fluid-bed mixing(spraying) and wet-mass extrusion, is an extremely versatile technique that hasseveral advantages over dry methods, including improved control of drugcontent, better uniformity for highly potent drugs (low-dose APIs) andproduction of granules with superior bulk density and compatibility (high- andlow-dose APIs). Wet granulation typically involves wet massing a blend of APIand excipients in a wet granulator followed by subsequent sieving and finallydrying (Aulton 2002). The most commonly used liquid for wet granulation iswater although non-aqueous solvents such as ethanol and isopropyl alcohol may

be used when water is unsuitable. While water is extremely economical andenvironmentally friendly, wet-granulation techniques are labour intensive andprocess times are inherently long due to wetting and drying stages ( Kristensen &Schaefer 1987). Such disadvantages may be overcome through the use of volatilenon-aqueous binder solutions, but these typically require specialized equipmentdue to the high flammability of the solvent. Moreover, during wet-granulationprocessing (milling, wet massing, drying and compression), phase transfor-mations may be induced including changes in polymorphic form, state ofsolvation and degree of crystallinity of the API ( Hendriksen et al. 1995). Thesephase transitions are known to significantly influence the physicochemical

properties of solid materials and, in particular, API activity (Yoshika et al.1995). An example of the importance of such phase transitions during wetgranulation has recently been reported by Wardrop et al. (2005). Abbott-232, a

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highly water-soluble, non-hygroscopic, potent uroselective a1A agonist, has beenshown to undergo a solution-mediated phase transformation from an anhydrateto an amorphous form during wet granulation, which subsequently decreasedthe potency of the API. Interestingly, the anhydrate would not reform fromthe monohydrate (formed during wet granulation) during the drying stages of the

process due to the presence of crystallization inhibitors within the formulation.Typical examples of crystallization inhibitors include polyvinylpyrollidone(PVP), hydropropyl methylcellulose (HPMC) and other high-molecular-weightpolymers that significantly increase the viscosity of the system and preventformation of a crystal lattice.

More recently, Tantry et al. (2007) demonstrated that the physical form oftheophylline manufactured in a solid dosage form is significantly influenced bythe molecular weight of the binding agent, the granulation method and thedrying temperature. In this study, a stable anhydrous form of theophylline wasmanufactured into tablets using a high-shear wet (aqueous-based) granulation

process. During the granulation process, theophylline monohydrate was formedthat was partially converted to a metastable anhydrous form during drying.Storage of these dosage forms at RHO33% caused complete metastableanhydrous to stable anhydrous conversion accompanied by a pronounceddecrease in the initial dissolution rate. The presence of PVP decreased theconversion of the metastable anhydrous to stable anhydrous theophylline, withhigh-molecular-weight PVP being more effective. Furthermore, increasing thedrying temperature from 45 to 558C significantly increased the metastableanhydrous to stable anhydrous conversion.

Although the presence of pharmaceutical excipients may significantly alter therate and/or extent of phase transformation and recrystallization during thewetting and drying stages of wet granulation, it has been shown that theirinclusion may significantly decrease product storage stability. Hydrochlorothia-zide, a drug substance with excellent solid-state stability, can undergo hydrolysisto form formaldehyde and 4-amino-6-chloro-1,3-benzenedisulphonamide. Desaiet al. (1996) have shown that the inclusion of povidone K-30 NF (PVP) as abinder and poloxamer 188 NF (Pluronic F68) as a wetting agent significantlyincreases drug hydrolysis during storage. Replacement of PVP with Starch 1500and removal of Pluronic F68 from the tablet formulation resulted in lower levelsof degradation. The increased drug degradation in the presence of PVP and/orPluronic F68 was attributed to the enhanced solubility of the drug, in the

moisture present in the tablets. While non-aqueous solvents may be employed toprevent aqueous-induced transitions and/or hydrolysis, phase transformationmay still occur during processing. Moreover, the use of non-aqueous granulatingfluids may also lead to a significant change in granule characteristics, such asfracture strength, bulk density and compactability ( Fichtner et al. 2007). It iswell accepted, therefore, that it is not only the properties of the API and theexcipients that significantly influence the final characteristics of the product butalso the conditions (amount/type of granulating liquid, granulation time, airflowrates and drying temperature/rate) of the wet-granulation method.

Dry methods are a suitable alternative to wet granulation particularly when

the API or excipients are sensitive to water/moisture and non-ambienttemperatures, conditions that are typical for wet granulation. Dry granulationtypically involves the compaction of powder blends through slugging or roller

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compaction. Slugging involves the manufacture of a large compressed tabletwhereas roller compaction pushes powder blends through two counter-rotatingrolls, producing a sheet of agglomerated material. In both cases, the formed solidcompact is milled to produce the granulate of the desired particle size range forcompression or filling. Given that dry granulation does not involve the use of

solvents, solution-mediated phase transformations are negated; however, drygranulation may introduce the possibility of phase transformation during theapplication of high-compression forces and localized heating while agglomeratingpowder blends (Zhang et al. 2004). APIs known to undergo phase transition uponexposure to mechanical stress are discussed in a mini-review by Brittain (2002).Typical examples of APIs that undergo transformation during compressioninclude caffeine and chlorpropamide. Interestingly, dry granulation processesproduce granules with an extremely high bulk density and low intragranularporosity in comparison with granules produced using alternative techniques(Li & Peck 1990). Furthermore, dry-granulated materials exhibit better

gravimetric flowability; however, the high-density granules produced using thisprocess have been shown to suffer from loss of tabletability, due to the significantnumber of particle defects and loss of plasticity introduced during processing(Malkowska & Khan 1983). This is extremely important, as the quality of thefinal dosage form is significantly influenced by the compaction properties of thegranular material ( Joiris et al. 1998). In addition to loss of tabletability andpossible phase transformation during compression, dry granulation may alsoresult in high levels of dust (problematic for potent API), poor compactionhomogeneity and high levels of adhesion to the production equipment.Consequently, while dry granulation is conceptually very simple with lowoperational costs, a considerable lack of process understanding limits its use(Gereg & Cappola 2002). These disadvantages combined with a willingness toaccept static agglomeration processes have led to wet granulation remaining thepreferred and most widely accepted method for size enlargement within thepharmaceutical industry. More recently, however, oral dosage form manufactur-ing technology is enjoying a significant renaissance, with a number of keyemerging technologies that may offer a suitable alternative to currently availableprocesses and more importantly negate the current drawbacks associated withprocessing pharmaceutical powders and solid dosage forms.

3. HME and FHMG: emerging technologies

HME and FHMG are two highly dynamic topics with the potential to radicallychange the way in which oral dosage forms and drug delivery platforms aremanufactured. FHMG is a non-ambient temperature process that uses meltablebinders to agglomerate fluidized dry powders whereas HME involves the use ofthermoplastic polymers for the production of controlled drug delivery systems.Both processes may be used to manufacture granules, pellets and tablets and inparticular HME may be used to produce highly innovative multiple medications.Moreover, such processes may be used to produce thermodynamically stable

solid solutions to improve the dissolution rate of poorly water-soluble drugs,one of the major challenges in dosage form development (Chokshi et al. 2005).Unlike conventional solid dosage form manufacturing techniques, both processes

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avoid the problems associated with drug instability, flammable solvents andtime-consuming drying processes, ultimately reducing the time required for

product manufacture (Walker et al. 2007a,b). Additionally, there is a significantreduction in the number of processing steps, no prerequisite compression/fluidityproperties are required and improved drug/polymer mixing and hence drugdistribution and product homogeneity may be observed (McGinity 2004).

4. Hot-melt extrusion

HME is an innovative drug delivery technology that is receiving increasedattention from both the pharmaceutical industry and the academic community.HME was first developed in the plastics industry and in its most basic form,

compacts, blends and converts a powder mix into a product of uniform densityand shape (Crawford 1998). At the most fundamental level, a single screwextruder consists of one rotating screw positioned inside a stationary barrel(figure 1), whereas more advanced machines involve twin-screw systems usingeither a co-rotating or counter-rotating screw configuration. As shown in figure 1,the barrel of an HME machine consists of three distinct zones: feed zone;compression zone; and a metering zone, all of which exert a different pressure onthe pharmaceutical powder. These three zones differ in the depth and/or pitch ofthe screw flights. The feed zone has an extremely large screw flight depth andpitch (figure 2), allowing for consistent feeding from the hopper and gentle

mixing of the API and excipients. At this stage of the process, the pressurewithin the extruder is at its lowest. The subsequent compression zone imparts ahigh degree of mixing and compression to the material by decreasing the screw

feed zone compression

zone

metering zone die

hopper (feed system) barrel heaters

drive unit

Figure 1. Depiction of a single screw extruder including the feed, compression and metering zones.

screw diameter

flight depth

helix anglepitch

Figure 2. Screw design depicting screw pitch and diameter, flight depth and helix angle.





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pitch and/or the flight depth, which results in a gradual increase in pressurealong the length of the compression zone (Breitenbach 2002). The primaryfunction of this zone is to melt, homogenize and compress the extrudate so that itreaches the metering zone in a form suitable for extrusion. The function of themetering zone is to ensure that the extrudate has a uniform thickness, a property

that is governed by the consistency of melt flow. Consequently, the meteringzone must eliminate any pulsating flow and the constant screw flight depth andpitch reflect this aim. While the screw pitch and flight depth are constant, thepressure in this zone far exceeds the pressure in the feed zone. The application ofthis continuous high pressure ensures a uniform delivery rate of molten materialthrough the extrusion die and hence a uniform product. Given that HME is anon-ambient process involving the use of thermoplastic polymers, heat iscommonly transferred to the powder mass through a combination of friction(rotation of screw in barrel) and barrel heaters.

HME technology offers several distinct advantages over manufacturing

techniques that have been typically used to produce orally administered soliddosage forms. The technique does not involve a granulation fluid and thus avoidsproblems associated with instability (McGinity 2004). Moreover, extrudedmaterials may be cut directly into tablets or pellets avoiding subsequentcompaction processes, typically required for wet- and dry-granulation tech-niques. Therefore, HME allows for the rapid production of solid dosage formswhile avoiding many of the current disadvantages of conventional manufacturingtechniques. HME is a non-ambient process that involves the use of thermoplasticpolymeric materials as carrier systems for the API. Although thermoplasticmaterials such as polyethylene ( PE) and polypropylene are well accepted withinthe plastics industry, such materials are not suitable for the manufacture oforally administered solid dosage forms. Consequently, only when pharma-ceutically approved polymeric materials (PVP, polyethylene oxide (PEO),Eudragit and PE glycol (PEG)) became widely available did HME emerge as asuitable drug delivery technology. While residence time within the extruder andhigh processing temperatures (required to melt the polymeric carrier) wereinitially projected as significant disadvantages of this technology, the use ofplasticizing agents and the introduction of twin-screw extruders negated suchconcerns. Typical plasticizing agents for HME include PEGs (Zhang & McGinity1999), triacetin (Follonier et al. 1994) and citrate esters (Aikten-Nichol et al.1996). However, APIs have also been shown to be effective plasticizers in many

cases (Repka & McGinity 2000). These agents (plasticizers) occupy sites alongthe polymer chain and prevent chainchain interactions significantly reducingthe frictional forces between chains, thus improving polymer chain mobility andprocessability (Doolittle 1954).

Initial investigations in this area focused on the effects of plasticizing agents,processing conditions and API loading on the physicochemical properties of theextruded dosage forms. Zhang & McGinity (1999) reported the influence ofpolymer molecular weight, API loading and the inclusion of PEG on thedissolution of chlorpheniramine from PEO matrix tablets. Drug release from thematrix was controlled by PEO erosion and by the diffusion of the API through a

swollen gel layer that developed at the surface of the tablets during dissolutionexperiments. In a further study, Crowley et al. (2002) investigated the thermalstability of PEO, illustrating that lower-molecular-weight PEO was more

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susceptible to degradation, and vitamin E and vitamin E tocopheryl succinatePEG 1000 (TPGS) were found to be highly suitable stabilizing agents. Aninvestigation by Liu et al. (2001) examined the properties of wax-based HMEtablets and granules and compared them with tablets/granules prepared using ahigh-shear melt granulation (MG) method. MG is a non-ambient single-step

high-shear granulation method in which powder agglomeration is promoted bythe addition of a low-melting-point binder ( Fichtner et al. 2007). Similar toHME, MG is a useful alternative to conventional wet-granulation processes whenthe use of solvents is not possible (Schaefer et al. 1990). The study by Liu et al.(2001) illustrated the potential use of low-melting (50608C processingtemperatures) wax materials and matrix carriers. Interestingly, tablets preparedusing HME were much harder and released the API (phenylpropanolamine)much more slowly than comparator tablets prepared using high-shear MG.Moreover, the uniformity of API within HME granules was much betterthan those prepared using high-shear MG and hence drug dissolution was

more consistent.While preliminary studies have focused on the effects of formulation andprocessing variables on the properties of the dosage form, subsequent scientificarticles have described the use of HME for the production of solid solutions andfor the development of mini-matrices. Early work by De Brabander et al.described the use of HME to prepare matrix mini tablets that provide less risk ofdose dumping, less inter- and intrasubject variability and high levels ofdispersion within the digestive tract (De Brabander et al. 2000). Furtherinvestigations by De Brabander et al . (2003) studied the manufacture ofsustained release multiple unit dosage forms (mini-matrices) using ethylcellulose, HPMC and ibuprofen. In relation to the preparation of drug deliverysystems with improved aqueous solubility, HME provides a suitable platform forthe preparation of solid solutions provided there is a high degree of miscibilitybetween the API and the polymeric carrier ( Leuner & Dressman 2000). Mehuyset al. (2004) described the use of HME for the production of a matrix-in-cylinderdevice for sustained release purposes. This system resulted in a fourfold increasein the bioavailability of propranolol when compared with a commerciallyavailable formulation (Inderal). The use of HME to produce solid solutions toimprove the dissolution properties of active agents has long been recognized.Owing to the non-ambient nature of the process, HME provides an efficienttechnology for the dispersion and solubilization of APIs within a thermoplastic

matrix. Given that improving the solubility, dissolution rate and, thus, in vivoabsorption properties of new drug candidates remains a major challenge in thedevelopment of new drug treatments, the emergence of a novel technology that iscapable of producing solid solutions while negating common manufacturingdisadvantages is highly beneficial. One major concern regarding the formation ofsolid solutions via this technique is the phase transition (recrystallization) thatmay occur upon storage leading to a significant reduction in the aqueoussolubility and unpredictable product performance.

Early research by Hulsmann et al. (2000) investigated the use of PEG, PVPand gelucire HME extrudates to improve the solubility of 17b-oestradiol. HME

extrudates significantly improved the solubility of this API with a reported30-fold increase in dissolution rate. More recently, Six et al. (2005) investigatedthe performance of itraconazole solid dispersions prepared by HME and





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compared the clinical performance of the extrudates to a marketed form,Sporanox. A further study by Verreck et al. (2005) examined the use ofsupercritical carbon dioxide (scCO2) as a temporary plasticizer during themanufacture of solid dispersions of itraconazole and polyvinylpyrrolidone-co-vinyl acetate 64 (PVP-VA 64). Given that the stability of a solid

dispersion/solution is governed by matrix mobility, temporary plasticizationmay provide a suitable method of avoiding post-manufacture recrystallization. Asignificant reduction in the processing temperatures was achieved using scCO2without any detrimental effects on the extrudates. Interestingly, the macroscopicmorphology was significantly altered due to expansion of the scCO2 at the die,resulting in foamed extrudate, increasing surface area, porosity and hygro-scopicity. Furthermore, milling efficiency was improved. Although considerableresearch has been conducted using PEO as a drug carrier in HME, Li et al. (2006)recently reported the use of PEO as a matrix carrier for improving the solubilityof a model, poorly water-soluble API (nifedipine). Hot-stage microscopy

illustrated that nifedipine could form miscible dispersions at temperaturesabove 1208C with complete loss of nifedipine crystallinity and a significantimprovement in dissolution rate compared with either pure nifedipine or aphysical mixture of PEO and nifedipine. In another study, the formation ofPEO/clotrimazole solid solutions using HME was reported by Prodduturi et al.(2005). Interestingly, the solid solution was shown to be unstable andrecrystallized after three months storage at 258C and 60% RH. The authorsproposed that the instability of the formulation was due to folding (occurredduring HME) and unfolding (occurred during storage) of linear PEO chains.Similarly, PVP was the focus of many early investigations into the feasibility ofHME but more recently it is enjoying a renaissance, particularly for thepreparation of solid solutions. Patterson et al. (2007) have recently reported theuse of PVP in the formation of glass solutions using carbamazepine,dipyridamole and indomethacin. HME materials exhibited improved solubilityin comparison with those prepared by spray drying, and it was shown that thestability of solid solutions may be greatly enhanced by the formation of hydrogenbonding between the parent polymer and the API.

Undoubtedly, due to the inherent advantages associated with HME, there isgrowing interest in this technology for the production of immediate andsustained release delivery systems, whether they are in the form of tablets,granules, pellets or films. Research to date has examined the formation of many

types of orally administered dosage forms and has identified the limitations aswell as the significant benefits this technology may afford. Interestingly, as thistechnology begins to gain momentum, the number of research articles beingpublished has dramatically increased. In order for HME to fulfil its true potentialnew research must address the major challenges facing oral dosage formdevelopment. Improving the solubility, dissolution rate and, thus, in vivoabsorption properties of new drug candidates remains a major challenge in thedevelopment of new drug treatments. Hence, there is continuing interest in thedevelopment of new processing technologies, and in particular, HME, to enhancethe dissolution of poorly water-soluble drugs. Recently published articles on

HME have focused on improving drug solubility through the formation of solidsolutions; however, understanding API stability in the dosage form remains amajor challenge. This coupled with the need to advance the simplistic nature of

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single-matrix systems to manufacture multi-functional dosage forms must beaddressed so that HME can open new scientific horizons and go substantiallybeyond the current state of the art.

5. Fluidized hot-melt granulation

Granulation is often used within the pharmaceutical industry to increase theaverage particle size within a powder blend so as to make the blend more amenableto subsequent compaction processes and hence improve the overall reproducibilityof solid dosage form manufacture. Granulated material may typically provideless segregation of the constituents of the powder, improve flowability andvery importantly improve powder compactability, leading to a highly uniform,acceptable product. It is common for APIs and other excipients to be mixed,granulated, sieved and dried prior to tabletting: processes that are pertinent to thesuccessful manufacture of acceptable dosage forms but are very time consuming.Although pharmaceutical granulation is an extremely laborious process, it is anextremely important unit operation given that the properties of the resultantgranules may significantly influence the dissolution rate, disintegration time,friability and hardness of the final solid dosage form. Moreover, the physicochem-ical properties of granules will ultimately influence their processability, fluidity andcompressibility (Sun & Grant 2001). Conventional granulation processes areemployed within the pharmaceutical industry to agglomerate powders to producegranules of the desired shape and size; factors that are pertinent to overalltabletability (Laitinen et al. 2004). Currently used methods are associated with

significant disadvantages including long process times, potential loss of APIactivity, poor compressibility, uneven and erratic flow through manufacturinghoppers and high development costs. Consequently, it is well accepted that a novelprocess negating such difficulties would be highly superior and dramaticallyimprove powder processability ensuring the reproducible production of elegantsolid dosage forms with high patient acceptability.

One such emerging technique is FHMG. Fluidized beds have severalapplications within the processing of orally administered solid dosage forms,most notably during drying and granulation. For the purposes of granulation,the majority of research conducted in this area has focused on the use of

binding fluids that are sprayed onto fluidized particles. FHMG differs significantlyin that it is a non-ambient process conducted at elevated temperatures tochange the physical nature of one or more of the components. Thus, FHMGinvolves the use of meltable binders to agglomerate fluidized dry powders (Walkeret al. 2006). FHMG avoids the use of solvents negating the problems associatedwith in-process hydrolysis and solvent removal. Furthermore, it does not requirepowders to possess high levels of fluidity and compressibility. Conventionalwet techniques typically involve transfer of powder mass which may involvelosses in transfer, contamination of manufacturing equipment, increasedprocessing and operator time and increased dust levels (issues that are particularly

pertinent when manufacturing dosage forms containing highly potent drugs).In contrast, FHMG appears to be a simple, rapid and safe process withsignificant advantages.





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The earliest work reported was conducted by Kojima & Nakagami (2001) andinvestigated the use of FHMG as a means of granulating micronized low-substituted hydroxypropyl cellulose (LH41). Although LH41 is extremelyfavourable as a controlled release matrix carrier, the poor flowability andcompressibility of this material has limited its use in standard tabletting

processes. Interestingly, FHMG was shown to preserve the controlled releaseproperties of LH41 while improving the flowability, hence improving subsequenttablet manufacture. As with all novel processes most fundamental, earlyinvestigations focus on investigating variables that significantly influence granuleproperties including process and formulation variables (Kristensen & Schaefer1987). In this respect, Kidokoro et al. (2002) investigated the use of FHMG as anovel granulation process using PEG and glyceryl monostearate as meltablebinders. One of the most interesting aspects of these early investigations was thattablet hardness and disintegration were not affected by tablet porosityhighlighting that tablets with high reproducibility may be processed under a

wide range of compression forces. Another interesting article by Kidokoro et al.(2003) investigated the effect of the crystallization behaviour of PEG 6000 on theproperties of granules prepared by FHMG. The authors demonstrated that theparticle size distribution of the resultant granules was significantly influenced bythe crystallization behaviour of the meltable binder. While early studies onFHMG were extremely promising and highlighted the significant potential forthe preparation of pharmaceutical granules, the detailed mechanism of granulegrowth and the relationship between the growth parameters and the properties ofthe granules that will ultimately determine the performance of the product werepoorly understood. As with any new process, identification of the relationshipsthat exist between granule characteristics, process parameters and formulationvariables must be established (Fung & Ng 2003). One of the first investigationsto examine granule growth mechanisms was conducted by Seo et al. (2002). Theeffect of binder droplet size and type of binder on granule growth mechanismswithin the fluid bed was investigated. Initial granule growth was shown to occurvia nucleation of filler particles (in this case lactose) in the molten binder dropletswhereas increased massing occurred due to coalescence between agglomerates.Interestingly, at high process temperatures, binder droplet size and binder typehad no significant effect on the average granule size at the end of the process. Thekinetics of breakage within the fluid bed during MG has been examined by Tanet al. (2004). In this study, mathematical models were developed and verified

using population balance modelling (PBE). Additionally, a new analytical PBEand discretized population balance equation were developed for the growth andnucleation process. A further investigation by Tan et al. (2005) quantified theaggregation and breakage rates within the fluidized bed during the MG process.Granulation rate was observed to increase with increased bed temperature usinga high-viscosity binder but granulation rate reached a plateau for less viscousbinders. Furthermore, granulation rate also increased when binders of a largerdroplet size and lower fluidizing velocity were employed. The overall kineticsduring the process has been identified to be a combination of particleaggregation, binder solidification and granule breakage (Tan et al . 2006).

Granule growth was shown to be directly dependent upon the amount of binderused and binder particle size. Moreover, increased fluidization velocity wasshown to reduce granule growth rate.

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One of the first studies conducted by our group investigated the MG oflactose and PEG using a fluidized bed granulator (Walker et al. 2006). Ratherthan spraying molten binder onto the fluidized particles, all the componentsincluding the binder were introduced to the fluid bed in the solid state. Theeffect of process parameters such as binder content and binder viscosity was

correlated to granulation time and particle size distribution. The experimentaldata indicated that after initial nucleation the granulation mechanism wasdependent upon binder content and binder viscosity. When the binder contentwas increased de-fluidization of the bed occurred and granulation moved to theslurry regime. Granulation with relatively low-viscosity binders resulted ingranule growth by coalescence; however, an increase in binder viscosity resultedin less coalescence and a lower granule growth rate. More recently, FHMG hasbeen used for the agglomeration of model pharmaceutical powders (Walkeret al. 2007a,b) and a meltable model API (ibuprofen). In this investigation,ibuprofen was used as the binder. Using a novel high-temperature method, the

compression properties of the granules were measured. It was found that thefractural modulus of the granules at non-ambient conditions was orders ofmagnitude lower than that measured under ambient conditions. Interestingly,after an initial period of nucleation only velocities within the high-shear regionof the fluidized bed were sufficient to promote granule deformation and,therefore, coalescence. Furthermore, dissipation of the viscous molten binder tothe surface of the agglomerate was the most important factor in the latterstages of the granulation process. From a pharmaceutical perspective, theinclusion of ibuprofen with PVP in the co-melt process proved to be highlysignificant. It was found that there was a significant decrease in the heat offusion associated with the melting of ibuprofen within the FHMG systems,suggesting loss of crystallinity.

In addition to characterizing the effect of process and formulationparameters on the final properties of the granules, we have investigated theuse of Raman spectroscopy for characterizing the granulation process withinthe fluid bed. In situ measurement of bed composition within the fluidized bed(three spatial dimensions) as a function of time has been investigated usingRaman spectroscopy (Walker et al. 2007a,b). Raman spectra were recordedfrom specific volumes of space and used to provide three-dimensional maps ofthe concentration and chemical structure of the particles in a fluidized bedwithin a relatively short time window. At the most basic level, the technique

measures particle density via the intensity of the Raman spectra. Moreimportantly, the data also provide information on the chemical structure of thefluidized particles.

FHMG has significant potential as a novel granulation process and is gainingincreased academic attention. This process does not involve the use of extraneousbinding fluids that may decrease API stability and produce significant phasetransformations during processing. Furthermore, hydrophobic (stearic acid ortriglycerides) andhydrophilic materials (PEG or poloxamer) maybe used to enhancethe dissolution rate of poorly soluble drugs, thereby yielding the possibility ofenhanced bioavailability. However, these benefits must be balanced against the

possibility of degradation of thermolabile drugs and the absence of a core knowledgebase within the pharmaceutical industry with regard to the optimization of the melt-granulation process. Indeed, while the wet-granulation process has been studied





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extensively in pharmaceutical and bulk chemical manufacture (Krycer et al. 1980),there is a paucity of information available with regard to the predictability andmodelling of the FHMG, a deficit that must be addressed.

6. Conclusion

HME and FHMG are two highly dynamic, interdisciplinary topics that provide acreative link between engineering and pharmaceutical sciences for the purposesof drug delivery. Research in these vibrant research areas is making significantadvances resulting in innovative, engineered drug delivery systems. These newscientific discoveries have significant potential for industrial exploitationproviding an ideas factory for future product developments. Moreover, focusin these key areas will ensure a constant stream of highly trained individuals withan interdisciplinary background and an ability to foster out-of-the-box

thinking, making them highly suitable for employment within an ever-changingpharmaceutical industry and more importantly capable of going significantlybeyond the state of the art to confront major research challenges.

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AUTHOR PROFILE

Gavin P. Andrews

Dr Gavin P. Andrews graduated from Queens University Belfast (QUB) with aBSc in chemistry in 1998 and was awarded an MSc in polymer engineering in1999. After receiving a PhD in pharmaceutics for a thesis entitled Thephysicochemical characterization of polymeric drug delivery platforms, he wasappointed (October 2002) as a research associate in the interdisciplinary MedicalPolymers Research Institute (MPRI), QUB. Dr Andrews held this position untilJanuary 2004 when he was appointed to a lectureship in pharmaceutics at theSchool of Pharmacy, QUB. In addition to holding a lectureship post inpharmaceutics, Dr Andrews is an academic partner of MPRI, a position that

enables him to maintain a strong relationship with industry, and is a memberand chartered chemist (CChem) of the Royal Society of Chemistry and achartered scientist (CSci) of the Science Council.

Dr Andrews research interests are focused on the combination of cuttingedge engineering technologies with fundamental pharmaceutical science tomanufacture innovative oral drug delivery platforms and medical devices.Dr Andrews research portfolio includes physicochemical characterization ofnovel polymeric networks, drugexcipient interactions and strategies to improvethe performance of both implanted drug delivery systems and orallyadministered solid dosage forms.

Dr Andrews research has received considerable funding from the pharma-ceutical industry, EU, Wellcome Trust, Gates Foundation (USA) and EPSRC.More recently, Dr Andrews received a competitive Promising Young Researchersto work alongside Prof. McGinity as a visiting scientist at the University ofTexas at Austin. While still at an early stage in his career, Dr Andrews hasauthored over 40 publications in the area of pharmaceutics and pharmaceuticaltechnology, co-authored a monograph for the Handbook of PharmaceuticalExcipients and has received competitive awards to present his research findingsat both national and international conferences.




Advances in solid dosage form manufacturing technology.

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