Extrusion and spheronization in the development of oral controlled-release dosage forms

1461-5347/99/$ – see front matter ©1999 Elsevier Science. All rights reserved. PII: S1461-5347(99)00136-4

▼ Conventional medication systems that requiremulti-dose therapy are not without problems.With a view to overcoming these problems, thecurrent trend in pharmaceutical research is to de-sign and develop new formulations, thereby en-hancing the therapeutic efficacy of existingdrugs. Moreover, the impetus for research intodrug delivery can be attributed to the exorbitantcost and large development period involved in‘new drug development’ with concomitantrecognition of the therapeutic advantages of con-trolled drug delivery.

Controlled release (CR) technology has rapidlyemerged over the past three decades as a new interdisciplinary science that offers novel ap-proaches to the delivery of bioactive agents intosystemic circulation at a predetermined rate. Thechoice of drug to be delivered, clinical needs, anddrug pharmacokinetics are some of the impor-tant considerations in the development of CRformulations, in addition to the relationship be-

tween the rate of drug release from the deliverysystem to the maximum achievable rate of drugabsorption into the systemic circulation. Byachieving a predictable and reproducible bioac-tive agent release rate for an extended period oftime, CR formulation can achieve optimumtherapeutic responses, prolonged efficacy, andalso decreased toxicity1.

The therapeutic advantages of CR systems overconventional dosage forms have been amplydocumented in the literature2,3. One of the im-portant advantages is the reduced dosing fre-quency, thereby improving patient complianceand therapeutic efficacy. In addition, the constantblood levels of the drug, unlike in conventionaldosage forms, leads to a minimization of drug-related side effects.

Although a variety of dosage forms have beendeveloped for the preparation of oral CR formu-lations, they broadly fall into two categories: sin-gle unit dosage forms and multiple (multiparticu-late) dosage forms.

Single unit dosage formsSingle unit dosage forms are defined as oraldosage forms that consist of single units, witheach unit containing one dose of the drug and in-tended to be administered singularly. There areseveral such dosage forms that have been devel-oped for the CR of various bioactive materials, ashas been reported in the literature and of whichmonolithic matrix-based tablets are the mostcommon single unit dosage form used for con-trolled drug delivery4,5. Advantages associatedwith such dosage forms include high drug load-ing, simple and cost-effective manufacturing op-erations, the availability of a wide range of excipi-ents and polymers for controlling drug release

Extrusion and spheronization in thedevelopment of oral controlled-releasedosage formsRajesh Gandhi, Chaman Lal Kaul and Ramesh Panchagnula

Rajesh Gandhi, Chaman Lal Kaul

and Ramesh Panchagnula*Department of Pharmaceutics

National Institute ofPharmaceutical

Education and ResearchSector 67, S.A.S. Nagar

Punjab 160 062India

*tel: 191 172 673848fax: 191 172 677185

e-mail: [email protected]

reviews research focus

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The concept of multiparticulate dosage forms was introduced in the

1950s. With the increasing use of multiparticulate controlled release

(CR) oral dosage forms, in recent times there has been a rise in inter-

est in the methods of preparing these dosage forms. A method that

has gained increased usage over the past few years is that of extru-

sion and spheronization. It has been extensively explored as a poten-

tial technique and also as a future method of choice for preparation

of multiparticulate CR dosage forms. In this review an attempt is

made to outline the general process of extrusion and spheronization

and to assess its importance in the development of multiparticulate

CR oral dosage forms.

and the possibility of using different mechanisms for drug re-lease control (such as diffusion controlled, swelling controlled,erosion controlled or a combination of all of these). Single unitdosage forms that have been used for controlled drug deliveryinclude drug-release controlling polymer membrane-coatedtablets and osmogen-controlled formulations6,7.

Multiple unit dosage formsThe concept of the multiple unit dosage form was initially in-troduced in the early 1950s. These forms play a major role inthe design of solid dosage form processes because of theirunique properties and the flexibility found in their manu-facture. These forms can be defined as oral dosage forms con-sisting of a multiplicity of small discrete units, each exhibitingsome desired characteristics.Together, these characteristic unitsprovide the overall desired CR of the dose.These multiple unitsare also referred to as pellets, spherical granules or spheroids.Pellets or spherical granules are produced by agglomeratingfine powders with a binder solution. These pellets usuallyrange in size from 0.5–1.5 mm and in some applications maybe as large as 3.0 mm (Ref. 8).

The use of pellets as a vehicle for drug delivery at a con-trolled rate has recently received significant attention. Appli-cations are found not only in the pharmaceutical industry butalso in the agribusiness (such as in fertilizer and fish food) andin the polymer industry9. There are numerous advantages of-fered by multiple unit dosage forms.

• Pellets disperse freely in the gastrointestinal (GI) tract, andso they invariably maximize drug absorption, reduce peakplasma fluctuation, and minimize potential side effectswithout appreciably lowering drug bioavailability10.

• Pellets also reduce variations in gastric emptying rates andoverall transit times.Thus inter- and intra-subject variabilityof plasma profiles, which is common with single unit regi-mens, is minimized11.

• High local concentration of bioactive agents, which may in-herently be irritative or anesthetic, can be avoided12.

• When formulated as modified-release dosage forms, pelletsare less susceptible to dose dumping than the reservoir-type,single unit formulations12.

• Better flow properties, narrow particle size distribution, lessfriable dosage form and uniform packing13,14.

• The pellets offer advantages to the manufacturer becausethey provide an ideal shape [low surface area to volumeratio] for the application of film coating. They can also bemade attractive because of the various shades of colour thatcan be easily imparted to them during the manufacturingprocess, thus enhancing the product elegance andorganoleptic properties12.

• Pellets also offer the advantage of flexibility for further modi-fications, such as compression to form tablets or coating toachieve the desired dosage-form characteristics15.

Methods of pellet preparationPellets are spheres of varying diameter and they may be manu-factured by using different methods according to the appli-cation and the choice of producer.

In a spray-drying process, aqueous solution of core materialsand hot solution of polymer is atomized into hot air, the waterthen evaporates and the dry solid is separated in the form ofpellets, usually by air suspension. In general, a spray-dryingprocess produces hollow pellets if the liquid evaporates at a ratefaster than the diffusion of the dissolved substances back intothe droplet interior or if due to capillary action dissolved sub-stances migrate out with the liquid to the droplet surface, leav-ing behind a void12,16.

In spray congealing a slurry of drug material that is insolu-ble in a molten mass is spray congealed to obtain discrete par-ticles of the insoluble materials coated with congealed sub-stances. A critical requirement for this process is that thesubstance should have a well-defined melting point or smallmelting zone12.

In fluidized bed technology a dry drug form is suspended ina stream of hot air to form a constantly agitated fluidized bed.An amount of binder or granulating liquid is then introducedin a finely dispersed form to cause a momentary reaction priorto vaporization.This causes the ingredients to react to a limitedextent, thereby forming pellets of active components. Usingthis process Govender and Dangor13 and Mathir et al.17 preparedand characterized pellets of Salbutamol and Chlorpheniraminemaleate, respectively.

In the rotary processor (rotogranulator) the whole cycle isperformed in a closed system.The binder solution and powdermix are added at a fixed rate on the plate of the spheronizer sothat the particles are stuck together and spheronized at thesame time. Using this process Robinson and Hollenbeck18 pre-pared acetaminophen pellets and, in a comparison with extru-sion–spheronization, they demonstrated that acceptable, im-mediate release pellets could be produced.

A novel method involving the use of a rotary shaker pel-letizer has been developed for making pharmaceutical spheres.It is essentially based on a laboratory shaker in which a cylin-drical bowl is attached to the platform of a rotary shaker. Spiralparticle motion combined with a high degree of particle bowlbottom friction and interparticulate collision in the bowl (feedwith plastic extrudates) results in plastic deformation of extru-date and the granule surface to form the spheres19.

A further technique used to prepare pellets is the layer build-ing method, in which a solution or suspension of binder and a

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drug is sprayed onto an inert core and the pellets are built layerafter layer. However, use of this technique is limited because ofthe smaller drug loading that can be layered effectively onto thecore material, thus making this technique unsuitable for drugswith large doses20.

Extrusion and spheronizationExtrusion and spheronization is currently one of the tech-niques used to produce pharmaceutical pellets.With each pro-duction technique, pellets with specific characteristics are ob-tained. The preparation of spherical granules or pellets byextrusion and spheronization is now a more establishedmethod because of its advantages over the other methods18,21

(Box 1), and the technique will now be described in detail.

Spheronization is a technique of Japanese origin that is some-times referred to as Merumerization, after the trademark of theFuji Denki Kogyo Company (Osaka, Japan). Although originallyinvented in 1964 by Nakahara22, it wasn’t until 1970 and thepublication of the process by Reynolds (Lilly Research, UK)14

and Conine and Hadley (Eli Lilly, Indianapolis, IN, USA)23 thatthe technique became widely known. In subsequent years thedetailed process of spheronization, including the individual pro-cessing variables based on extrusion and spheronization, waspublished by J.B. Schwartz’s group and the whole process wasreduced to a series of pharmaceutical operations, each of whichis associated with a number of individual parameters24,25.

Process and equipmentIn basic terms, the extrusion and spheronization process in-volves four steps:

• granulation – preparation of the wet mass;

• extrusion – shaping the wet mass into cylinders;

• spheronization – breaking up the extrudate and roundingoff the particles into spheres;

• drying – drying of the pellets.

Different steps, parameters and equipment used in the processare summarized in Fig. 1.

The first step of the extrusion and spheronization cycle con-sists of the preparation of the wet mass. Different types ofgranulators are used to perform the mixing of the powderblend and the granulation liquid. There are three types ofprocessors used to mix different constituents of the powderblend. The most commonly used granulator is a planetarymixer18, although in various cases use of a high shear mixer,sigma blade mixer26 and a continuous granulator27 has alsobeen reported. However, it is important to note that high shearmixers introduce a large amount of heat into the mass duringgranulation, which may cause evaporation of the granulationliquid because of a rise in temperature, thereby influencing theextrusion behaviour of the wet mass. This may be avoided bycooling the granulation bowl28.

ExtrusionExtrusion is the second step of the process and consists ofshaping the wet mass into long rods, which are more com-monly termed ‘extrudate’. The extrusion process is used notonly in the pharmaceutical industry but also in the food, ce-ramic and polymer industries. The extrusion process is cur-rently used as an alternative method for the manufacture ofcompletely water-soluble tablets29.

Types of extrusion devices have been grouped into fourmain classes; that is, screw, sieve and basket, roll and ram ex-truders. A screw extruder, as the name implies, utilizes a screwto develop the necessary pressure to force the material to flowthrough the uniform openings, producing uniform extru-dates30. In the sieve and basket extruders the granulate is fed bya screw or by gravity into the extrusion chamber in which arotating or oscillating device processes the plastic massthrough the screen. The basket type extruder is similar to thesieve extruder except that the sieve or screen is part of a verti-cal, cylindrical wall31. The third class of extruders are the rollextruders and these are also known as ‘pellet mills’.Two typesof roll extruders are available31,32. One extruder is equippedwith two contrarotating wheels, of which one or both are per-forated, and the second type of roll extruder has a perforatedcylinder that rotates around one or more rollers that dischargethe materials to the outside of the cylinder. The final type ofextruder is an experimental device called the ram extruder.Theram extruder is believed to be the oldest type of extruder andfeatures a piston riding inside a cylinder or channel that isused to compress material and force it through an orifice onthe forward stroke. Fielden et al.32 compared the extrusion andspheronization behaviour of wet mass processed by a ram ex-truder and a cylinder extruder and concluded that they are notalways equivalent.

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Box 1. Advantages of the extrusion andspheronization process

Ease of operationHigh throughput with low wastageNarrower particle size distributionProduction of pellets with low friabilityProduction of pellets that are suited for film coatingMore sustained and better controlled drug-release profilewhen compared with other techniques

SpheronizationThe third step of the extrusion and spheronization process in-volves the dumping of the cylinders onto the spheronizer’s spin-ning plate, known as the friction plate, upon which the extrudateis broken up into smaller cylinders with a length equal to theirdiameter. A spheronizer is a device that consists of a vertical hol-low cylinder (bowl) with a horizontal rotating disk (frictionplate) located inside.The friction plate has a grooved surface toincrease the frictional forces. Two types of geometry of thegrooves exist; more common is the cross-hatch geometry inwhich the grooves intersect each other at 908 angles, whereas theother pattern is radial geometry in which grooves emanate fromthe centre like the spokes of a bicycle wheel.The spheronizationof a product usually takes 2–10 minutes, and a rotational speedof between 200–400 rpm for the friction plate is satisfactory toobtain highly spherical pellets9,23. A special type of spheronizer,designed by NICA systems, features a lip around the rim of thefriction plate that is claimed to reduce the milling effect of theplate in order to produce a smaller amount of fines30.

The fourth and final step of the process is the drying of thepellets.The pellets can be dried at room temperature32 or at anelevated temperature in the fluidized-bed drier18, in an oven33,in a forced circulation oven13 or in a microwave oven34. Pelletquality is dependent on the type of dryer used. According toBataille et al.34, oven drying provides less porous and harderminigranules and a more homogenous surface than those driedby a microwave oven. Dyer et al.35 prepared ibuprofen pelletsthat were dried either by tray drying or fluidized-bed drying,and they showed that the drying technique has a quantifiableeffect on the diametral crushing strength and elasticity of thepellets, their in vitro release, and a qualitative effect on the sur-face characteristics of ibuprofen pellets.

Pellet formationNumerous mechanisms of pellet formation have been sug-gested. The overall process of spheronization can be divided

into various stages in terms of the changes in the shape of theextrudate. According to Rowe36, extruded plastic cylinders arerounded in the form of pellets because of frictional forces.Cylinders transform into cylinders with rounded edges then todumb-bells and elliptical particles and eventually to perfectspheres. Baert and Remon28 suggested that another pellet-forming mechanism might also exist that is based on frictionalforces as well as rotational forces. In this mechanism a twistingof the cylinder occurs after the formation of a cylinder withrounded edges, finally resulting in the breaking of the cylinderinto two distinct parts with both parts featuring a round and aflat side. Because of the rotational and the frictional forces in-volved in the spheronization process, the edges of the flat sidefold together like a flower, forming the cavity observed in cer-tain pellets. Figure 2 shows both pellet-forming mechanisms.

The process of extrusion and spheronizaton is a multi-stepprocess that involves a number of parameters that have a finalbearing on the characteristics of the obtained pellets. Moisturecontent is an extremely important parameter in the extrusion andspheronization process. It is necessary to give the powder mass itsplasticity so that it can be extruded and shaped afterwards. It was

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Figure 1. Flow diagram showing differentsteps, process parameters and equipmentinvolved in extrusion and spheronization toproduce spherical controlled release pellets.

Granulatingliquid

Powder drymixing

Granulatortype

Mixer

Wet mixing

Extruder

Extrusion

Spheronizer

Spheronization

Dryer

Drying

Coater

Coating

Coatingsolution

Extruder type

Screenopening sizeExtrusiontemperature

Spheronizertype

GranulationliquidMixing time

Extrusionspeed

Dryer typeDrying temperature

Plate typePlate speedSpheronization timeSpheronizer load

Figure 2. Pellet-forming mechanism according to: (a) Rowe36 – I.Cylinder; II. Cylinder with rounded edges; III. Dumb-bell; IV. Ellipse; V.Sphere. (b) Baert – I. Cylinder; II. Rope; III. Dumb-bell; IV. Sphere witha cavity outside; V. Sphere. [Reproduced with permission from Ref. 9.]

I

I

(b)

(a)

II

II

III

III

IV

IV

V

V

shown that there is a certain limit of moisture content at whichpellets of an acceptable quality are produced. If the moisturecontent is less than a certain lower limit, a lot of dust will be in-troduced during spheronization which will result in a largeyield of fines. If moisture content is more than a certain upperlimit then an overweighed mass and agglomeration of individ-ual pellets during spheronization are caused because of an ex-cess of water at the surface of pellet32. The extent of moisturecontent also influences the mechanical strength, friability, in-ternal porosity and the particle-size distribution of pellets.

Ostuka et al.37 reported that the internal porosity of sphericalgranules decreases with increasing water concentration, weightloss after the friability test increases with a decreasing amountof water and the quantity of water influences the mechanicalstrength of granules. Moisture content also affects the shape andsize of granules38. Gazzaniga et al.39 found differences in the fri-ability and particle size of pellets when the powder mass waswetted with different quantities of water.

Starting materialThe physical nature of the starting material influences the par-ticle size, hardness, and sphericity as well as the release rate ofthe included drug. There is not only the obvious difference inpellet quality produced from different compositions but alsothe difference when different types of the same product areused25.The use of similar products but from different suppliershas also been found to change the characteristics of the pel-let40,41. Pellets prepared with three types of microcrystallinecellulose (MCC) – Avicel® PH-101, Emcocel®, Unimac® – MGfrom different manufacturers featured differences in size androundness when processed under the same conditions40. Thephysical properties of two types of commercial MCC, AvicelPH-101 and Microcel MC show differences during the step ofmoistening, thereby affecting the particle size and hardness ofthe pellets obtained42.The difference in release rate in differenttypes of dissolution medium has been observed between pel-lets containing only MCC and those containig MCC withsodium carboxymethyl cellulose (NaCMC). This difference isbecause a gel-like structure was formed in water through thepresence of NaCMC with MCC, whereas the pellets containingonly MCC remain unchanged in aqueous medium resulting ina greater rate of release43.

Granulation liquidThe use of different amounts of water as a granulation liquidalone or in combination with alcohol affects the hardness andparticle size distribution of the final pellets. The most com-monly used granulating liquid is water, although in some casesthe use of alcohol or a water–alcohol mixture has also been re-ported9. The effect of the alcohol content in a water–alcohol

mixture has been extensively studied by Millili and Schwartz44.Binary mixtures of theophylline and Avicel PH-101 (10:90w/w) were found to form pellets when granulated with 90%ethylalcohol in water–alcohol mixture. Differences in friabilityand dissolution were observed between water granulated- and95% ethylalcohol in water–alcohol mixture-granulated pellets.Increasing the water content in the granulation liquid leads toan increase in the hardness of the pellets. The increase in thehardness was correlated with a slower in vitro release rate oftheophylline. Gazzaniga et al.39 reported that when b-Cyclodextrin (b-CD) was used to form pellets using water asthe granulating liquid, the poor quality of the extrudates, interms of plasticity and sticking, invariably lead to irregularlyshaped pellets and agglomerates with broad size distribution.In this respect, preliminary promising results were obtained bylowering the solubility of b-CD in the wetting liquid throughthe use of water–alcohol mixtures.This probably improves theplasticity of the wetted mass and thus the feasibility of theoverall process.

ExtrudersSeveral studies appear in the literature regarding the influenceof the type of extruder on the size distribution, sphericity anddensity of pellets14,36,41.The studies have shown that pellets ob-tained from two types of extruder had differed in sphericityand in particle size distribution because of a shift in the opti-mal amount of granulation liquid needed with each extruderor because of the difference in the length-to-radius ratio of the extrusion screen used45,46. According to Reynolds14 andRowe36, an axial screw extruder produces a more dense ma-terial compared with the radial screw extruder; the latter has ahigher output but also produces a greater rise in the tempera-ture of the mass during processing.

Extrusion screen propertiesPellet quality is dependent on the extrusion screen, which ischaracterized by two parameters: the thickness of the screenand the diameter of the perforations. Changing one of thesetwo parameters influences the quality of the extrudate andhence the pellets. Baert et al.46 reported the difference in extru-date quality when they were obtained by extrusion with dif-ferent screen thicknesses. The screen with low thicknessformed a rough and loosely bound extrudate, whereas thescreen with high thickness formed smooth and well-bound ex-trudate because of the higher densification of the wet mass inthe screen with the greatest thickness.

Similarly, the diameter of the perforations determines thesize of pellets, and a larger diameter in the perforations willproduce pellets with a larger diameter when processed underthe same conditions47,48. An increase in the extruder screen

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opening size was found to result in an increase in the hardnessof the tablets made from these pellets25.

Extrusion speedThe total output of the extruder is mainly governed by the ex-trusion speed.The output should be as high as possible for eco-nomical reasons, but several authors state that an increase inthe extrusion speed can influence the size and surface proper-ties of the final pellets47–49. Several studies show that the sur-face impairments, such as roughness and sharkskinning, be-come more pronounced with increasing speed47,48.The surfaceeffects of extrudate lead to pellets of lower quality because theextrudate will break up unevenly during the initial stages ofthe spheronization process, resulting in a number of fines anda wide particle-size distribution49.

Extrusion temperatureExtrusion temperature influences the pellet quality by affectingthe moisture content. The rise in temperature during the ex-trusion cycle could dramatically alter the moisture content ofgranules because of evaporation of the granulation liquid.Thismay lead to a difference in the quality of the extrudate pro-duced at the beginning of the batch and at the end of thebatch. Evaporation of water during extrusion is possible be-cause most of the water is available as free water50. Extrusiontemperature control becomes an important parameter when aformulation with a thermolabile drug is processed. To avoid arise in the temperature during an extrusion cycle, use of screwextruder with a cooling jacket around the barrel to keep thetemperature of the given formulation between predeterminedlimit has been reported51,52.

Spheronizer specificationsPellet quality is also dependent on spheronizer load. It mainlyaffects the particle size distribution, bulk and tap density of thefinal pellets9. The yield of pellets of a specific range decreaseswith an increase in the spheronizer speed and at a low spher-onizer load, and increases with extended spheronization timeat a higher spheronizer load53,54. Barrau et al.54 reported that anincreasing spheronizer load decreased the roundness and in-creased the hardness of pellets, whereas yield in the majoritysize range remained unchanged. Hellen et al.55 reported thatthe bulk and tap density increased and the size of the pelletsdecreased with an increasing spheronizer load.

The spheronization speed affects the particle size of pellets.In the initial stages of the spheronization process, an increase inthe smaller fractions is seen, probably because of the greaterdegree of fragmentation. In contrast, a decreasing amount offines and a higher amount of particles with faster spheroniz-ation speed correlating with an increased mean diameter was

also observed27,49,56. The hardness56, roundness49, bulk andtapped density55, porosity49,56, friability56, flow rate57 and sur-face structure56 of pellets are also affected by a change in thespheronization speed.

Spheronization time mainly affects the particle size distribu-tion53 and bulk and tap density55.57 of pellets. A wide range ofresults have been witnessed when assessing the importance ofthis parameter in formulations containing mixtures of MCC.These results include an observed increase in diameter, a nar-rower particle size distribution, a change in the bulk and tapdensity and a change in the yield of a certain size range with anextended spheronization time53.

Development of oral CR formulationsThe advantages of using small spherical pellets or beads in oralcontrolled drug delivery are well documented.The pellets pro-vide a smoother absorption profile from the GI tract, becausethe beads pass gradually from the stomach through the pyloricsphincter into the small intestine at a steady rate. Pellets can belayered with drug and coated with various polymers to controlthe release rates. Further, different types of pellets with differentrelease rates can be combined in a simple capsule to provide thedesired CR profile (Fig. 3). Betageri et al.58 have described threeapproaches to the preparation of sustained release pellets.

• The first approach involves the placement of the drug in aninsoluble matrix in which the eluting medium penetratesthe matrix and the drug diffuses out of the matrix and intothe surrounding pool for ultimate absorption.

• The second approach involves enclosing the drug particleswith a polymer coat. In this case, the portion of the drugthat has been dissolved in the polymer coat diffuses throughan unstirred film of liquid into the surrounding fluid.

• The third approach is eroding beads in which the drug is re-leased as the bead matrix erodes or dissolves.

In the first two cases the constant area of diffusion, togetherwith a constant diffusion path length and constant drug con-centration, can achieve a controlled rate of drug release. On thebasis of the above approaches, the CR formulations prepared byextrusion and spheronization are mainly divided into two cat-egories: coated pellets and matrix pellets.

Coated pelletsControlled drug release from pellets is conventionally achievedby polymer coating. In many applications neutral pellets (non-pareil seeds) are used as raw materials that are coated with theactive ingredients and then with release-retarding substances.According to the USP/NF monograph for sugar spheres59,neutral pellets consist mainly of sucrose and corn starch. The

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monograph specifies an upper limit of 4% for the water con-tent and the variation in composition is 62.5–91.5% sucrosewith the remainder consisting mainly of starch60. In the othercase, the pellets containing active ingredients are prepared andthen coated with a suitable rate-controlling polymer.

In this case MCC is mainly used for the preparation of pelletscontaining active ingredients. Microcrystalline cellulose has theideal physical properties, including moisture-retaining and dis-tribution ability for extrusion and spheronization.This is mostlikely because of the favourable rheological properties of its wetmass61. In some cases, cellulose ethers, hydroxypropylmethylcellulose (HPMC) and hydroxyethyl cellulose (HEC) are used asa pelletization aid62. Recently, the use of b-Cyclodextrin aloneor in combination with different grades of MCC has also beenreported39.The final prepared coated pellets can either be filledinto two-piece hard gelatin capsules or compressed into tablets.

Coating materialsFilm coating is effectively used to modify the release of activeingredients from pellets. Porter63 has defined the materials thatare found to be suitable for the production of CR coatings.

• Mixtures of waxes (such as beeswax and carnauba wax)with glyceryl monostearate, stearic acid, palmitic acid, glyc-eryl monopalmitate and cetyl alcohol.These provide a coat-ing that dissolves slowly or breaks down within the GI tract.

• Shellac and zein – polymers that remain intact until the pHcontents become less acidic.

• Ethylcellulose provides a membrane around the dosage formand remains intact throughout the GI tract. However, it does

permit water to penetrate the film, dissolve the drug anddiffuse out again.

• Acrylic resins, which have similar properties to ethylcellu-lose as a diffusion-controlled drug release coating material.

• Cellulose acetate (triacetate and diacetate) – these provide abarrier coating and release depends on the pore structure ofthe membrane.

• Silicone elastomers – polymers are plastic-coating materialsand drug liberation depends on the leaching of the drugfrom the inert matrix by GI fluid penetration into pores ofplastic matrix.

Various studies have been reported in the literature on theuse of coated pellets for CR. Controlled release beads of theo-phylline were developed by using ethyl cellulose as a coatingmaterial and were found to release theophylline in a controlledmanner64. Similarly, Venkatesh and Sanghavi65 used extrusionand spheronization to prepare pindolol drug pellets that werecoated with ethyl cellulose and eudragit RS100, and reportedthat drug release was influenced by the coating level and pH ofthe dissolution medium. Schultz and Kleinebudde66 preparedan acetaminophen system based on coated pellets containing anosmotic active ingredient, coated with a semi-permeable mem-brane of cellulose acetate, and the active ingredients were re-leased according to zero-order kinetics.

Aqueous polymeric dispersion coatingAqueous colloidal dispersions (latex and pseudolatex) ofwater-insoluble polymers are now increasingly used for coat-ing solid dosage forms. The advantages of using such systems

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Figure 3. Hypothetical drug blood level vs timeprofile, showing the relationship betweencontrolled release and conventional release drugdelivery. A 5 controlled release; B 5 prolongedrelease; C 5 conventional release.

Time (h)

Dru

g bl

ood

leve

l (am

ount

mL−

1 )

IneffectiverangeC

B

A

Therapeuticrange

Toxicrange

include efficient and predictable drug release, without possibleagglomeration of the beads or pellets during the coatingprocess. In addition, the use of toxic organic solvents in theprocess can be avoided.The mechanism of film formation fromaqueous dispersions is a complex process. The aqueous poly-mer dispersion is sprayed onto the solid particles with suitableequipment and, as water evaporates, colloidal particles areforced to come together to form a film. Plasticizers are added tothe film-forming polymer in order to improve the film-form-ing characteristics and to achieve a film with the desired per-meability and drug release characteristics. Dyer et al.67 have pre-pared ibuprofen pellets by extrusion and spheronization andused an aqueous polymeric dispersion of polymethacrylates,ethylcellulose and silicon elastomer films in the coating. Theapplication of a polymeric membrane to uncoated cores hadthe effect of retarding drug release.

Matrix pellets, systems and classificationSustained release from pellets is conventionally achieved bypolymeric coating. There is growing interest in the develop-ment of matrix pellet formulations because, in practice, poly-meric coating is associated with various problems68.

• The process is time consuming and expensive.

• Film thickness is variable.

• There may be cracks in the film or aging of the polymercoating.

• The drug release profile is not reproducibile because of in-consistent film coating.

• Coating is dependent on the optimization of several param-eters during the production process.

Amongst the innumerable methods used for controlling thedrug release from a pharmaceutical dosage form, the matrixsystem is the most frequently applied method.The matrix sys-tem is a heterogeneous dispersion of drug particles in a solidmatrix, which can either be biodegradable or nonbiodegrad-

able and controls the drug release by diffusion through the ma-trix, by erosion of the matrix, or by a combination of both diffusion and erosion69–71. To define a matrix, the followingproperties must be considered:

• chemical nature of support (generally the supports areformed by polymeric nets);

• the physical state of the drug (dispersion under molecularor particulate form, or both);

• the matrix and alteration in volume as a function of time;

• the routes of administration (oral administration remainsthe most widely used but other routes are adaptable);

• the release kinetics model (in accordance with Higuchi’sequation, these systems are considered to have a linear re-lease as a function of the square root of time).

The matrix-based systems can be classified on the basis ofthe following criteria70:

• matrix structure;

• release kinetics (must be zero-order release);

• CR properties (diffusion, erosion and swelling);

• chemical nature and properties of the applied materials.

With regard to the last criterion, the matrix system can beclassified into five main classes (Table 1).

Several studies have shown that it is possible to formulate ma-trix pellets using extrusion and spheronization. Different Avicelproducts25, blends of Avicel products72, a series of release-retard-ing agents73, and Avicel with waxes74 have been incorporated intobead formulations to retard drug release. A product with Aviceland sodium carboxymethyl cellulose content showed a slowerrate of release in water25,72; this has been attributed to the for-mation of a gel plug in the USP dissolution basket.The formationof a gel plug is probably due to coalescence of beads in the basket,but importantly, the purpose of multi-unit dosage forms is lost.

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Table 1. Matrix system classification

Hydrophilic Inert Lipidic Biodegradable Resin matrices

Unlimited swelling, delivery Inert in nature Delivery by diffusion Nonlipidic in nature Drug release from drug–resinby diffusion complexControlled delivery through Controlled delivery by Delivery by surface Controlled delivery by Release depends on the limited swelling diffusion erosion surface erosion surrounding ionic environmentHPMC, HEC, HPC Ethyl cellulose Carnauba wax Poly(anhydride), Ion exchange resin

Bees wax PLGA matricesPrecirol

Abbreviations: HPMC, hydroxypropylmethyl cellulose; HEC, hydroxyethyl cellulose; HPC, hydroxypropyl cellulose; PLGA, copolymer (L-lactic/glycolic acid).

Bioavailability studies of a hydrochlorothiazide pelletformulation consisting of Avicel RC-581 (containing 11%NaCMC) did not suggest a slow rate of release in vivo43.The re-lease of indobufen can be modified by using combinations ofpH adjusters (citric acid, sodium citrate, tartaric acid and fu-maric acid) and polymeric dispersions and by employing Avi-cel PH-101 as a spheronizing aid.The presence of pH adjustersin pellet formulations affects the microenvironment of thedrug molecule, producing different CR profile patterns, al-though the extent of slow release was limited49 (80% releasedin 4 h).

Polymeric dispersions Aquacoat ECD 30 and Eudragit RS 30 Dwere used in combination with Avicel PH-101 or Avicel RC-591to produce acetaminophen and ibuprofen beads. Ibuprofen re-lease was retarded significantly when formulated at low drugloading (10%) with higher amounts of polymeric dispersion.Avicel RC-591 was an effective aid in successful spheronization ata higher drug loading and when greater amounts of polymericdispersions were used (as presented by Goskonda, S.R.,Upadrashta, S.M. and Hileman, G.A. at the American Associationof Pharmaceutical Scientists’ Midwest Regional Meeting, 1992,Chicago, IL, USA). In another study using a zwitterion (isoelec-tric point ~pH 5.2) as a model drug, it was found that the com-bination of Eudragit RS-30 D with an organic acid as a pH modi-fier (fumaric acid and succinic acid) and Avicel RC-591 in thebead could yield a product that exhibits sustained release75,76.

Release rate modificationVarious release-retarding materials have been incorporated tomodify the release rate. Chitosan and Avicel RC-591 were usedas matrix materials for retarding drug release33,77. Peh andYuen78 prepared matrix pellets using glyceryl monostearatewith a satisfactory in vitro dissolution rate.The authors reported

that the rate of drug release could be modified in a predictablemanner by varying the amount of glycerylmonostearate in theformulation. Blanque et al.79 utilized a combination of glyceryl-monostearate and barium sulphate, the water-insoluble filler,to retard the drug-release rate. Neau et al.80 reported the fea-sibility of employing Carbopol® 974, NF resin as a sustained-release modifying agent. In these studies, the authors utilizedthe chemical interaction between electrolytes and Carbopol®

974P to reduce the tackiness of the latter in pellet formu-lations. They also successfully prepared Chlorpheniraminemaleate/MCC pellets with up to 55% w/w Carbopol® 974P byincorporating strong electrolytes such as sodium chloride, cal-cium chloride, magnesium chloride and aluminium chloride.

A recent study indicated that diltiazem hydrochloride releasecould be modified by using magnesium stearate as a hy-drophobic release modifier81. The feasibility of using plasticmaterials, such as HPMC, as a binder and release modifier wasalso tested, and the authors reported that because of the plasticnature of HPMC, formulations were difficult to spheronize.However, the cylindrical extrudate, obtained as the final prod-uct, showed a CR profile. The incorporation of waxes into aMCC matrix resulted in faster release from beads because ofmatrix interruption, whereas thermal treatment of the samebeads resulted in sustained drug release64. Of several waxes,only a few waxes, such as spermaceti, precirol, beeswax andcastor wax, proved to be sufficiently effective in retarding drugrelease.

However, little research into this approach has been per-formed because of a lack of excipients and polymers with therequired physical characteristics, thus making them unsuitableto be used for extrusion and spheronization.At present, variousCR formulations that utilize pellets are available, and some aresummarized in Table 2.

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Table 2. Different controlled-release marketed products in the form of pellets

Formulations Active components Manufacturers

Betacap TR capsules Propanolol hydrochloride Natco PharmaColdact TR capsules Phenylpropanolamine hydrochloride Natco Pharma

and chlorpheniramine maleateDilgard XL ER capsules Diltiazem hydrochloride CiplaFEFOL®-Z SR capsules Zn + iron + folic acid SmithKline Beecham PharmaceuticalsIbubid TR capsules Ibuprofen Natco PharmaIndocap® capsules Indomethacin Jagsonpal PharmaSudafed SA capsules Pseudoephedrine hydrochloride Borroughs–WellcomeTheo-24 SR capsules Anhydrous theophylline Searle PharmaceuticalsTheolong SR lungules Theophylline SOL PharmaVentorlin CR capsules Salbutamol Glaxo India

Abbreviations: CR, controlled release; SA, sustained action; SR, sustained release; TR, timed release.

ConclusionsExtrusion and spheronization is an effective technique for thepreparation of CR multiparticulate formulations of bioactiveagents. There are currently various multiparticulate CR formu-lations available, and the success of this process is largely de-pendent on its advantages over other techniques.The sphericalgranules or pellets produced by this technique feature a regu-lar shape with uniformity in size and density. When dry, thespheroids have an extremely low friability and are ideallysuited for film coating. In addition, the process is capable ofhigh throughput with low wastage and easy operation. Withthe increasing use of multiparticulate CR formulations, it is en-visaged that extrusion and spheronization will become a popu-lar and well known process in the near future.

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170


In brief…

Imperial College Innovations (London, UK) has agreed a licensing option with Millennium BioTherapeutics (Cambridge, MA, USA) for the use of patent-protected leptin antagonist technology. Robert Lechler has developed the technology withinImperial College Innovations, the technology development company for the Imperial College of Science, Technology andMedicine, and his group is evaluating the effects of leptin and its antagonists on immune system activity.

Leptin, primarily associated with obesity, has been found to increase in primary immune response and to reverse thereduction in the hypertensive response induced by starvation, a result with implications of immunization, particularly inareas of malnutrition. Leptin antagonists may have an immunosuppressive effect, with potential for exploitation intransplantation or treatment of autoimmune disorders.

Millennium BioTherapeutics is a majority owned subsidiary of Millennium Pharmaceuticals and has acquired the option forthe field of human immunosuppressive therapy, and is also providing reagents for Lechler’s group. Jonathan Gee, ChiefExecutive of Imperial College Innovations commented, ‘This is another example of the excellent research carried out withinImperial College having real commercial potential, an issue of increasing importance in universities. I anticipate that thiswork could prove extremely valuable in the development of novel therapies in different areas including cancer andimmunosuppression.’

In the May issue of Pharmaceutical Science & Technology Today …

Update – latest news and views

Potential for plasmid DNAs vaccines for the new millenniumKhushroo E. Shroff, Larry R. Smith, Yaela Baine and Terry J. Higgins

Targeting endocytosis and motor proteins to enhance DNA persistenceSarah F. Hamm-Alvarez

Coated dosage forms for colon-specific drug deliveryClaudia S. Leopold

Imaging techniques for assessing drug delivery in manStephen P. Newman and Ian R. Wilding

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Documents

Extrusion and spheronization in the development of oral controlled-release dosage forms