reviews I research focus
`
`PSTT Vol. 2, No. 4 April 1999
`
`Von the
`Extrus or and sphuo
`
`raAed-release coleve_opr-r_c-rci- of CODa_ cm-rt
`acsage fo-nrs
`Rajesh Gandhi, Chaman Lal Kaul and Ramesh Panchagnula
`
`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.
`
`Rajesh Gandhi,
`Chaman Lal Kaul
`and Ramesh Panchagnula.
`'Department of Pharmaceutics
`National Institute of
`Pharmaceutical
`EducatiOn and Research
`Sector 67, S.A.S. Nagar
`Punjab '60 062
`India
`'tel: +91 172 673848
`fax: 1-91 172 677185
`e-mail: niper@chd.nic.in
`
`V Conventional medication systems that require
`multi-dose therapy are not without problems.
`With a view to overcoming these problems, the
`current trend in pharmaceutical research is to de-
`sign and develop new formulations, thereby en-
`hancing the therapeutic efficacy of existing
`drugs. Moreover, the impetus for research into
`drug delivery can be attributed to the exorbitant
`cost and large development period involved in
`'new drug development' with concomitant
`recognition of the therapeutic advantages of con-
`trolled drug delivery.
`Controlled release (CR) technology has rapidly
`emerged over the past three decades as a new
`interdisciplinary science that offers novel ap-
`proaches to the delivery of bioactive agents into
`systemic circulation at a predetermined rate. The
`choice of drug to be delivered, clinical needs, and
`drug pharmacokinetics are some of the impor-
`tant considerations in the development of CR
`formulations, in addition to the relationship be-
`
`tween the rate of drug release from the delivery
`system to the maximunraclievable rate of drug
`absorption into the-. systemic circulation. By
`achieving a predictable and reproducible bioac-
`tive agent release rate for an extended period of
`time, CR formulation can achieve optimum
`therapeutic responses, prolonged efficacy, and
`also decreased toxicity'.
`The therapeutic advantages of CR systems over
`conventional dosage forms have been amply
`documented in the literature23. One of the im-
`portant advantages is the reduced dosing fre-
`quency, thereby improving patient compliance
`and therapeutic efficacy. In addition, the constant
`blood levels of the drug, unlike in conventional
`dosage forms, leads to a minimization of drug-
`related side effects.
`Although a variety of dosage forms have been
`developed for the preparation of oral CR foi'mu-
`lations, they broadly fall into two categories: sin-
`gle unit dosage forms and multiple (multiparticu-
`late) dosage forms.
`
`Single unit dosage forms
`Single unit dosage forms are defined as oral
`dosage forms that consist of single units, with
`each unit containing one dose of the drug and in-
`tended to be administered singularly. There arc
`several such dosage forms that have been devel-
`oped for the CR of various bioactive materials, as
`has been reported in the literature and of which
`monolithic matrix-based tablets are the most
`common single unit dosage form used for con-
`trolled drug delivery4,5. Advantages associated
`with 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
`
`160 (cid:9)
`
`1461-53471991$ - see front matter ©1999 Elsevier Science. All rights reserved. PII: 51461-5347(99)00136-4
`
`Exhibit 1036
`ARGENTUM
`IPR2018-00080
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`PSTT Vol. 2, No. 4 April 1999
`
`research focus I reviews
`
`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 unit
`dosage forms that have been used for controlled drug delivery
`include drug-release controlling polymer membrane-coated
`tablets and osmogen-controlled formulations6'7.
`
`Multiple unit dosage forms
`The concept of the multiple unit dosage form was initially in-
`troduced in the early 1950s. These forms play a major role in
`the design of solid dosage form processes because of their
`unique 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 exhibiting
`some desired characteristics. Together, these characteristic units
`provide the overall desired CR of the dose.These multiple units
`are also referred to as pellets, spherical granules or spheroids.
`Pellets or spherical granules are produced by agglomerating
`fine powders with a binder solution. These pellets usually
`range in size from 0.5-1.5 mm and in some applications may
`be 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 but
`also in the agribusiness (such as in fertilizer and fish food) and
`in the polymer industry'. There are numerous advantages of-
`fered by multiple unit dosage forms.
`
`• Pellets disperse freely in the gastrointestinal (GI) tract, and
`so they invariably maximize drug absorption, reduce peak
`plasma fluctuation, and minimize potential side effects
`without appreciably lowering drug bioavailability19.
`• Pellets also reduce variations in gastric emptying rates and
`overall transit times. Thus inter- and intra-subject variability
`of plasrha profiles, which is common with single unit regi-
`mens, is minimized''.
`• High local concentration of bioactive agents, which may in-
`herently be irritative or anesthetic, can be avoidedia.
`• When formulated as modified-release dosage forms, pellets
`are less susceptible to dose dumping than the reservoir-type,
`single unit formulacions'2.
`• Better flow properties, narrow particle size distribution, less
`friable dosage form and uniform packing23.24.
`• The pellets offer advantages to the manufacturer because
`they provide an ideal shape [low surface area to volume
`ratio] for the application of film coating. They can also be
`made attractive because of the various shades of colour that
`can be easily imparted to them during the manufacturing
`process, thus enhancing the product elegance and
`organoleptic properties''-.
`
`• Pellets also offer the advantage of flexibility for further modi-
`fications, such as compression to form tabl4s,or coating to
`achieve the desired dosage-form characteristic& 5.
`
`Methods of pellet preparation
`Pellets 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 materials
`and hot solution of polymer is atomized into hot air, the water
`then evaporates and the dry solid is separated in the form of
`pellets, usually by air suspension. In general, a spray-drying
`process produces hollow pellets if the Irquid evaporates at a rate
`faster than the diffusion of the dissolved substances back into
`the 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 the
`substance should have a well-defined melting point or small
`melting zone 12 .
`In fluidized bed technology a dry drug form is suspended in
`a stream of hot air to form a constantly agitated fluidized bed.
`An amount of binder or granulating liquid is then introduced
`in a finely dispersed form to cause a momentary reaction prior
`to vaporization. This causes the ingredients to react to a limited
`extent, thereby forming pellets of active components. Using
`this process Govender and Dangor" and Mathir et al.'7 pApared
`and characterized pellets of Salbutamol and Chlorpheniramine
`maleace, respectively.
`In the rotary processor (rotogranulator) the whole cycle is
`performed in a closed system. The binder solution and powder
`mix are added at a fixed rate on the plate of the spheronizer so
`that the particles are stuck together and spheronized at the
`same time. Using this process Robinson and Hallenbeck"! 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. Spiral
`particle motion combined with a high degree of particle bowl
`bottom friction and interparticulate collision in the bowl (feed
`with 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 layer
`after layer. However, use of this technique is limited because of
`the smaller drug loading that can be layered effectively onto die
`core material, thus making this technique unsuitable for drugs
`with large doses'''.
`
`Extrusion and spheronization
`Extrusion 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 by
`extrusion and spheronization is now a more established
`method because of its advantages over the other methods' 8. 21
`(Box 1), and the technique will now be described in detail.
`
`•
`
`Box 1. Advantages of the extrusion and
`spheronization process
`
`Ease of operation
`High throughput with low wastage
`Narrower particle size distribution
`Production of pellets with low friability
`Production of pellets that are suited for film coating
`More sustained and better controlled drug-release profile
`when compared with other techniques
`
`Spheronization is a technique of Japanese origin that is some-
`times referred to as Merumerization, after the trademark of the
`Fuji Denlci Kogyo Company (Osaka, Japan). Although originally
`invented in 1964 by Nalcaliara", it wasn't until 1970 and the
`!Publication of the process by Reynolds (Lilly Research, UK)14
`and Conine and Hadley (Eli Lilly, Indianapolis, IN, USA)23 that
`the technique became widely known. In subsequent years the
`detailed proCess of spheronization, including the individual pro-
`cessing variables based on extrusion and spheronization, was
`published by J.B. Schwartz's group and the whole process was
`reduced to a series of pharmaceutical operations, each of which
`is associated with a number of individual parameters24,23.
`
`Process and equipment
`In 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 rounding
`off the particles into spheres;
`• drying — drying of the pellets.
`
`1 62
`
`Different steps, parameters and equipment used in the process
`are summarized in Fig. 1.
`The first step of the extrusion and spheronizatitifi cycle con-
`sists of the preparation of the wet mass. Different types of
`granulators are used to perform the mixing of the powder
`blend and the granulation liquid. There are three types of
`processors used to mix different constituents of the powder
`blend. The most commonly used granulator is a planetary
`mixer' 8, although in various cases use of a high shear mixer,
`sigma blade mixer's and a continuous granulator27 has also
`been reported. However, it is important to note that high shear
`mixers introduce a large amount of heat into the mass during
`granulation, which may cause evaporation of the granulation
`liquid because of a rise in temperaturerthereby influencing the
`extrusion behaviour of the wet mass. This may be avoided by
`cooling the granulation bowl'-s.
`
`Extrusion
`Extrusion is the second step of the process and consists of
`shaping the wet mass into long rods, which are more com-
`monly termed 'extrudate'. The extrusion process is used not
`only 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 of
`completely water-soluble tabletsl9.
`Types of extrusion devices have been grouped into four
`main classes; that is, screw, sieve and basket, roll and ram ex-
`truders. A screw extruder, as the name implies, utilizes a screw
`to develop the necessary pressure to force the material to flow
`through the uniform openings, producing uniform extru-
`dates30. In the sieve and basket extruders the granulate is fed by
`a screw or by gravity into the extrusion chamber in which a
`rotating or oscillating device processes the plastic mass
`through the screen. The basket type extruder is similar to the
`sieve extruder except that the sieve or screen is part of a verti-
`cal, cylindrical wal131. The third class of extruders are the roll
`extruders and these are also known as 'pellet mills'. Two types
`of roll extruders are available' 1 '32. One extruder is equipped
`with two contrarotating wheels, of which one or both are per-
`forated, and the second type of roll extruder has a perforated
`cylinder that rotates around one or more rollers that discharge
`the materials to the outside of the cylinder. The final type of
`extruder is an experimental device called the ram extruder. The
`rarn extruder is believed to be the oldest type of extruder and
`features a piston riding inside a cylinder or channel that is
`used to compress material and force it through an orifice on
`the forward stroke. Fielden et UI. 32 compared the extrusion and
`spheronization behaviour of wet mass processed by a ram ex-
`truder and a cylinder extruder and concluded that they are not
`always equivalent.
`
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`p571. Vol. 2, No. 4 April 1999
`
`research focus I reviews
`
`Granulating Powder dry
`liquid mixing
`
`V
`
`Coating
`solution
`
`Figure 1. Flow diagram showing different
`steps. process parameters and equipment
`involved in extrusion and spherization to
`produce spherical controlled rektse pellets.
`
`;Wet mixing (cid:9)
`
`I Extrusion : (cid:9)
`
`iSpheronization
`
`• Granulato (cid:9)
`type (cid:9)
`• Granulation (cid:9)
`liquid (cid:9)
`• Mixing time (cid:9)
`
`• Extruder type
`• Extrusion
`speed
`• Screen
`opening size
`• Extrusion
`temperature
`
`• Dryer type
`• Drying temperature
`
`• Spheronizer
`type
`• Plate type
`• Plate speed
`• Spheronization time
`• Spheronizer load
`
`Spheronization
`The 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 extrudate
`is broken up into smaller cylinders with a length equal to their
`diameter. A spheronizer is a device that consists of a vertical hol-
`low cylinder (bowl) with a horizontal rotating disk (friction
`plate) located inside. The friction plate has a grooved surface to
`increase the frictional forces. Two types of geometry of the
`grooves exist; more common is the cross-hatch geometry in
`which the grooves intersect each other at 90° angles, whereas the
`other pattern is radial geometry in which grooves emanate from
`the centre like the spokes of a bicycle wheel. The spheronization
`of a product usually takes 2-10 minutes. and a rotational speed
`of between 200-400 rpm for the friction plate is satisfactory to
`obtain highly spherical pellets9•23. A special type of spheronizer,
`designed by NICA systems, features a lip around the rim of the
`friction plate that is claimed to reduce the milling effect of the
`plate in order to produce a smaller amount of fines30.
`The fourth and final step of the process is the drying of the
`pellets. The pellets can be dried at room temperature32 or at an
`elevated temperature in the fluidized-bed drier:8, in an oven33,
`in a forced circulation oven's or in a microwave oven34. Pellet
`quality is dependent on the type of dryer used. According to
`Bataille et al.s#, oven drying provides less porous and harder
`minigranules and a more homogenous surface than those dried
`by a microwave oven. Dyer et 01.3.5 prepared ibuprofen pellets
`that were dried either by tray drying or fluidized-bed drying,
`and they showed that the drying technique has a quantifiable
`effect on the diametral crushing strength and elasticity of the
`pellets, their in vitro release, and a qualitative effect on the sur-
`face characteristics of ibuprofen pellets.
`
`Pellet formation
`Numerous mechanisms of pellet formation have been sug-
`gested. The overall process of spheronization can be divided
`
`e
`
`into various stages in terms of the changes in the shape of the
`extrudate. According to Rowe36, extruded plastic cylinders are
`rounded in the form of pellets because of frictional forces.
`Cylinders transform into cylinders with rounded edges then to
`dumb-bells and elliptical particles and eventually to perfect
`spheres. Baert and Remon28 suggested that another pellet-
`forming mechanism might also exist that is based on frictional
`forces as well as rotational forces. In this mechanism a twisting
`of the cylinder occurs after the formation of a cylinder with
`rounded edges, finally resulting in the breaking of the cylinder
`into two distinct parts with both parts featuring a round and a
`flat side. Because of the rotational and the frictional forces in-
`volved in the spheronization process, the edges of the flat side
`fold 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-step
`process that involves a number of parameters that hat a final
`bearing on the characteristics of the obtained pellets. Moisture
`content is an extremely important parameter in the extrusion and
`spheronization process. It is necessary to give the powder mass its
`plasticity so that it can be extruded and shaped afterwards. It was
`
`Figure 2. Pellet-forming mechanism according to: (a) Rowe' - I.
`Cylinder: II. Cylinder with rounded edges; Ill. Dumb-bell; IV. Ellipse; V.
`Sphere. (b) Ravi - I. Cylinder; II. Rope; III. Dumb-bell; IV. Sphere with
`a cavity outside; V. Sphere. (Reproduced with permission from Ref. 9.1
`
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`reviews I research focus
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`PSTT Vol. 2, No. 4 April 1999
`
`shown that there is a certain limit of moisture content at which
`pellets of an acceptable quality are produced. If the moisture
`content is less than a certain lower limit, a lot of dust will be in-
`troduced during spheronization which will result in a large
`yield of fines. If moisture content is more than a certain upper
`limit 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 pellet. The extent of moisture
`content also influences the mechanical strength, friability, in-
`ternal porosity and the particle-size distribution of pellets.
`Ostuka et CII.37 reported that the internal porosity of spherical
`granules decreases with increasing water concentration, weight
`loss after the friability test increases with a decreasing amount
`of water and the quantity of water influences the mechanical
`Ainstrength of granules. Moisture content also affects the shape and
`Iliac of granules38. Gazzaniga et x1.39 found differences in the fri-
`ability and particle size of pellets when die powder mass was
`wetted with different quantities of water.
`
`Starting material
`The physical nature of the starting material influences the par-
`ticle size, hardness, and sphericity as well as the release rate of
`the included drug. There is not only the obvious difference in
`pellet quality produced from different compositions but also
`the difference when different types of the same product are
`used25. The use of similar products but from different suppliers
`has also been found to change the characteristics of the pel-
`let40 41.
`(cid:9) prepared with three types of microcrystalline
`cellulose (MCC) — Avicel® PH-1 0 1, Emcocelo, Unimac® — MG
`from different manufacturers featured differences in size and
`roundness when processed under the same conditions42. The
`physical properties of two types of commercial MCC, Avicel
`101 and Microcel MC show differences during the step of
`moistening, thereby affecting the particle size and hardness of
`the pellets obtainetha.The difference in release rate in different
`types of dissolution medium has been observed between pel-
`lets containing only MCC and those containig MCC with
`sodium carboxymethyl cellulose (NaCMC). This difference is
`because a gel-like structure was formed in water through the
`presence of NaCMC with MCC, whereas the pellets containing
`only MCC remain unchanged in aqueous medium resulting in
`a greater rate of release43.
`
`Granulation liquid
`The use of different amounts of water as a granulation liquid
`alone or in combination with alcohol affects the hardness and
`particle size distribution of the final pellets. The most com-
`monly used granulating liquid is water, although in some cases
`the use of alcohol or a water—alcohol mixture has also been re-
`ported9. The effect of the alcohol content in a water—alcohol
`
`164
`
`mixture has been extensively studied by Millili and Schwartz'''.
`Binary mixtures of theophylline and Avicel PH-1 01 (10:90
`w/w) were found to form pellets when granulated with 90%
`ethylalcohol in water—alcohol mixture. Differences in friability
`and dissolution were observed between water granulated- and
`95% ethylalcohol in water—alcohol mixture-granulated pellets.
`Increasing the water content in the granulation liquid leads to
`an increase in the hardness of the pellets. The increase in the
`hardness was correlated with a slower in vitro release rate of
`theophylline. Gazzaniga et a1.39 reported that when 13-
`Cyclodextrin (P-CD) was used to form pellets using water as
`the granulating liquid, the poor quality of the extrudates, in
`terms of plasticity and sticking, invariably lead to irregularly
`shaped pellets and agglomerates with,brdad size distribution.
`In this respect, preliminary promising results were obtained by
`lowering the solubility of (3-CD in the wetting liquid through
`the use of water—alcohol mixtures. This probably improves the
`plasticity of the wetted mass and thus the feasibility of the
`overall process.
`
`Extruders
`Several studies appear in the literature regarding the influence
`of the type of extruder on the size distribution. sphericity and
`density of pelletsI 4' 36• 41. The studies have shown that pellets ob-
`tained from two types of extruder had differed in sphericity
`and in particle size distribution because of a shift in the opti-
`mal amount of granulation liquid needed with each extruder
`or because of the difference in the length-to-radius ratio of
`the extrusion screen used45,46. According to Reynolds:4 and
`Rowe3 6, an axial screw extruder produces a more dense ma-
`terial compared with the radial screw extruder.; the latter has a
`higher output but also produces a greater rise in the tempera-
`ture of tile mass during processing.
`
`Extrusion screen properties
`Pellet quality is dependent on the extrusion screen, which is
`characterized by two parameters: the thickness of the screen
`and the diameter of the perforations. Changing one of these
`two parameters influences the quality of the extrudate and
`hence 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 thickness
`formed a rough and loosely bound extrudate, whereas the
`screen with high thickness formed smooth and well-bound ex-
`Exudate because of the higher densification of the wet mass in
`the screen with the greatest thickness.
`Similarly, the diameter of the perforations determines the
`size of pellets, and a larger diameter in the perforations will
`produce pellets with a larger diameter when processed under
`the same conditions47.48. An increase in the extruder screen
`
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`research focus (cid:9)
`
`reviews
`
`opening size was found to result in an increase in the hardness
`of the tablets made from these pellets25.
`
`Extrusion speed
`The 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 in
`the extrusion speed can influence the size and surface proper-
`ties of the final pellets47-0. Several studies show that the sur-
`face impairments, such as roughness and sharkskinning, be-
`come more pronounced with increasing speed47.48.The surface
`effects of extrudate lead to pellets of lower quality because the
`extrudate will break up unevenly during the initial stages of
`the spheronization process, resulting in a number of fines and
`a wide particle-size distribution°.
`
`Extrusion temperature
`Extrusion temperature influences the pellet quality by affecting
`the moisture content. The rise in temperature during the ex-
`trusion cycle could dramatically alter the moisture content of
`granules because of evaporation of the granulation liquid, This
`may lead to a difference in the quality of the extrudate pro-
`duced at the beginning of the batch and at the end of the
`batch. Evaporation of water during extrusion is possible be-
`cause most of the water is available as free waters°. Extrusion
`temperature control becomes an important parameter when a
`formulation with a thermolabile drug is processed. To avoid a
`rise in the temperature during an extrusion cycle, use of screw
`extruder with a cooling jacket around the barrel to keep the
`temperature of the given formulation between predetermined
`limit has been reported".52.
`
`Spheronizer specifications
`Pellet quality is also dependent on spheronizer load. It mainly
`affects the particle size distribution, bulk and tap density of the
`final pellets9. The yield of pellets of a specific range decreases
`with an increase in the spheronizer speed and at a low spher-
`onizer load, and increases with extended spheronization time
`at a higher spheronizer load53.54. Barran et a1.54 reported that an
`increasing spheronizer load decreased the roundness and in-
`creased the hardness of pellets, whereas yield in the majority
`size range remained unchanged. Hellen et al.ss reported that
`the bulk and tap density increased and the size of the pellets
`decreased with an increasing spheronizer load.
`The spheronization speed affects the particle size of pellets.
`In the initial stages of the spheronization process, an increase in
`the smaller fractions is seen, probably because of the greater
`degree of fragmentation. In contrast, a decreasing amount of
`fines and a higher amount of particles with faster spheroniz-
`ation speed correlating with an increased mean diameter was
`
`also observed27.49.56. The hardness-56, roundness49, bulk and
`tapped density55, porosity49.56, friability56, flow rates7 and sur-
`face structure56 of pellets are also affected 3y,a change in the
`spheronization speed.
`Spheronization time mainly affects the particle size distribu-
`tions" and bulk and tap densityss 37 of pellets. A wide range of
`results have been witnessed when assessing the importance of
`this 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 bulls and tap
`density and a change in the yield of a certain size range with an
`extended spheronization time53.
`
`Development of oral CR formulationt
`The advantages of using small spherical pellets or beads in oral
`controlled drug delivery are well documented. The pellets pro-
`vide a smoother absorption profile from the GI tract, because
`the beads pass gradually from the stomach through the pyloric
`sphincter into the small intestine at a steady rate. Pellets can be
`layered with drug and coated with various polymers to control
`the release rates. Further, different types of pellets with different
`release rates can be combined in a simple capsule to provide the
`desired CR profile (Fig. 3). Betageri et al.58 have described three
`approaches to the preparation of sustained release pellets.
`
`• The first approach involves the placement of the drug in an
`insoluble matrix in which the eluting medium penetrates
`the matrix and the drug diffuses out of the matrix and into
`the surrounding pool for ultimate absorption.
`• The second approach involves enclosing the drug particles
`with a polymer coat. In this case, the portion of le drug
`that has been dissolved in the polymer coat diffuses through
`an 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, together
`with a constant diffusion path length and constant drug con-
`centration, can achieve a controlled rate of drug release. On the
`basis of the above approaches, the CR formulations prepared by
`extrusion and spheronization are mainly divided into two cat-
`egories: coated pellets and matrix pellets.
`
`Coated pellets
`Controlled drug release from pellets is conventionally achieved
`by polymer coating. In many applications neutral pellets (non-
`pareil seeds) are used as raw materials that are coated with the
`active ingredients and then with release-retarding substances.
`According to the USP/NF monograph for sugar spheress9,
`neutral pellets consist mainly of sucrose and corn starch. The
`
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`

`PSTT Vol. 2, No. 4 April 1999
`
`research focus I reviews
`
`Table 1. Matrix system classification
`
`Hydrophilic
`
`Inert
`
`Lipidic
`
`Biodegradable
`
`Resin matrices
`
`Unlimited swelling, delivery
`by diffusion
`Controlled delivery through
`limited swelling
`HPMC, HEC, HPC
`
`Inert in nature
`
`Delivery by diffusion
`
`Nonlipidic in nature
`
`Controlled delivery by
`diffusion
`Ethyl cellulose
`
`Delivery by surface
`erosion
`Carnauba wax
`Bees wax
`Precirol
`
`Controlled delivery by
`surface erosion
`Poly(anhydride),
`PLGA matrices
`
`Drug release from drug—resin
`complex
`Release depends on the
`surrounding ionic environment
`Ion exchange resin
`
`Abbreviations: HPMC, hydroxypropylmethyl cellulose; HEC, hydroxyethyl cellulose; HPC, hydroxypropyl cellulose; PLGA, copolymer (L-lactichlycolic
`
`include efficient and predictable drug release, without possible
`agglomeration of the beads or pellets during the coating
`process. In addition, the use of toxic organic solvents in the
`process can be avoided.The mechanism of film formation from
`aqueous dispersions is a complex process. The aqueous poly-
`mer dispersion is sprayed onto the solid particles with suitable
`equipment and, as water evaporates, colloidal particles are
`forced to come together to form a film. Plasticizers are added to
`the 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." have pre-
`pared ibuprofen pellets by extrusion and spheronization and
`used an aqueous polymeric dispersion of polymethacrylates,
`ethylcellulose and silicon elastomer films in the coating. The
`application of a polymeric membrane to uncoated cores had
`the effect of retarding drug release.
`
`Matrix pellets, systems and classification
`Sustained release from pellets is conventionally achieved by
`polymeric coating. Ther