Granulation Process

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The Granulation Process 101 Basic Technologies for Tablet Making Michael D. Tousey T A tablet with good characteristics is not made on a tablet press; it is made in the granulation process. Joining particles within a given granulation process will improve flow and compression characteristics, reduce segregation, improve content uniformity, and eliminate excessive amounts of fine particles. The results will be improved yields, reduced tablet defects, increased productivity, and reduced down time
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  his article presents the basic technologies for preparingpowders for tablet making. Granulation is the process of collecting particles together by creating bonds betweenthem.Bonds are formed by compression or by using abinding agent.Ifone were to make tablets from granulated sugarversus powdered sugar,for example,powdered sugar would bedifficult to compress into a tablet and granulated sugar wouldbe easy to compress.Powdered sugar’s small particles have poorflow and compression characteristics.These small particleswould have to be compressed very slowly for a long period of time to make a worthwhile tablet.Unless the powdered sugaris granulated,it could not efficiently be made into a tablet thathas good tablet characteristics such as uniform content or con-sistent hardness.The granulation process combines one or morepowders and forms a granule that will allow the tableting processto be predictable and will produce quality tablets within the re-quired tablet-press speed range.A tablet formulation contains several ingredients,and the ac-tive ingredient is the most important among them.The re-maining ingredients are necessary because a suitable tablet can-not be composed ofactive ingredients alone.The tablet may require variations such as additional bulk,improved flow,bet-ter compressibility,flavoring,improved disintegration charac-teristics,or enhanced appearance.Ifthe active ingredient in a formulation represents a very small portion ofthe overall tablet,then the challenge is to en-sure that each tablet has the same amount ofactive ingredient.Sometimes,blending the ingredients is not enough.The activeingredient may segregate from the other ingredients in the blend-ing process.The ingredients may be incompatible because of particle size,particle density,flow characteristics,compressi-bility,and moisture content.These incompatibilities can causeproblems such as segregation during blending or during trans-fer ofthe product to the press as well as separation ofthe ac-tive on the tablet press.Granulating the active by itselfand then blending it with therest ofthe ingredients is one solution to the segregation prob-lem.Or,all or most ofthe ingredients could be granulated to-gether.The best course ofaction to ensure that each tablet con-tains the correct amount ofactive ingredient,especially iftheactive is only a small percentage ofthe tablet ingredients,is tomix the active thoroughly with some or most ofthe other ingre-dients and then granulate the blend (i.e.,form the blend intogranules).Each granule would contain a little ofeach ofthe in-gredients,and the active ingredient would be distributed evenly  8  Pharmaceutical Technology  TABLETING & GRANULATION 2002  www.pharmtech.com The Granulation Process 101 Basic Technologies for Tablet Making Michael D.Tousey Michael D. Tousey  is the technicalservices director and owner of DoradoInternational, Inc., a pharmaceuticalequipment and training company, 152Wilkerson Drive, Westminster, SC 29693,tel. 864.647.5400, mike@doradointernational.com.   T A tablet with good characteristics is notmade on a tablet press;it is made in thegranulation process.Joining particleswithin a given granulation process willimprove flow and compressioncharacteristics,reduce segregation,improve content uniformity,and eliminateexcessive amounts of fine particles.Theresults will beimproved yields,reducedtablet defects,increased productivity,andreduced down time.The objective of theprocess is to combine ingredients toproduce a quality tablet.    I   M   A   G   E   1   0   0  10  Pharmaceutical Technology  TABLETING & GRANULATION 2002  www.pharmtech.com throughout the blend.The link between particles in each gran-ule must hold the particles together and keep them from break-ing apart before they are compressed.Ifthe active ingredient represents a high overall percentageofthe total tablet,then the active must flow,compress,and ejectfrom the tablet press and disintegrate properly.Even in this case,most actives do not cooperate.To solve this problem,the activemust be granulated by itself,blended with the other ingredi-ents in the formulation,and compressed on the tablet press.The nature ofthe active must be understood and its character-istics may have to be improved to make this process work.Someactives are very fine,small particles that are lighter than otherparticles.Even ifthe active is the correct size it may not flowsmoothly,and flowability is very important to making a goodtablet.Furthermore,the active could be the right particle sizeand it may flow well,but it may not blend well with the otheringredients.The active may be too dry or too moist,which pre-vents proper compression.Once the challenges to making anactive perform well are determined,the objective can be iden-tified and granulation can begin.This article explains in simple terms the fundamentals of the granulation process.Three basic techniques are used toprepare powders for compression into a tablet:direct com-pression,wet granulation,and dry granulation.Ten differentformulations would probably require that the powders for eachofthe formulations be prepared in various combinations.Thisarticle investigates the three techniques and discusses how todetermine which method is best for individual formulations. Direct compression Direct compression is used when a group ofingredients can beblended,placed onto a tablet press,and made into a perfect tabletwithout any ofthe ingredients having to be changed.Powdersthat can be blended and compressed are commonly referred toas directly compressible or as direct-blend formulations. Blendingthe powders,putting them onto a tablet press,and seeing whathappens is the most direct way to make a tablet.Sometimes thetablet will fall apart,the active ingredient won’t be in all thetablets (no content uniformity),or all the powders won’t fit intothe die cavity (the place where powders are filled on the tabletpress).Simply blending powders does not form a granule.Whenpowders do not compress correctly,they must be granulated.Nevertheless,not all products must be granulated.Many processesare unnecessarily implemented because the objective and rea-son for choosing a process path were incorrect.Before choosinga means to process a formula,the best course ofaction is to putthe product on the press to see what happens. Excipients Ingredients in a tablet other than the active ingredient are called excipients. Excipients can help powders become more fluid.Thisfluid motion is very important for transferring powders intothe die cavity for compaction.Many years ago a high-speedtablet press could produce 50 tablets/min.Now a tablet pressthat runs this slowly is called a laboratory development press, and it is good only for basic feasibility studies.Today’s high-speed tablet presses can produce up to 12,000 tablets/min,andthe average tablet press speed is 3000 tablets/min.Therefore,excipients are used not only to enhance the performance ofac-tive ingredients,but also to simply make the active work betteron the tablet press.Many types ofexcipients are used in tablet formulations tohelp in other ways.They include ● binders,which help powders fuse or link particles to oneanother ● fillers,which bulk up a tablet ● lubricants,which prevent powders from sticking to the metalcomponents ofthe tablet press and tablet-press tooling ● disintegrants,which help the tablet break up after it is ingestedby the patientSeveral other excipients can be added to a formula to improveflow,compression,hardness,taste,and tablet performance. Flowability As mentioned previously,press speed requires powders to bevery fluid,a property commonly referred to as  product flowa-bility. Good flow characteristics are necessary because the me-chanical action ofthe tablet press requires a volume offill.Asshown in Figure 1,the volume offill represents the actual tabletweight.A tablet press does not weigh the precise amount ofpow-der for each tablet.To achieve consistent tablet weights,the for-mula must be designed to flow consistently and to fill volumet-rically.Thus the powders in the formula must possess a consistentparticle-size distribution and density to attain proper flow andachieve volume offill (i.e.,tablet weight).In other words,thepowders must flow consistently to attain consistent results. Compressibility Other excipients in a formula enhance the ability ofthe pow-ders to compact.All powders have very different characteris-tics.Remember your first chemistry class and the sessions dur-ing which you began to understand the periodic table? Thebasic structure ofan atom has physical characteristics:shape,density,and structure.Compressing a tablet ofmany differentpowders that have varying physical characteristics can be dif- Figure 1:  A tablet press does not weigh the granulation; weight isequal to the volume of fill within the die cavity. (Figure provided byThomas Engineering Inc.)  Pharmaceutical Technology  TABLETING & GRANULATION 2002  11 ficult.Think about the example ofmaking a snowball to throwat your buddy:Ifthe snowflakes are rather large and wet,thenthey compact very easily into a snowball.However,ifthesnowflakes are very light,fluffy,and dry,then compaction ismore difficult.Every kid knows that to make a snowball withlight,fluffy,and dry snowflakes,they must hold the snowballtogether for a longer period oftime (dwell time) and be care-ful not to overcompress.Ifthe snowball is overcompressed,then the flakes no longer lock together but instead laminate(flatten out) and fall apart.The same is true ofpowders usedin pharmaceutical tablets.Ifthe formula has some ofbothcharacteristics—large particles with high moisture content andsmall,dry particles—then the tablet may or may not compresswell and probably will have difficulty holding together.One of the main reasons to granulate powders is to make them morecompressible. Wet granulation When powders are very fine,fluffy,will not stay blended,or willnot compress,then they must be granulated. Fluffy  is not a tech-nical term,but it fits the problem well;it means that the re-quired quantity ofpowder physically will not fit into the diecavity on the tablet press.The volume offill (bulk density) isgreater than that which is mechanically allowed.Wet granulation,the process ofadding a liquid solution topowders,is one ofthe most common ways to granulate.Theprocess can be very simple or very complex depending on thecharacteristics ofthe powders,the final objective oftablet mak-ing,and the equipment that is available.Some powders require the addition ofonly small amountsofa liquid solution to form granules.The liquid solution canbe either aqueous based or solvent based.Aqueous solutionshave the advantage ofbeing safer to deal with than solvents.Al-though some granulation processes require only water,many actives are not compatible with water.Water mixed into thepowders can form bonds between powder particles that arestrong enough to lock them together.However,once the waterdries,the powders may fall apart.Therefore,water may not bestrong enough to create and hold a bond.In such instances,aliquid solution that includes a binder (pharmaceutical glue) isrequired.Povidone,which is a polyvinyl pyrrolidone (PVP),isone ofthe most commonly used pharmaceutical binders.PVPis not soluble in water,so a solvent must be used to carry thePVP particles in a liquid solution.When PVP and a solvent aremixed with powders,PVP formsa bond with the powders duringthe process,and the solvent evap-orates (dries).Once the solvent hasbeen dried and the powders haveformed a more densely held mass,then the granulation is milled.This process results in the forma-tion ofgranules.Many different types ofbindersexist.Some binders,called wet binders, only work when added asa solution.Dry binders are preprocessed powders that whenmixed with other powders help bind the ingredients together.Binders that can be used wet or dry are also available. Density The density ofeach granule is increased by increasing theamount ofbinding solution as well as the mechanical action of the mixer.Therefore,controlling the amounts ofsolution,binder,and mechanical action allows one to control the strength anddensity ofthe granule.Machines that are used for this processare called  granulators. Granulators can be low shear,mediumshear,or high shear. Shear  is the amount ofmechanical forceofthe granulator.A low-shear granulator uses very little me-chanical force to combine powders and binding solution.Thefluid-bed granulator,the most commonly used low-shear granu-lator,uses a high volume ofair flow to elevate powders in achamber while a binding solution is sprayed onto the particlesto form a light bond.A fluid-bed granulator does not impartmechanical energy but instead relies on the powder character-istics and the binding solution to form the lightly held powdersinto granules.A low-shear granulator will not produce a densegranule,and a high-shear granulator will not produce a lightgranule.Again,the objective must be understood before thegranulation equipment is chosen.Figure 2 shows a Lodige,a high-shear mixer.The high speedofits mechanical sweeps produces a very dense granule.Themain objective ofa granulator is to produce the correct gran-ule density.One granulator will not work for all powders.Over-granulating or overdensifying powders can produce a very ex-cellent granule,but the granule could be too dense.For example,ifthe objective is to make an effective headache remedy and theproduct is overgranulated,then the tablet may take a long timeto disintegrate and dissolve into the blood stream.Ifmy headache remedy takes two hours to work,I probably won’t bein business very long. Traditional wet granulation Traditional wet granulation,which is still commonly used,is theprocess ofmixing and adding solution and then transferring theproduct to a tray dryer (see Figure 3). Wet massing  is the processofadding a solution to a blended powder and mixing for a pre-determined period oftime at a given mechanical speed.Oncethe process is complete,the wet mass is milled,spread on trays, Figure 2: (a) A fluid-bed granulator (Glatt,Ramsey,NJ); (b) the fluid-bed process; (c) a Lodige high-shear mixer (Littleford Brothers,Florence,KY); (d) internal view of a Lodige mixer.  12  Pharmaceutical Technology  TABLETING & GRANULATION 2002  www.pharmtech.com and dried in a tray dryer.The wet mass usually is passed througha low-shear mill and then dried for 8–24 h.A drying process thatis too short will produce granules that have entrapped moisture;ifthe process is too long,then the granules become very dry andfriable.Ifgranules that have been dried only on the outside reachthe tablet press,then moisture will escape the granules duringcompression and cause the granules to stick to the tablet-presstooling,a problem called case hardening. Air flow and temperature control must be uniform through-out the entire drying chamber ofa tray dryer.Ifthe dryer haspoor air circulation,then the product on the top trays will be-come drier than the product on the bottom trays.Overly dry product breaks apart easily and is no longer in a granular state.When an overly dry granulationis milled,it produces fine dry particles commonly referred to as  fines. Fines do not flow wellon a tablet press and thereby cause weight variations.In addi-tion,fines do not compress well and can contribute to cappingand lamination,which are common tablet defects.On the other hand,compressing the lower-tray granulations,which may contain too much moisture,can cause granules tostick to the tablet-press tooling,another situation that producesdefective tablets.The error that is most common to granula-tion processes is the mixing ofoverdried granules,overwettedgranules,and good granules.Once this mixture is on the tabletpress,the full range ofthe previously described problems en-sues:capping,lamination,picking,sticking,and tablet weightand hardness variation. Problems on the tablet press Measurement and sampling within a tray dryer can reveal po-tential problems before they reach the tablet press,but prob-lems with granulation may not show up until the productreaches the tablet press.Capping and lamination can be con-trolled to some extent by making the tablet high in the die andby slowing the machine down and extending dwell time,whichgives the granules and powders time to lock together and forma good tablet.Ifmoisture escapes the case-hardened granule,then the product sticks to the punches.This problem is called  picking  or sticking. The press operator can increase pressure toallow the granules that are stuck to themetal punch tip to restick or adhere tothe tablet instead ofthe tooling.Whencompressing case-hardened granules,making the tablet softer may help pre-vent entrapped moisture from reach-ing the surface ofthe granule.However,this course ofaction may result intablets that are too soft,thereby failingto completely eliminate the problem of granulation sticking in the punch tips.In these circumstances,press operatorsoften remove the punches and polishthem.Polishing the punches with a pasteleaves a slight residue that acts as amold-release agent and halts the stick-ing for a short period oftime.Clean-ing the punch tips with isopropyl alcohol,however,hindersmold release,and the sticking problem reappears.Operatorsmust question whether the polishing is truly a better choicethan the simple application ofa mold-release agent.Many sticky granulations require a few minutes to fine-tune on a tablet press,and once the settings for weight,thickness,and hardness are just right,the sticking will be minimized and may completely disappear.Stopping the press once the sticking problem is eliminatedrequires that the start-up cycle on the tablet press begin again,including polishing ofthe punches (or adding a mold-releaseagent).This cycle can become endless.An entire industry is fo-cused on punch-polishing equipment and technology,the so-called Band-Aid approach.Ifpunches must be polished duringa run,then perhaps the granulation process is incorrect.Blameshould not fall to the tablet press,press tooling,polishing,orthe press operator;the problem shoould be corrected in thegranulating department.A common complaint about product development is that anadequate quantity ofactive ingredients is not available to prop-erly study real granulation problems.Substitutes are sometimesused that do not replicate the active ingredient correctly,mak-ing feasibility studies difficult.Once a product is scaled up,thereal problems that weren’t fully discovered in development hitthe production floor.When the problems are met head on atthe production level,the solution often is to polish the punches.In reality,the product may not have been fully developed andmay remain a problem while it is in production. Dry granulation The dry granulation process is used to form granules withoutusing a liquid solution because the product to be granulated may be sensitive to moisture and heat.Forming granules withoutmoisture requires compacting and densifying the powders.Dry granulation can be conducted on a tablet press using sluggingtooling or on a roller compactor commonly referred to as a chilsonator  (see Figure 4).When a tablet press is used for dry granulation,the powders may not possess enough natural flowto feed the product uniformly into the die cavity,resulting in Figure 3:  A tray drying oven (O’HaraTechnologies,Inc.,Richmond Hill,ON,Canada). Figure 4:  A chilsonator with mill (Fitzpatrick,Elmhurst,IL).
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