2 TABLET MANUFACTURE FORMULATION AND PROCESSING Why are tablets the most popular dosage form for medicines?Tablet compressionWhat is a ‘good’ tablet?Tablet constituentsDirect CompressionGranulationSieving/millingBlendingCommon Tablet ProblemsQuestions
3 WHY TABLETS?90% of medicines are taken orally with the majority being tablets. Other routes of administration include injections, inhalation, rectal and topical. Why are tablets the most common means of drug delivery?
4 WHY TABLETS? Can be self administered Painless Accurate dose delivery Portable and discreetCan be packaged to aid patient complianceEasily identifiable (colour, shape, size, logo etc)Simple to useLow cost of manufactureNormally stable to heat and moistureNot easily contaminated with micro-organismsGood bioavailability for most drugsRelease can be modified
5 TABLET MANUFACTUREIn order to make a ‘good’ tablet the powder to be compressed must have the correct characteristics:The powder must be able to flow freelyThe powder must be compressible (bind together to form a tablet)The powder must be homogenous (uniform mix of active and excipient)The tablet must be able to be ejected freely from the die without damage
6 TABLET COMPRESSION Lower punch drops as die passes feed frame Powder fills to ‘over-fill’Lower punch rises to expel excess (weight control)Upper punch enters diePass between compression rollerUpper punch withdraws and lower punch risesTablet ejected by tablet take-off plate
7 What Is A ‘Good’ Tablet? Must contain the correct amount of active This is measured during the process by ATW and U of W measurementsHave suitable physical propertiesHardnessFriabilityThickness/DiameterDisintegration/dissolutionIn order to ensure a good tablet is made the granule may need pre-conditioning and addition of excipients will be necessary
8 GRANULE MANUFACTUREThree principle methods of preparing powder formulations for compressionDirect CompressionWet GranulationDry Granulation
9 DIRECT COMPRESSIONThis is the ideal option but is rarely achievable due to:Active particle size/density mismatch with excipients causing poor homogeneityLarge quantity per tablet of poorly compressible active resulting in weak friable tablets
10 DIRECT COMPRESSION Process flow for direct compression Dispense Security SieveLubricant BlendCompress
11 Problems Associated With Direct Compression If the material is a powder rather than a granule:it will have poor flow characteristics, which can lead to uneven tablet weights.The pressure transmission through a powder mass is poor, due to low packing density. Consequently particles do not ‘knit’ together very readily.Powders, especially fine ones tend to blow out of the die at the top and seep out at the bottomDusty powders tend to mix with oil/grease and eventually cause sticking of the punches in the dies or turret bores.Powders containing two or more components may segregate. The heavier or smaller particle size components separate to the bottom of the bulk, this is made worse by the vibration of the Tablet Press.Direct compression materials are more expensive than non-DC equivalents
12 Advantages of Direct Compression Few stages involvedLow handling costsLosses near zeroNo water or heat involvedReduces the risk of degradation of the active
13 PROCESS AIDSRegardless of whether a tablet is manufactured by direct compression or granulation, processing aids will be required:These materials are called excipients and are either:DiluentsLubricantsDisintegrantsGlidantsBindersDirect compression formulations will contain as a minimum diluents, disintegrants and lubricants.N.B. some excipients have more than one function
14 DILUENTSA diluent is simply an ingredient that is used as a bulking agent to make tablets large enough to handle and swallow.Diluents must therefore be:Pharmacologically inertCheapNo supply issuesCompatibleStableProcessableDiluents are commonly easily compressible especially in DC formulations.Examples include:Micro-crystalline celluloseLactoseDi-calcium phosphate
15 LUBRICANTSLubricants are materials that lubricate powder mixes and aid tablet ejection.Without lubrication powder may stick to the punches especially if is too moist.Lubricants are typically added at a late stage and blended for the shortest possible time as they have adverse effects.Adverse effects if over-blended are poor compressibility and increased dissolution due to waxy layer covering the surface of the granuleExamples include:Magnesium StearateStearic AcidTalc
16 GLIDANTS Glidants are materials that improve the flow of powder mixes An example is Colloidal Silicon DioxideMost powders, without the aid of flow agents, simply cannot flow at speeds required for high speed tabletting.Flow agents can decrease the capacity of powders to form bridges, create rat holes and stick to contact surfaces.Good flow into the die will lead touniform tablet weight as the volume ofmaterial flowing into the die will be constant
17 DISINTEGRANTSA material to promote disintegration of the tablet when swallowedEnhances water penetration by wicking effectIncreases porositySwells in contact with water and breaks cohesive bondsExamples include:StarchCroscarmelloseSodium Starch GlycollateCrospovidone
18 BINDERS A material that imparts cohesiveness to the formulation Helps bind powder particles into granules during granulationHelps bind granules together during the compression processExamples include:Hydroxy propyl methyl cellulose (HPMC in water)Starch paste in warm waterGelatinPolyvinyl pyrrolidone (PVP)
19 WHY GRANULATE? To improve powder flow. To improve compressibility. To reduce fines.To control the tendency of powders to segregate.To control density.To capture and fuse small quantities of active material.
20 TRADITIONAL WET GRANULATION Dispense Security Sieve Granulate Dry Moisture Test Sieve/Mill Lubricant Blend Compress
21 TRADITIONAL WET GRANULATION Most commonly performed using a high shear mixer e.g. ‘Fielder’ but can be performed using low shear e.g. ‘Hobart’.Fielder Granulator:Two blades, main blade and chopperMain blade speed is typically rpmChopper blade up to 3000rpmMain blade mixes and chopper breaks wet mass to form granules
22 TRADITIONAL WET GRANULATION Powders are loaded into the bowl and mixed for a defined time before granulation startsGranulating solution added at defined rate or sprayed (binder is usually incorporated into the solution)Wet mass is chopped to form granuleGranulation end point can be measured by current draw on main bladeProcess is controlled by the mixing times/speeds before and after addition of the granulating solution and the amount of solution added.Process relies on the binder and/or water soluble elements dissolving upon granulation, then on drying forming a solid bridge between particles.
23 ADVANTAGES OF WET GRANULATION Increases cohesivenessGood for high dose/poorly compressible drugsFor example Kalms has large amount of poorly compressible HopsGood for distributing soluble low dose drugsFor example in Kwells the hyoscine is added to the granulating solutionPrevents segregation of actives
24 DISADVANTAGES OF WET GRANULATION Processing parameters are derived by trial and errorMixing time varies with batch size and can be sensitive to variation in starting materialsDanger of over granulationCost (multi-stage process)Incompatibilities (chemical instability with moisture or subsequent drying)
25 A TYPICAL WET GRANULATION FORMULATION Wet BinderPolyvinyl pyrrolidone (PVP)Increases granule size strength and compressibilityEnhances dissolution relative to DCGranulation process aidMicro-crystalline celluloseReduces water/energy requirementsReduces process sensitivityLess risk of over granulationEasier wet massing and screeningIntra granular fillerLactoseBetter wet binding than insoluble fillersIntra-granular disintegrantCroscarmellose sodium
26 DRYING The removal of water or liquid to form a dry solid It is necessary as too much residual water can result in:Poor flowPoor lubrication (sticking to punches)Chemical instabilitySusceptibility to microbial growth2 main methodsTray dryingFluidised Bed DryingOthers include microwave and vacuum drying(not commonly used)
27 TRAY DRYING Fan assisted convection of hot air over loaded trays Not commonly used due to:Large floor spaceManual handlingLabour intensiveLong drying times (up to 24 hours)Can get non-uniform dryingCan result in hard caked product
28 FLUIDISED BED DRYINGHeated air is pulled through the bed of material in aremovable bowl.Filters prevent fines from escapingTemperature can be controlled by probes monitoringinput, output and bed temperaturesAirflow is adjusted according to particle size and densityMost efficient drying (minutes vs. hours)
29 SIEVING AND MILLINGSieving of the granule may be performed to remove large particles that may then be milled to reduce sizeOversize or all of the dried granule may be milled.Various types of mill are usually used depending upon the process requirementsMills used routinely at GR Lane include Comill (Cone mill), Apex and Tornado.
30 MILLING Comills (cone mills) produce granule of more uniform size and shape than Apex or Tornado millswith a smaller proportion of finesFines are powders that are very smalland ‘dusty’, which will pass througha 200 mesh screen.Fines impede the flow, do not compresswellMills may also be used to ‘de-lump’granules without reducing particle size.
31 MILLING Apex mills have the rotational shaft in a horizontal orientation vsTornado that is verticalTornado mills have 360° mill screens andconsequently produce marginally less finesthan an Apex mill that has a 180° screen.Both tornado and apex mills can be usedwith varying numbers of blades that throwmaterial against the mesh that controls themaximum particle sizeHammers may also be used. These pulverisethe material to a finer particle size
32 SPRAY GRANULATIONThis is when granulation and drying is combined in a one-pot processGranulation solution is sprayed into a fluidised bedThere is a greater degree of control over the size of granules formed.Control is via spray rate, inlet temperature and air flow.There are less losses by this methodGranule has an even moisture distributionHoweverHigher attrition may lead to finesControl of rates is criticalLonger process time (may lead to de-mixing)
33 DRY GRANULATING Dry granulating, also called slugging, or roller compaction, involves the pressing of mixedpowders into an object to be reground into aprecise powder.This action increases particle density, improvespowder flow and captures fines.Useful for materials which are sensitive to heatand/or moisture.Can be performed on tablet press followed by millingor by using specialised equipmentHowever pressure during dry granulation canresult in:granules with low porosityWeaker tabletsMay produce tablets with longer disintegration timeDusty process
34 BLENDING There are many different types of blenders Y cone blendersDouble cone blendersDrum blendersIBC blendersMajority are low shear tumble blenders. GR Lane hasopted for IBC blending to reduce handlingBlend studies are performed todetermine the determine theoptimum endpointGiven enough time, componentswill pass from an unblended stateto a relatively homogenous blend andback to an unblended state.
35 COMMON TABLET PROBLEMS Weight variationFriability variationCappingLaminatingChippingCrackingSticking/FilmingPickingBinding
36 WEIGHT VARIATIONWeight variation can be caused by a number of factors:Poor flow of granuleGranule too wetInsufficient glidantPoor granule homogeneityOver or under-blendedMaterial has settled over timeSeparation of fines in hopperPoor formulationTablet press set-upDropping punchesSticking punchesFeed frame speedUneven wear or damaged tooling
37 POOR FRIABILITY Poor friability can be caused by a number of factors: Low hardnessTablet press set-upOverblendingPoor granuleToo dryundergranulatedinsufficient bindertoo many finesInappropriate tablet shape
38 CAPPINGCapping is the term used, when the upper or lower segment of the tablet separates horizontally, either partially or completely from the main body of a tablet and comes off as a cap, during ejection from the tablet press, or during subsequent handling.Reason: Capping is usually due to the air–entrapment in a compact during compression, and subsequent expansion of tablet on ejection of a tablet from a die.Causes related to the formulation areLarge amount of finesGranule too dryGranule too wetInsufficient lubricantCauses related to the press:Ringing in diesLower punch remains below the face of die during ejection.Incorrect adjustment of take-off blade.High turret speedPossible remedial actions are:Move position of compression in dieAdjust take-off bladeSlow down press
39 LAMINATIONLamination is the separation of a tablet into two or more distinct horizontal layers.Reason: Air–entrapment during compression and subsequent release on ejectionCauses related to the formulation:Over lubrication of formulaOily material in formulaCauses related to the tablet press:Rapid relaxation of the peripheral regions of a tablet, on ejection from a die.Rapid decompressionPossible remedial action:Use tapered dies, i.e. upper part of the die bore has an outward taper of 3° to 5°.Use pre-compression step. Reduce turret speed and reduce the final compression pressure.
40 CHIPPING There are number of causes of chipping that can be due to: Machine setupInsufficient dwell timeCompression force too lowTooling wearworn punchesPoor granuletoo much finesGranule too dryInsufficient binderExcessive lubricantNot homogenous mixPossible remedial actionsIf clawed tooling, remove clawsIncrease pressureSlow down press
41 CRACKINGCracking is where small, fine cracks observed on the upper and lower central surface of tablets, or very rarely on the sidewallReason: It is observed as a result of rapid expansion of tablets, especially when deep concave punches are usedCauses related to the granule:Large size of granules.Too dry granulesCauses related to the tablet press:Tablet expands on ejection due to air entrapmentDeep concavities cause cracking while removing tabletsToo much pressurePossible remedial action:Use tapered dieUse special take-off plateReduce compression force
42 STICKING/FILMINGSticking refers to the tablet material adhering to the die wall.Filming is a slow form of sticking and is largely due to excess moisture in the granulation.Reason: Improperly dried or improperly lubricated granules.Possible remedial action:Increase pressure.Reduce speed.
43 PICKINGPicking is the term used when a small amount of material from a tablet is sticking to and being removed off from the tablet-surface by a punch face.The problem is more prevalent on the upper punch faces. The problem worsens with time into the run because more and more material is added to the already stuck material on the punch face.Common causes related to the granule:Excessive moisture in granulesToo little or improper lubricationToo warm granules when compressing.Too much binder.Common causes related to the tablet press:Rough or scratched punch facesUnpolished toolingInsufficient pressurePossible remedial actions:Increase compression pressurePolish tooling by handReduce press speed
44 BINDINGBinding in the die, is the term used when the tablets adhere or tear in the die. A film is formed in the die and ejection of tablet is hindered. With excessive binding, the tablet sides are cracked and they may crumble apartReason: Binding is usually due to excessive amount of moisture in granules, lack of lubrication and/or use of worn dies.Causes due to worn dies:Poorly finished diesRough dies due to abrasionPossible remedial action:Clean the dies properlyIf worn die is due to abrasion investigate use of other steelsReducing pressure in the tablet press may decrease binding.
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