Evaluation of tablets
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Evaluation of tablets Evaluation of tablets Document Transcript

  • TABLETTablet is solid unit dosage form in which one usualdose is accurately placed. It is basically oral route ofadministration other route of tablets include vaginaltablets, rectal and implantation tablets.TYPES OF TABLETSORAL TABLETS FOR INGESTION These tablets are meant to be swallowed intact along witha sufficient quantity of potable water. Exception ischewable tablet. Over 90% of the tablets manufacturedtoday are ingested orally. This shows that this class offormulation is the most popular world wide and the majorattention of the researcher is towards this direction.Standard compressed tabletsMultiple compressed tabletsCompression coated tabletLayered tabletInlay tabletModified Release tabletDelayed action tabletTargeted tabletFloating tablet 1
  • Colon targeting tabletChewable tabletDispersible tablet2- TABLETS USED IN THE ORAL CAVITYThe tablets under this group are aimed release API in oralcavity or to provide local action in this region. The tabletsunder this category avoids first-pass metabolism,decomposition in gastric environment, nauseaticsensations and gives rapid onset of action. The tabletsformulated for this region are designed to fit in properregion of oral cavity.Lozenges and trochesSublingual tabletBuccal tabletDental conesMouth dissolved tablet3- TABLETS ADMINISTERED BY OTHER ROUTESThese tablets are administered by other route except forthe oral cavity and so the drugs are avoided from passingthrough gastro intestinal tract. These tablets may beinserted into other body cavities or directly placed belowthe skin to be absorbed into systemic circulation from thesite of application.Vaginal tabletImplants 2
  • 4- TABLETS USED TO PREPARE SOLUTIONThe tablets under this category are required to bedissolved first in water or other solvents beforeadministration or application. This solution may be foringestion or parenteral application or for topical usedepending upon type of medicament used.Effervescent tabletSoluble tabletOral tablets for ingestion:1- Standard compressed tabletsThese are the standard uncoated tablets made by eitherdirect compression or wet granulation or dry granulationor double compaction.FIGURE.1. STANDARD COMPRESSED TABLETThey may be used for local action in gastro-intestinal tractor systemic action. When the tablet exert local action, theyare formulated as more water insoluble by means ofselecting slow dissolving excipients and thus provide localaction for long time period. e.g., antacids and adsorbents.The drugs that produce systemic action have someaqueous solubility and designed to disintegrate anddissolve quickly so that the drug can be quickly absorbedand produce systemic action. 3
  • 2- Multilayered tabletsWhen two or more active pharmaceutical ingredients areneeded to be administered simultaneously and they areincompatible, the best option for the formulationpharmacist would be to formulate multilayered tablet. Itconsists of several different granulations that arecompressed to form a single tablet composed of two ormore layers and usually each layer is of different colour toproduce a distinctive looking tablet. Each layer is fed fromseparate feed frame with individual weight control. Dustextraction is essential during compression to avoidcontamination. Therefore, each layer undergoes lightcompression as each component is laid down. This avoidsgranules intermixing if the machine vibrates.For example, admixture containing Phenylephedrin HCLand Ascorbic Acid with ParacetamolCompression coated tabletsThis type of tablet has two parts, internal core andsurrounding coat. The core is small porous tablet andprepared on one turret. For preparing final tablet, a biggerdie cavity in another turret is used in which first the coatmaterial is filled to half and then core tablet ismechanically transferred, again the remaining space isfilled with coat material and finally compression force isapplied. This tablet readily lend itself in to a repeat actiontablet as the outer layer provides the initial dose while theinner core release the drug later on. But, when the corequickly releases the drug, entirely different blood level isachieved with the risk of over dose toxicity. To avoid 4
  • immediate release of both the layers, the core tablet iscoated with enteric polymer so that it will not release thedrug in stomach while, the first dose is added in outersugar coating. Even so, coating operation requiresinterpretation while manufacturing and dawdling themanufacturing process. Sometimes, inner core may be ofliquid formulation to provide immediate release of coreafter the coat gets dissolved.FIGURE.3. COMPRESSION COATED TABLETLayered tabletsA layered tablet for the controlled release of activesubstances in a liquid medium comprising at least oneactive substance-containing, layered matrix with contactsurfaces to the liquid medium which are at least partiallyprovided with a cover layer delaying or preventing theactive substance release, is characterized by the fact thatthe cover layer is at least one additional layer lying withthickness gradients on contact surfaces of the layered,prefabricated matrix, or that the matrix is at least oneadditional layer lying with thickness gradients on contactsurfaces of the layered, prefabricated cover layer, whichadditional layer is applied by pressing powdery orgranular material on the layered, prefabricated matrix oron the layered, prefabricated cover layer. 5
  • Inlay tabletsA type of layered tablet in which instead the core tabletbeing completely surrounded by coating, top surface iscompletely exposed. While preparation, only the bottom ofthe die cavity is filled with coating material and core isplaced upon it. When compression force is applied, somecoating material is displaced to form the sides andcompress the whole tablet. It has some advantages overcompression coated tablets:i) Less coating material is required.ii) Core is visible, so coreless tablets can be easilydetected.iii) Reduction in coating forms a thinner tablet and thusfreedom from capping of top coating.FIGURE.4. INLAY TABLETS3- Modified release tabletThe main aim behind formulation of this dosage form is torelease the medicament slowly for long time duration afteradministration of a single tablet.More over, these type offormulations are generally used to target the site specificreleases. 6
  • FIGURE.5. GRAPHICAL COMPARISON OF BLOODCONCENTRATION V/S TIMEA widespread use of this type of tablet is seen in presentscenario, as well as many researchers have concentratedtheir attention in this direction.4- Delayed action tabletEnteric coated tablet is such an example of delayed actiontablet. This formulation is preferred when,i) Drugs that irritates gastric mucosa e.g., aspirin or strongelectrolytesii)Drugs that produce nausea and vomiting.iii)Drugs is sensitive to low pH e.g., erythromyciniv)When it’s necessary to release the drug undiluted. e.g.,intestinal antibacterial, antiseptic agents, intestinalvermifuge, etc. 7
  • The commonly used coating agents are: Cellulose acetatephthalate, Hydroxy methyl propyl phthalate, polyvinylacetate phthalate, Eudragit®, etc. This dosage form isintended to hydrate and begin to dissolve in duodenum(pH 4 to 6) or in small intestine where pH increases to 7 to8. The presence of esterases or bile salts like surface activeagents plays a role in drug release.5- Targeted tabletWhen we need to release the drug at a specific site in theelementary tract, targeted drug delivery is a preferredoption. Depending upon the composition and releasemechanism of a tablet, the drug is delivered to a particularregion. Under this category, we have two types of tablet:I.Gastro retentive Tablet (floating tablets)This type of dosage form is to be opted when API release isdesired in stomach (Antacids, APIs used against H.pyloriinfection) or site of absorption is either stomach or upperpart of small intestine.FIGURE.10. FLOATING TABLETII. Colonic tabletsWhen the aim is to deliver the drug into colon withoutdilution in other regions of gastrointestinal tract or thedrug has poor absorption in stomach or small intestine, 8
  • colonic drug delivery is an answer of choice. The pH in thisregion varies from 6.4 - 7 and presence of microbial floraplays as important role in drug release especially in thisregion. Various mechanisms are adopted for drug releasein this area are coating with pH sensitive polymer e.g.,Eudragit®S100, Eudragit® L100, biodegradable polymerlike polymers which are sensitive to colonic bacteria,bioadhesive polymers which selectively sticks to colonicmucosa e.g., polycarbophils or polyethans, redox sensitivepolymers that respond to redox potential in colon whichexpresses the total metabolic and bacterial action.6- Chewable tabletThe patients who have difficulty in swallowing tabletswhole or for children who have not yet learnt to swallow atablet, chewable tablet serves as an attractive alternative.The added advantage of this medication is that it can betaken at any time or when water is not available. Mannitolis normally used as a base due to low hygroscopy andmore importantly, it gives pleasant, cooling sensation.Antacid tablets are invariably prepared as chewable toobtain quick ingestion relief as well as the antacid dose istoo large to swallow and the activity is related to particlesize. Another example is multivitamin tablet which apatient can take as a daily dose.7- Dispersible tabletThese tablets disintegrate either rapidly in water, todisperse instantaneously in the mouth to be swallowedwithout the aid of water. So, it’s preferred for pediatric 9
  • patients who cannot swallow a solid dosage form. Alsohelpful for patients having prolonged illness who areprone to nauseatic sensations if they have to swallow atablet. The added advantage of this formulation is fasteronset of action as compared to standard compressedtablet. The properties of the water dispersible tablet, suchas porosity, hardness, disintegration time and increase inviscosity after dispersion are necessary to investigateduring manufacturing which decides the productperformance. The common examples of API formulated inthis dosage form are analgesics e.g., aspirin, ibuprofen, etc.Tablets used in the oral cavity:1- Lozenges and trochesThe tablet is a flat faced at least about 18mm in diameterand meant to suck and dissolves in the mouth. Thecompressed tablet is called troches and the tabletsproduced by fusion or candy molding process are calledlozenges. Flavours and sweeteners are added to maketablets palatable. The tablet generally contains sucrose orlactose and gelatin solution to impart smooth taste.Lozenges for local action in mouth/ throat are: antiseptics,antibiotics, demulcents, antitussive agents or astringents.To produce systemic action: multivitamin tablet.2- Sublingual tabletThey are to be placed under the tongue and produceimmediate systemic effect by enabling the drug absorbeddirectly through mucosal lining of the mouth beneath thetongue. 10
  • FIGURE.11. SUBLINGUAL TABLETSThe drug absorbed from stomach goes to mesentericcirculation which connects to stomach via portal vein.Thus, absorption through oral cavity avoids first-passmetabolism. The tablets are usually small and flat,compressed lightly to keep them soft. The tablet mustdissolve quickly allowing the API to be absorbed quickly.It’s designed to dissolve in small quantity of saliva. Afterthe tablet is placed in the mouth below the tongue, thepatient should avoid eating, drinking, smoking andpossibly talking in order to keep the tablet in place.Swallowing of saliva should also be avoided since thesaliva may contain dissolved drug. Bland excipients areused to avoid salivary stimulation. Due to inconvenience inadministration, this dosage form is prepared only forthose API(s) for which the only satisfactory nonparenteralmethod is this route. For example, Glyceryl trinitrate(vasodilator) and Isoprinosine sulphate (bronchodilator).3- Buccal tabletCompleteness of drug absorption is desired but fast drugabsorption is not intended. The tablets are designed not todisintegrate. They are flat elliptical or capsule shapedtablets as it can be easily held between gum and cheek. It’splaced near the opening of parotid duct to provide themedium to dissolve the tablet. 11
  • FIGURE.12. BUCCAL TABLETSSince this tablet is to be kept for 30-60 minutes in oralcavity, care should be taken to see that all the ingredientsare finely divided to avoid gritty or irritating sensation.This tablet is most often used when replacementhormonal therapy is to be administered. Antifungal drugsare preferred to be administered by this route. e.g.,Miconazole – under preclinical trial – still not in market.4- Dental conesThese tablets are designed to be loosely packed in theempty socket remaining following a tooth extraction.FIGURE.13. DENTAL CONESMain purpose behind the use of this tablet is either toprevent multiplication of bacteria in the socket byemploying a slow releasing antibacterial compound or toreduce bleeding by an astringent or coagulant containingtablet. It’s formulated to dissolve or erode slowly inpresence of a small volume of serum or fluid over 20-40minutes period. 12
  • 5- Mouth Dissolved tablets/ Rapidly Dissolvingtablets:Known as orally disintegrating tablets, they are also calledmouth-dissolving, fast-dissolving, rapid-melt, porous,orodispersible, quick dissolving. These kinds of tablets arepreferred when fast action or relief is desired. Mostcommonly used drugs under this formulation are theagents active against migraine. The tablets are designed todisintegrate as well as dissolve within one minute or somewithin 10 seconds of oral administration in limitedquantity of saliva. They liquefy on tongue and patientswallows the liquid, without the need of water. A numberof techniques are used to prepare these tablets, includinglyophilization, soft direct compression.Tablets administered by other routes:1- Vaginal tabletThis tablet undergoes slow dissolution and drug release invaginal cavity of women. The shape is kept ovoid or pearshaped to facilitate retention in vagina. The tablet shouldbe made compatible with plastic tube inserters which aredesigned to place the tablet in the upper region of vaginaltract. These tablets generally release antibacterial,antiseptics or astringents to treat vaginal infections orrelease steroids for systemic absorption.2- ImplantsThese tablets are inserted into subcutaneous tissue bysurgical procedures where they are very slowly absorbedover a period of a month or a year. A special injector witha hollow needle and plunger is used to administer the rod 13
  • shaped tablet for other shapes, surgery is required. Thetablets may be pellet, cylindrical or rosette shaped withdiameter not more than 8mm. They are sterile formulationwithout excipients and made hard with large particle sizeto achieve gradual drug release. The tablets are producedby a sterile single punch hand operated machine in whichthe die cavity is filled with hand since the material doesnot normally flow well. Mainly, these tablets are preparedto deliver growth hormones to food producing animalsand ear is the preferred site for administration of the drug.Tablets used to prepare solution:Effervescent tabletThe oral dosage forms are the most popular way of takingmedication despite having some disadvantages like slowabsorption and thus onset of action is prolong. This can beovercome by administrating the drug in liquid from but,many drugs have limited level of stability in liquid form.So, effervescent tablets acts as an alternative dosage form.The tablet is added into a glass of water just beforeadministration and the drug solution or dispersion is to bedrunk immediately. The tablet is quickly broken apart byinternal liberation of CO2 in water due to interactionbetween tartaric acid and citric acid with alkali metalcarbonates or bicarbonates in presence of water.FIGURE.14. EFFERVESCENT TABLETS 14
  • Due to liberation in CO2 gas, the dissolution of API inwater as well as taste masking effect is enhanced. Theadvantages of effervescent tablets compared with otheroral dosage forms includes an opportunity for formulatorto improve taste, a more gentle action onSoluble tabletTablets are solids of uniform shape and dimensions,usually circular, with either flat or convex faces, thedistance between faces being less than the diameter.Water soluble tablets are intended for application afterdissolution in water and contain an active ingredientshould be totally soluble in water at used concentrations.All the excipients used to formulate these tablets arerequired to be completely soluble in water including theglidants, binders, etc.Advantages and disadvantages of tablet as adosage form.The advantages are listed below:I.Large scaleManufacturing is feasible in comparison to other dosageforms. Therefore,economy can be achieved. 15
  • II.Accuracy of doseis maintained since tablet is a solid unit dosage form.III. Tailor made release profile can be achieved.IV. Longer expiry period and minimum microbial spillageowing to lower moisture content.V. As tablet is not a sterile dosage form, stringentenvironmental conditions are not required in the tabletdepartment.VI. Ease of packaging (blister or strip) and easyhandling over liquid dosage form.VII. Easy totransport in bulk. Emergency supply supplies can becarried by patients.VIII.Organolepticproperties (taste, appearance and odour) are bestimproved by coating oftablet.IX. Product identification is easy and markings done withthe help of grooved punches and printing with edible ink.X. Different types of tablets are available like buccal,floating, colon targeting, effervescent, dispersible, soluble,and chewable,etc.XI. In composition to parenterals dosage form, a doctoror a nurse is not required for administration. I.e. selfadministration ispossible. 16
  • XII. In comparison tocapsules, tablets are more tamperproof.The disadvantages are listed below:I.It is difficultto convert a high dose poorly compressible API into atablet of suitable sizefor human use.II.Difficult toformulate a drug with poor wettability, slow dissolutioninto a tablet.III. Slow onset of action as compared to parenterals,liquid orals and capsules.IV. The amount of liquid drug (e.g. Vitamin E,Simethicone) that can be trapped into a tablet is very less.V. Difficult to swallow for kids, terminally ill andgeriatric patients. 17
  • Tablets ManufacturingIntroductionThe manufacture of oral solid dosage forms such as tabletsis a complex multi-stage process under which the startingmaterials change their physical characteristics a numberof times before the final dosage form is produced.Traditionally, tablets have been made by granulation, aprocess that imparts two primary requisites to formulate:compactibility and fluidity. Both wet granulation and drygranulation (slugging and roll compaction) are used.Regardless of weather tablets are made by directcompression or granulation, the first step, milling andmixing, is the same; subsequent step differ. Numerous unitprocesses are involved in making tablets, includingparticle size reduction and sizing, blending, granulation,drying, compaction, and (frequently) coating. Variousfactors associated with these processes can seriouslyaffect content uniformity, bioavailability, or stability.Manufacturing process 18
  • Manufacturing process1- Dispensing(weighing and measuring)Dispensing is the first step in any pharmaceuticalmanufacturing process. Dispensing is one of the mostcritical steps in pharmaceutical manufacturing; asduring this step, the weight of each ingredient in themixture is determined according to dose.2- SizingThe sizing (size reduction, milling, crushing, grinding,pulverization) is an impotent step (unit operation)involved in the tablet manufacturing.In manufacturing of compressed tablet, the mixing orblending of several solid ingredients ofpharmaceuticals is easier and more uniform if theingredients are approximately of same size. Thisprovides a greater uniformity of dose. A fine particlesize is essential in case of lubricant mixing withgranules for its proper function.3- Powder blendingIn the tablet pressing process, the main guideline is toensure that the appropriate amount of activeingredient is in each tablet. Hence, all the ingredientsshould be well-mixed. If a sufficiently homogenousmix of the components cannot be obtained with 20
  • simple blending processes. The successful mixing ofpowder is acknowledged to be more difficult unitoperation because, unlike the situation with liquid,perfect homogeneity is practically unattainable. BLENDIND MACHINEMethod:Doubling method: If we have to mix different type ofmaterial (active ingradient or excipients ) with differentquantity. Firstly mix smallest quantity material with samequantity of other material then mix that quantity which wegained after mixing material with other same quantity ofpowder and so on. By adopting this method uniformmixing can be achieved. 21
  • 4- GranulationIn the pharmaceutical industry, granulation refers to theact or process in which primary powder particles aremade to adhere to form larger, multiparticle entities calledgranules. It is the process of collecting particles togetherby creating bonds between them. Bonds are formed bycompression or by using a binding agent. Granulation isextensively used in the manufacturing of tablets.The granulation process combines one or more powdersand forms a granule that will allow tableting process to bewithin required limits. This way predictable andrepeatable process is possible and quality tablets.Why Granulation?Granulation is carried out for various reasonsTO make the material flowable: Many powders, becauseof their small size, irregular shape or surfacecharacteristics, are cohesive and do not flow well.Granules produced from such a cohesive system will belarger and more isodiametric, both factors contributing toimproved flow properties.To prevent segregation: Segregation is due to differencesin the size or density of the component of the mix.Normally, the smaller and/or denser particles tend toconcentrate at the base of the container with the largerand/or less dense ones on the top. An ideal granulationwill contain all the constituents of the mix in the correct 22
  • proportion in each granule and segregation of granuleswill not occur.To make it compressible: Some powders are difficult tocompact even if a readily compactable adhesive isincluded in the mix, but granules of the same powders areoften more easily compacted. This is associated with thedistribution of the adhesive within the granule and is afunction of the method employed to produce the granule.For example, if one were to make tablets from granulatedsugar versus powdered sugar, powdered sugar would bedifficult to compress into a tablet and granulated sugarwould be easy to compress. Powdered sugar’s smallparticles have poor flow and compression characteristics.These small particles would have to be compressed veryslowly for a long period of time to make a worthwhiletablet. Unless the powdered sugar is granulated, it couldnot efficiently be made into a tablet that has good tabletcharacteristics such as uniform content or consistenthardness.Ideal characteristics of granulesThe ideal characteristics of granules include uniformity,good flow, and compactibility. These are usuallyaccomplished through creation of increased density,spherical shape, narrow particle size distribution withsufficient fines to fill void spaces between granules,adequate moisture (between 1-2%), and incorporation ofbinder, if necessary.The effectiveness of granulation depends on the followingproperties 23
  • i) Particle size of the drug and excipientsiii) Volume of binder (less or more)iv) Wet massing time ( less or more)v) Amount of shear applied to distribute drug, binder andmoisture.vi) Drying rate ( Hydrate formation and polymorphism)Wet granulation1 The most widely used process of agglomerationingpharmaceutical industry is wet granulation. Wetgranulation process simplyinvolves wet massing of thepowder blend with a granulating liquid, wet sizinganddrying Imortant steps involved in the wet granulation.i) Mixing of the drug and excipient.ii) Preparation of binder solutioniii) Mixing of binder solution with powder mixture to formwet mass.iv) Coarse screening of wet mass using a suitable sieve.v) Drying of moist granules.vi) Screening of dry granules through a suitable sieve.vii) Mixing of screened granules with disintegrant, glidant,and lubricant.Limitation of wet granulation 24
  • i) The greatest disadvantage of wet granulation is its cost.It is an expensive process becauseof labor, time, equipment, energy and space requirements.ii) Loss of material during various stages of processingiii) Stability may be major concern for moisture sensitiveor thermo labile drugsiv) Multiple processing steps add complexity and makevalidation and control difficult.v) An inherent limitation of wet granulation is that anyincompatibility between formulation components isaggravated.Dry granulationIn dry granulation process the powder mixture iscompressed without the use of heat and solvent. It is theleast desirable of all methods of granulation. The two basicprocedures are to form a compact of material bycompression and then to mill the compact to obtain agranules. Two methods are used for dry granulation. Themore widely used method is slugging, where the powder isprecompressed and the resulting tablet or slug are milledto yield the granules. The other method is to precompressthe powder with pressure rolls using a machine such asChilosonator.AdvantagesThe main advantages of dry granulation or slugging arethat it uses less equipments and space. It eliminates theneed for binder solution, heavy mixing equipment and the 25
  • costly and time consuming drying step required for wetgranulation. Slugging can be used for advantages in thefollowing situations:i) For moisture sensitive material( Active ingradient) .ii) For heat sensitive material.iii)For improved disintegration since powder particles arenot bonded together by a binder.Disadvantagesi) It requires aspecialized heavy duty tablet press to formslugii) It does not permit uniform colour distribution as canbe.iii) Achieved with wet granulation where the dye can beincorporated into binder liquid.iv) The process tends to create more dust than wetgranulation, increasing the potential contamination.steps in dry granulationi) Milling of drugs and excipientsii) Mixing of milled powdersiii) Compression into large, hard tablets to make slugiv) Screening of slugsv) Mixing with lubricant and disintegrating agentvi) Tablet compression 26
  • Two main dry granulation processesSlugging processGranulation by slugging is the process of compressing drypowder of tablet formulation with tablet press having diecavity large enough in diameter to fill quickly. Theaccuracy or condition of slug is not too important. Onlysufficient pressure to compact the powder into uniformslugs should be used. Once slugs are produced they arereduced to appropriate granule size for final compressionby screening and milling.Factors which determine how well amaterial may slugi)Compressibilityor cohesiveness of the materii) Compression ratio of powderiii) Density of the powderiv) Machine typev) Punch and die sizevi) Slug thicknessvii) Speed of compressionviii) Pressure used to produce slug 27
  • Roller compactionThe compaction of powder by means of pressure roll canalso be accomplished by a machine called chilsonator.Unlike tablet machine, the chilsonator turns out acompacted mass in a steady continuous flow. The powderis fed down between the rollers from the hopper whichcontains a spiral auger to feed the powder into thecompaction zone. Like slugs, the aggregates are screenedor milled for production into granules.Formulation for dry granulationThe excipients used for dry granulation are basically sameas that of wet granulation or that of direct compression.With dry granulation it is often possible to compact theactive ingredient with a minor addition of lubricant anddisintegrating agent. Fillers that are used in drygranulation include the following examples: Lactose,dextrose, sucrose, MCC, calcium sulphate, Sta-Rx® etc.Granule lubricationAfter granulation, a final lubrication step is used to ensurethat the tableting blend does not stick to the equipmentduring the tableting process. This usually involves lowshear blending of the granules with a powdered lubricant,such as magnesium stearate or stearic acid. 28
  • 5- DryingDrying is a most important step in the formulation anddevelopment of pharmaceutical product. It is important tokeep the residual moisture low enough to prevent productdeterioration and ensure free flowing properties. Thecommonly used dryer includes Fluidized bed dryer,Vacuum tray dryer, Microwave dryer, Spray dryer, Freezedryer, Turbo - tray dryer, Pan dryer, etc.6- Tablet compressionAfter the preparation of granules (in case of wetgranulation) or sized slugs (in case of dry granulation) ormixing of ingredients (in case of direct compression), theyare compressed to get final product. The compression isdone either by single punch machine (stamping press) orby multi station machine (rotary press). 29
  • Single punch compression machine 30
  • Rotary Press7- Tablet CoatingCoated tablets are defined as tablets covered with one ormore layers of mixture of various substances such asnatural or synthetic resins ,gums ,inactive and insolublefiller, sugar, plasticizer, polyhydric alcohol ,waxes,authorized colouring material and some times flavoringmaterial . 31
  • Coating may also contain active ingredient. Substancesused for coating are usually applied as solution orsuspension under conditions where vehicle evaporates.Type of tablet coating process1- Sugar coating : Compressed tablets may be coated withcoloured or uncoloured sugar layer 30-50% size also multistage process2- Film coating is deposition of a thin film of polymersurrounding the tablet core (spry). Film coating is morefavored over sugar coating 2-3 % over all size, sigle stageprocess.TABLE.26. COMPARISON BETWEEN FILM COATING ANDSUGAR COATINGFEATURES FILM COATING SUGAR COATINGTablet: Retain contour of Rounded with original high degree ofAppearance core. Usually not polish as shiny as sugar coat typeWeight increase 30-50%because of 32
  • coating material 2-3%Logo or ‘break Not possiblelines’ PossibleProcessOperator training Process tends Considerablerequired itself to automation and easy training of operatorAdaptability to Difficulty mayGMP High ariseProcess stages Usually single Multistage stage processFunctionalcoatings Easily adaptable Not usually for controlled possible apart release from enteric coatingAspects of tablet coatingi) Avoid irritation of oesophagus and stomach 33
  • ii) Avoid bad tasteiii) Avoid inactivation of drug in the stomachiv) Improve drug effectivenessv) Prolong dosing intervalvi) Improve dosing intervalvii) Improve patient complianceII. Technologyi) Reduce influence of moistureii) Avoid dust formationiii) Reduce influence of atmosphereiv) Improve drug stability8- PackagingPharmaceutical manufacturers have to pack theirmedicines before they can be sent out for distribution. Thetype of packaging will depend on the formulation of themedicine.What is packaging ?Packaging is defined as the collection differentcomponents which surround the pharmaceutical productfrom the time of production until its use.Importance of packaging• Protect against all adverse external influencesthat can alter the properties of the product.• Protect against biological contamination. 34
  • • Protect against physical damage.• Carry the correct information and identificationof the product.Functions of packagingContainmentNot to leak, nor allow diffusion and permeationStrong enough to hold the contents during handlingProtectionLightMoistureOxygenBiological contaminationMechanical damageCounterfeitingMaterial characteristicsAdditional qualities required�It must preserve the physical properties of all dosage forms and protect them against damage or breakage.�It must not alter the identity of the product.�It must preserve the characteristics properties of the product to comply specifications.� It must protect product against undesirable chemical,biological or physical entities. 35
  • Choosing appropriate primary packProduct characteristics/sensitivity�Hygroscopicity�Physical degradation�Chemical degradation�Drug release properties�Mechanical properties�Photosensitivity�Gas liberation tendency�Dimensional aspectsSelection of packaging material�Moisture barrier requirements�Light barrier requirements�Gas barrier requirements�Chemical propertiesType of packingStrip packing of colored sugar coated tabletsSelection of special vials for special productsProper design of blisters 36
  • Evaluation of tabletsIntroductionTh e quantitative evaluation and assessment of a tablet‘schemical, physical and bioavailability properties areimportant in the design of tablets and to monitor productquality. These properties are important since chemicalbreakdown or interactions between tablet components mayalter the physical tablet properties, and greatly affect thebioavailability of the tablet system.There are various standards that have been set in the variouspharmacopoeias regarding the quality of pharmaceuticaltablets. These include the diameter, size, shape, thickness,content, content uniformity, weight, hardness, disintegrationand dissolution characters. The diameters and shape dependson the die and punches selected for the compression oftablets. The remaining specifications assure that tablets donot vary from one production lot to another. The followingstandards or quality control tests should be carried out oncompressed tablets .1. General appearance2. Size and shape3. Organoleptic properties4. Content5. Content uniformity6. Weight variation7. Mechanical strength(hardness, friability)8. Disintegration9. Dissolution 37
  • General AppearanceThe general appearance of tablets, its visual identityand overall ‘elegance’ is essential for consumeracceptance, control of lot-to-lot uniformity andgeneral tablet-to-tablet uniformity and formonitoring the production process. The control ofgeneral appearance involves measurement ofattributes such as a tablet’s size, shape, color,presence or absence of odour, taste, surface textureand consistency .According to Drugs And CosmeticsAct, 1940 :General requirements shall includes compliancewith colour, consistency, clarity, stability, freedomfrom foreign matter or fungal growth defects likechipping and capping of tablets, motteled apperancetablets, cracking of coating and other charactersticsdefects that can be precieved by visual inspection. 38
  • Tablets Size and shapeThe shape and dimensions of compressed tablets aredetermined by the type of tooling during the compressionprocess. At a constant compressive load, tablets thicknessvaries with particle size distribution and packing of thepowder mix being compressed and with tablet weight.Tablet thickness is consistent from batch to batch or within abatch only if the tablet granulation or powder blend isadequately consistent in particle size and particle sizedistribution, if the punch tooling is of consistent length, and ifthe tablet press is clean and in good working condition. Thethickness of individual tablets may be measured with amicrometer, which permits accurate measurements andprovides information of the variation between tablets. Tabletthickness should be controlled within a ±5% variation of astandard value. Any variation in thickness within a particularlot of tablets or between manufacturer’s lots should not beapparent to the unaided eye for consumer acceptance of theproduct. In addition, thickness must be controlled to facilitatepackaging.The physical dimensions of the tablet along with the densityof the material in the tablet formulation and theirproportions, determine the weight of the tablet. The size andshape of the tablet can also influence the choice of tabletmachine to use, the best particle size for granulation,production lot size that can be made, the best type of tabletingprocessing that can be used, packaging operations, and thecost of production. 39
  • Organoleptic propertiesColor is a vital means of identification for manypharmaceutical tablets and is also usually important forconsumer acceptance. The color of the product must beuniform within a single tablet, from tablet to tablet and fromlot to lot. Non uniformity of coloring not only lack estheticappeal but could be associated by the consumer with nonuniformity of content and general poor product quality. Nonuniformity of coloring is usually referred to as mottling.The eye cannot differentiate small differencesin color nor can it precisely define color andefforts have been made to quantitate colorevaluations.Reflectance spectrophotometry, colorimetricmeasurements and micro reflectancephotometer have been used to measure coloruniformity and gloss on a tablet surface .Odor may also be important for consumer acceptanceof tablets and can provide an indication of the qualityof tablets.As the presence of an odor in a batch of tabletscould indicate a stability problem, such as thecharacteristic odor of acetic acid in degradingaspirin tablets. 40
  • However, the presence of an odor may be characteristicof the drug (e.g. vitamins), added ingredients (e.g.flavoring agent) or the dosage form (e.g. film-coated lets).Taste is also important for consumer acceptance of certaintablets (e.g. chewable tablets) and many companies utilizetaste panels to judge the preference of different flavors andflavor levels in the development of a product. Tastepreference is however subjective and the control of taste inthe production of chewable tablets is usually based on thepresence or absence of a specified taste. 41
  • Content of active ingradientsAs mentioned earlier a physical sound tablet may not producethe desired effect. To evaluate tablet’s potential for efficacy,the amount of drug per tablet need to be moniterd from tabletto tablet and batch to batch.Determine the amount of active ingradient by the method like%age purity and calculate the amount of active ingradient pertablet.According to Drugs And Cosmetics Act, 1940 :The content of active ingradients, other than vitamins,enzymes and antibiotics, in patent or proprietarymedicines shall not less than 90 per cent and not morethan 110 per cent of labeled content ; however, forenzymes and vitamins, only for lower limit of 90 per centshall apply. In all dry formulations containing antibiotics,the limit shall be 90 to 130 percent of labeled contents andin case of liquid antibiotics formulations, the limit shall be90 to 140 per cent of labellad contents.Method:According to I.P :Determine the amount of active ingradientby the method described in assay and calculate the amount ofactive ingradient per tablet. The result lies within the range ofactive ingradient stated in the monograph of specific tablet. This range is based on the requirement that 20 tablets, are used in assay. Where 20 tablets can not be obtained, a smaller number, which must not be less than 5, may be 42
  • used, but to allow for sampling errors the tolerances are windened in accordance with Table 1 apply when the stated limits are between 90 and 110 percent. For limits other than 90 to 110 per cent, proportionately smaller or larger allowances should be made. Table 1Weigth of active Subtract from lower Add to the upperingradient in each tablet limit for samples of limit for samples of 15 10 5 15 10 50.12 g or less 0.2 0.7 1.6 0.3 0.8 1.8More than o.12 g 0.2 0.5 1.2 0.3 0.6 1.5But less than 0.3g0.3 g or more 0.1 0.2 0.8 0.2 0.4 1.0 43
  • Content Uniformity Test ForTabletsThe content uniformity test is used to ensure that everytablet contains the amount of drug substance intended withlittle variation among tablets within a batch. Due to increasedawareness of physiological availability, the content uniformitytest has been included in the monographs of all coated anduncoated tablets and all capsules intended for oraladministration.Factor effecting uniformity of contens:(1)Nonuniform distribution of drug substance throuhtout thepowder mixture or granulation.(2)segregation of the powder mixture or granulation duringthe various manufacturing processes.(3)Tablet weight variation.It is official test which is prescribed by I.P. Test is applicable on what type of tablets??This test is applicable to tablets that contain very potentdrugs like digoxin, digitoxin etc. Mostly this test is appliedwhen these type of tablets cantain 10 mg or less than 10 mgor less than 10 per cent w/w of active ingradient. For tabletscontaining more than one active ingradient carry out the testfor each active ingardient. 44
  • The test for uniformity of content is not applicableto tablets containing multivitamins and traceelements.Method:Determine the content of active ingradient in each of 10dosage units taken at random using the method given in themonograph or by any suitable analytical method.Aceptance limits:The preparation complies with the test if each individualcontent is 85 to 115 per cent of average content. Thepreparation fails to comply with the test if more than oneindividual content is outside these limits or if one individualcontent is outside the limits of 75 to 125 per cent of theaverage content. If one individual content is outside the limitsof 85 to 115 per cent of average content but within the limitsof 75 to 125 percent, Repeat the determination using another20 dosage units.The preparation complies with the test if not more than one ofthe individual content of the total sample of 30 dosage units isoutside 85 to 115 per cent of the average content and none isoutside the limits of 75 to 125 per cent of the average content. 45
  • Weight variationTablet degisned to contain a specific amount of drug in aspecific tablet formula, the weight of tablet being made isroutinely measured to help ensure that tablet containproper drug. It is method to check the uniformity ofweight of tablet.Importance:Weight variation is quality control method to checkthe uniformity of tablets in lot to lot and batch tobatch.It is official method prescribed by I.P.Method:For weight variation weigh individually 20 tablets. averageweight is calculated by adding weight of all individual twentytablets divided by no. of tablets here no. of tablets are twentyso divided by 20. The individual tablet weights are thencompared to the average weight.The IP has provided limits for the average weight of uncoatedcompressed tablets. Twenty tablets are weighed individuallyand the average weight is calculated. The individual tabletweights are then compared to the average weight. Not morethan two of the tablets must differ from the average weight by 46
  • not more than the percentages stated in Table 1. No tabletmust differ by more than double the percentage.Average weight (Uncoated and film coated Percent differencetablets)80mg or less than 80mg 10More than 80 mg but less than 250 mg 7.5More than 250 mg 5Table 1: Weight variation requirementsExample:Weight variation of Tablet Arthgesic.Weigh individually 20 tablets. Calculate its average weightand then apply the limits according to I.P. According to I.P.more than 250 mg tablet average weight percentagedifference can be 5%. So apply 5% percentage difference.Sr.No. Weight of tablet12 780mg3 820mg4 780mg5 830mg6 810mg7 800mg8 780mg9 770mg10 810mg11 830mg12 830mg 47
  • 13 830mg14 770mg15 790mg16 790mg17 780mg18 790mg19 780mg20 830mgAverage weight = total weight/no.of tablets =16110/20 = 805.5so average weight of tablet is 805.5 apply I.P.standard. According to I.P. more than 250 mg tablet averageweight percentage difference can be 5%. So apply 5%percentage difference.805.5-40.275=765.2805.5=+40.275=845.77Range is b/w 765.2 – 845.77Now compare each tablet within this range.During comparing no tablet is out of computingrange. So sample is passed. 48
  • Mechanical strength of tabletsThe mechanical strength of a tablet provides a measure ofthe bonding potential of the material concerned and thisinformation is useful in the selection of excipients. Anexcessively strong bond may prevent rapid disintegration andsubsequent dissolution of a drug. If bonding is very weak itmay break very easily during handling packaging,transporatation.The mechanical properties of pharmaceutical tablets arequantifiable by the friability, hardness or crushing strength ,crushing strength-friability values, tensile strength and brittlefracture Index. Hardness or Crushing strength FriabilityThe strength of a tablet plays a very important role in itsmarketing and dissolution. The mechanical strength of tabletor granules can be determined by its hardness and throughfriability test. 49
  • Hardness of TabletsHardness may be defined as the resistance of tabletsto capping, abrasion or breakage under conditionsof storage, transportation and handling.Tablet hardness have been associated with other tabletproperties such as density and porosity. Hardnessgenerally increase with normal storage of tablets anddepends on the shape, chemical properties, binding agentand pressure applied during compression .It is non-official quality control method. It is notprescribed by I.P.Hardness test:The small and portable hardness tester wasmanufactured and introduced by Monsanto in the Mid1930s. It is now designated as either the Monsanto orStokes hardness tester.The instrument measures the force requiredto break the tablet when the force generatedby a coil spring is applied diametrally to thetablet. 50
  • MONSANTO HARDNESS TESTERThe Strong-Cobb Pfizer and Schleuniger apparatus whichwere later introduced measures the diametrically appliedforce required to break the tablet. PFIZER TESTERHardness which is now more appropriately calledcrushing strength determinations are made during tablet 51
  • production and are used to determine the need forpressure adjustment on tablet machine.The strength of a tablet can be determinedby breaking it between second and thirdfingers with the thumb acting as a fulcrum. Ifthere is a “click” sound, the tablet is deemedto have acceptance strength.If the tablet is too hard, it may not disintegrate in therequired period of time to meet the dissolutionspecifications; if it is too soft, it may not be able towithstand the handling during subsequent processingsuch as coating or packaging and shipping operations.The force required to break the tablet is measured inkilograms and a crushing strength of 4Kg is usuallyconsidered to be the minimum for satisfactory tablets.Oral tablets normally have a hardness of 4 to 10kg ;however, hypodermic and chewable tablets are usuallymuch softer ( 3 kg ) and some sustained release tablets aremuch harder (10 -20 kg ). 52
  • Friability Test for TabletsFriabiltyIt is may be defined as the excessive breakness of tabletsduring mechanical shocks of handling in manufacture,packaging, and shipping.Friction and shock are the forces that most often cause tabletsto chip, break.Why we test friability?Tablet hardness is not absolute indicator of strength sincesome formulations, when compressed into very hard tablets,tend to “cap” on attrition, losing there crown portions.Therefore another measure of tablets strength, its friability isoften measured.They not only lack elegance and consumer acceptance butalso spoil the areas of manufacturing such as coating andpackaging.In friability test the tablets are prone to abrasion henceenabling us to check for the tablet strength under applicationof force in different manner.Friability is affected by various external and internal factorslike:1) Punches that are in poor condition or worn at their surfaceedges, resulting in ‘whiskering’ at the tablet edge and showhigher than normal friability values. 53
  • 2) Friability test is influenced by internal factors like themoisture content of tablet granules and finished tablets.Moisture at low and acceptable level acts as a binderFriability is official method because it isprescribed by I.P. Tablet Friability Tester 54
  • Method :The friability test is closely related to tablet hardness and isdesigned to evaluate the ability of the tablet to withstandabrasion in packaging, handling and shipping. It is usuallymeasured by the use of the Roche friabilator. Ten tablets areweighed and placed in the apparatus where they are exposedto rolling and repeated shocks as they fall 6 inches in eachturn within the apparatus. After four minutes of thistreatment or 100 revolutions, the tablets are weighed and theweight compared with the initial weight. The loss due toabrasion is a measure of the tablet friability. The value isexpressed as a percentage. A maximum weight loss of notmore than 1% of the weight of the tablets being tested duringthe friability test is considered generally acceptable and anybroken or smashed tablets are not picked up . Normally, whencapping occurs, friability values are not calculated. A thicktablet may have less tendency to cap whereas thin tablets oflarge diameter often show extensive capping, thus indicatingthat tablets with greater thickness have reduced internalstress .FRIABILITY TEST FOR TABLETS:The friability test is carried out in an instrument called afriabilator. A friability testing apparatus should stimulate theconditions that the product will be exposed to during theprocess of production. This test is a method to determine 55
  • physical strength of uncoated tablets upon exposure tomechanical shock.The commonly used friabilator in laboratories is the Rochefriabilator . ROCHE FRIABILATOR This instrument consists of a plastic chamber for placing thetablets which is attached to a horizontal axis. The drum has aninside diameter of 287mm and is about 38mm in depth, made ofa transparent synthetic polymer with polished internal surface.A set of pre weighed tablets [if one tablet weigh 650mg or lessthen approx 6.5g of total weight should be taken and for morethan 650mg/tablet weight, 10 tablets should be taken] (3) areplaced in the plastic chamber revolving at 24-25rpm for 4 min.The tablets are subjected to combined effects of abrasion andshock. The tablets are dropped at a distance of six inches oneach revolution. 56
  • If the tablet size or shape becomes irregular adjust the drumso that base forms an angle of about 10 degrees with benchtop and the tablets fall freely when drum is rotated.The instrument is operated for 100 revolutions after whichthe tablets are dusted and reweighed.Conventional compressed tablets that lose less than 0.5% to1% of weight are considered acceptable.Most effervescent tablets and some chewable tablets undergohigh friability weight loss which is an indication for thespecial stack packing that is required for these types oftablets.In case of hygroscopic tablets a humidity-controlledenvironment (relative humidity less than 40%) is requiredfor testing.Tablets prone to capping during the test are consideredunfit for commercial use. 57
  • Tablet DisintegrationFor a drug to be absorbed from a solid dosageform after oral administration, it must first be insolution, and the first important step toward thiscondition is usually the break-up of the tablet; aprocess known as disintegration.In the past, the only release index required for a tablet was itsdisintegration time which does not necessarily measure thephysiological availability of the drug in a patient. Studies haveshown that the agitation of the gastric contents during normalcontractions is quite mild in contrast to the turbulentagitation produced in the disintegration test apparaus . Thelow order magnitude of agitation in the stomach producessubstantially higher disintegration in vivo than thoseobtained using the USP apparatus. Furthermore, the particlesof the disintegrated tablets are not dispersed throughout thestomach but remains as an aggregate. Thus, the tabletdisintegration test is limited to manufacturing control of lot-to-lot variations in individual products and is not a measureof bioavailability. Nevertheless, it is used to provide a simpleand useful means for monitoring and controlling the quality oftablets.  Theories of disintegration  Disintegration Test  Disintegration Tests of Dosage forms 58
  •  Disintegration Tests : Pharmacopoeial comparison  Disintegration ApparatusTheories of disintegration of Tablets :Several mechanisms of tablet disintegration have beenproposed. Some of these are given below. Even though theseconcepts are listed separately, inter-relationships probablyoccur in almost all tablet formulations.(i) Evolution of gasIf a gas is evolved by a chemical reaction when the tabletcomes into contact with water, then the tablet willdisintegrate. This is the basis for the manufacture ofeffervescent tablets. An example of such a reaction is ofsodium bicarbonate with citric and tartaric acids, which yieldscarbon dioxide. Peroxides incorporated in certainformulations decompose in the presence of oxygen and thisalso causes disintegration.(ii) Heat of wettingThe heat produced when a tablet is immersed in water causesthe entrapped air in the tablet to expand and exert sufficientpressure to disintegrate the tablet .(iii) Effect of water absorptionThe water absorbed by the tablet initiate disintegration, butthis depends on the solubility of the drug and otheringredients present . If tablet have high solubility its 59
  • disintegration increase due to initiation of breakage ofbinding between the granules or molecules of tablet.(iv) SwellingThe grains of the disintegrant, particularly of starches, swellin the presence of water and exert pressure on the granules toforce them apart. Shangraw et al reported that tablets ofwater insoluble drugs disintegrated faster with starches thanthose of water soluble drugs due to the diminished waterabsorption capacity of the starches in the latter case.(v) Porosity of tabletsIt has been shown that penetration of water into a tablet isproportional to its mean pore diameter or porosity. Theporosity and permeability of tablets decrease as the tablettingpressure is increased , and as the porosity decreases, thedisintegration time increases. Though no quantitativerelationships have been reported between disintegration andpenetration times, generally short disintegration times areassociated with rapid fluid penetration.Disintegration Test:Disintegration test is widely used in the pharmaceuticalindustry for evalution of disintigration capability offormulations (ex:tablets) and quality control of differentdosage forms.Applications of Disintegration test :1.Disintegration test is a simple test which helps in thepreformulation stage to the formulator. 60
  • 2. It helps in the optimisation of manufacturing variables,such as compressional force time3.This test is also a simple in-process control tool to ensureuniformity from batch to batch and among different tablets.4.It is also an important test in the quality control of tablets.Advantages of Disintegration tests:This test is simple in concept and in practice.It is very useful in preformulation, optimisation and in qualitycontrol.Disadvantages:Disintegration test cannot be relied upon for the assurance ofbioavailability.Disintegration Tests : PharmacopoeialcomparisonDisintegration tests are performed as per the pharmacopoeialstandards. Disintegration is a measure of the quality of theoral dosage form like tablets and capsules. Each of thepharmacopoeia like the USP, BP, IP etc each have their ownset of standards and specify disintegration tests of their own.USP, European pharmacopoeia and Japanese pharmacopoeiahave been harmonised by the International conference onHarmonisation and are interchangeable.The disintegration test is performed to find out the time ittakes for a solid oral dosage form like a tablet or capsule tocompletely disintegrate. 61
  • The time of disintegration is a measure of the quality. This isbecause, for example, if the disintegration time is too high; itmeans that the tablet is too highly compressed or the capsuleshell gelatin is not of pharmacopoeial quality or it may implyseveral other reasons. And also if the disintegration time isnot uniform in a set of samples being analysed, it indicatesbatch inconsistency and lack of batch uniformity.DISINTEGRATION METHOD:The disintegration test is a measure of the time requiredunder a given set of conditions for a group of tablets todisintegrate into particles which will pass through a 10 meshscreen. Generally, the test is useful as a quality assurance toolfor conventional dosage forms. The disintegration test iscarried out using the disintegration tester which consists of abasket rack holding 6 plastic tubes, open at the top andbottom, the bottom of the tube is covered by a 10-meshscreen. The basket is immersed in a bath of suitable liquidheld at 37oC, preferably in a 1L beaker. For compresseduncoated tablets, the testing fluid is usually water at 37o C butsome monographs direct that simulated gastric fluid be used.If one or two tablets fail to disintegrate, the test is repeatedusing 12 tablets. For most uncoated tablets, the BP requiresthat the tablets disintegrate in 15minutes (although it variesfor some uncoated tablets) while for coated tablets, up to2hours may be required. The individual drug monographsspecify the time disintegration must occur to meet thePharmacopoeial standards.The disintegration test for each dosage form is given in thepharmacopoeia. There are some general tests for typical 62
  • types of dosage forms. However, the disintegration testprescribed in the individual monograph of a product is tobe followed. If the monograph does not specify anyspecific test, the general test for the specific dosage formmay be employed. Some of the types of dosage forms andtheir disintegration tests are:1.Uncoated tablets-Tested using distilled water as medium at 37+/-2 C at 29-32 cycles per minute; test is completed after 15 minutes. Itis acceptable when there is no palpable core at the end ofthe cycle (for at least 5 tablets or capsules) and if the massdoes not stick to the immersion disc.2.Coated tablets-The same test procedure is adapted but the time ofoperation is 30 minutes.3.Enteric coated/ Gastric resistant tablets-The test is carried out first in distilled water (at roomtemperature for 5 min.; USP and no distilled water per BPand IP), then it is tested in 0.1 M HCL(upto 2 hours; BP) orStimulated gastric fluid (1 hour; USP) followed byPhosphate buffer, pH 6.8 (1 hour; BP) or Stimulatedintestinal fluid without enzymes (1 hour; USP). 63
  • Disintegration Test Apparatus(as per I.P.):The apparatus consists of a basket rack assembly, a 1-litrebeaker, a thermostatic arrangement for heating the fluid and amechanical device for raising and lowering the basket in theimmersion fluid at a constant frequency rate.Basket-rack assembly: The basket-rack assembly is rigid andsupports six cylindrical glass tubes, 77.5±2.5 mm long, 21.5mm in internal diameter and with a wall thickness of about2mm. The tubes are held vertically by two superimposedtransparent plastic plates, 90±2mm in diameter and6.75±1.75 mm thick perforated by six holes having the samediameter as the tubes. The holes are equidistant from thecentre of the plate and equally spaced from one another.Attached to the under side of lower plate is woven stainlesssteel wire cloth with a plain square weave with 2.0±0.2 mmmesh apertures and with a wire diameter of 0.65±0.045mm.The upper plate is covered with a stainless steel discperforated by six holes, each about 24+or-2 mm in diameter,which fits over the tubes and holds them between the plasticplate and the upper open ends of the glass tubes. A suitablemeans is provided to suspend the basket rack the entirebasket-rack assembly is movable by reciprocating motorwhich is fixed to the apex of the basket-rack assembly fromthe raising and lowering device using a point on its axis. This motor device for raising or lowering it smoothly at aconstant frequency of between 28 and 32 cycles per minutethrough a distance of 50 to 60 mm. The time required byupward stroke is equal to time required for downward strokedirection should be smooth not abrupt. 64
  • Discs: a cylindrical disc for each tube, each 20.7±0.15mmthick in diameter and 9.5± 0.15mm thick, made of transparentplastic with a relative density of 1.18 to 1.20, and pirced withfive holes, each 2 mm in diameter. One in the center and theother four spaced equally on a circle of radius 6mm from thecenter of the disc. Four equally-spaced grooves are cut in thelateral surface of the disc in such a way that at the uppersurface of the disc they aye 9.5 mm wide and 2.55 mm deepand the lower surface 1.6 mm square. DISINTEGRTION APPARATUSMedium: The assembly in suspended in the liquid medium ina suitable vessel, preferably a 1 litre beaker. The volume ofthe liquid is such that the wire mesh at its highest point is atleast 25mm below the surface of the liquid, and at its lowerpoint is at least 25 mm above the bottom of the beaker. At notime should the top of the basket-rack assembly becomesubmerged. There is a thermostatic arrangement for heating 65
  • the liquid and maintaining the temperature at 37 oC ±2 degreecelsius.Disintegration Test Method as per I.P.Introduce one tablet or capsule into each tube and, ifdirected in the appropriate general monograph, add a discto each tube. Suspend the assembly in the beakercontaining the tube specified liquid and operate theapparatus for the specified liquid and operate theapparatus for the specified time given in individualmonograph. Remove the assembly from the liquid. Thetablet or capsules pass the test if all of them havedisintegrated.If the 1 or 2 tablet fail to disintegrate, repeat the test on 12additional tablets; Not less than 16 of the total of 18tablets tested disintegrate.If the tablet adhere to the disc and the preparation underexamination is fail to comply, repeat the test omitting thedisc. The preparation complies with the test if all thetablets in the repeat test is disintegrate.For uncoated tablets :Use water as the liquid. Add a disc to each tube.Operate the apparatus for 15 minutes. Unlessotherwise stated in individual monograph. Examinethe state of the tablets fail to comply because of 66
  • adherence to discs, repeat the test on a further 6tablets omitting the discs. The tablets comply withthe test if all 6 tablets have disintegrated.For coated tablets :Use water as the liquid. Add a disc to each tube.Operate the apparatus for minutes. Unlessotherwise stated in individual monograph. Examinethe state of the tablets if any of tablets has notdisintegrated, repeat the test with0.1 M hydrochloricacid. The tablets comply the with the test if all 6tablets have disintegrated in the acidic medium.For coated tablets :Carry out the test described above but operate theapparatus for 30 minutes. Unless otherwise stated inindividual monograph.If coated tablets fail to comply because of adherenceto discs, repeat the test on a further 6 tabletsomitting the discs. The tablets comply with the test ifall 6 tablets have disintegrated.For enteric coated tablets :Apparatus: Use the apparatus for the tablets describedabove. 67
  • Method: Put one tablet into each tube, suspend theassembly in the beaker containing 0.1M hydrochloric acidand operate without the discs for 2 hours, unlessotherwise stated in the individual monograph. Remove theassembly from the liquid. No tablet shows signs of cracksthat would allow the escape of the content ofdisintegration, apart from fragments of coating.Replace the liquid in the beaker with mixed phosphatebuffer pH 6.8, add a disc to each tube and operate theapparatus for a further 60 minutes. Remove the assemblyfrom the liquid. If the tablet fails to comply because ofadherence to discs, repeat the test on a further 6 tabletswithout the discs. The tablets pass the test if all six havedisintegrated. 68
  • Dissolution testDissolution:Dissolution is the process by which a solid solute enters asolution.Dissolution is pharmaceutically defined as the rate of masstransfer from a drug substance into the dissolution mediumor solvent under standardized conditions of liquid/solidinterface, temperature and solvent composition. It is adynamic property that changes with time and explains theprocess by which a homogenous mixture of a solid or a liquidcan be obtained in a solvent. It happens to chemically occur bythe crystal break down into individual ions, atoms ormolecules and their transport into the solvent.Dissolution is considered one of the most important qualitycontrol tests performed on pharmaceutical dosage forms andis now developing into a tool for predicting bioavailability,and in some cases, replacing clinical studies to determinebioequivalence. Dissolution behaviour of drugs has asignificant effect on their pharmacological activity. In fact, adirect relationship between in vitro dissolution rate of manydrugs and their bioavailability has been demonstrated.Solid dosage forms may or may not disintegrate when theyinteract with gastrointestinal fluid following oraladministration depending on their design (Figure ). Fordisintegrating solid oral dosage forms, disintegration usuallyplays a vital role in the dissolution process since it determinesto a large extent the area of contact between the solid and 69
  • liquid. However it is well known that considerable dissolutionof the drug can take place before complete disintegration ofthe dosage form, a phenomenon which depends largely on themechanism of disintegration and certain physicochemicalproperties of the drug, such as its solubility. This could beimportant when considering the motility of the drug ordosage form, and the release of the drug at specific sites, inthe gastrointestinal tract. Thus, correlations have beenestablished between disintegration times and dissolutionrates for various pharmaceutical tablets. It should be noted,however, that there is not always an automatic correlationbetween disintegration and dissolution, especially for drugswith very low dissolution rates.For many drugs, particularly those that are poorlysoluble in the gastric fluid, the rate-limiting step in theabsorption process is the dissolution rate and adissolution rate determination can therefore be auseful guide to comparative bioavailability.Since drug absorption and physiological availability dependon the availability of the drug substance in the dissolved state,suitable dissolution characteristics are important property fora satisfactory tablet. The dissolution test measures theamount of time required for certain percentage of the drugsubstance in a tablet to go into solution under a specified setof conditions. It describes a step towards physiologicalavailability of the drug substance, but it is not designed tomeasure the safety or efficacy of the tablet being tested. Itprovides in vitro control procedure to eliminate variationamong production batches. The dissolution medium must be 70
  • aqueous and the pH of the medium should be controlled andshould simulate in vivo conditions. The dissolution mediumshould be 0.1M HCl and pH 6.8 buffer to simulate thebiological extremes.. Studies have shown that low agitationmust be used (i.e. in the order of 50rpm) and that the tabletmust not be subjected to abrasion in keeping with the mildagitation in the gastrointestinal tract 45 .Figure : Schematic diagram of the dissolution processDissolution testing is widely used in the pharmaceuticalindustry for optimization of formulation and quality control ofdifferent dosage forms.Dissolution test is mainly used for poorsoluble drugs(tablets or capsules).Dissolution test as per I.P.Dissolution apparatus: There are two types ofaaparatus. Dissolution apparatus 1: An assemblyconsisting of the foolowing. 71
  • DISSOLUTION APPARATUS FIGUREa. A cylindrical vessel, A, made of borosilicate glass orany other suitable transparent material, with ahemispherical bottom and with a nominal capacity of1000ml and an inside diameter of 98-106mm.thevessel has a flanged upper rim and is fitted with a lidthat has a number of opening one of which is central.b. A motor with a speed of rotation of the paddlewithin the 4% of that specified in the individualmonograph. The motor is fitted with a stirring 72
  • element which consists of a drive shaft and bladeforming a paddle, BThe blade passes through the diameter of the shaft so thatthe bottom of the blade is flush with the bottom of theshaft. The shaft is flush with the bottom of the shaft. Theshaft is positioned so that its axis is within 2mm of the axisof the vessel and lower edge of the blede is 23 to 27mmfrom the inside bottom of the vessel. The apparatusoperates insuch a way that the paddle rotates smoothy.c. A water bath set to maintain the dissolution medium at36.5o to 37.5 o. the bath liquid is kept in constant andsmooth motion during the test. The vessel is securelyclamped in the water bath in such a way that thedisplacement vibration from other equipment, includingthe water circulation device, is minimused.Apparatus 2: 73
  • figure 2The assembly is same as in apparatus1 except that in thestirring element the paddle is replaced by basket, D(figure-2). The metallic shaft rotates smoothly. The basketconsists of two components. The top part, with a vent, isattached to the shaft C, it it fitted with three spring clips, orother suitable means, that allow removal of the lower partof introduction of the prepration under examination andthat firmly hold the lower part for introduction of theprepration under examination and that firmly hold thelower part of the basket concentric with the axis of thevessel during rotation. The lower detachable part of thebasket is made of welded-steam cloth, with a wirethickness of 0.254mm diameter with narrow rim of sheetmetal around the top and the bottom. The basket may beplated with a 2.5mm layer of gold for use with acidicmedia. The distance between the inside bottom of the 74
  • vessel and the basket is maintained at 23 to 27 mm duringthe test.Time. Where a single time specification is given in themonograph, the test may be concluded in a shorter periodif the requirement for the minimum amount dissolved ismet. If two or more times are specified, specimen are to bewithdrawn only at the stated times, within a tolerance of± 2 per cent.MethodConventional and proloned-release solid dosage formsPlace the stated volume of the dissolution medium. Freefrom dissolved air, in to the vessel of the apparatus.Assemble the apparatus and warm the dissolutionmedium to 36.5o to 37.5 o . unless otherwise stated, placeone dosage unit in the apparatus, taking care to exclude airbubbles from the surface of the dosage unit. Whenapparatus 1 is used, allow the tablet to sink to the bottomof the vessel prior to the rotation of the paddle. A suitabledevice such as a wire of glass helix may be used to keephorizontal at the bottom of the vessel tablets that wouldother wise float.When Apparatus 2 is used, place the tablet in a dry basketat the beginning of each test. Lower the basket intoposition before rotation. Operate the apparatusimmediately at the speed of rotation specified in theindividual monograph within the time interval specified inthe individual monograph. Withdraw a specimen from azone midway between the surface of the dissolutionmedium and the top of the roating blade or basket, not lessthan 10 mm from the wall of the vessel. Except in the case 75
  • of single sampling, add a volume of the sampleswithdrawn. Where two or more tablets are directed to beplaced together in the apparatus, carry out six replicatetests.For each of the tablet tested, calculate the amount ofdissolved active ingradient in solution as a percentage ofthe stated amount. Where two or more tablets are placedtogether, determine for each test the amount of activeingradient in solution per tablet and calculate as apercentage of the stated amount.Acceptance criteriaConventional-release dosage formsUnless otherwise specified, the requirements aremet if the quantities of active substance dissolvedfrom the dosage units conform to table 1. If theresults do not conform to the requirement at stageS1 given in table, continue testing with additionaldosage units through stages S2 and S3 unless theresults conform at stage s2. Table 1 NumberStage Tested Acceptance Criteria S1 6 Each unit is not less than D*+ 5%. S2 6 Average of 12 units (S1 + S2) is equal to or greater than D, and no unit is less than D* 15%. S3 12 Average of 24 units (S1 + S2 + S3) is equal 76
  • NumberStage Tested Acceptance Criteria to or greater than D, not more than 2 units are less than D 15%, and no unit is less than D 25%.*D is the amount of dissolved active ingradientspecified in the individual monograph, expressed asa percentage of the labeled content.**Percentages of the labeled content. Table 2 NumberStage Tested Acceptance Criteria L1 6 No individual value lies outside each of the stated ranges and no individual value is less than the stated amount at the final test time. L2 6 The average value of the 12 units( L1 +L2) lies within each of the stated ranges and is not less than stated amount at the final test time, none is more than 10 per cent of the labeled content outside each of the stated ranges and none is more than 10 percent of labeled amount below the stated amount of final test time. L3 12 The average value of the 24 units (L1 + L2 + L3) Lies within each of the stated ranges, and is not less than the stated amount at the final test time; not more than 2 of 24 77
  • NumberStage Tested Acceptance Criteria units are more than 10 per cent of labeled content outside each of the stated ranges; not more than 2 of the 24 units are more than 10 percent of labeled content below the stated amount at the final test time; and none of the units is the more than 20 per cent of labeled content outside each of the stated ranges or more than 20 per cent of labelled content below the stated amount at the final test time.Prolonged-release dosage formsUnless otherwise specified, the requirements are met ifthe quantities of acive substance dissolved from thedosage units conform to table 2. If the result do notconform to the reuirements at stage L1given in the table,continue testing with additional dosage units throughstages L2 and L3 unless unless the test conform at stageL2. The limits embrace each value of D, the amountdissolved at each specified dosing interval.Modified-release dosage forms. Use method A or MethodB.Method AAcid stage. Place 750 ml of 0.1 M hydrochloric acid in thevessel, and assemble the apparatus. Warm the dissolutionmedium to 36.5o to 37.5 o. Place one dosage unit in theapparatus, cover the vessel and operate the apparatus atthe specified rate. After 2 hours of operation in the acidic 78
  • medium, withdraw an aliquot of the liquid and proceedimmediately as directed under buffer stage. Perform theanalysis of aliquot using suitable assay method.Buffer stage. Complete the operations of adding the bufferand adjusting the pH within 5 minutes. With the apparatusoperating at the rate specified, add to the medium invessel 250 ml of a 0.2 m solution of trisodium phosphatedodecahydrate that has been warmed to 36.5o to 37.5 o.adjust if necessary with 2M hydrochloric acid or 2Msodium hydroxide to a Ph of 6.8± 0.05.Method BAcid stage. Place 1000 ml of 0.1 M hydrochloric acid in thevessel, and assemble the apparatus. Warm the dissolutionmedium to 36.5o to 37.5 o. Place one dosage unit in theapparatus, cover the vessel and operate the apparatus atthe specified rate. After 2 hours of operation in the acidicmedium, withdraw an aliquot of the liquid and proceedimmediately as directed under buffer stage. Perform theanalysis of aliquot using suitable assay method.Buffer stage. Use buffer that has previously been warmedto36.5o to 37.5 o. Drain the acid from the vessel and add 1000ml of pH 6.8 buffer, prepared by mixing 3 volumes of 0.1Mhydrochloric acid with 1 volume of 0.2 M solution oftrisodium phosphate dodecahydrate and adjusting, if nenecessary with 2M hydrochloric acid or 2M sodiumhydroxide to a Ph of 6.8± 0.05. Continue to operate theapparatus for 45 minutes Or for specified time. At the end ofthe period, withdraw an aliquot of the liquid and perform theanalysis aliquot using suitable assay method. 79
  • Acceptation criteriaAcid stage. Unless otherwise specified, the requirements ofthis part of the test are met if the quantities, based on thepercentage of labelled content of active substancedissolved from the units tested conform to table 3.Continue the testing through the 3 levelsunless the results of both acid and bufeer stages conformat an earier level. Table 3 NumberStage Tested Acceptance Criteria A1 6 No individual value exceeds 10 per cent dissolved. A2 6 Average of 12 units (A1 + A2) is not more than 10 per cent dissolved, and no individual unit is greater than 25 per cent dissolved. A3 12 Average of 24 units (A1 + A2+ A3) is not more than 10 per cent dissolved, and no individual unit is greater than 25 per cent dissolved.Buffer stage. Unless otherwise specified, the requirementsof this part of the test are met if the quantities, based onthe percentage of the labelled content of active substancedissolved from the units tested conform to table 4.Continue the testing through 3 level unless the test of bothacid and buffer stages conform at an earlier level. Thevalue of D in table 4is 75 per cent dissolved unlessotherwise specified. The quantity D is specified total 80
  • amount of active substance dissolved in both the acid andbuffer stages, expressed as a percentage of the labelledcontent. Table 4 NumberStage Tested Acceptance Criteria S1 6 Each unit is not less than D*+ 5%. S2 6 Average of 12 units (S1 + S2) is equal to or greater than D, and no unit is less than D* 15%. S3 12 Average of 24 units (S1 + S2 + S3) is equal to or greater than D, not more than 2 units are less than D 15%, and no unit is less than D 25%. 81
  • RefrencesText book of Industrial pharmacy Theory andPratice by Leon and lachman.Dispensing pharmacy by Copper and Gunn.Indian pharmacopeia 2005.Usp pharmacopeia.www.wikipedia.comwww.google.comwww.ncbi.com 82