What is a tablet ?Submitted by on Sun, 11/15/2009 - 22:55 What will you gain?

1.1 Why do we need toconvert an active pharmaceutical ingredient into a suitable dosage form?

1.2What is a tablet?

1.3 Advantages anddisadvantages of tablet as a dosage form

1.1 Why do we need to convert an active pharmaceutical ingredient into asuitable dosage form? (1-5)

Active pharmaceutical compounds (drugs) are used for the treatment of a diseaseor for prophylactic purpose. An Active Pharmaceutical Ingredient (API) mayexist in solid, liquid or semisolid form. They are rarely prescribed to thepatients as such i.e. without adding excipients, since the desired effectmay not be obtained. Earlier, it was thought that excipients are inert innature but, in recent time it is well known that excipients can greatly modifythe intended effect of a drug. The API and excipients are suitably processedin pharmaceutical industry to convert them into dosage forms such as tablet,capsule, suspension, solution, etc. The selection of excipients and processingof drug excipients mixture is as important as API itself.

Patient acceptability can be improved by controlling the organoleptic properties.Dosage form provides desired therapeutic level of a drug.

1.2 What is a tablet? (1-5)

It is a solid dosage form each containing a unit dose of one or more medicament/s.Tablets are solid, flat or biconvex discs prepared by compressing a drug or amixture of drugs with or without suitable excipients.

Tabletsmay be swallowed whole or being chewed. Some are dissolved or dispersed inwater before administration. Some are put in oral cavity, where the activeingredient is liberated at a predetermined rate. Implants or passeries may alsobe presented in form of tablet.

Tablet may vary in shape and differ greatly in size and weight depending onthe amount of medicinal substance and the intended mode of administration.

1.3 Advantages and disadvantages of tablet as a dosage form. (1-5)

The advantages are listed below:

I.Large scalemanufacturing is feasible in comparison to other dosage forms. Therefore,economy can be achieved.

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 tablet department.

VI. Ease of packaging (blister or strip) and easyhandling over liquid dosage form.

VII. Easy totransport in bulk. Emergency supply supplies can be carried by patients.

VIII.Organolepticproperties (taste, appearance and odour) are best improved 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. self administration ispossible.

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 a tablet of suitable sizefor human use.

II.Difficult toformulate a drug with poor wettability, slow dissolution into 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.

VI. Patients undergoing radiotherapy cannot swallowtablet.

Key Phrases

Ø Reasons to go for dosage form

i) To control organoleptic properties

ii) Achieve desired therapeutic level of drug

Ø The most widely used dosage form is tablet

Ø  Advantages

i) Accurate dose

ii) Tailor made release profiles

iii) Longer expiry period

iv) Stringent environmental condition is NOT required

v) Easy handling

Ø Disadvantages

i) Slow onset of action

ii) Large amount of liquid cannot be incorporated

iii) Difficulty in swallowing especially for geriatric and pediatric patients

Types of tabletsSubmitted by on Sun, 12/06/2009 - 19:49

1.4 Types of Tablets

What will you gain?

1.4.1 Oral tablets foringestion

1.4.2 Tablets used in theoral cavity

1.4.3 Tabletsadministered by other routes

1.4.4 Tablets used toprepare solution

With advancement in technology and increase in awareness towards modification instandard tablet to achieve better acceptability as well as bioavailability,newer and more efficient tablet dosage forms are being developed. The mainreasons behind formulation of different types of tablets are to create adelivery system that is relatively simple and inexpensive to manufacture,provide the dosage form that is convenient from patient’s perspective andutilize an approach that is unlikely to add complexity during regulatoryapproval process. To understand each dosage form, tablets here are classifiedby their route of administration and by the type of drug delivery system theyrepresent within that route.

Table.1. Various Types Of Tablets

1.4.1 ORALTABLETS FOR

INGESTION

1.4.1.1 Standardcompressed tablets

1.4.1.2 Multiplecompressed tablets

I. Compression coated tablet

II. Layered tablet

III. Inlay tablet

1.4.1.3 Modified Release tablet

1.4.1.4 Delayed action tablet

1.4.1.5 Targeted tablet

I. Floating tablet

II. Colon targeting tablet

1.4.1.6 Chewable tablet

1.4.1.7 Dispersible tablet

1.4.2 TABLETSUSED IN THE ORAL

CAVITY

1.4.2.1 Lozenges andtroches

1.4.2.2 Sublingual tablet

1.4.2.3 Buccal tablet

1.4.2.4 Dental cones

1.4.2.5 Mouth dissolvedtablet

1.4.3 TABLETSADMINISTERED BY

OTHER ROUTES

1.4.3.1 Vaginal tablet

1.4.3.2 Implants

1.4.4 TABLETSUSED TO PREPARE

SOLUTION

1.4.4.1 Effervescenttablet

1.4.4.2 Hypodermic tablet

1.4.4.3 Soluble tablet

1.4.1 Oral tablets for ingestion (1-3)

These tablets are meant to be swallowed intact along witha sufficient quantity of potable water. Exception is chewable tablet. Over 90%of the tablets manufactured today are ingested orally. This shows that thisclass of formulation is the most popular world wide and the major attentionof the researcher is towards this direction.

1.4.1.1 Standard compressed tablets

These are the standard uncoated tablets made by either direct compressionor wet granulation or dry granulation or double compaction.

1) Figure.1. Standard Compressed Tablet

They may be used for local action in gastro-intestinal tract or systemic action.When the tablet exert local action, they are formulated as more water insolubleby means of selecting slow dissolving excipients and thus provides local actionfor long time period. e.g., antacids and adsorbents. The drugs that producesystemic action have some aqueous solubility and designed to disintegrate anddissolve quickly so that the drug can be quickly absorbed and produce systemicaction. Generally, an API exhibits bioavailability depending upon BiopharmaceuticalClass, which is based on water solubility and gastro-intestinal membrane permeabilitycriteria. But, it can be altered by appropriate selection of excipients andprocessing technology.

1.4.1.2 Multiple compressed tablets

The tablets in this category are prepared for two reasons: to separate physicallyor chemically incompatible ingredients and to produce repeat action/ prolongedaction tablet.

The tablet manufacturing machine is generally operated at relatively lowerspeed than for standard compression tablet. There are three categories underthis class:

I.Layered tablets – two to three component system.

II.Compression coated tablets – tablet within a tablet.

III.Inlay tablet – coat partially surrounding the core.

The layered tablet is preferred over compression coated tablet as the surfacecontact is less and the production is simple and more rapid.

I. Multilayered tablets

When two or more active pharmaceutical ingredientsare needed to be administered simultaneously and they are incompatible, thebest option for the formulation pharmacist would be to formulate multilayeredtablet. It consists of several different granulations that are compressed toform a single tablet composed of two or more layers and usually each layer isof different colour to produce a distinctive looking tablet. Each layer is fedfrom separate feed frame with individual weight control. Dust extraction isessential during compression to avoid contamination. Therefore, each layerundergoes light compression as each component is laid down. This avoidsgranules intermixing if the machine vibrates.

For example, admixture containing Phenylephedrin HCLand Ascorbic Acid with Paracetamol.

Paracetamol + phenylephedrine Hydrochloride → one layer

Paracetamol + ascorbic acid → another layer.

Figure.2. Multilayered Tablet

2) II. Compression coated tablets

This type of tablet has two parts, internal core and surrounding coat. Thecore is small porous tablet and prepared on one turret. For preparing finaltablet, a bigger die cavity in another turret is used in which first the coatmaterial is filled to half and then core tablet is mechanically transferred,again the remaining space is filled with coat material and finally compressionforce is applied. This tablet readily lend itself in to a repeat action tabletas the outer layer provides the initial dose while the inner core release thedrug later on. But, when the core quickly releases the drug, entirely differentblood level is achieved with the risk of over dose toxicity. To avoid immediaterelease of both the layers, the core tablet is coated with enteric polymer sothat it will not release the drug in stomach while, the first dose is addedin outer sugar coating. Even so, coating operation requires interpretation whilemanufacturing and dawdling the manufacturing process. Sometimes, inner coremay be of liquid formulation to provide immediate release of core after thecoat gets dissolved.

Figure.3. Compression Coated Tablet

III. Inlay tablets (4)

A type of layered tablet in which instead the coretablet being completely surrounded by coating, top surface is completelyexposed. While preparation, only the bottom of the die cavity is filled withcoating material and core is placed upon it. When compression force is applied,some coating material is displaced to form the sides and compress the wholetablet. It has some advantages over compression coated tablets:

i)Less coatingmaterial is required.

ii)Core is visible,so coreless tablets can be easily detected.

iii)Reduction in coating forms a thinner tablet and thus freedom from cappingof top coating.

Figure.4. Inlay Tablets

1.4.1.3 Modified Release tablets

The main aim behind formulation of this dosage form is to release the medicamentslowly for long time duration after administration of a single tablet.

Figure.5. Graphical Comparison Of Blood ConcentrationV/S Time

A widespread use of this type of tablet is seen in present scenario, as wellas many researchers have concentrated their attention in this direction. Thisis mainly because of improvement in patient’s compliance as the dosage frequencyis reduced, patient can take an undisturbed sleep at night, it’s also beneficialfor psychiatric patients who forget to take their tablets regularly and thedose related side effects and toxicities are reduced. Any adjuvant that canalter water uptake rate, swelling and gelling characteristics of Matrixing agentscan alter the release rate of API e.g., electrolytes in HPMC matrix tablet.It’s also possible to achieve pulsed drug release. Weakly basic drugs exhibitgood solubility at low pH while less soluble at high pH conditions, which canresult in incomplete drug release for sustained release formulations. The drugrelease can be modified by providing suitable micro environmental pH in thetablet e.g., acidic polymer, succinic acid, etc. Similarly, inclusion of alkalinepolymers results in desirable drug release of acidic drugs. On the other hand,formulation of this type of dosage form presents challenge for the formulator:increases the cost of manufacturing, chances of burst drug release and dropin drug release rate in terminal phase and thus incomplete release on API. Incase of accidental poisoning, the doctor has to deal with special treatment

problems. Due to large size, patient may feel difficulties in swallowing asthe matrixing agent to drug ratio is high. Classic approaches are usually basedon adaptation of either film coated or multiparticulate technologies or thoseinvolving slow release matrices.

Coating technology (6)

It combines semi permeable coatings and osmotic tablet cores to produce “zeroorder release” technology. Attention is also focused to trigger drug releaseat critical time point e.g., to achieve drug release 1 -2 hours before the patientawakens. Alza’s prolific research activities have yielded a technology called“Ringcap” which is based on a tablet, preferentially film coated, partiallycoated with a series of rings whose respective thickness provides the meansof moderating the rate at which the drug is released from final dosage form.

Figure.6. Ringcap (Coated) Tablet

Matrix technology

Classically matrix products exhibit first order (or perhaps square-root-of-time)drug release characteristics. In order to achieve zero order release characteristics,it’s necessary to employ specially designed materials or strategies that seekto manipulate tablet structure or geometry. Combination of conventional HPMCmatrix technology with upper and lower layer. This helps to moderate drug releaseby increase in surface area with concomitant reduction in drug concentrationwithin the device.

Figure.7. Matrix Tablet

Release of medicament can followvarious mechanisms (2)

i) Diffusion is rate limiting

Diffusion is driving force where the movement of drug molecules occurs fromhigh concentration in the tablet to lower concentration in gastro intestinalfluids. This movement depends on surface area exposed to gastric fluid, diffusionpathway, drug concentration gradient and diffusion coefficient of the system.

Figure.8. Diffusion Release Pattern

In practice, we can follow either of the two methods,

1.The drug is formulated in an insoluble matrix; the gastric fluid penetratesthe dosage form and dissolves the medicament and release the drug through diffusion.

2.The drugparticles are coated with polymer of defined thickness so as the portion ofdrug slowly diffuse through the polymer to maintain constant drug level inblood.

ii)Dissolution is rate limiting

The drugs with poor water solubility (BCS class 2 and4) are inherently sustained release forms. While for water soluble drugs, it’spossible to incorporate a water insoluble carrier to reduce dissolution of thedrug particles are coated with this type of materials e.g. Polyethylene Glycol.One may skip the use of disintegrating agent to promote delayed release.

iii) Osmotic pressure is rate limiting

Osmosis is a phenomenon in which the flow of liquidoccurs from lower concentration to higher concentration through a semipermeable membrane which allows transfer of liquid only. The whole drug iscoated with a semi permeable membrane with a hole on one end of tablet made bya laser beam. The gastric fluid penetrates through the membrane, solubilizesthe drug and increases the internal pressure which pumps the drug solution outof the aperture and releases the drug in gastric environment. The delivery rateis constant provided that the excess of drug present inside the tablet. But, itdeclines to zero once the concentration drops below saturation.

Figure.9. Osmotic Release Pattern

iv) Release is controlled by ion exchange

Ion exchangers are water insoluble resinous materialscontaining salt forming anionic or cationic groups. While manufacturing, thedrug solution is mixed with resin and dried to form beads which are tableted.The drug release depends upon high concentration of charged ions in gastrointestinal tract where, the drug molecules are exchanged and diffused out ofthe resin into the surrounding fluid. This mechanism relies upon the ionicenvironment of resin and not pH or enzyme on absorption site.

1.4.1.4 Delayed action tablets

Enteric coated tablet is such an example of delayed action tablet. Thisformulation is preferred when,

i)The APIirritates gastric mucosa e.g., aspirin or strong electrolytes

ii)Drugs that produce nausea and vomiting.

iii)API is sensitive to low pH e.g., erythromycin

iv)When it’s necessary to release the drug undiluted. e.g.,intestinal antibacterial, antiseptic agents, intestinal vermifuge, etc.

The commonly used coating agents are: Celluloseacetate phthalate, Hydroxy methyl propyl phthalate, polyvinyl acetatephthalate, Eudragit®, etc. This dosage form is intended to hydrateand begin to dissolve in duodenum (pH 4 to 6) or in small intestine where pHincreases to 7 to 8. The presence of esterases or bile salts like surfaceactive agents plays a role in drug release.

1.4.1.5 Targeted tablets

When we need to release the API at a specific site inthe elementary tract, targeted drug delivery is a preferred option. Dependingupon the composition and release mechanism of a tablet, the drug is deliveredto a particular region. Under this category, we have two types of tablet:

I. Gastro retentive Tablet

This type of dosage form is to be opted when APIrelease is desired in stomach (Antacids, APIs used against H.pylori infection)or site of absorption is either stomach or upper part of small intestine.

Figure.10. Floating Tablet

To retain the drug for longer time period in stomach,following approaches can be used:

i) Low density tablet (effervescent or noneffervescent)

ii) Tablets that can expand in gastricenvironment (swelling or by unfolding) and thus increasing the size so that itcannot cross the pyloric sphincter.

iii) Using mucoadhesivepolymers that stick to mucosa of stomach and provide slow drug release.

Supine position is to beavoided and also high level of fluid is necessary or if the swellingformulation leaves stomach before it swells it’s ineffective. Drugs like Diazepam, Levodopa, Benserazide,and Ciprofloxacin are successfully marketed in this formulation.

II. Colonic tablets (7,8)

When the aim is to deliver the drug into colonwithout dilution in other regions of gastrointestinal tract or the drug haspoor absorption in stomach or small intestine, colonic drug delivery is ananswer of choice. The pH in this region varies from 6.4 - 7 and presence ofmicrobial flora plays as important role in drug release especially in thisregion. Various mechanisms are adopted for drug release in this area are coating with pH sensitivepolymer e.g., Eudragit®S100, Eudragit® L100,biodegradable polymer like polymers which are sensitive to colonic bacteria,bioadhesive polymers which selectively sticks to colonic mucosa e.g.,polycarbophils or polyethans, redox sensitive polymers that respond to redoxpotential in colon which expresses the total metabolic and bacterial action.

1.4.1.6 Chewable tablets

The patients who have difficulty in swallowingtablets whole or for children who have not yet learnt to swallow a tablet,chewable tablet serves as an attractive alternative. The added advantage ofthis medication is that it can be taken at any time or when water is not available.Mannitol is normally used as a base due to low hygroscopy and more importantly,

it gives pleasant, cooling sensation. Antacid tablets are invariably preparedas chewable to obtain quick ingestion relief as well as the antacid dose is toolarge to swallow and the activity is related to particle size. Another exampleis multivitamin tablet which a patient can take as a daily dose.

1.4.1.7 Dispersible tablet (9)

These tablets disintegrate either rapidly in water,to form a stabilized suspension, or disperse instantaneously in the mouth to beswallowed without the aid of water. So, it’s preferred for pediatric patientswho cannot swallow a solid dosage form and the API is unstable if formulated inliquid formulation. Also helpful for patients having prolonged illness who areprone to nauseatic sensations if they have to swallow a tablet. The addedadvantage of this formulation is faster onset of action as compared to standardcompressed tablet. The properties of the water dispersible tablet, such as porosity,hardness, disintegration time and increase in viscosity after dispersion arenecessary to investigate during manufacturing which decides the productperformance. The common examples of API formulated in this dosage form areanalgesics e.g., aspirin, ibuprofen, etc.

1.4.2 Tablets used in the oral cavity (1-3)

The tablets under this group are aimed release API inoral cavity or to provide local action in this region. The tablets under thiscategory avoids first-pass metabolism, decomposition in gastric environment,nauseatic sensations and gives rapid onset of action. The tablets formulatedfor this region are designed to fit in proper region of oral cavity.

1.4.2.1 Lozenges and troches

The tablet is a flat faced at least about 18mm indiameter and meant to suck and dissolves in the mouth. The compressed tablet iscalled troches and the tablets produced by fusion or candy molding process arecalled lozenges. Flavours and sweeteners are added to make tablets palatable.The tablet generally contains sucrose or lactose and gelatin solution to impartsmooth taste. Lozenges for local action in mouth/ throat are: antiseptics,antibiotics, demulcents, antitussive agents or astringents. To produce systemicaction: multivitamin tablet.

1.4.2.2 Sublingual tablets

They are to be placed under the tongue and produceimmediate systemic effect by enabling the drug absorbed directly throughmucosal lining of the mouth beneath the tongue.

Figure.11. Sublingual Tablets

The drug absorbed from stomach goes to mesentericcirculation which connects to stomach via portal vein. Thus, absorption throughoral cavity avoids first-pass metabolism. The tablets are usually small andflat, compressed lightly to keep them soft. The tablet must dissolve quicklyallowing the API to be absorbed quickly. It’s designed to dissolve in smallquantity of saliva. After the tablet is placed in the mouth below the tongue,the patient should avoid eating, drinking, smoking and possibly talking inorder to keep the tablet in place. Swallowing of saliva should also be avoidedsince the saliva may contain dissolved drug. Bland excipients are used to avoidsalivary stimulation. Due to inconvenience in administration, this dosage formis prepared only for those API(s) for which the only satisfactory nonparenteralmethod is this route. For example, Glyceryl trinitrate (vasodilator) andIsoprinosine sulphate (bronchodilator).

1.4.2.3 Buccal tablets

Completeness of drug absorption is desired but fast drug absorption is notintended. The tablets are designed not to disintegrate. They are flat ellipticalor capsule shaped tablets as it can be easily held between gum and cheek. It’splaced near the opening of parotid duct to provide the medium to dissolve thetablet.

Figure.12. Buccal Tablets

Since this tablet is to be kept for 30-60 minutes inoral cavity, care should be taken to see that all the ingredients are finelydivided to avoid gritty or irritating sensation. This tablet is most often usedwhen replacement hormonal therapy is to be administered. Antifungal drugs arepreferred to be administered by this route. e.g., Miconazole – underpreclinical trial – still not in market.

1.4.2.4 Dental cones

These tables are designed to be loosely packed in theempty socket remaining following a tooth extraction.

Figure.13. Dental Cones

Main purpose behind the use of this tablet is eitherto prevent multiplication of bacteria in the socket by employing a slowreleasing antibacterial compound or to reduce bleeding by an astringent orcoagulant containing tablet. It’s formulated to dissolve or erode slowly inpresence of a small volume of serum or fluid over 20-40 minutes period.

1.4.2.5 Mouth Dissolved tablets/ Rapidly Dissolving tablets (10)

Known to the FDA as orally disintegrating tablets,they are also called mouth-dissolving, fast-dissolving, rapid-melt, porous,orodispersible, quick dissolving. These kinds of tablets are preferred whenfast action or relief is desired. Most commonly used drugs under thisformulation are the agents active against Migraine. The tablets are designed todisintegrate as well as dissolve within one minute or some within 10 seconds oforal administration in limited quantity of saliva. They liquefy on tongue andpatient swallows the liquid, without the need of water. A number of techniquesare used to prepare these tablets, including lyophilization, soft directcompression. Matrices having an API and high porosity are also being preparedusing sublimation process. Urea, urethane, ammonium carbonate, ammoniumbicarbonate, hexamethylene, benzoic acid, naphthalene and camphor are commonlyused for sublimation processing as they they volatize rapidly. After removal bysublimation, these inert volatile substances leave the matrices with a highporosity. Disintegrants and sugar based excipients, such as sodium starchglycolate, cross carmellose sodium, mannitol, xylitol, dextrose, fructose,maltose and polydextrose have been incorporated in almost all the orallydisintegrating dosage forms (ODDFs). Loading of drug is made by preparing ablank and drug is post loaded. Generally the drug in solution is added afterwhich the solvent evaporates. Taste masking poses numerous challenges since thedrug product dissolves in mouth, any taste of drug must be covered, either byflavoring technique or by micro encapsulation or nanoencapsulation. A majordrawback of most of these systems is that the packaging system needs a higherdegree of protection due to the lower hardness and more friability of theporous nature of tablets, except the DuraSolv technology of CIMA Labs, whichare suitable for rigors of bulk bottle packaging. Keep the orally disintegrating tablet in theblister pack inside the outer foil pouch until the patient is ready to take themedicine. Make sure that operator’s hands are dry and peel open the blister toremove the tablet. Place the tablet on tongue and let it dissolve. These dosageforms have become a delivery system of choice for most patients as they providecomfort for administration throughout the day. Pharmaceutical companies, on the

other hand, benefit from value addition in terms of product life-cyclemanagement in today’s market.

1.4.3 Tablets administered by other routes (1-3)

These tablets are administered by other route exceptfor the oral cavity and so the drugs are avoided from passing through gastrointestinal tract. These tablets may be inserted into other body cavities ordirectly placed below the skin to be absorbed into systemic circulation fromthe site of application.

1.4.3.1 Vaginal tablets

This tablet undergoes slow dissolution and drugrelease in vaginal cavity of women. The shape is kept ovoid or pear shaped tofacilitate retention in vagina. The tablet should be made compatible withplastic tube inserters which are designed to place the tablet in the upperregion of vaginal tract. These tablets generally release antibacterial,antiseptics or astringents to treat vaginal infections or release steroids forsystemic absorption.

1.4.3.2 Implants

These tablets are inserted into subcutaneous tissueby surgical procedures where they are very slowly absorbed over a period of amonth or a year. A special injector with a hollow needle and plunger is used toadminister the rod shaped tablet for other shapes, surgery is required. Thetablets may be pellet, cylindrical or rosette shaped with diameter not morethan 8mm. They are sterile formulation without excipients and made hard withlarge particle size to achieve gradual drug release. The tablets are producedby a sterile single punch hand operated machine in which the die cavity isfilled with hand since the material does not normally flow well. Mainly, thesetablets are prepared to deliver growth hormones to food producing animals andear is the preferred site for administration of the drug.

1.4.4 Tablets used to prepare solution

The tablets under this category are required to bedissolved first in water or other solvents before administration orapplication. This solution may be for ingestion or parenteral application orfor topical use depending upon type of medicament used.

1.4.4.1 Effervescent tablets (11)

The oral dosage forms are the most popular way oftaking medication despite having some disadvantages like slow absorption andthus onset of action is prolong. This can be overcome by administrating thedrug in liquid from but, many APIs have limited level of stability in liquidform. So, effervescent tablets acts as an alternative dosage form. The tabletis added into a glass of water just before administration and the drug solution

or dispersion is to be drunk immediately. The tablet is quickly broken apart byinternal liberation of CO2 in water due to interaction betweentartaric acid and citric acid with alkali metal carbonates or bicarbonates inpresence of water.

Figure.14. Effervescent Tablets

Due to liberation in CO2 gas, thedissolution of API in water as well as taste masking effect is enhanced. Theadvantages of effervescent tablets compared with other oral dosage formsincludes an opportunity for formulator to improve taste, a more gentle actionon patient’s stomach and marketing aspects. To manufacture these tablets,either wet fusion or heat fusion is adopted. The tablets are compressed softenough to produce an effervescent reaction that is adequately rapid. Watersoluble lubricants are used to prevent an insoluble scum formation on watersurface. To add sweetness to the formulation, saccharin is added since sucroseis hygroscopic and add too much of bulk to the tablet. The manufacturing shallbe done under controlled climatic condition to avoid effervescent reaction. Thepackaging is done under 25% RH at 25ºC. Hands of the consumers and atmosphericmoisture after opening the container can also result in loss of productquality. The most commonly used effervescent tablet today is aspirintablet.

1.4.4.2 Hypodermic tablets

These tablets contain one or more readily watersoluble ingredients and are intended to be added in water for injection ofsterile water to form a clear solution which is to be injected parenterally.They were widely used by rural physician due to its portability. One bottle ofsterile water was carried by the doctor to prepare many types of injectables.It can be used for medicaments whose stability in water is very poor.

1.4.4.3 Soluble tablets (12)

Tablets are pre-formedsolids of uniform shape and dimensions, usually circular, with either flat orconvex faces, the distance between faces being less than the diameter. Watersoluble tablets are intended for application after dissolution in water andcontain an active ingredient should be totally soluble in water at usedconcentrations. All the excipients used to formulate these tablets are requiredto be completely soluble in water including the glidants, binders, etc. So,

manufacturing of this kind of tablets are challenge for the formulator.Companies manufacturing these tablets have patented them.

Figure.15. Soluble Tablets

Key Phrases

Ø When two or more active pharmaceutical ingredients are needed to be administeredsimultaneously and they are incompatible, the best option for the formulationpharmacist would be to formulate multilayered tablet.

Ø When we need to release the medicament slowly for long time duration afteradministration of a single tablet we go for modified release formulation.

Ø When we need to release the API at a specific site in the elementary tract,targeted drug delivery is a preferred option.

Ø Dispersible tablets disintegrate either rapidly in water, to form astabilized suspension, or disperse instantaneously in the mouth to beswallowed without the aid of water

Ø Sublingual tablet is designed to dissolve in small quantity of saliva andused when immediate action within few minutes is desired.

Ø Buccal tablet is most often used when replacement hormonal therapy is tobe administered.

Ø Implants are inserted into subcutaneous tissue by surgical procedures wherethey are very slowly absorbed over a period of a month or a year.

Formulation of tabletsSubmitted by on Sun, 12/06/2009 - 19:50

1.5 Formulation

Ø What will you gain?

1.5.1

Excipient and their functionalities

1.5.2Diluents

1.5.3Binders

1.5.4Disintegrants

1.5.5Antifrictional Agents

1.5.6Miscellaneous Excipients

1.5.1 Excipient and their functionalities (13-15)

Excipient means anycomponent other than the active pharmaceutical ingredient(s) intentionallyadded to the formulation of a dosage form. Many guidelines exist to aid inselection of non toxic excipients such as IIG (Inactive Ingredient Guide), GRAS(Generally Regarded As Safe), Handbook of Pharmaceutical Excipients and others.

While selecting excipientsfor any formulation following things should be considered wherever possible:keep the excipients to a minimum in number minimize the quantity of eachexcipients and multifunctional excipients may be given preference overunifunctional excipients.

Excipients play a crucial role in design of thedelivery system, determining its quality and performance. Excipients thoughusually regarded as nontoxic there are examples of known excipient inducedtoxicities which include renal failure and death from diethylene glycol,osmotic diarrhoea caused by ingested mannitol, hypersensitivity reactions fromlanolin and cardiotoxicity induced by propylene glycol.

Excipients are chosen intablet formulation to perform a variety of functions like

i) For providing essential manufacturing technology functions (binders, glidants,lubricants may be added),

ii) For enhancing patient acceptance (flavors, colourants may be added),

iii) For providing aid in product identification (colourants may be added),

iv) For Optimizing or modifying drug release (disintegrants, hydrophilic polymers,wetting agents, biodegradable polymers may be added),

v) For enhancing stability (antioxidant, UV absorbers may be added)

Various excipients used in tablet formulation and their functionalities.(1, 4, 16)

Table.2. Excipient With Their Functions In Tablet Formulation

EXCIPIENT FUNCTION

Diluents or Fillers Diluentsmake the required bulk of the tablet when the drug dosage itself is inadequateto produce tablets of adequate weight and size.

Binders or Granulatingagents or Adhesives

Bindersare added to tablet formulations to add cohesiveness to powders, thusproviding the necessary bonding to form granules, which under compaction forma cohesive mass or a compact which is referred to as a tablet.

Disintegrants Adisintegrant is added to most tablet formulations to facilitate a breakup ordisintegration of the tablet when placed in an aqueous environment.

Antifrictional Agents

Lubricants Lubricantsare intended to reduce the friction during tablet formation in a die and alsoduring ejection from die cavity.

Antiadherents Antiadherentsare added to reduce sticking or adhesion of any of the tablet granulation orpowder to the faces of the punches or to the die wall.

Glidants Glidantsare intended to promote the flow of tablet granulation or powder mixture fromhopper to the die cavity by reducing friction between the

particles.

MISCELLANEOUS

Wetting agents Wetting agents are added to tablet formulation to aid water uptake duringdisintegration and assist drug dissolution.

Dissolution retardants Dissolutionretardants as the name suggest, retards the dissolution of activepharmaceutical ingredient(s).

Dissolution enhancers Dissolutionenhancers as the name suggest, enhance the dissolution rate of activepharmaceutical ingredient(s).

Adsorbents Adsorbentsare capable of retaining large quantities of liquids without becoming wet;this property of absorbent allows many oils, fluid extracts and eutecticmelts to be incorporated into tablets.

Buffers Buffersare added to provide suitable micro environmental pH to get improvedstability and / or bioavailability.

Antioxidants Antioxidantsare added to maintain product stability, they act by being preferentiallyoxidized and gradually consumed over shelf life of the product.

Chelating agents Chelatingagents are added to protect against autoxidation; they act by formingcomplexes with the heavy metal ions which are often required to initiate oxidativereactions.

Preservatives Preservativesare added to tablet formulation in order to prevent the growth ofmicro-organisms.

Colours Coloursare added to tablet formulation for following purposes: to disguise offcolour drugs, product identification and for production of more elegantproduct.

Flavours Flavoursare added to tablet formulation in order to make them palatable enough incase of chewable tablet by improving the taste.

Sweeteners Sweetenersare added to tablet formulation to improve the taste of chewable tablets.

 

Ø Key Phrases

Ø Tablet formulations are usually designed to satisfy following criteria-Patient acceptability; accuracy and uniformity of drug content;manufacturability; optimal drug dissolution and stability.

Ø Excipients are any component other than active pharmaceutical ingredient(s)intentionally added to the formulation of a dosage form.

Ø Excipients play a crucial role in design of the delivery system, determiningits quality and performance.

Ø Various excipients used in tablet formulation are diluents, binders, disintegrants,lubricants, antiadherents, glidants, wetting agents, dissolution retardants,dissolution enhancers, absorbents, buffers, antioxidants, chelating agents,preservatives, colours, flavours, sweeteners, etc.

1.5.2 Diluents (Fillers)

What will you gain?

1.5.2.1Introduction

1.5.2.2Classification of diluents

1.5.2.2.1 Organic diluents

1.5.2.2.2 Inorganic diluents

1.5.2.2.3 Co-processed diluents

1.5.2.1 Introduction (1, 17)

In order to facilitate tablethandling during manufacture and to achieve targeted content uniformity, thetablet size should be kept above 2-3 mm and weight of tablet above 50 mg. Manypotent drugs have low dose (for e.g. diazepam, clonidine hydrochloride) in suchcases diluents provide the required bulk of the tablet when the drug dosageitself is inadequate to produce tablets of adequate weight and size. Usuallythe range of diluent may vary from 5-80%. Diluents are also synonymously knownas fillers. Diluents are often added to tablet formulations for secondaryreasons like to provide better tablet properties such as:

i)To provide improved cohesion

ii)To allow direct compression manufacturing

iii)To enhance flow

iv)To adjust weight of tabletas per die capacity

No matter for what purpose they (diluents) are addedthey must meet certain basic criteria for satisfactory performance in tabletdosage form. They are as follows:Diluent should not react with the drug substance and moreover it shouldnot have any effect on the functions of other excipients, it should not haveany physiological or pharmacological activity of its own, it should haveconsistent physical and chemical characteristics, it should neither promote norcontribute to segregation of the granulation or powder blend to which they areadded, it should be able to be milled (size reduced) if necessary in order tomatch the particle size distribution of the active pharmaceutical ingredient,it should neither support microbiological growth in the dosage form norcontribute to any microbiological load, it should neither adversely affect thedissolution of the product nor interfere with the bioavailability of activepharmaceutical ingredient, it should preferably be colourless or nearly so.

1.5.2.2 Classification of diluents (16,17)

Tabletdiluents or fillers can be divided into following categories:

i)Organic materials - Carbohydrate and modified carbohydrates.

ii)Inorganic materials – Calcium phosphates and others.

iii)Co-processed Diluents.

Carbohydrate substances such as sugars, starches and celluloses may also functionas binders during wet granulation process. Whereas when used in direct compressionsystem, they serve as the diluent. The inorganic diluents, do not exhibit bindingproperties when used in wet granulation and direct compression.

Tablet diluent or fillermay also be classified on the basis of their solubility in water as soluble andinsoluble.

Table.3. Classification Of Diluents Based On Their Solubility

INSOLUBLE TABLET FILLERS OR DILUENTS

SOLUBLE TABLET FILLERS OR DILUENTS

Starch

Powderedcellulose

Microcrystallinecellulose

Calciumphosphates, etc.

Lactose

Sucrose

Mannitol

Sorbitol,etc.

Selection of diluent shouldbe done after considering properties of diluent such as: Compactibility,flowability, solubility, disintegration qualities, hygroscopicity, lubricityand stability.

1.5.2.2.1 Organic diluents (1,17-20)

Carbohydrates

Sugar and Sugaralcohols

Lactose α-lactosemonohydrate, spray dried lactose and anhydrous lactose are widely used asdiluent.

Characteristics of α -Lactosemonohydrate (hydrous)Lactosemonohydrate is not directly compressible and therefore it is suitable for use

in wet granulation.

Ithas poor flow properties.

α-lactosemonohydrate is water soluble.

Itproduces a hard tablet and the tablet hardness increases on storage.

Disintegrantis usually needed in lactose containing tablets.

Drugrelease rate is usually not affected.

Itis usually unreactive, except for discoloration when formulated with aminesand alkaline materials (i.e. browning or maillard reaction).

Itcontains approximately 5% moisture and hence is a potential source ofinstability especially with moisture sensitive drugs.

Itis inexpensive.

Itis commercially available under the trade name of: PharmatoseÒ and Respitose® manufactured by DMV International.

Characteristics ofLactose spray driedIt is directlycompressible diluent.

It exhibits free flowingcharacteristics.

It needs high compressionpressures in order to produce hard tablets.

Its compressibility isadversely affected if dried below 3% moisture.

It has high dilutionpotential.

It is more prone todarkening in the presence of excess moisture, amines and other compounds dueto the presence of a furaldehyde.

Usually, neutral or acidlubricant should be used when spray dried lactose is employed.

Expensive compared toanhydrous and hydrous lactose.

It is commerciallyavailable as Spray Process 315® manufactured by Foremost FarmsUSA.

Characteristics ofLactose anhydrousLactose anhydrous is adirectly compressible diluent.

It does not exhibit freeflowing property.

It can pick up moisture atelevated humidity as a result of which changes in tablet dimensions may occur.

It does not undergo amaillard reaction to the extent shown by spray dried lactose, although thismay occur in some cases to a slight degree.

It is inexpensive.

It is commerciallyavailable as Pharmatose® DCL 21 manufactured by DMV Pharma.

Starch

Characteristics of Compressible Starch(Pregelatinized)Itis a directly compressible diluent.

Ithas better flow compared to unmodified starch.

Italso shows high compressibility as the aggregated granules undergo plastic

deformation on compression.

Itpossesses good binding properties.

Italso possesses disintegrant activity.

Itrequires high pressure in order to produce a hard tablet.

Forgood flow, it requires a flow promoter.

Itis prone to softening when combined with large amounts of magnesium stearate.

Itis commercially available under the trade name of Starch 1500 LMÒ manufactured by Colorcon.

Sucrose

Characteristics of Sucrose or sugarItrequires high machine pressures, especially in cases with over wettedgranulations.

Itis water soluble.

Itpossesses good binding properties.

Itis slightly hygroscopic.

Itis inexpensive.

Itproduces gritty mouth feel (i.e., it is not free from grittiness).

Itis a calorie contributor and is cariogenic.

Mannitol

Characteristics of MannitolMannitola sugar alcohol is an optical isomer of Sorbitol.

Itexhibits poor flow properties.

Itrequires high lubricant content.

Itis probably the most expensive sugar used as a tablet diluent and is watersoluble.

Itis widely used in chewable tablets because of its negative heat of solution,its slow solubility and its mild cooling sensation in mouth.

Itcan be used in vitamin formulation, where moisture sensitivity may create aproblem.

Itis comparatively non hygroscopic.

Itis free from grittiness.

Itpossesses low caloric value and is noncariogenic.

Itis commercially available under the brand name ParteckÒM manufactured by EMD Chemicals .Other commercial products are PearlitolÒ and MannogemÒ.

Sorbitol

Characteristics of SorbitolSorbitol is often combinedwith mannitol formulations in order to reduce diluent cost.

It is highly compressiblediluent and is water soluble.

It is hygroscopic innature.

It has good mouth feel andsweet cooling taste.

It is free fromgrittiness.

It possesses low caloricvalue and is noncariogenic.

It is commerciallyavailable as SorbifinÒ and NeosorbÒ .

Poorlyabsorbed sugar alcohols such as Sorbitol and mannitol can decrease smallintestinal transit time. Therefore absorption may be altered for the drugs thatare preferentially absorbed from this region.

Celluloses (1,17,

21)

Powderedcellulose

Characteristics of Powdered cellulosePowdered celluloseproducts consist of finely divided amorphous and crystalline α-celluloseparticles.

Powdered cellulose may beused alone or together with other fillers such as lactose, calciumphosphates, dextrans and others.

It possesses poorcompressibility and exhibits poor flow properties.

It has poor bindingproperties and low dilution potential.

It is water insoluble.

It possesses some degreeof inherent lubricity.

It is inexpensive.

It is commerciallyavailable under the trade name of ElcemaÒG-250

manufactured by Degussa Corporation.

Microcrystallinecellulose

Characteristics of Microcrystalline celluloseMicrocrystalline cellulose(MCC) is highly compressible and is perhaps the most widely useddirect-compression tablet diluent.

Hard tablets, at lowcompression pressures, are usually obtained when MCC is used as tabletdiluent.

It undergoes plasticdeformation on compression and hence it is more sensitive to lubricants.

It exhibits fairflowability.

It exhibits bindingproperties.

It also possessesdisintegrant activity and thus promotes fast tablet disintegration.

It is water insoluble.

MCC is expensive.

Silicified MCC (SMCC-ProsolvÒ) provides increased compactibility, enhanced flowand improved uniformity compared to MCC (AvicelÒ manufactured by FMC Biopolymer)

SMCC is more suitable forcohesive poorly compressible ingredients in direct compression formulation.

Other commercial productis EmcocelÒ manufactured by Penwest Pharmaceutical Co.

1.5.2.2.2 Inorganic diluents (17,22)

Calcium phosphates

The calcium phosphates, here includes, the dihydrateand anhydrous form of dibasic calcium phosphate and tribasic calcium phosphate.

They are granular insoluble materials.They are widely used both as wet granulation and direct compressiondiluents in tablet formulation. Bulk density of calcium phosphates is higherthan that of organic fillers. They are used extensively in vitamin and mineralpreparations. Dibasic calcium phosphate dihydrate is also commonly known asdicalcium phosphate, calcium hydrogen phosphate dihydrate and secondary calciumphosphate dihydrate.

Dibasic calcium phosphate is available commerciallyunder the trade name Di-TabÒ (manufactured by Rhone-Poulenc) and EmcompressÒ (Manufactured by E.MendellCo.).An anhydrous form of dibasic calcium phosphate is available commerciallyunder the trade name A-TabÒ (manufactured by Rhone-Poulenc). Fujicalin®,a novel commercially available free flowing spherically granulated dicalciumphosphate anhydrous (SGDCPA) for direct tableting was compared with directlycompressible dicalcium phosphate dihydrate (DCPD) and it was found that SGDCPAexhibited same good flowability and better compactibility. Whereas in contrastto DCPD, SGDCPA exhibited significant uptake of moisture when exposed torelative humidity exceeding 70 %.Tribasic calcium phosphate is also commonlyreferred as tricalcium phosphate, tricalcium orthophosphate and hydroxyapatite.Tribasic calcium phosphate is available under the trade name Tri-TabÒ.

Characteristic ofCalcium PhosphatesThey are directlycompressible and are characterized by brittle fracture on compression duringtableting process.

Hard tablets are producedwhen calcium phosphates are used as diluents.

They exhibit good flowproperties.

They are non hygroscopic.

They are inexpensive.

They are abrasive innature and hence can cause wear of tablet tooling.

Sometimes their alkalinityis a major source of drug instability.

1.5.2.2.3 Co-processed diluents (17,23)

Co-processing means combining two or more materialsby an appropriate process. The products so formed are physically modified in

such a special way that they do not loose their chemical structure andstability. Now a days direct compression technique has been one of thewell-accepted methods of tablet manufacture. An extensive range of materials fromvarious sources have been developed and marketed as directly compressiblediluents such as lactose, starch, cellulose derivatives, inorganic substance,polyalcohols, and sugar-based materials. In addition to the development ofdirectly compressible excipients by modifying just a single substance,co-processing of two or more components has been applied to produce compositeparticles or co-processed excipients. The composite particles or co-processedexcipients are introduced in order to provide better tableting properties thana single substance or the physical mixture.

Table.4. List Of Co-Processed Excipients Used To AchieveBetter Tableting Properties

TRADE NAME MANUFACTURER DESCRIPTION

Fast Flo lactose® Foremost Whey Products

It is spray processedlactose which is a mixture of crystalline α-lactose monohydrate andamorphous lactose.

Microcellac®

   75% lactose and 25% MCC

(MicroCrystalline Cellulose)Ludipress®

   93% α-lactose

monohydrate, 3.5% polyvinylpyrrolidone, and 3.5% crospovidone.

Nu-Tab®

 Ingredient Technology Sucrose 95-97%, invert

sugar 3-4% and magnesium stearate 0.5%

Di-Pac®

 Amstar Corp. Sucrose 97% and modified

dextrins 3%Sugartab®

 E.Mendell Co. Inc. Sucrose 90-93% and invert

sugar 7-10%.

Emdex® E.Mendell Co. Inc. Dextrose 93-99% andmaltose 1-7%

Cal-Tab®

 Ingredient Technology Calcium sulfate 93% and

vegetable gum 7%

Cal-Carb®

 Ingredient Technology Calcium carbonate 95% and

maltodextrins 5%Calcium 90®

 Ingredient Technology Calcium carbonate

(minimum) 90% and Starch, NF (maximum) 9%

KeyPhrases

Ø Diluents make the required bulk of the tablet when the drug dosage itselfis inadequate to produce tablets of adequate weight and size.

Ø Diluents are often added to tablet formulations for secondary reasons liketo provide better tableting properties.

Ø Tablet diluents or fillers can be divided into following categories:

i) Organic materials

ii) Inorganic materials

iii) Co-processed diluents

Ø Tablet diluents or fillers may also be classified on the basis of theirsolubility in water as soluble diluent and insoluble diluent.

Ø Microcrystalline cellulose (MCC) is perhaps the most widely used direct-compressiontablet filler.

Ø Co-processing means combining two or more materials by an appropriateprocess.

Ø The composite particles or co-processed excipients are introduced to providebetter tableting properties than a single substance or the physical mixture.

1.5.3 Binders ( Adhesives, Granulating agent)

Whatwill you gain?

1.5.3.1 Why to go for Granulation?

1.5.3.2 GranulationProcesses

1.5.3.3 Types of Binders

1.5.3.4 Direct compression (DC) Binders

1.5.3.5 Mechanismof granule formation

1.5.3.6 Near Infrared(NIR) spectroscopy : A toolfor granulation endpoint measurement

1.5.3.7 Factors tobe considered in Granulation

1.5.3.8 Evaluationtests for Binders/Granules

Binder is one ofan important excipientto be addedin tablet formulation.In simpler words, binders oradhesives are thesubstances that promotescohesiveness. It is utilizedfor converting powderinto granules througha process knownas Granulation. Granulationis the unitoperation by whichsmall powdery particlesare agglomerated intolarger entities calledgranules.

1.5.3.1 Why to go for Granulation? (24)

Powders/Granules intended for compression into tablets must possesstwo essential properties : flow property and compressibility.

Flowproperty/Fluidity is requiredto produce tabletsof a consistentweight and uniformstrength. Compressibility is requiredto form a

stable, intact compact masswhen pressure isapplied. These two objectivesare obtained byadding binder totablet formulation andthen proceeding forgranulation process. Granules soformed should possess acceptable flow property and compressibility. Somedrugs exhibit poor fluidity andcompressibility. In suchcases binders haveto be addedfor improving flowproperty and compressibility.

Other reasons forGranulation process are to improveappearance, mixing properties,to avoiddustiness, to densify material, toreduce segregation, in generalto either eliminateundesirable properties or to improvethe physical andchemical properties offine powders.

1.5.3.2 Granulation Processes (24)

The standard methods frequently used today in tablet manufacturingare granulation and direct compression. Granulation technique includeswet granulation and dry granulation/slugging methods wherein bindersare added in solution/suspension form and in dry form respectively.In Direct Compression, binders possessing direct compressibility characteristicsare used. Binder when used in liquid form gives better binding actionas compared to when used in dry form.

1.5.3.3 Types of Binders (18,25-28)

Table.5. Classification Of Binders

Sugars Natural  Binders Synthetic/Semisynthetic  Polymer

Sucrose Acacia MethylCellulose

Liquid Tragacanth Ethyl

glucose Cellulose

  Gelatin HydroxyPropyl Methyl Cellulose ( HPMC)

  StarchPaste

HydroxyPropyl Cellulose

  Pregelatinized Starch SodiumCarboxy Methyl Cellulose

  AlginicAcid

Polyvinyl Pyrrolidone (PVP)

  Cellulose Polyethylene Glycol (PEG)

    Polyvinyl Alcohols

    Polymethacrylates

Table.6. Commonly Used Binders

BINDER CATEGORY MANUFACTURER

Starch 1500ÒPartially Pregelatinized MaizeStarch

Colorcon

MethocelÒ Hydroxy Propyl Methyl Cellulose Dow Chemicals

WalocelÒHM Hydroxy Propyl Methyl Cellulose

Wolff-Cellulosics

Natural Starch andChemical Company

LuvitecÒ Polyvinylpyrrolidone BASF Company

LuvicrossÒ Polyvinylpyrrolidone BASF Company

LuvicaprolactamÒ Polyvinylcaprolactam BASF Company

Table.7. Characteristics Of Commonly Used Binder

BINDER SPECIFIEDCONCENTRATION COMMENTS

Starch Paste 5-25%w/w- Freshly prepared starch paste isused as a binder.

- Its method of preparation is very crucial.

Pregelatinized Starch (PGS)

[Partially and FullyPGS]

5-10%w/w

(Direct Compression)

5-75%w/w

(Wet Granulation )

- It is starchthat have beenprocessed chemically and/ormechanically to ruptureall or partof the granulesin the presenceof water andsubsequently dried.

-It contains 5%free amylose, 15% freeamylopectin and 80%unmodified starch.

- Obtained from maize, potato or rice starch.

- It is multifunctional excipientused as atablet binder, diluent,disintegrant and flowaid.

- They enhance bothflow and compressibility andcan be usedas binders inDirect Compression aswell as WetGranulation.

- High purity PGSallow simplified processingas they swellin cold waterand therefore reducetime/costs compared withtraditional starch pastepreparation.

Hydroxypropyl Methyl Cellulose(HPMC)

2-5%w/w- Comparable to Methyl Cellulose.

- Used as abinder in eitherwet or drygranulation processes.

Polyvinyl Pyrrolidone (PVP)

0.5-5%w/w- Soluble in both water and alcohol.

- Used in wet granulation process.

- Itis also addedto powder blendsin the dryform and granulatedin situ bythe addition ofwater, alcohol or hydroalcoholic solution.

- Valuable binder for chewable tablets.

- The drug release is not altered onstorage.

Polyethylene Glycol (PEG) 6000

10-15%w/w- Used as a meltable binder.

- Anhydrous granulatingagent where wateror alcohol cannotbe used .

- Itmay prolong disintegration timewhen concentration is5% or higher

- It improves the plasticity of otherbinders.

1.5.3.4 Direct compression (DC) Binders (29)

Dueto ease of manufacture, product stability and high efficiency, the use ofDirect Compression for tableting has increased. For Direct Compression,directly compressible binders are required which should exhibit adequate powdercompressibility and flowability. Direct Compression binders should be selectedon the basis of compression behavior, volume reduction under applied pressureand flow behavior in order to have optimum binding performance. The choice andselection of binders is extremely critical for Direct Compression tablets.

Table.8. Commonly Used Dc Binders

Dc  Binder Class Manufacturer

AvicelÒ (PH 101) MCCa FMC Corporation

SMCCÒ (50) SMCCb Penwest Pharmaceutical

UNI-PUREÒ(DW) Partially PGScNational Starch

& Chemical

UNI-PUREÒ (LD) Low density starch National Starch &Chemica

DC LactoseÒ DC lactose anhydrous Quest International Group

DI TABÒ DC-DCPDd Rhodi

a– Microcrystalline Cellulose, b – Silicified Microcrystalline Cellulose, c –Pregelatinized Starch, d – Dibasic Calcium Phosphate Dihydrate

Table.9. Characteristics Of Dc Binders

Flow Behavior DI TABÒ> SMCCÒ(50) > DC LactoseÒ , UNI PUREÒ(DW) > AvicelÒ (PH 101) > UNI PUREÒ(LD)

Compressibility UNI PUREÒ(LD) > SMCCÒ(50) , AvicelÒ(PH 101) > UNI PUREÒ(DW) , DC LactoseÒ > DITABÒ

Crushing Strength UNI PUREÒ(LD) > SMCCÒ(50) > UNI PUREÒ(DW) > AvicelÒ(PH 101) > DCLactoseÒ > DI TABÒ

1.5.3.5 Mechanism ofgranule formation (30)

Granulesare formed in three stages:

Nucleation:Here, the particles adhere due toliquid bridges which are the initiation step of Granulation. These adheredparticles play a role of nucleus for further enlargement of granules.

Transition: Enlargement of nucleus takes place by two possiblemechanisms. Individual particle adhere to the nucleus or two or more nucleicombine among themselves.

Ball growth or enlargement of thegranule:Ball growth occurs either by Coalescence or Breakage or Abrasion Transfer orLayering. In Coalescence a larger granule is formed when two or more granulesare united. In Breakage granules break and the fragments of granule adhere toother granules. This forms a layer of material over intact granules. InAbrasion Transfer granule material are abraded through attrition by theagitation of granule bed and abraded material adheres to other granulesresulting into enlarged granules. In layering particles adheres to the alreadyformed granules increasing their size.

1.5.3.6Near Infrared (NIR)spectroscopy : A tool forgranulation end pointmeasurement (31)

NIR Spectroscopy is applicable formonitoring of wet granulation process when impeller torque method cannot beapplied. Watano et al determined the granulation end point using agitatedfluidized bed where in IR moisture sensor was installed. The properties of thewet mass obtained from NIR are independent of granulator equipment variablessuch as impeller design. Even the powder blending efficiency in the dry mixingphase can be monitored inline by NIR. NIR spectroscopy could be an excellenttool in wet granulation measurement.

1.5.3.7 Factors to be considered in Granulation (24,30,32)

Compatibility

The primary criteria is the compatibility of binder with theAPI & other tablet components. This is traditionally found bychoosing appropriate stability study design. Currently Differential ScanningCalorimetry (DSC) is used to ascertain compatibility.

Characteristics ofdrugs and other excipients

The drugs characteristics like itscompressibility, particle size,surface area, porosity,hydrophobicity, solubility inbinder are importantwhile fixing agranulation process. Thedrug that exhibits

poor compressibility requiresthe use ofa strong binder (liquid glucose, sucrose, etc.) whilethe drugs thatexhibit good compressibility canbe successfully handledusing a weakbinder ( starch paste etc.,).Fine and porousparticles requires higheramount of liquidbinder as comparedto coarse particles. Hydrophilic drug/excipients exhibitingabsorption characteristics requirehigher volume ofbinder as comparedto hydrophobic drug/excipients. The granulequality (size , friability) isgoverned by thesolubility of thedrug in thegranulation solution.

Spreading of Binder

Spreadingof binder/granulation solutionon the powderblend is ofparamount importance insuccessful granulation. A binderthat spreads easilyon particles issuperior as comparedto that whichshows poor wettingquality. HPMC is asuperior binder forparacetamol as comparedto PVP.

Type and quantity ofBinder

The uniformityof the particlesize, hardness, disintegrationand compressibility ofthe granulation depends on typeand quantity of binder added to formulation. As for example hard granulations

results due to stronger binder or a highly concentrated binder solution whichrequire excessive compression force during tableting. On theother hand, fragile granulationsresults due to insufficient quantityof binder whichsegregates easily. Larger quantitiesof granulating liquidproduce a narrowerparticle size rangeand coarser andhard granules i.e.The proportion of fine granulates particle decreases. Therefore theoptimum quantity ofliquid needed toget a givenparticle size shouldbe known inorder to keepa batch to batch variationsto a minimum.

Temperature andViscosity

The temperature and viscosity of binder is alsoimportant. Fluid (less viscous) binder exhibit good spreading behavior.

Method of Addition ofBinder

Themethod of addition of binder is also important. PVP canbe used assolution as abinder or itmay be dryblended with powdersand later activatedby adding water. Distribution ofbinder is favoredif it isdispersed instead ofpouring it.

Mixing Time

The mixing time also determines quality ofgranules. If the wetmassing time ishigher (resulting into hard

granules), the tablets mayfail the dissolutiontest in certaincases since drugrelease from hardgranules is altered.

Material ofConstruction of Granulator

Thematerial of constructionof granulator determinesthe volume ofbinder required aswell as granulesize distribution. Anyvessel wall whichare wetted easilyby binder demandsthe need ofhigher volume ofbinder. As for examplevessel wall madeup of Stainless Steelrequire higher volumeof binder ascompared to vesselmade up ofplastics (PMMA – Polymethylmethacrylateand PTFE –Polytetrafluoroethylene i.e. Teflon).In case ofPMMA and PTFEdue to highcontact angle, allgranulating liquid isforced immediately intothe powder bedand gives narrowparticle size distribution.While in caseof steel, due toless contact angleliquid layer formedon the wallsurface which inturn causes inhomogeneousdistribution of liquidover the powder

bed resulting into broadergranule size.

Type of Granulator

FluidizedBed Granulator producesporous granules ascompared to HighShear Granulators.

Process Variables

Higherdegree of densificationof the granules results due to higher impellerspeed as wellas longer wetmassing time. And also there istendency of agglomeration since liquid saturation increases. Consequently,impeller speed and wet massing time affect the granule size.

Apparatus Variables

Theapparatus variables inHigh Shear Mixerhave a largereffect on granulegrowth than inFluidized Bed Granulatorsbecause the shearforces are dependenton the mixerconstruction. The size andshape of themixing chamber, impeller andchopper vary indifferent High ShearMixers.

Impeller Movement

Adhesionof wetted mass to the vessel is less if impeller movement is helical. Thisgives a narrower granule size and few lumps. In case of High Shear Mixers,adhesion of wetted mass to the vessel is a problem which can be reduced byproper construction of the impeller or by coating the vessel withPolytetrafluoroethylene i.e. Teflon.

1.5.3.8 Evaluationtests for Binders/Granules (1)

Compactness, physical and chemical stability,rapid production capability, efficacy are some of the characteristics that maketablet a ruling dosage form. These characteristics depend on the quality ofgranules from which it is made. The characteristics of granules produced areaffected by formulation and process variables. So it becomes essential toevaluate the granule characteristics to monitor its suitability for tableting.

Particle Size and ParticleSize Distribution

The particle sizeof granules affectthe average tabletweight, tablet weight variation, disintegration time,granule friability,granulation flowability andthe drying ratekinetics of wetgranulations. Therefore the effectsof granule sizeand size distributionon the quality of tablet shouldbe determined by formulator. Themethods usually adoptedfor measurement ofparticle size andparticle size distributionincludes Microscopy, Sieving, Conductivity test.

Surface Area

Surfacearea of thedrug effects upondissolution rate especiallyin cases wheredrug have limitedwater solubility. Thetwo most commonmethods for surfacearea determination are GasAdsorption and AirPermeability.

Density

Granuledensity, True Density, Bulk Densitymay influence compressibility, tablet porosity, flow property, dissolution andother properties. Higher compressionload is required in case of dense and hard granules which in turn increases thetablet disintegration anddrug dissolution times.Density is usually determined by pycnometer.

% Compressibility

Compressibility isthe ability ofpowder to decreasein volume under pressure. Compressibility is a measure that isobtained from density determinations.

% Compressibility =(Tapped density – Bulk density/Tapped density)*100

Compressibility measuresgives idea aboutflow property ofthe granules asper CARR’S Indexwhich is asfollows :

Table.10. Carr’s Index

% Compressibility Flow  Description

5 – 15 Excellent

12 – 16 Good

18 – 21 Fair

23 – 28 Poor

28 – 35 Poor

35 – 38 Very Poor

> 40 Extremely Poor

Flow Properties

It is veryimportant parameter to be measuredsince it affectsthe mass ofuniformity of thedose. It isusually predicted fromHausner Ratio andAngle Of ReposeMeasurement.

Hausner Ratio = TappedDensity / Bulk Density

Table.11. Hausner Ratio

HAUSNER RATIO TYPE OFFLOW

Lessthan 1.25

GoodFlow

1.25 – 1.5 Moderate

Morethan 1.5

PoorFlow

Angle of Repose (Φ) is themaximum angle betweenthe surface ofa pile ofpowder and horizontalplane. It isusually determined byFixed Funnel Methodand is themeasure of theflowability of powder/granules.

Φ = tan-1

(h / r) where, h = height of heap of pile

r = radius of base of pile

Table.12.Angle Of Repose (Φ)

ANGLEOF REPOSE

TYPEOF FLOW

< 25 Excellent

25 – 30 Good

30 – 40 Passable

> 40 VeryPoor

Friability

Friabilityis important sinceit affects inparticle size distributionof granules affecting compressibility intotablet, tablet weight variation,granule flowability. Friability isdetermined carrying outTumbler Test orusing Friability Tester( Roche Friabilator ) and% loss isdetermined.

Moisture Content

It affects the granule flowability,compressibility as well as the stability of moisture sensitive drug andtherefore should be determined to evaluate the quality of granule.

Key Phrases

ØBinders areadded in tablet formulation to have required flow property andcompressibility of powders.

ØWetGranulation, Dry Granulation/Slugging, Direct Compression are major granulemanufacturing methods.

ØDirectCompression Binders are more efficient than conventional binders.

ØPregelatinizedStarch is used as multifunctional excipient: tablet binder (wet granulatingagent as well as direct compression binder), diluent, disintegrant and flowaid.

ØPolyethyleneGlycol used as meltable binder.

ØGranules areformed in three stages: Nucleation, Transition and Ball Growth.

ØNIR a tool forgranulation end point measurement and is better than torque impeller method.

ØCompatibilityof binder with API and other excipients, characteristics of binder, processvariables, and apparatus variables affects the quality of granules.

ØGranules haveto be evaluated in order to measure its suitability for tableting.

1.5.4Disintegrants

What will you gain?

1.5.4.1Introduction

1.5.4.2Mechanism of tablet disintegrants

1.5.4.3Methods of addition of disintegrants

1.5.4.4Types of disintegrants

1.5.4.5Factors affecting disintegration

1.5.4.1 Introduction

Bioavailabilityof a drug depends in absorption of the drug, which is affected by solubility ofthe drug in gastrointestinal fluid and permeability of the drug acrossgastrointestinal membrane. The drugs solubility mainly depends on physical –chemical characteristics of the drug. However, the rate of drug dissolution isgreatly influenced by disintegration of the tablet.

Thedrug will dissolve at a slower rate from a nondisintegrating tablet due toexposure of limited surface area to the fluid. The disintegration test is anofficial test and hence a batch of tablet must meet the stated requirements ofdisintegration.

Disintegrants, an important excipient of thetablet formulation, are always added to tablet to induce breakup of tablet whenit comes in contact with aqueous fluid and this process of desegregation ofconstituent particles before the drug dissolution occurs, is known asdisintegration process and excipients which induce this process are known asdisintegrants.

The objectives behind addition ofdisintegrants are to increase surface area of the tablet fragments and toovercome cohesive forces that keep particles together in a tablet.

Figure.16. Schematic Representation Of Tablet Disintegration And Subsequent Drug Dissolution

1.5.4.2 Mechanism of tablet disintegrants (16,29,33-39)

The tablet breaks to primary particles byone or more of the mechanisms listed below:-

I.By capillary action

II.By swelling

III.Because ofheat of wetting

IV.Due to disintegrating particle/particle repulsive forces

V.Due todeformation

VI.Due torelease of gases

VII.By enzymaticaction

By Capillary Action

Disintegration by capillary actionis always the first step. When weput the tablet into suitable aqueous medium, the medium penetrates into thetablet and replaces the air adsorbed on the particles, which weakens theintermolecular bond and breaks the tablet into fine particles. Water uptake bytablet depends upon hydrophilicity of the drug /excipient and on tabletingconditions. For these types ofdisintegrants maintenance of porous structure and low interfacial tensiontowards aqueous fluid is necessary which helps in disintegration by creating ahydrophilic network around the drug particles.

By Swelling

Perhaps the most widely accepted general mechanism ofaction for tablet disintegration is swelling Tablets with high porosity showpoor disintegration due to lack of adequate swelling force. On the other hand,sufficient swelling force is exerted in the tablet with low porosity. It isworthwhile to note that if the packing fraction is very high, fluid is unableto penetrate in the tablet and disintegration is again slows down.

Figure.17. Disintegration Of Tablet By Wicking And Swelling

Because of heat of wetting (air expansion)

Whendisintegrants with exothermic properties gets wetted, localized stress isgenerated due to capillary air expansion, which helps in disintegration oftablet. This explanation, however, is limited to only a few types ofdisintegrants and can not describe the action of most modern disintegratingagents.

Due to disintegrating particle/particle repulsiveforces

Anothermechanism of disintegration attempts to explain the swelling of tablet madewith ‘non-swellable’ disintegrants. Guyot-Hermann has proposed a particlerepulsion theory based on the observation that nonswelling particle also causedisintegration of tablets. theelectric repulsive forces between particles are the mechanism of disintegrationand water is required for it. Researchers found that repulsion is secondary towicking.

Due to deformation

Hesshad proved that during tablet compression, disintegranted particles getdeformed and these deformed particles get into their normal structure when theycome in contact with aqueous media or water. Occasionally, the swellingcapacity of starch was improved when granules were extensively deformed during

compression. This increase in size of the deformed particles produces a breakup of the tablet. This may be a mechanism of starch and has only recently begunto be studied

Figure.18. Disintegration By Deformation And Repulsion

Due to release of gases

Carbondioxide released within tablets on wetting due to interaction betweenbicarbonate and carbonate with citric acid or tartaric acid. The tabletdisintegrates due to generation of pressure within the tablet. Thiseffervescent mixture is used when pharmacist needs to formulate very rapidlydissolving tablets or fast disintegrating tablet. As these disintegrants arehighly sensitive to small changes in humidity level and temperature, strictcontrol of environment is required during manufacturing of the tablets. Theeffervescent blend is either added immediately prior to compression or can beadded in to two separate fraction of formulation.

By enzymatic reaction

Here,enzymes presents in the body act as disintegrants. These enzymes destroy thebinding action of binder and helps in disintegration

Table.13. Disintegrating Enzymes

ENZYMES BINDER

Amylase Starch

Protease Gelatin

Cellulase Cellulose and it’sderivatives

Invertase Sucrose

1.5.4.3 Methods of addition of disintegrants

The method ofaddition of disintegrants is also a crucial part. Disintegrating agent can beadded either prior to granulation (intragranular) or prior to compression(after granulation i.e. extragranular) or at the both processing steps.Extragranular fraction of disintegrant (usually, 50% of total disintegrantrequires) facilitates breakup of tablets to granules and the intragranularaddition of disintegrants produces further erosion of the granules to fineparticles.

1.5.4.4 Types ofdisintegrants (34,40-42)

Starch

Starchwas the first disintegrating agent widely used in tablet manufacturing. Before1906 potato starch and corn starch were used as disintegrants in tabletformulation. However, native starches have certain limitations and have beenreplaced by certain modified starches with specialized characteristics.

The mechanism of action of starch is wickingand restoration of deformed starch particles on contact with aqueous fluid andin doing so release of certain amount of stress which is responsible fordisruption of hydrogen bonding formed during compression.

Lowenthal& Wood proved that the rupture of the surface of a tablet employing starchas disintegrant occurs where starch agglomerates were found. The conditionsbest suited for rapid tablet disintegration are sufficient number of starchagglomerates, low compressive pressure and the presence of water.

Theconcentration of starch used is also very crucial part. If it is below theoptimum concentration then there are insufficient channels for capillary actionand if it is above optimum concentration then it will be difficult to compressthe tablet.

Pregelatinized starch

Pregelatinizedstarch is produced by the hydrolyzing and rupturing of the starch grain. It is

a directly compressible disintegrants and its optimum concentration is 5-10%.The main mechanism of action of Pregelatinized starch is through swelling.

Modified starch

Tohave a high swelling properties and faster disintegration, starch is modifiedby carboxy methylation followed by cross linking, which is available in marketas cross linked starch. One of them is SODIUM STARCH GLYCOLATE. Even lowsubstituted carboxymethyl starches are also marketed as ExplotabÒ and Primojel®.

Mechanismof action of this modified starches are rapid and extensive swelling withminimum gelling. And its optimum concentration is 4-6 %. If it goes beyond itslimit, then it produces viscous and gelatinous mass which increases thedisintegration time by resisting the breakup of tablet. They are highlyefficient at low concentration because of their greater swelling capacity.

Table.14. List Of Disintegrants

DISINTEGRANTS CONCENTRATIONIN GRANULES (%W/W)

SPECIAL COMMENTS

Starch USP 5-20 Higher amount is required, poorly compressible

Starch 1500 5-15 -

Avicel®(PH 101,PH 102)

10-20 Lubricant properties and directly compressible

Solka floc® 5-15 Purified wood cellulose

Alginic acid 1-5 Acts by swelling

Na alginate 2.5-10 Acts by swelling

Explotab® 2-8 Sodium starch glycolate, superdisintegrant.

Polyplasdone®(XL) 0.5-5 Crosslinked PVP

Amberlite® (IPR 88) 0.5-5 Ion exchange resin

Methyl cellulose, Na CMC,HPMC

5-10 -

AC-Di-Sol® 1-3 Direct compression

2-4 Wet granulation

Carbon dioxide _ Created insitu in effervescenttablet

Cellulose and itsderivatives

Sodium carboxy methylcellulose (NaCMC and CARMELLOSE sodium) has highly hydrophilicstructure and is soluble in water. But when it is modified by internallycrosslinking we get modified crosslinked cellulose i.e. Crosscarmellose sodiumwhich is nearly water insoluble due to cross linking. It rapidly swells to 4-8times its original volume when it comes in contact with water.

Microcrystalline cellulose (MCC)

MCC exhibit very good disintegrating properties because MCC is insoluble and act bywicking action. The moisture breaks the hydrogen bonding between adjacentbundles of MCC. It also serves as an excellent binder and has a tendency todevelop static charges in the presence of excessive moisture content.Therefore, sometimes it causes separation in granulation. This can be partiallyovercome by drying the cellulose to remove the moisture.

Alginates

Alginatesare hydrophilic colloidal substances which has high sorption capacity.Chemically, they are alginic acid and salts of alginic acid. Alginic acid isinsoluble in water, slightly acidic in reaction. Hence, it should be used inonly acidic or neutral granulation. Unlike starch and MCC, alginates do notretard flow and can be successfully used with ascorbic acid, multivitaminformulations and acid salts of organic bases.

Ion-exchange resin

Ionexchange resin (AmbreliteÒ IPR-88) has highest water uptake capacity than otherdisintegrating agents like starch and Sodium CMC. It has tendency to adsorbcertain drugs.

Miscellaneous

Thismiscellaneous category includes disintegrants like surfactants, gas producing

disintegrants and hydrous aluminium silicate. Gasproducing disintegrating agents is used in soluble tablet, dispersibletablet and effervescent tablet.

PolyplasdoneÒXL and PolyplasdoneÒXL10 act by wicking, swelling and possibly somedeformation recovery. Polyplasdone®XL do not reduce tablet hardness,provide rapid disintegration and improved dissolution. Polyplasdone®

as disintegrating agent has small particle size distribution that impart asmooth mouth feel to dissolve quickly. Chewable tablet does not requireaddition of disintegrant.

Superdisintegrants

As day’s passes, demand for faster disintegrating formulation is increased. So,pharmacist needs to formulate disintegrants i.e. Superdisintegrants which are effective at lowconcentration and have greater disintegrating efficiency and they are moreeffective intragranularly. But have one drawback that it is hygroscopictherefore not used with moisture sensitive drugs.

And this superdisintegrants act by swelling and due to swelling pressure exerted inthe outer direction or radial direction, it causes tablet to burst or theaccelerated absorption of water leading to an enormous increase in the volumeof granules to promote disintegration.

Figure.19. Mechanism of superdisintegrants by swelling

Table.15. List Of Superdisintegrants

SUPERDISINTEGRANTS EXAMPLE OF MECHANISM OF ACTION

SPECIAL COMMENT

Crosscarmellose®

 

Ac-Di-Sol®

 

Crosslinked cellulose

-Swells 4-8 folds in < 10 seconds.

-Swelling and wicking both.

-Swells in two dimensions.

-Direct compression or granulation

 

Nymce ZSX®

Primellose®

Solutab®

 

Vivasol®

 

 

-Starch free

Crosspovidone

Crosspovidon M®

Kollidon®

Polyplasdone®

Crosslinked PVP -Swells very little and returns to original size after compression butact by capillary action

-Water insoluble and spongy in nature so get porous tablet

Sodium starch glycolate

Explotab®

Primogel®

Crosslinked starch

-Swells 7-12 folds in <30seconds

-Swells in three dimensions and high level serve as sustain releasematrix

Alginic acid NF

Satialgine®Crosslinked alginic acid

-Rapid swelling in aqueous medium or wicking action

-Promote disintegration in both dryor wet granulation

Soy polysaccharides

Emcosoy®Natural super disintegrant

  -Does not contain any starch or sugar. Used in nutritional products.

Calcium silicate   -Wicking action-Highly porous,

-light weight

-optimum concentration is between 20-40%

1.5.4.5 Factors affectingdisintegration

Effect of fillers (43,44)

Thesolubility and compression characteristics of fillers affect both rate and mechanism

of disintegration of tablet. If soluble fillers are used then it may causeincrease in viscosity of the penetrating fluid which tends to reduceeffectiveness of strongly swelling disintegrating agents and as they are watersoluble, they are likely to dissolve rather than disintegrate. Insolublediluents produce rapid disintegration with adequate amount of disintegrants.

Chebliand cartilier proved that tablets made with spray dried lactose (water solublefiller) disintegrate more slowly due to its amorphous character and has nosolid planes on which the disintegrating forces can be exerted than the tabletmade with crystalline lactose monohydrate.

Effect of binder

Asbinding capacity of the binder increases, disintegrating time of tabletincreases and this counteract the rapid disintegration. Even the concentrationof the binder can also affect the disintegration time of tablet.

Effect of lubricants(16,34)

Mostly lubricants are hydrophobic and they are usually used in smaller size than anyother ingredient in the tablet formulation. When the mixture is mixed,lubricant particles may adhere to the surface of the other particles. Thishydrophobic coating inhibits the wetting and consequently tabletdisintegration.

Lubricanthas a strong negative effect on the water uptake if tablet contains nodisintegrants or even high concentration of slightly swelling disintegrants. Onthe contrary, the disintegration time is hardly affected if there is somestrongly swelling disintegrants are present in the tablet. But there is oneexception like sodium starch glycolate whose effect remains unaffected in thepresence of hydrophobic lubricant unlike other disintegrants.

Effect of surfactants

Table.16. The Effects Of Various Surfactants

Surfactant Remarks

Sodium lauryl sulfateGood-various drugs

Poor - various drugs

Polysorbate 20 Good

Polysorbate 40 & 60 Poor

Polysorbate 80 Good

Tweens Poor

Poly ethylene glycol Poor

(Good – decrease indisintegration time, Poor – increase in disintegration time)

Sodiumlauryl sulphate increased absorption of water by starch or had a variableeffect on water penetration in tablets. Surfactants are only effective withincertain concentration ranges. Surfactants are recommended to decrease thehydrophobicity of the drugs because the more hydrophobic the tablet the greaterthe disintegration time.

Aokiand fukuda claimed that disintegrationtime of granules of water-soluble drugs did not seem to be greatlyimproved by the addition of nonionicsurfactant during granulation , but the desired effect of a surfactant appeared when granule weremade of slightly soluble drugs. The speed of water penetration was increased bythe addition of a surfactant.

Key Phrases

Ø Disintegrantsare added to tablet to induce breakup when it comes in contact with aqueousfluid.

Ø Disintegrationby capillary action or by swelling is the major mechanism for disintegrants.

Ø Disintegrantcan be added intragranular or extragranular or at both stages.

Ø Superdisintegrantshave greater efficiency at low concentration and hence, their demand isincreasing day by day.

1.5.5Antifrictional Agents

Whatwill you gain?

1.5.5.1 Lubricants

1.5.5.1.1Classification of lubricants

1.5.5.1.1.1 WaterInsoluble Lubricants

1.5.5.1.1.2Water Soluble Lubricants

1.5.5.2 Antiadherents

1.5.5.3 Glidants

1.5.5.1 Lubricants(4,16)

Lubricantsare the agents that act by reducing friction by interposing an intermediatelayer between the tablet constituents and the die wall during compression andejection. Solid lubricants, act by boundary mechanism, results from theadherence of the polar portions of molecules with long carbon chains to themetal surfaces to the die wall. Magnesium stearate is an example of boundarylubricant. Other is hydrodynamic mechanism i.e. fluid lubrication where twomoving surfaces are separated by a finite and continuous layer of fluidlubricant. Since adherence of solid lubricants to the die wall is more thanthat of fluid lubricants, solid lubricants are more effective and morefrequently used.

Sinceprimarily lubricants are required to act at the tooling or material interface,lubricants should be incorporated in the final mixing step, after granulation is complete. When hydrophobiclubricants are added to a granulation, they form a coat around the individualparticles (granules), which may cause an increase in the disintegration timeand a decrease in the drug dissolution rate. Presence of lubricants may resultsin a less cohesive and mechanically weaker tablet because it may interfere withthe particle – particle bonding.

Surfacearea is important parameter for deciding lubricant efficiency. Lubricants withhigh surface area are more sensitive to changes in mixing time than lubricantwith low surface area. Therefore lubricant mixing time should be kept minimum.

Toolingused to compress the tablet is important for deciding type and level oflubricant used. Additional lubricant is often added to the tablet formulationsthat are to be compressed with curved face punches.

Further,the amount of lubricant increases as the particle size of the granulationdecreases but its concentration should not exceed to 1% for producing maximumflow rate.

Lackof adequate lubrication produces binding which can results in tablet machinestrain and can lead to damage of lower punch heads, lower cam track, die seatsand the tooling itself. And it may also yield tablets with scratched edges andare often fractured at the top edges. With excessive binding the tablet may becracked and fragmented by ejection.

1.5.5.1.1 Classificationof lubricants

Lubricantare classified according to their water solubility i.e. water insoluble andwater soluble. Selection of lubricant is depends partly on mode ofadministration, type of tablet, desired disintegration and dissolutionproperties, physicochemical properties of granules or powder and cost.

1.5.5.1.1.1 Water Insoluble Lubricants

Waterinsoluble lubricants are most effective and used at reduced concentration thanwater soluble lubricants. Since theselubricants function by coating ,their effectiveness is related with their surface area, extent of particle sizereduction, time, procedure of additionand length of mixing.

Table.17. List Of Insoluble Lubricants

INSOLUBLELUBRICANTS CONCENTRATION COMMENTS

Stearates(Magnesium Stearate, Calcium Stearate, Sodium stearate)

0.25 -1 Reduce tablet strength; prolong disintegration; widely used.

Talc 1 -2 Insoluble but not hydrophobic; moderately effective.

Sterotex 0.25 – 1 -

Waxes 1 - 5 -

Stearowet 1 - 5 -

Glyceryl behapate(Compritol®888) 1 - 5 Both lubricant and binder;

Liquid paraffin Up to 5 Dispersion problem; inferior to stearates

1.5.5.1.1.2 Water Soluble Lubricants

WaterSoluble Lubricants are used when a tablet is completely soluble or when uniquedisintegration and dissolution characteristics are required. Tablet containingsoluble lubricant shows higher dissolution rate than tablet with insolublelubricants. Physical mixture of this lubricant i.e. SLS or MLS with stearatescan lead to the best compromise in terms of lubricity, tablet strength anddisintegration.

Table.18. List Of Soluble Lubricants

WATER SOLUBLE LUBRICANTS CONCENTRATION RANGE (%W/W)

Boric acid 1

Sodium benzoate 5

Sodium oleate 5

Sodium acetate 5

Sodium Lauryl sulfate(SLS) 1 – 5

Magnesium lauryl sulfate(MLS) 1 - 2

1.5.5.2 Antiadherents (4, 16)

Somematerial have strong adhesive properties towards the metal of punches and diesor the tablet formulation containing excessive moisture which has tendency toresult in picking and sticking problem. Therefore antiadherents are added,which prevent sticking to punches and die walls.

Talc,magnesium stearate and corn starch have excellent antiadherent properties.Vegan had suggested that silicon oil can be used as antiadherent.

Table.19. List Of Antiadherents

ANTIADHERENT RANGE(%W/W) COMMENT

Talc 1 – 5 Lubricant withexcellent antiadherents properties

Cornstarch 3 – 10 Lubricant withexcellent antiadherents properties

Colloidal silica 0.1 – 0.5

Does not givesatisfactory results due to small surface area. Cab-O-Sil® andSyloid®

DL-Leucine 3 – 10Water solublelubricant; excellent antiadherents properties

Sodium laurylsulfate <1 Antiadherents with

water soluble lubricant

Stearates <1 Antiadherents withwater insoluble lubricant

1.5.5.3 Glidants (4, 16)

GLIDANTSare added to the formulation to improve the flow properties of the materialwhich is to be fed into the die cavity and aid in particle rearrangement withinthe die during the early stages of compression. If the flow properties areextremely poor then glidants are ineffective and consideration of force freemechanisms may be necessary. Starch is a popular glidant because it hasadditional value of disintegrant. Concentration of starch is common up to 10%,but should be limited otherwise it will worsen the flow of material. Talc is aglidant which is superior to starch; its concentration should be limitedbecause it has retardant effect on dissolution-disintegration profile.

Silaceousmaterial like colloidal silica i.e. syloid, pyrogenic silica (0.25%), hydratedsodium silioaluminate (0.75%) are also successfully used to induce flow.

Glidantsact by interposing their particles between those of material and lower theoverall interparticulate friction of the system by virtue of their reducedadhesive tendencies. Similar to lubricants, they are required at the surface offeed particles and they should be in fine state of division and appropriatelyincorporated in the mixture.

KeyPhrases

ØLubricants areadded to reduce the friction during compression.

ØAntiadherentsavoid sticking to die walls and picking by punches.

ØGlidantsimprove the flow property of material/granules.

1.5.6 Miscellaneous Excipients

Whatwill you gain?

1.5.6.1 Wetting Agents

1.5.6.2 Dissolution Retardants

1.5.6.3 Dissolution Enhancers

1.5.6.4 Adsorbents

1.5.6.5 Buffers

1.5.6.6 Antioxidants

1.5.6.7 Chelating Agents

1.5.6.8 Preservatives

1.5.6.9 Colourants

1.5.6.10 Flavours

1.5.6.11 Sweeteners

1.5.6.1 Wetting Agents

Wetting Agents in tablet formulationaid water uptake and thereby enhancing disintegration and assisting in drugdissolution. Incorporation of anionic surfactant like Sodium Lauryl Sulphate(SLS) is known to enhance the dissolution.It has been established that SLSimproves permeation of drug through biological membrane since it destroys the

path through which drug has to pass and thus minimizing the path length for thedrug to travel. Wetting agents are mainly added when hydrophobic drug is to beformulated into tablet. SLS, Sodium diisobutyl sulfosuccinate are used aswetting agent in tablet formulation.

1.5.6.2 DissolutionRetardants

Dissolution Retardants are incorporated into tabletformulation only when controlled release of drug is required. Waxy materialslike stearic acid and their esters can be used as dissolution retardants.

1.5.6.3 Dissolution Enhancers

They are the agents that alter themolecular forces between ingredients to enhance the dissolution of solute inthe solvent. Fructose, Povidone, Surfactants are used as dissolution enhancer.

1.5.6.4 Adsorbents (4)

Adsorbents are the agents that canretain large quantities of liquids. Therefore liquids like Vitamin E can beincorporated into tablets by addition of adsorbents .Most commonly usedadsorbents in pharmaceuticals are anhydrous calcium phosphate, starch,magnesium carbonate, bentonite, kaolin, magnesium silicate, magnesium oxide andsilicon dioxide. Generally the liquid to be adsorbed is first mixed with theadsorbent prior to incorporation into the formulation. Silicon dioxide whenadded can play as both glidant and an adsorbent role in the formula.

1.5.6.5 Buffers

Buffers are added to maintain a required pH since achange in pH may cause significant alteration in stability. Most commonly usedbuffering agent in tablet formulation includes sodium bicarbonate, calciumcarbonate, and sodium citrate.

1.5.6.6 Antioxidants

Antioxidants are added in tablet formulation toprotect drug from undergoing oxidation. Antioxidants undergo oxidation in placeof drug or they block the oxidation reaction or they act as synergists to otherantioxidants. Chelators may also act as antioxidant. Most commonly usedantioxidants include ascorbic acid andtheir esters , alpha-tocopherol , ethylene diamine tetra acetic acid , sodiummetabisulfite , sodium bisulfite , Butylated Hydroxy Toluene (BHT) , ButylatedHydroxy Anisole (BHA) , citric acid , and tartaric acid .

1.5.6.7 Chelating Agents

Chelating agents tend to form complexes with traceamount of heavy metal ions inactivating their catalytic activity in the

oxidation of medicaments. Ethylenediamine tetracetic acid and its salts,Dihydroxy Ethyl Glycine, Citric Acid and Tartaric Acid are most commonly usedchelators.

1.5.6.8Preservatives

Preservatives may be a part of tablet formulation inorder to prevent the growth of microorganisms in tablet formulation. Parabenslike methyl, propyl, benzyl, butyl p-hydroxy benzoate are used aspreservatives.

1.5.6.9 Colourants(1, 4,16)

Colourants neither contribute to therapeutic activitynor do they improve product bioavailability or stability but are incorporatedinto tablets for purposes like to facilitate identification of similar lookingproducts with in a product line to avoid mix ups, to facilitate identificationof products of similar appearance that exist in the lines of different manufacturers, to overcome colour change onaging, disguising of off-colour drugs, for brand image in the market, toenhance the aesthetic appearance of the product to have better patientacceptance. Most widely used colourants are dyes and lakes which are FD & Cand D & C approved. Dyes are generally applied as solution especially inthe granulating agent. Lakes are usually employed as dry powders for colouring.In general, direct compression tablets are coloured with lakes because nogranulation step is used. Natural colourants can be used and generally they donot require the FDA certification before use in drug products. One of theimportant advantage in using lakes is reduced risk of interaction between thedrug and other ingredients as well as colour development is rapid which reducesprocessing time .While employing wet granulation , care should be taken toprevent colour migration during drying . In any coloured tablet, theformulation should be checked for resistance to colour changes on exposure tolight. Reflectance Spectrophotometry, Tristimulus Colourimetric Measurementsand Microreflectance Photometer used to measure the colour uniformity and glosson a tablet surface.

Table.20. Some Commonly Used Pharmaceutical Colourants (Synthetic)

FD &C COLOUR

COMMONNAME

Red 3 Erythrosine

Red 40 Allura red AC

Yellow 5 Tartrazine

Yellow 6 Sunset Yellow

Blue 1 Brilliant Blue

Blue 2 Indigotine

Green 3 Fast Green

1.5.6.10 Flavours(1,4)

Flavors are commonly used to improvethe taste of chewable tablets as well as mouth dissolved tablets. Flavors areincorporated either as solids (spray dried flavors) or oils or aqueous (watersoluble) flavors. Solids that is dry flavors are easier to handle and generallymore stable than oils. Oil is usually added at the lubrication step because ofits sensitivity to moisture and their tendency to volatilize when heated duringdrying. It may also be adsorbed onto an excipient and added during thelubrication process. The maximum amount of oil that can be added to granulationwithout affecting tableting characteristics is 0.5 to 0.75 %w/w. aqueousflavors are less used because of its instability on aging.

1.5.6.11 Sweeteners(1,4,45)

Sweeteners are added primarily to chewabletablets.

Table.21. Some Of The Sweeteners Used In Tablet Formulation

NATURALSWEETENERS

ARTIFICIALSWEETENERS

Mannitol

Lactose

Sucrose

Dextrose

Saccharin

Cyclamate

Aspartame

Saccharinis 500 times sweeter than sucrose. Its major disadvantages are that it has abitter aftertaste and is carcinogenic. Even cyclamate is carcinogenic.Aspartame is about 180 times sweeter than sucrose. The primary disadvantage ofaspartame is its lack of stability in the presence of moisture. When aspartameis used with hygroscopic components, it will be necessary to determine itsstability under conditions in which the product can adsorb atmospheric

moisture. Aspartame is available in market under the brand NutrasweetÒ manufactured and marketed by Nutrasweet Company.

Key Phrases

ØOnly FD&Cand D&C approved colourants can be incorporated into tablet formulation.

ØFlavours andSweeteners are one of the important ingredients of chewable and mouthdissolving tablet formulation.

Ideal properties of API for formulating tabletsSubmitted by on Sun, 12/06/2009 - 19:52

1.6Ideal Properties of API for formulating tablets (46)

What will you gain?

The desirable properties of API for formulatingtablets :

1.6.1 Highpurity

1.6.2 Highstability

1.6.3 Goodcompatibility with excipients

1.6.4Optimum bulk powder properties

1.6.5 Optimumand uniform particle size – particle size distribution

1.6.6Spherical shape

1.6.7 Goodflowability

1.6.8

Optimum moisture content

1.6.9 Goodcompressibility

1.6.10 Absence of static charge on surface

1.6.11 Good organoleptic properties

1.6.12 Miscellaneous

1.6.1 High Purity

APIhas to be in pure form otherwise impurities can catalyze series of chemicalreactions, e.g. in case of hydrocortisone impurity of cupric ion causesoxidation of ketone functional group.API should meet specifications given in the respectivePharmacopoeia.

1.6.2 High stability

TheAPI should be stable against photolysis, oxidation, hydrolysis, etc. to keepthe formulation a simple one. Sensitiveparticles require careful handling during manufacturing.

1.6.3 Good compatibility withexcipients (47)

In order to formulate a tablet oneneed to add excipient along with API.There should not be any kind of interaction between excipient andAPI. Excipients have to be inert in nature. However there are some reported examples ofAPI-excipient interactions like Lisinopril reacts with lactose and undergoesbrowning reaction leading to darkening on storage. So, avoid the use of lactose and use otherfillers for API containing primary amine.To ascertain drug and excipient interaction, 1:1 mixture is prepared andstored under accelerated/ICH conditions.The amount of drug degraded shall be determined to select the mostsuitable excipient.

1.6.4 Optimum bulk powder properties

Bulkpowder properties have to be optimum to:

i) Preventsegregation.

ii) Have optimum size tablet particularly for lowpotency-low density API.

iii) Have good flow.

1.6.5 Optimum and Uniform particle size-particle size distribution

APIshould have uniform particle size and close particle size distribution becauseit has pronounce effect on uniformity of content, uniformity of weight,disintegration time, granule friability, drying rate kinetics of wetgranulation, flowability, compressibility, stability, dissolution,bioavailability, etc. The flow andcompression characteristics are important from the viewpoint of industrialpharmacist. Strong tablets are obtained if fine particles are used due toincrease in surface area and surface energy.

1.6.6 Spherical shape

The shape of particles decides flowability. Sphericalshaped particles exhibit good flow as compared to needle shaped particles. Particles with irregular shape may exhibithindered flow due to interlocking between particles. This point is very important since it isdirectly related with weight of tablet and uniformity.

1.6.7 Good flowability (48-50)

Flow is important for having uniformity of weight and uniformity of drugcontent. It can be measured using angleof repose, Carr’s index and Hausner ratio.

The methods used to improve flow are summarizedbelow

i)Addition of glidants

ii) Addition of fines:Addition of fines up to certain extent improves flow. This is because offilling of void space and decrease in surface roughness.

iii)    By wet granulation: Wet granulation gives regularsphere shaped granules and removes static charge if present on particlesurface. Thus, flow property improved.

iv) By densification with help of slugging.

1.6.8 Optimum moisture content (51-53)

Moisture content has to be optimumbecause of the following reasons:

i)Total lack of moisture results into brittle tablet.

ii) Moisture affects flow, which in turn affectsuniformity of content.

iii)High amount of moisture gives stickiness, which willaffect compaction.

iv)Picking/sticking may be observed.

Moisture content can be controlled by:

i)Use of anhydrous salts.

ii)Use of non-aqueous solvent.

iii) Optimum drying time.

iv) Addition of finely powdered adsorbent like magnesiumoxide.

1.6.9 Good compressibility (1,2,4,5,54)

API should exhibit good compressibility.However this depends upon its intrinsic nature like:

(A) Elasticity:

The particles deform under the effect of pressure ina die but they revert back to original state on removal of applied pressurei.e. on ejection. Such tablets mayexhibit capping and or lamination. Theintrinsic nature of particle can be changed by:

i)Wet massing

ii)Pre-compression

iii)Plastic tabulating matrix (micro crystallinecellulose)

Elastic material is less suitable fordirect compression.

(B)Plasticity:

Plastic material gets bonded after viscoelasticdeformation. Viscoelastic deformation istime dependent. Hence, the crushingstrength is dependent on the time that tablet spends in a die. Changing the turret speed can change dwelltime. Plastic materials may exhibitviscoelastic deformaiton.

(C) Brittle fracture:

A particle fractures into small particles onapplication of pressure in a die.Brittle fracture also promotes tableting. Brittle materials are less lubricantsensitive as compared to plastic materials.A blend of lactose and MCC is widely used in industry to get advantagesof brittle materials and plastic materials.

1.6.10 Absence of static charge onsurface (55)

It is important because of the following reasons:

i)Affects uniformity of dose and weight variation (flow worsen if attractive forcesgenerated).

ii) During mixing it may cause segregation and lead tonon-uniformity of content if API and excipients are charged.

iii) Charged API may adhere to feed frame and result intoserious damage to tablet equipment.

In order to remove charge certain treatments can be givenlike granulation, addition of diluents or lubricant, surface coating with helpof colloidal silica, etc.

1.6.11 Good organoleptic properties

Many API are unpalatable and unattractive in their natural form. In such cases, tablet formulation require certaincare. API has to be checked for colourand taste.

I. Colour

Ideally API should be colourless. For colouredAPI, the following steps shall be considered:

i)Select appropriate excipient to avoid mottling.

ii)Incorporate API in smallest particle size.

iii)Incorporate colour in dry form along with binder andactivate mixture by addition of water or other activator.

iv)Coating can be applied to conceal non-uniform colour(sugar coated multivitamin tablet).

II. Taste

It is very important for tablets because they come in contact with tastebuds. Ideally API should have notaste. But sometimes it might haveunpleasant taste like bitter e.g. Chloramphenicol, Clindamycin, etc. The following taste masking options can betried:

i)Use of prodrugto decrease API solubility in saliva or to reduce affinity for taste receptor e.g. Chloramphenicol Palmitate.

ii)Sugar coating or film coating.

iii)Addition of sweeteners like mannitol in cause of fastdissolving tablet or chewable tablet.

iv) Use of drug-ion exchange adsorbent in formulation.

v)Drug β-cyclodextrin complex may exhibit goodtaste profile and good compressibility as well.

1.6.12 Miscellaneous points

i)API should notexhibit sublime characteristics

ii)Liquid APIs areless suitable for tablet formulation.One of the options is conversion of liquid in pseudosolid (mix liquidAPI with adsorbents). A combination ofValproic acid and Sodium Valproate is a typical example of converting a liquidinto pseudosolid.

iii)BCS class IV drugs are difficult to formulate ifdissolution and bioavailability requirements are to meet as per regulatoryagencies.

Key Phrases

ØHigh Purity toavoid contamination and degradation.

ØHigh stabilityagainst photolysis, oxidation, hydrolysis, etc.

ØGood compatibility with excipients. For example, avoid use of lactose with drugswith primary amine functional group.

ØOptimum bulk powder properties to prevent segregation and to have good flow.

ØOptimum particle size and size distribution to have uniformity of weight, uniformity of content,good flow and compressibility.

ØSpherical shapeto avoid interlocking between the particles and thus to aid flow.

ØGood flow tohave uniformity of weight and uniformity of drug content

ØOptimum amountof moisture to avoid problems like brittle tablet, picking/sticking, etc.

ØGood compressibility to have nicely bonded tablet.

ØAbsence of static charge on the surface to prevent demixing and damage to tabletingequipment by adhering to feed frame.

ØGood organoleptic properties to have better patient acceptance.

ØMiscellaneous: Convert liquid API to pseudosolid e.g.Valproic acid and Sodium valproate, etc.

Operations involved in tablet manufacturing Submitted by on Sun, 12/06/2009 - 19:52

1.7 Operations involved in tablet manufacturing(1-3)

What will you gain?

1.7.1 Introduction

1.7.2 Dispensing (weighing and measuring)

1.7.3 Sizing

1.7.4 Powder blending

1.7.5 Granulation

1.7.6 Drying

1.7.7 Tablet compression

1.7.8 Auxillary equipments

1.7.9 Packaging

1.7.1 Introduction

The manufacture of oral solid dosageforms such as tablets is a complex multi-stage process under which the startingmaterials change their physical characteristics a number of times before thefinal dosage form is produced.

Traditionally, tablets have been made by granulation, aprocess that imparts two primary requisites to formulate: compactibility andfluidity. Both wet granulation and dry granulation (slugging and rollcompaction) are used. Regardless of weather tablets are made by directcompression or granulation, the first step, milling and mixing, is the same;subsequent step differ.

Numerous unit processes are involved in making tablets, includingparticle size reduction and sizing, blending, granulation, drying, compaction,and (frequently) coating. Various factors associated with these processes canseriously affect content uniformity, bioavailability, or stability.

Figure.20. Various Unit Operation Sequences In Tablet Manufacturing

Figure.21. Typical Manufacturing Process Of Tablet

Table.22. Typical Unit Operation Involved In Wet Granulation, Dry Granulation And Direct Compression(13)

WET GRANULATION DRY GRANULATION DIRECT COMPRESSION

1.Millingand mixing of drugs and excipients

1.Millingand mixing of drugs and excipients

1. Milling and mixing of drugs and excipients

2.Preparationof binder solution

2.Compressioninto slugs or roll compaction

2.Compression of tablet

3.Wetmassing by addition of binder solutionor granulating solvent

3.Millingand screening of slugs and compacted powder

 

4. 4.  

Screeningof wet mass

Mixingwith lubricant and disintegrant

5.Dryingof the wet granules

5.Compressionof tablet

 

6.Screeningof dry granules

   

7.Blendingwith lubricant and disintegrant to produce “running powder”

   

8.Compressionof tablet

   

1.7.2 Dispensing (weighing and measuring)

Dispensing is the first step in anypharmaceutical manufacturing process. Dispensing is one of the most criticalsteps in pharmaceutical manufacturing; as during this step, the weight of eachingredient in the mixture is determined according to dose.

Dispensing may be done by purely manualby hand scooping from primary containers and weighing each ingredient by handon a weigh scale, manual weighing with material lifting assistance like Vacuumtransfer and Bag lifters, manual or assisted transfer with automated weighingon weigh table, manual or assisted filling of loss-in weight dispensing system,automated dispensaries with mechanical devices such as vacuum loading systemand screw feed system.

Issues likeweighing accuracy, dust control (laminar air flow booths, glove boxes), duringmanual handling, lot control of each ingredient, material movement into and outof dispensary should be considered during dispensing.

1.7.3 Sizing

The sizing (size reduction, milling, crushing, grinding,pulverization) is an impotent step (unit operation) involved in the tabletmanufacturing.

In manufacturing of compressed tablet, the mixing or blending of several solidingredients of pharmaceuticals is easier and more uniform if the ingredientsare approximately of same size. This provides a greater uniformity of dose. Afine particle size is essential in case of lubricant mixing with granules forits proper function.

Advantages associated with size reduction in tabletmanufacture are as follows:

i) It increases surface area, which may enhance an active ingredient’s dissolutionrate and hence bioavailability.

ii)Improved the tablet-to-tablet content uniformity by virtue of the increased number ofparticles per unit weight.

iii)Controlled particle size distribution of dry granulation or mix to promote better flow ofmixture in tablet machine.

iv)Improved flow properties of raw materials.

v)Improved colour and/or active ingredient dispersion in tablet excipients.

vi)Uniformly sized wet granulation to promote uniform drying.

There are also certain disadvantages associated with this unit operation if notcontrolled properly. They are as follows:

i)A possible change in polymorphic form of the active ingredient, rendering it lessor totally inactive, or unstable.

ii) A decrease in bulk density of active compound and/or excipients, which may causeflow problem and segregation in the mix.

iii)An increase in surface area from size reduction may promote the adsorption of air, which mayinhibit wettability of the drug to the extent that it becomes the limitingfactor in dissolution rate.

A number of different types of machinemay be used for the dry sizing or milling process depending on whether gentle screeningor particle milling is needed. Theranges of equipment employed for this process includes Fluid energy mill,Colloidal mill, Ball mill, Hammer mill, Cutting mill, Roller mill, Conicalmill, etc.

1.7.4 Powder blending

The successful mixing of powder is acknowledged to be moredifficult unit operation because, unlike the situation with liquid, perfecthomogeneity is practically unattainable.

In practice, problems also arise because of the inherent cohesiveness andresistance to movement between the individual particles. The process is furthercomplicated in many system, by the presence of substantial segregationinfluencing the powder mix. They arise because of difference in size, shape,and density of the component particles.

The powder/granules blendingare involved at stage of pre granulation and/or post granulation stage oftablet manufacturing. Each process of mixing has optimum mixing time and soprolonged mixing may result in an undesired product. So, the optimum mixingtime and mixing speed are to be evaluated. Blending step prior to compressionis normally achieved in a simple tumble blender. The Blender may be a fixedblender into which the powders are charged, blended and discharged. It is nowcommon to use a bin blender which blends.

In special cases of mixing a lubricant, over mixing shouldbe particularly monitered.

The various blenders used include “V”blender, Oblicone blender, Container blender, Tumbling blender, Agitated powderblender, etc.

But now a days tooptimize the manufacturing process particularly in wet granulation the variousimproved equipments which combines several of processing steps (mixing,granulation and/or drying) are used. They are “Mixer granulator” or “High shearmixing machine”.

1.7.5 Granulation

Following particle size reduction andblending, the formulation may be granulated, which provides homogeneity of drugdistribution in blend.

1.7.6 Drying

Drying is a most important step in the formulation anddevelopment of pharmaceutical product. It is important to keep the residualmoisture low enough to prevent product deterioration and ensure free flowingproperties.

The commonly used dryer includes Fluidized – bed dryer,Vacuum tray dryer, Microwave dryer, Spray dryer, Freeze dryer, Turbo - traydryer, Pan dryer, etc.

1.7.7 Tablet compression

After the preparation of granules (in case of wetgranulation) or sized slugs (in case of dry granulation) or mixing ofingredients (in case of direct compression), they are compressed to get finalproduct. The compression is done either by single punch machine (stampingpress) or by multi station machine (rotary press).

The tablet pressis a high-speed mechanical device. It 'squeezes' the ingredients into therequired tablet shape with extreme precision. It can make the tablet in manyshapes, although they are usually round or oval. Also, it can press the name ofthe manufacturer or the product into the top of the tablet.

Each tablet is made bypressing the granules inside a die, made up of hardened steel. The die is adisc shape with a hole cut through its centre. The powder is compressed in thecentre of the die by two hardened steel punches that fit into the top andbottom of the die.

The punches and dies are fixed to a turret that spins round.As it spins, the punches are driven together by two fixed cams - an upper camand lower cam. The top of the upper punch (the punch head) sits on the uppercam edge .The bottom of the lower punch sits on the lower cam edge.

The shapes of the two camsdetermine the sequence of movements of the two punches. This sequence isrepeated over and over because the turret is spinning round.

The force exerted on the ingredients in the dies is verycarefully controlled. This ensures that each tablet is perfectly formed. Becauseof the high speeds, they need very sophisticated lubrication systems. Thelubricating oil is recycled and filtered to ensure a continuous supply.

Common stages occurring during compression

Stage 1: Top punch is withdrawn from the dieby the upper cam

Bottom punch is low in the die so powder falls in through the hole and fills the die

Stage 2: Bottom punch moves up to adjust the powderweight-it raises and expels some powder

Stage 3: Top punch is driven into the die by upper cam

Bottom punch is raised by lower cam

Both punch heads pass between heavy rollers to compress the powder

Stage 4: Top punch is withdraw by the upper cam

Lower punch is pushed up and expels the tablet

Tablet is removed from the die surface by surface plate

Stage 5: Return to stage 1

Figure.22. Stage Occurring During Compression

1.7.8 Auxiliary Equipments (1)

I. Granulation Feeding Device:

In many cases, speed of die table is such that the time ofdie under feed frame is too short to allow adequate or consistent gravityfilling of die with granules, resulting in weight variation and contentuniformity. These also seen with poorly flowing granules. To avoid theseproblems, mechanized feeder can employ to force granules into die cavity.

  II.Tablet weight monitoring devices:-

High rate of tablet output withmodern press requires continuous tablet weight monitoring with electronicmonitoring devices like Thomas Tablet Sentinel,Pharmakontroll and Killan control System-MC. They monitors force at eachcompression station by starin gage technology which is then correlated withtablet weight.

III. Tablet Deduster : -

In almost all cases, tablets coming out of a tablet machinebear excess powder on its surface and are run through the tablet deduster toremove that excess powder.

IV.  Fette machine

Fette machine is device that chills the compressioncomponents to allow the compression of low melting point substance such aswaxes and thereby making it possible to compress product with low metingpoints.

1.7.9 Packaging

Pharmaceuticalmanufacturers have to pack their medicines before they can be sent out fordistribution. The type of packaging will depend on the formulation of themedicine.

'Blister packs' are a commonform of packaging used for a wide variety of products. They are safe and easyto use and they allow the consumer to see the contents without opening thepack. Many pharmaceutical companies use a standard size of blister pack. Thissaves the cost of different tools and to change the production machinerybetween products. Sometimes the pack may be perforated so that individual tabletscan be detached. This means that the expiry date and the name of the producthave to be printed on each part of the package. The blister pack itself mustremain absolutely flat as it travels through the packaging processes,especially when it is inserted into a carton. This poses interesting problemsfor the designers. Extra ribs are added to the blister pack to improve itsstiffness.

Key Phrases

The manufacturing of tablet involves numerous unitprocesses including

ØParticle size reduction and sizing

ØBlending

ØGranulation

ØDrying,compaction

ØCoating.

Manufacturing methods of tabletsSubmitted by on Sun, 12/06/2009 - 19:53

1.8 Manufacturing methods

1.8.1 Direct compression(1-3,5,17)

Whatwill you gain?

1.8.1.1 Introduction.

1.8.1.2 The events thatmotivates the industry people to use direct compression technique.

1.8.1.3 Merits

1.8.1.4 Merits over wet granulation process

1.8.1.5 Demerits

1.8.1.6 Manufacturing steps for direct compression

1.8.1.7 Direct compression Excipients

1.8.1.7.1 An ideal directcompression excipient should possessthe following attributes.

1.8.1.7.2 Major excipients required in directcompression.

1.8.1.1 Introduction

In early days, most of the tablets require granulation of the powdered ActivePharmaceutical Ingredient (API) and Excipients. At the availability of newexcipients or modified form of old excipients and the invention of new tabletmachinery or modification of old tablet machinery provides an ease inmanufacturing of tablets by simple procedure of direct compression.

Amongst the techniques used to prepare tablets, directcompression is the most advanced technology. It involves only blending andcompression. Thus offering advantage particularly in terms of speedyproduction. Because it requires fewer unit operations, less machinery, reducednumber of personnel and considerably less processing time along with increasedproduct stability.

Definition:

The term “direct compression” is defined as the processby which tablets are compressed directly from powder mixture of API andsuitable excipients. No pretreatment of the powder blend by wet or drygranulation procedure is required.

1.8.1.2 The events that motivates the industry people to use direct compression technique

I.Commercial availability of the directly compressible excipients possessing both goodcompressibility and good flowability.

For example,Spray dried lactose, Anhydrous lactose, Starch-1500, microcrystallinecellulose, Di-PacÒ, Sorbitol

II.Major advancesin tablet compression machinery:

i)Improved positive die feeding,

ii)Precompression of powder blend.

1.8.1.3 Merits

i)Direct compression is more efficient and economical process as compared to otherprocesses, because it involves only dry blending and compaction of API andnecessary excipients.

ii)The most important advantage of direct compression iseconomical process.

Reducedprocessing time, reduced labor costs, fewer manufacturing steps, and lessnumber of equipments are required, less process validation, reduced consumptionof power.

iii)Elimination of heat and moisture, thus increasing notonly the stability but also the suitability of the process for thermolabile andmoisture sensitive API’s.

iv)Particle size uniformity.

v)Prime particle dissolution.

In case of directly compressed tablets afterdisintegration, each primary drug particle is liberated. While in the case oftablets prepared by compression of granules, small drug particles with a larger

surface area adhere together into larger agglomerates; thus decreasing thesurface area available for dissolution.

vi)The chances of batch-to-batch variation are negligible,because the unit operations required for manufacturing processes is fewer.

vii)Chemical stability problems for API and excipient would be avoided.

viii)Providesstability against the effect of aging which affects the dissolution rates.

1.8.1.4 Merits over wet granulation process

The variables faced in the processing of the granulescan lead to significant tableting problems. Properties of granules formed canbe affected by viscosity of granulating solution, the rate of addition ofgranulating solution, type of mixer used and duration of mixing, method andrate of dry and wet blending. The above variables can change the density andthe particle size of the resulting granules and may have a major influence onfill weight and compaction qualities. Drying can lead to unblending as solubleAPI migrates to the surface of the drying granules.

1.8.1.5 Demerits

Excipient Related

i)Problems in theuniform distribution of low dose drugs.

ii)High dose drugs having high bulk volume, poorcompressibility and poor flowability are not suitable for direct compression.

For example, Aluminium Hydroxide, Magnesium Hydroxide

iii) The choice of excipients for direct compression isextremely critical. Direct compression diluents and binders must possess bothgood compressibility and good flowability.

iv) Many active ingredients are not compressible eitherin crystalline or amorphous forms.

v) Direct compression blends may lead to unblendingbecause of difference in particle size or density of drug and excipients.Similarly the lack of moisture may give rise to static charges, which may leadto unblending.

vi) Non-uniform distribution of colour, especially intablets of deep colours.

Process Related

i)Capping, lamination, splitting, or layering of tablets is sometimes related to airentrapment during direct compression. When air is trapped, the resultingtablets expand when the pressure of tablet is released, resulting in splits orlayers in the tablet.

ii)In some cases require greater sophistication inblending and compression equipments.

iii) Direct compression equipments are expensive.

1.8.1.6 Manufacturing steps for direct compression

Direct compression involvescomparatively few steps:

i)Milling of drug and excipients.

ii) Mixing of drug and excipients.

iii) Tablet compression.

Figure.23. Manufacturing Steps For Direct Compression

1.8.1.7 Direct compression Excipients

Direct compression excipients mainly includediluents, binders and disintegrants. Generally these are common materials thathave been modified during the chemical manufacturing process, in such a way toimprove compressibility and flowability of the material.

The physicochemical properties of the ingredientssuch as particle size, flowability and moisture are critical in directcompression tableting. The success of direct compression formulation is highlydependent on functional behavior of excipients.

1.8.1.7.1 An ideal direct compression excipient should possess the following attributes

i)It should havegood compressibility.

ii)It should possess good hardness after compression,that is material should not possess any deformational properties;otherwise this may lead to capping andlamination of tablets.

iii) It should have good flowability.

iv) It should be physiologically inert.

v) It should be compatible with wide range of API.

vi) It should be stable to various environmentalconditions (air, moisture, heat, etc.).

vii) It should not show any physical or chemical change inits properties on aging.

viii) It should have high dilution potential. i.e. Able to incorporate high amount of API.

ix) It should be colourless, odorless and tasteless.

x) It should accept colourants uniformity.

xi) It should possess suitable organoleptic propertiesaccording to formulation type, that is in case of chewable tablet diluentshould have suitable taste and flavor. For example mannitol produces coolingsensation in mouth and also sweet test.

xii) It should not interfere with bioavailability andbiological activity of active ingredients.

xiii)It should beeasily available and economical in cost.

1.8.1.7.2 Major excipients required in directcompression

I.Diluents

II.Binders

III.Disintegrants

Diluents

Selectionof direct compression diluent is extremely critical, because the success orfailure of direct compression formulation completely depends on characteristicsof diluents. There are number of factors playing key role in selection of

optimum diluent. Factors like- Primary properties of API (particle size andshape, bulk density, solubility), the characteristics needed for processing(flowability, compressibity), and factors affecting stability (moisture, light,and other environmental factors), economical approach and availability of material.

Afterall, one can say that raw material specifications should be framed in such away that they provide an ease in manufacturing procedures and reduce chances ofbatch to batch variation. This becomes possible only when the raw materialspecifications reflect most of properties of diluents as mentioned in section1.5.

Binders (56)

Binders are the agents used to impart cohesive qualitiesto the powdered material. The quality of binder used has considerable influenceon the characteristic of the direct compression tablets. The direct compressionmethod for preparing tablets requires materials which are not only free flowingbut also sufficiently cohesive to act as binder.

Key Phrases

Ø Directcompression is one of the most advanced technologies to prepare tablets.

Ø It requiresonly blending and compression of excipients.

Ø It is aneconomical process.

Ø It is suitablefor heat and moisture sensitive API.

It is notsuitable for very low and very high dose drugs.

1.8.2 Granulation (1,4,5,57)

What will you gain?

1.8.2.1Introduction

1.8.2.2Wet granulation

1.8.2.2.1 Introduction

1.8.2.2.2 Important steps involved in the wetgranulation

1.8.2.2.3 Limitation of wet granulation

1.8.2.2.4 Special wet granulation techniques

1.8.2.2.4.1 High shear mixture granulation

1.8.2.2.4.2 Fluid bed granulation

1.8.2.2.4.3 Extrusion and Spheronization

1.8.2.2.4.4 Spray drying granulation

1.8.2.2.5 Lists of equipments for wet granulation

1.8.2.2.6 Current topics related to wetgranulation

1.8.2.3Dry granulation

1.8.2.3.1 Introduction

1.8.2.3.2 Advantages

1.8.2.3.3 Disadvantages

1.8.2.3.4 Steps in dry granulation

1.8.2.3.5 Two main dry granulation processes

1.8.2.3.5.1Slugging process

1.8.2.3.5.2 Roller compaction

1.8.2.3.6 Formulation for dry granulation

1.8.2.3 Advancement in Granulations

1.8.2.3.1 Steam Granulation

1.8.2.3.2 Melt Granulation/ThermoplasticGranulation

1.8.2.3.3 Moisture

Activated Dry Granulation

1.8.2.3.4 MoistGranulation Technique (MGT)

1.8.2.3.5 Thermal Adhesion Granulation Process(TAGP)

1.8.2.3.6 Foam Granulation

1.8.2.1 Introduction

Granulation may be defined as a size enlargement processwhich converts small particles into physically stronger & largeragglomerates.

Granulation method can be broadly classified into twotypes:

Wet granulation and Dry granulation

Ideal characteristics of granules

The ideal characteristics of granules include sphericalshape, smaller particle size distribution with sufficient fines to fill voidspaces between granules, adequate moisture (between 1-2%), good flow, goodcompressibility and sufficient hardness.

The effectiveness of granulation depends on thefollowing properties

i) Particle size ofthe drug and excipients

ii) Type of binder (strong or weak)

iii) Volume of binder (less or more)

iv) Wet massing time ( less or more)

v) Amount of shear applied

vi) Drying rate ( Hydrate formation and polymorphism)

1.8.2.2 Wet granulation

1.8.2.2.1 Introduction

The most widely used process of agglomerationin pharmaceutical industry is wet granulation. Wet granulation process simplyinvolves wet massing of the powder blend with a granulating liquid, wet sizingand drying.

1.8.2.2.2 Important steps involved in the wetgranulation

i) Mixing of thedrug(s) and excipients

ii) Preparation of binder solution

iii) Mixing of binder solution with powder mixture to formwet mass.

iv) Coarse screening of wet mass using a suitable sieve(6-12 # screens).

v) Drying of moist granules.

vi) Screening of dry granules through a suitable sieve(14-20 # screen).

vii)  Mixing of screened granules with disintegrant,glidant, and lubricant.

1.8.2.2.3 Limitation of wet granulation

i) The greatestdisadvantage 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 processing

iii) Stability may be major concern for moisture sensitiveor thermo labile drugs

iv) Multiple processing steps add complexity and makevalidation and control difficult

v) An inherent limitation of wet granulation is that anyincompatibility between formulation components is aggravated.

1.8.2.2.4 Special wet granulation techniques

i) High shearmixture granulation

ii) Fluid bed granulation

iii) Extrusion-spheronization

iv)Spray drying

1.8.2.2.4.1 High shear mixture granulation

High shear mixture has been widely used in Pharmaceuticalindustries for blending and granulation. Blending and wet massing isaccompanied by high mechanical agitation by an impeller and a chopper. Mixing,densification and agglomeration are achieved through shear and compaction forceexerted by the impeller.

Advantages:

i) Short processingtime

ii) Less amount of liquid binders required compared withfluid bed.

iii) Highly cohesive material can be granulated.

1.8.2.2.4.2 Fluid bed granulation

Fluidization is the operation by which fine solids aretransformed into a fluid like state through contact with a gas. At certain gasvelocity the fluid will support the particles giving them free mobility withoutentrapment.

Fluid bed granulation is a process by which granules areproduced in a single equipment byspraying a binder solution onto a fluidized powder bed. The material processedby fluid bed granulation are finer, free flowing and homogeneous.

1.8.2.2.4.3 Extrusion and Spheronization

Itis a multiple step process capable of making uniform sized spherical particles.It is primarily used as a method to produce multi-particulates for controlledrelease application.

Advantages:

i) Ability toincorporate higher levels of active components without producing excessivelylarger particles.

ii) Applicable to both immediate and controlled releasedosage form.

1.8.2.2.4.4 Spray drying granulation

It is a unique granulation technique that directlyconverts liquids into dry powder in a single step. This method removes moistureinstantly and converts pumpable liquids into a dry powder.

Advantages:

i) Rapid process

ii) Ability to be operated continuously

iii) Suitable for heat sensitive product

1.8.2.2.5 Lists of equipments for wet granulation

High Shear granulation:

i)Little ford Lodgie granulator

ii)Little ford MGT granulator

iii)Diosna granulator

iv)Gral mixer

Granulator with drying facility:

i)Fluidized bed granulator

ii) Day nauta mixer processor

iii)Double cone or twin shell processor

iv)Topo granulator

Special granulator:

i)Roto granulator

ii)Marumerizer

1.8.2.2.6 Current topics related to wet granulation

I. Hydrate formation

For example, theophylline anhydrous duringhigh shear wet granulation transfers to theophylline monohydrate. The midpointconversion occurs in three minutes after the binder solution is added.

For online monitoring of the transformation from one form to another, Ramanspectroscopy is most widely used.

II.   Polymorphic transformation

Thedrying phase of wet granulation plays a vital role for conversion of one formto another.

Forexample, glycine which exist in three polymorphs that is a, β, g . gis the most stable form and ais the metastable form. The stable Glycine polymorph (g) converts to metastable form (a) when wet granulated with microcrystallinecellulose.

1.8.2.3 Dry granulation

1.8.2.3.1 Introduction

In dry granulation process the powder mixture iscompressed without the use of heat and solvent. It is the least desirable ofall methods of granulation. The two basic procedures are to form a compact ofmaterial by compression and then to mill the compact to obtain a granules. Twomethods are used for dry granulation. The more widely used method is slugging,where the powder is precompressed and the resulting tablet or slug are milledto yield the granules. The other method is to precompress the powder withpressure rolls using a machine such as Chilosonator.

1.8.2.3.2 Advantages

The main advantages of dry granulation or slugging arethat it uses less equipments and space. It eliminates the need for bindersolution, heavy mixing equipment and the costly and time consuming drying steprequired for wet granulation. Slugging can be used for advantages in thefollowing situations:

i) For moisturesensitive material

ii) For heat sensitive material

iii) For improved disintegration since powder particlesare not bonded together by a binder

1.8.2.3.3 Disadvantages

i) It requires aspecialized heavy duty tablet press to form slug

ii) 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.

1.8.2.3.4 Steps in dry granulation

i) Milling of drugsand excipients

ii) Mixing of milled powders

iii) Compression into large, hard tablets to make slug

iv) Screening of slugs

v) Mixing with lubricant and disintegrating agent

vi) Tablet compression

1.8.2.3.5 Two main dry granulation processes

1.8.2.3.5.1 Slugging process

Granulation by slugging is the process of compressing drypowder of tablet formulation with tablet press having die cavity large enoughin diameter to fill quickly. The accuracy or condition of slug is not tooimportant. Only sufficient pressure to compact the powder into uniform slugsshould be used. Once slugs are produced they are reduced to appropriate granulesize for final compression by screening and milling.

Factors which determine how well a material may slug

i) Compressibilityor cohesiveness of the mater

ii) Compression ratio of powder

iii) Density of the powder

iv) Machine type

v) Punch and die size

vi) Slug thickness

vii) Speed of compression

viii) Pressure used toproduce slug

1.8.2.3.5.2 Roller compaction

The compaction ofpowder by means of pressure roll can also be accomplished by a machine calledchilsonator. Unlike tablet machine, thechilsonator turns out a compacted mass in a steady continuous flow. The powderis fed down between the rollers from the hopper which contains a spiral augerto feed the powder into the compaction zone. Like slugs, the aggregates arescreened or milled for production into granules.

1.8.2.3.6 Formulation for dry granulation

The excipients used for dry granulation are basicallysame as that of wet granulation or that of direct compression. With drygranulation it is often possible to compact the active ingredient with a minoraddition of lubricant and disintegrating agent. Fillers that are used in drygranulation include the following examples: Lactose, dextrose, sucrose, MCC,calcium sulphate, Sta-Rx® etc .

Examples of some tabletformulation prepared by dry granulation:

Aspirin tablet Aspirin effervescenttablet

Rx Rx

Starch Sodiumbicarbonate

Cab-o-sil® Citricacid

Aspirin Fumaricacid

Aspirin

Antacid tablet

Rx

Aluminumhydroxide

Magnesiumhydroxide

Magnesiumcarbonate

Sucrose

PEG

1.8.2.3 Advancement in Granulations

1.8.2.3.1 SteamGranulation

It is modification of wet granulation. Here steam is used as a binder insteadof water. Its severalbenefits includes higherdistribution uniformity, higher diffusionrate into powders, morefavourable thermal balanceduring drying step, steamgranules are more spherical, have large surfacearea hence increaseddissolution rate ofthe drug fromgranules, processing time isshorter therefore morenumber of tablets areproduced per batch, compared tothe use oforganic solvent water vapouris environmentally friendly,no health hazardsto operators, no restrictionby ICH ontraces left inthe granules, freshly distilledsteam is sterileand therefore thetotal count canbe kept undercontrol, lowers dissolution rateso can beused for preparationof taste maskedgranules without modifyingavailability of thedrug. But the limitation is that it is unsuitable for thermolabiledrugs. Moreover special equipments

are required andare unsuitable forbinders that cannotbe later activatedby contact withwater vapour.

1.8.2.3.2 Melt Granulation / Thermoplastic Granulation (24)

Here granulation is achieved by the addition of meltable binder. That isbinder is in solid state at room temperature but meltsin the temperature range of 50 – 80˚C. Melted binder then acts like a bindingliquid. There is no need of drying phase since dried granulesare obtained by cooling it to room temperature. Moreover, amount of liquidbinder can be controlled precisely and the production andequipment costs are reduced. It is useful for granulating watersensitive material and producing SR granulation or solid dispersion. But thismethod is not suitable for thermolabilesubstances. When water solublebinders are needed, Polyethylene Glycol (PEG) is usedas melting binders. When waterinsoluble binders areneeded, Stearic acid, cetyl or stearylalcohol, various waxes andmono-, di-, & triglycerides are usedas melting binders.

1.8.2.3.3 MoistureActivated Dry Granulation (MADG) (58)

It involves moisture distribution andagglomeration. Tablets prepared using MADG method has better contentuniformity. This method utilizes very little granulating fluid. It decreasesdrying time and produces granules with excellent flowability.

1.8.2.3.4 Moist Granulation Technique (MGT) (59)

A small amount granulating fluid is addedto activate dry binder and to facilitate agglomeration. Thena moisture absorbing material like Microcrystalline Cellulose (MCC) isadded to absorb any excess moisture. By adding MCCin this way drying step isnot necessary. It is applicable for developing a controlled release formulation.

1.8.2.3.5 ThermalAdhesion Granulation Process (TAGP) (60)

It is applicable for preparing direct tableting formulations. TAGP isperformed under lowmoisture content or low contentof pharmaceutically acceptable

solvent by subjectinga mixture containingexcipients to heatingat a temperaturein the rangefrom about 30ºCto about 130ºCin a closedsystem under mixingby tumble rotationuntil the formationof granules. Thismethod utilizes lesswater or solventthan traditional wetgranulation method. Itprovides granules withgood flow propertiesand binding capacityto form tabletsof low friability, adequate hardnessand have ahigh uptake capacityfor active substanceswhose tableting ispoor.

1.8.2.3.6 FoamGranulation (61)

Here liquid binders are added as aqueous foam. Ithas several benefitsover spray(wet) granulationsuch as itrequires less binderthan Spray Granulation, requires lesswater to wetgranulate, rate ofaddition of foamis greater thanrate of additionof sprayed liquids, nodetrimental effects ongranulate, tablet, or invitrodrug dissolution properties, no pluggingproblems since useof spray nozzlesis eliminated, no overwetting, useful forgranulating water sensitiveformulations, reduces drying time, uniform

distribution of binderthroughout the powderbed, reduce manufacturing time, lessbinder required forImmediate Release (IR) andControlled Release (CR)formulations.

Key Phrases

Ø In wet granulation process a granulating liquid isused to facilitate the agglomeration process. Wet granulation has been andcontinues to be the most widely used agglomeration process. Typically wetmassing of pharmaceutical powder is carried out in the high shear mixturebefore wet screening and dried in fluidized bed equipment.

Ø  In the dry granulation process granulation takesplace without utilizing liquid. In this process dry powder particles may bebrought together mechanically by compression into slug or by rolledcompaction.

Ø  Steam Granulation, Melt Granulation, MADG, MGT,TAGP, Foam Granulation are some ofthe new advancements ingranulation and showbetter quality granuleformation as comparedto conventional granulationmethods.

Tablet coatingSubmitted by on Sun, 12/06/2009 - 19:54

1.9 Tablet coatingWhat will you gain?

1.9.1Introduction

1.9.2Aspects of tablet coating

1.9.3

Basic principle of tablet coating

1.9.4Type of tablet coating process

1.9.4.1 Sugar coating

1.9.4.2 Film coating

1.9.4.3 Enteric coating

1.9.4.3.1 Enteric sugar coating

1.9.4.3.2 Enteric film coating

1.9.4.3.3Controlled release coating

1.9.4.4 Specialized coating

1.9.4.4.1 Compressed coating

1.9.4.4.2 Electrostatic coating

1.9.4.4.3 Dip coating

1.9.4.4.4 Vacuum film coating

1.9.5Equipments

1.9.6Processing parameters

1.9.1 Introduction (1-3,5)

Coatedtablets are defined as “tablets covered with one or more layers of mixture ofvarious substances such as natural or synthetic resins ,gums ,inactive andinsoluble filler, sugar, plasticizer, polyhydric alcohol ,waxes,authorized colouring materialand some times flavoring material .

Coatingmay also contain active ingredient. Substances used for coating are usuallyapplied as solution or suspension under conditions where vehicle evaporates.

1.9.2 Aspects oftablet coating

I.   Therapy

i) Avoid irritation of oesophagus and stomach

ii) Avoid bad taste

iii) Avoid inactivation of drug in the stomach

iv) Improve drug effectiveness

v) Prolong dosing interval

vi) Improve dosing interval

vii) Improve patient compliance

II.  Technology

i) Reduce influenceof moisture

ii) Avoid dust formation

iii) Reduce influence of atmosphere

iv) Improve drug stability

v) Prolong shelve life

III. Marketing

i) Avoid bad taste

ii) Improve product identity

iii) Improve appearance and acceptability

1.9.3 Basic principle of tabletcoating

The principle of tablet coating is relativelysimple. Tablet coating is theapplication of coating composition to moving bed of tablets with concurrent useof heated air to facilitate evaporation of solvent.

Basicprinciples involve

i) Insulation whichinfluences the release pattern as little as possible and does not markedlychange the appearance.

ii) Modified release with specific requirement andrelease mechanism adapted to body function in the digestive tract

iii) Colour coating which provides insulation or iscombined with modified release coating.

1.9.4 Type of tablet coating process

1.9.4.1 Sugar coating (1,3,5)

Compressedtablets may be coated with coloured or uncoloured sugar layer. The coating iswater soluble and quickly dissolves after swallowing. The sugarcoat protectsthe enclosed drug from the environment and provides a barrier to objectionabletaste or order. The sugar coat also enhances the appearance of the compressedtablet and permit imprinting manufacturing’s information. Sugar coatingprovides a combination of insulation, taste masking, smoothing the tablet core,colouring and modified release. The disadvantages of sugar coating are the timeand expertise required in the coating process and thus increases size, weightand shipping costs.

Sugar coating process involves five separateoperations:

I. Sealing/Water proofing: provides a moisture barrier and harden the tablet surface.

II. Subcoating:causes a rapid buildup to round off the tablet edges.

III. Grossing/Smoothing:smoothes out the subcoated surface and increases the tablet size topredetermine dimension.

IV. Colouring: givesthe tablet its colour and finished size.

V. Polishing:produces the characteristics gloss.

I. Sealing/Waterproofing

Priorto applying any sugar/water syrup, the tablet cores must be sealed, thoroughlydried and free of all residual solvents.

The seal coat provides a moisture barrier and hardnessthe surface of the tablet in order to minimize attritional effects. Coretablets having very rapid disintegration rates conceivably could start thedisintegration process during the initial phase of sugar coating. The sealantsare generally water-insoluble polymers/film formers applied from an organicsolvent solution. The quantities of material applied as a sealing coat willdepend primarily on the tablet porosity, since highly porous tablets will tendto soak up the first application of solution, thus preventing it from spreadinguniformly across the surface of every tablet in the batch. Hence, one or morefurther application of resin solution may be required to ensure that the tabletcores are sealed effectively.

Common materials used as a sealant include Shellac, Zine,Cellulose acetate phthalate (CAP), Polyvinylacetate phthalate,Hyroxylpropylcellulose, Hyroxypropylmethylcellulose etc.

II. Subcoating

Subcoating is the actual start of the sugar coatingprocess and provides the rapid buildup necessary to round up the tablet edge.It also acts as the foundation for the smoothing and colour coats.

Generally two methods are used for subcoating:

i) The applicationof gum based solution followed by dusting with powder and then drying. Thisroutine is repeated until the desired shape is achieved.

ii) The application of a suspension of dry powder ingum/sucrose solution followed by drying.

Thus subcoating is a sandwich of alternate layer of gumand powder. It is necessary to remove the bulk o the water after eachapplication of coating syrup.

Table.23. Typical Binder Solution Formulation For Subcoating(1)

  %W/W %W/W

Gelatin 6 3.3

Gum acacia (powdered) 8 8.7

Sucrose (powdered) 45 55.3

Distilled water to100

to100

Table.24. Typical Dusting Powder Formulation For Subcoating(1)

  %W/W %W/W

Calciumcarbonate

40.0 -

Titaniumdioxide

5.0 1.0

Talc,asbestos free

25.0 61.0

Sucrose(powdered )

28.0 38.6

Gumacacia (powdered)

2.0 -

Table.25. Typical Suspension Subcoating Formulation(1)

  %W/W

Sucrose 40.0

Calciumcarbonate

20.0

Talc,asbestos free

12.0

Gumacacia(powdered)

2.0

Titaniumdioxide

1.0

Distilledwater

25.0

III. Grossing/ smoothing

The grossing/smoothing process is specifically for smoothing and filing theirregularity on the surface generated during subcoating. It also increases thetablet size to a predetermined dimension.

If the subcoating is rough with highamount of irregularities then the use of grossing syrup containing suspendedsolids will provide more rapid buildup and better filling qualities. Smoothingusually can be accomplished by the application of a simple syrup solution(approximately 60-70 % sugar solid). This syrup generally contains pigments,starch, gelatin, acacia or opacifier if required.

Small quantities of coloursuspension can be applied to impart a tint of the desired colour when there areirregularities in coating.

IV.Colour coating

This stage is often critical in the successfulcompletion of a sugar coating process and involves the multiple application ofsyrup solution (60-70 % sugar solid) containing the requisite colouring matter.Mainly soluble dyes were used in the sugar coating to achieve the desiredcolour, since the soluble dye will migrate to the surface during drying. Butnow a days the insoluble certified lakes have virtually replaced the solubledyes in pharmaceutical tablet coating. The most efficient process for colourcoating involves the use of a predispersed opacified lake suspension.

V. Polishing

Sugar-coated tablets needs to be polished to achievea final elegance. Polishing is achieved by applying the mixture of waxes likebeeswax, carnubawax, candelila wax or hard paraffin wax to tablets in polishingpan.

1.9.4.2 Film Coating

Film coating is more favored over sugar coating.

Table.26. Comparison Between Film Coating And Sugar Coating(1)

FEATURES FILM COATING SUGAR COATINGTablet:

Appearance

 

 

Retain contour of original core.Usually not as shiny as sugar

 

Rounded with high degree of polish

 

 

Weightincrease because of coating material

 

Logoor ‘break lines’

coat type

 

 

2-3%

 

 

Possible

 

 

 

30-50%

 

 

Not possibleProcess

Operatortraining required

 

 

Adaptabilityto GMP

 

Processstages

 

Functionalcoatings

 

Process tends itself to automation and easy training of operator

 

High

 

Usually single stage

 

Easily adaptable for controlled release

 

Considerable

 

 

 

Difficulty may arise

 

Multistage process

 

Not usually possible apart from enteric coating

Process description (1)

Film coating is deposition of a thin film of polymer surrounding thetablet core. Conventional pan equipmentsmay be used but now a day’s more sophisticated equipments are employed to havea high degree of automation and coating time.The polymer is solubilized into solvent.Other additives like plasticizers and pigments are added. Resulting solution is sprayed onto a rotatedtablet bed. The drying conditions causeremoval of the solvent, giving thin deposition of coating material around eachtablet core.

Process details (1)

Usually spray process is employed in preparation of filmcoated tablets. Accela cota is theprototype of perforated cylindrical drum providing high drying aircapacity. Fluidized bed equipment hasmade considerable impact where tablets are moving in a stream of air passingthrough the perforated bottom of a cylindrical column. With a smaller cylindrical insert, the streamof cores is rising in the center of the device together with a spray mistapplied in the middle of the bottom. Forfluidized bed coating, very hard tablets (hardness > 20 N) have to be used.

Basic process requirements for film coating (2)

The fundamental requirements are independent of theactual type of equipments being used and include adequate means of atomizingthe spray liquid for application to the tablet core, adequate mixing andagitation of tablet bed, sufficient heat input in the form of drying air toprovide the latent heat of evaporation of the solvent. This is particularlyimportant with aqueous-based spraying and good exhaust facilities to removedust and solvent laden air.

Development of film coating formulations (1)

If the following questions are answered concomitantlythen one can go for film coating:

i) Is it necessaryto mask objectionable taste, colour and odor?

ii) Is it necessaryto control drug release?

iii) What tablets size, shape, or colour constrains mustbe placed on the developmental work?

Colour, shape and size of final coated tablet areimportant for marketing and these properties have a significant influence onthe marketing strategies. An experiencedformulator usually takes the pragmatic approach and develops a coatingformulations modification of one that has performed well in the past. Spraying or casting films can preliminarilyscreen film formulations. Cast films cabis prepared by spreading the coating composition on teflon, glass or aluminumfoil surface using a spreading bar to get a uniform film thickness. Sprayed films can be obtained by mounting aplastic-coated surface in a spray hood or coating pan.

Coating formula optimization (1)

Basic formula is obtained from past experience or from various sourcesin the literature. Modifications arerequired to improve adhesion of the coating to the core, to decrease bridgingof installations, to increase coating hardness, etc. Usually concentration of colorant andopaquant are fixed to get predetermined shade.Common modification is to alter polymer-to-plasticizer ratio or additionof different plasticizer/ polymer.Experimentation of this type can be best achieved by fractional

Materials used in film coating (1,13)

I. Film formers, which may be enteric or nonenteric

II. Solvents

III. Plasticizers

IV. Colourants

V. Opaquant-Extenders

VI. Miscellaneous coating solution components

I. Filmformers (1)

Ideal requirements of film coating materials aresummarized below:

i) Solubility insolvent of choice for coating preparation

ii) Solubility requirement for the intended use e.g. freewater-solubility, slow water-solubility or pH -dependent solubility

iii) Capacity to produce an elegant looking product

iv) High stability against heat, light, moisture, air andthe substrate being coated

v) No inherent colour, taste or odor

vi) High compatibility with other coating solutionadditives

vii) Nontoxic with no pharmacological activity

viii) High resistanceto cracking

ix) Film former should not give bridging or filling ofthe debossed tablet

x) Compatible to printing procedure

Commonly used film formersare as follow

i. HydroxyPropyl Methyl Cellulose (HPMC)

Itis available in different viscosity grades. It is a polymer of choice for airsuspension and pan spray coating systems because of solubility characteristicin gastric fluid, organic and aqueous solvent system.

Advantagesinclude: it does not affect tablet disintegration and drug availability, it ischeap, flexible, highly resistant to heat, light and moisture, it has no tasteand odor, colour and other additives can be easily incorporated.

Disadvantageincludes: when it is used alone, thepolymer has tendency to bridge or fill the debossed tablet surfaces. So mixture of HPMC and other polymers/plasticizers is used.

ii. MethylHydroxy Ethyl Cellulose (MHEC)

It is available in wide variety of viscosity grades. It is not frequently used as HPMC becausesoluble in fewer organic solvents.

iii. EthylCellulose (EC)

Depending on the degree of ethoxy substitution, differentviscosity grades are available. It is completely insoluble in water and gastricfluids. Hence it is used in combinationwith water-soluble additives like HPMC and not alone. Unplasticized ethyl cellulose films arebrittle and require film modifiers to obtain an acceptable filmformulation. Aqua coat is aqueouspolymeric dispersion utilizing ethyl cellulose.These pseudolatex systems contain high solids, low viscositycompositions that have coating properties quite different from regular ethylcellulose solution.

iv. HydroxyPropyl Cellulose (HPC)

It is soluble in water below 40oc (insolubleabove 45 oC), gastric fluid and many polar organic solvents. HPC is extremely tacky as it dries fromsolution system. It is used for sub coatand not for colour or glass coat. Itgives very flexible film.

v. Povidone

Degree ofpolymerization decides molecular weight of material. It is available in four viscosity grades i.e.K-15, K-30, K-60 and K-90. Averagemolecular weight of these grades is 10000, 40000, 160000 and 360000respectively. K-30 is widely used astablet binder and in tablet coating. Ithas excellent solubility in wide variety of organic solvents, water, gastricand intestinal fluids. Povidone can becross-linked with other materials to produce films with entericproperties. It is used to improvedispersion of colourants in coating solution.

vi. Sodium carboxy methylcellulose

It is available in medium, high andextra high viscosity grades. It iseasily dispersed in water to form colloidal solutions but it is insoluble inmost organic solvents and hence not a material of choice for coating solutionbased on organic solvents. Filmsprepared by it are brittle but adhere well to tablets. Partially dried films of are tacky. So coating compositions must be modified withadditives.

viii. Polyethyleneglycols (PEG)

Lower molecular weightsPEG (200-600) are liquid at room temperature and are used as plasticizers. High molecular weights PEG (900-8000series)are white, waxy solids at room temperature.Combination of PEG waxes with CAP gives films that are soluble ingastric fluids.

ix. Acrylate polymers

It is marketed underthe name of EudragitÒ. EudragitÒE is cationic co-polymer. OnlyEudragitÒE is freely soluble in gastric fluid up to pH 5 andexpandable and permeable above pH 5.This material is available as organic solution (12.5% inisopropanol/acetone), solid material or 30% aqueous dispersion. EudragitÒRL & RS are co-polymers with low content ofquaternary ammonium groups. These areavailable only as organic solutions and solid materials. They produce films for delayed action (pHdependent).

II. Solvents(1)

Solvents are used to dissolve ordisperse the polymers and other additives and convey them to substratesurface.

Idealrequirement are summarized below:

i) Should be eitherdissolve/disperse polymer system

ii) Should easilydisperse other additives into solvent system

iii) Small concentration of polymers (2-10%) should not inan extremely viscous solution systemcreating processing problems

iv) Should be colourless, tasteless, odorless, inexpensive,inert, nontoxic and nonflammable

v) Rapid dryingrate

vi) No environmental pollution

Mostly solvents are used either alone or incombination with water, ethanol, methanol, isopropanol, chloroform, acetone,methylene chloride, etc. Water is moreused because no environmental and economic considerations. For drugs that readily hydrolyze in presenceof water, non aqueous solvents are used.

III. Plasticizers(1)

As solvent is removed, most polymeric materials tend topack together in 3-D honey comb arrangement.

“Internal” or “External” plasticizing technique is used to modifyquality of film. Combination ofplasticizer may be used to get desired effect.Concentration of plasticizer is expressed in relation to the polymerbeing plasticized. Recommended levels ofplasticizers range from 1-50 % by weight of the film former. Commonly used plasticizers are castor oil,PG, glycerin, lower molecular weight (200-400 series), PEG, surfactants,etc. For aqueous coating PEG and PG aremore used while castor oil and spans are primarily used for organic-solventbased coating solution. Externalplasticizer should be soluble in the solvent system used for dissolving thefilm former and plasticizer. Theplasticizer and the film former must be at least partially soluble or misciblein each other.

IV. Colourants(1)

Colourants can be used in solution form or in suspensionform. To achieve proper distribution ofsuspended colourants in the coating solution requires the use of the powderedcolourants (<10 microns). Most commoncolourants in use are certified FD & C or D & C colourants. These are synthetic dyes or lakes. Lakes are choice for sugar or film coating asthey give reproducible results.Concentration of colourants in the coating solutions depends on thecolour shade desired, the type of dye, and the concentration ofopaquant-extenders. If very light shadeis desired, concentration of less than 0.01 % may be adequate on the otherhand, if a dark colour is desired a concentration of more than 2.0 % may berequired. The inorganic materials (e.g.iron oxide) and the natural colouring materials (e.g. anthrocyanins,carotenoids, etc) are also used to prepare coating solution. Magenta red dye is non absorbable in biologicsystem and resistant to degradation in the gastro intestinal track. OpasrayÒ (opaque colour concentrate for film coating) andOpadryÒ (complete film coating concentrate) are promoted asachieving less lot-to-lot colour variation.

V. Opaquant-Extenders(1)

These are very fine inorganic powder used to provide morepastel colours and increase film coverage.These inorganic materials provide white coat or mask colour of thetablet core. Colourants are veryexpensive and higher concentration is required.These inorganic materials are cheap.In presence of these inorganic materials, amount of colourants requireddecreases. Most commonly used materialsare titanium dioxide, silicate (talc &aluminum silicates), carbonates

(magnesium carbonates), oxides (magnesium oxide) & hydroxides (aluminumhydroxides). Pigments were investigated in the production of opaque films andit was found that they have good hiding power and film-coated tablets havehighlighted intagliations.

VI. Miscellaneous coating solution component (1)

Flavors, sweeteners, surfactants, antioxidants,antimicrobials, etc. may be incorporated into the coating solution.

1.9.4.3 Enteric coating (1, 2, 13)

Thistype of coating is used to protect tablet core from disintegration in the acidenvironment of the stomach for one or more of the following reasons:

i) To preventdegradation of acid sensitive API

ii) To preventirritation of stomach by certain drugs like sodium salicylate

iii) Delivery of API into intestine

iv) To provide a delayed release component for repeataction tablet

Several kinds of enteric layer systems are nowavailable

Onelayer system - The coating formulation is applied in one homogeneous layer,which can be whites-opaque or coloured.Benefit is only one application needed.

Twolayer system - To prepare enteric tablets of high quality and pleasingappearance the enteric formulation is applied first, followed by colouredfilm. Both layers can be of entericpolymer or only the basic layer contains enteric polymer while top layer is fastdisintegrating & water-soluble polymer

Ideal properties of entericcoating material are summarized as below

i) Resistance togastric fluids

ii) Susceptible/permeableto intestinal fluid

iii) Compatibility with most coating solution componentsand the drug substrate

iv) Formation of continuous film

v) Nontoxic, cheapand ease of application

vi) Ability to be readily printed

Polymers used for entericcoating are as follow

i. Celluloseacetate phthalate (CAP)

It is widely used in industry. Aquateric is reconstituted colloidaldispersion of latex particles. It is composedof solid or semisolid polymer spheres of CAP ranging in size from 0.05 - 3microns. Cellulose acetate trimellitate(CAT) developed as an ammoniated aqueous formulation showed faster dissolutionthan a similar formulation of CAP.

Disadvantagesinclude: It dissolves above pH 6 only, delays absorption of drugs, it ishygroscopic and permeable to moisture in comparison with other enteric polymer,it is susceptible to hydrolytic removal of phthalic and acetic acid changingfilm properties. CAP films are brittle and usually used with otherhydrophobic film forming materials.

ii. Acrylate polymers

Eudragit®L & Eudragit®Sare two forms of commercially available enteric acrylic resins. Both of them produce films resistant togastric fluid. Eudragit®L& S are soluble in intestinal fluid at pH 6 & 7 respectively. Eudragit®L is available as anorganic solution (Isopropanol), solid or aqueous dispersion. Eudragit®S is available only as anorganic solution (Isopropanol) and solid.

iii Hydroxy propyl methyl cellulose phthalate

HPMCP50, 55 & 55-s (also called HP-50, HP-55 & HP-55-s) is widely used. HP-55 is recommended for general entericpreparation while HP-50 & HP-55-s for special cases. These polymers dissolve at a pH 5-5.5.

iii. Polyvinylacetate phthalate

Itis similar to HP-55 in stability and pH dependent solubility.

1.9.4.3.1 Enteric sugar coating (2)

Here the sealing coat is tailored to include one of the enteric polymersin sufficient quantity to pass the enteric test for disintegration. The sub coating and subsequent coating stepsare then as for conventional sugar coating.

1.9.4.3.2Enteric film coating (2)

Enteric polymers are capable of forming a direct film ina film coating process. Sufficientweight of enteric polymer has to be used to ensure an efficient entericeffect. Enteric coating can be combinedwith polysaccharides, which are enzyme degraded in colon e.g. Cyclodextrin& galactomannan.

1.9.4.3.3Controlled release coating (2)

Polymers like modified acrylates, water insolublecellulose (ethyl cellulose), etc. used for control release coating.

1.9.4.4 Specialized coating (1)

1.9.4.4.1 Compressed coating

This type of coating requires a specialization tabletmachine. Compression coating is not widely used but it has advantages in somecases in which the tablet core cannot tolerate organic solvent or water and yetneeds to be coated for taste masking or to provide delayed or entericproperties to the finished product and also to avoid incompatibility byseparating incompatible ingredients.

1.9.4.4.2Electrostatic coating

Electrostatic coating is an efficient method ofapplying coating to conductive substrates. A strong electrostatic charge isapplied to the substrate. The coating material containing conductive ionic speciesof opposite charge is sprayed onto the charged substrate. Complete and uniformcoating of corners and adaptability of this method to such relativelynonconductive substrate as pharmaceutical is limited.

1.9.4.4.3 Dip coating

Coating is applied to the tablet cores by dippingthem into the coating liquid. The wet tablets are dried in a conventionalmanner in coating pan. Alternative dipping and drying steps may be repeatedseveral times to obtain the desired coating. This process lacks the speed,versatility, and reliability of spray-coating techniques. Specialized equipmenthas been developed to dip-coat tablets, but no commercial pharmaceuticalapplication has been obtained.

1.9.4.4.4 Vacuum film coating

Vacuum film coating is a new coating procedure thatemploys a specially designed baffled pan.The pan is hot water jacketed, and it can be sealed to achieve a vacuumsystem. The tablets are placed in the sealed pan, and the air in the pan isdisplaced by nitrogen before the desired vacuum level is obtained. The coatingsolution is then applied with airless spray system. The evaporation is causedby the heated pan, and the vapour is removed by the vacuum system. Becausethere is no high-velocity heated air, the energy requirement is low and coatingefficiency is high. Organic solvent can be effectively used with this coatingsystem with minimum environmental or safety concerns.

1.9.5 Equipments

Three general types of equipments are available

1. Standard coating pan

e.g., Pellegrin pan system

Immersion sword system

Immersion tube system

2. Perforated pan system

e.g., Accela cota system

Hicoater system

Glattcoater system

Driacoated system

3. Fluidized bed coater

1.9.6 Process parameters

Air capacity:This value represents the quantity of water or solvent that can be removedduring the coating process which depends on the quantity of air flowing through

the tablet bed, temperature of the air and quantity of water that the inlet aircontains.

Coating composition: The coating contains the ingredients that are to be applied on thetablet surface and solvents which act as carrier for the ingredients.

Tablet surface area: It plays an important role for uniform coating. The total surface areafor unit weight decreases significantly from smaller to larger tablets.Application of a film with the same thickness requires less coatingcomposition. In the coating process only a portion of the total surface iscoated. Continuous partial coating and recycling eventually results in fullycoated tablets.

Equipment efficiency: Tablet coaters use the expression “coating efficiency” a value obtainedby dividing the net increase in coated tablet weight by the total nonvolatilecoating weight applied to the tablet. Ideally 90-95 % of the applied filmcoating should be on the tablet surface. Coating efficiency for conventionalsugar coating is much less and 60% would be acceptable. The significantdifference in coating efficiency between film and sugar coating relates to thequantity of coating material that collects on the wall.

Key Phrases

Ø The sugar coating involves several steps like,sealing, subcoating, colour coating and printing.

Ø Sugar coatingprocess yields elegant and highly glossed tablet.

Ø Newertechniques utilize spraying systems and varying degree of automation toimprove coating efficiency and product uniformity.

Ø Film coatingis deposition of a thin film of polymer surrounding the tablet core.

Ø Film coatingis more favored than sugar coating because weight increase is 2-3%, singlestage process, easily adaptable to controlled release, it retains colour oforiginal core, high adaptability to GMP, automation is possible, etc.

Ø Accela cotaand fluidized bed equipments arewidely used for film coating

Ø Basic formulais obtained from past experience or from literature and modifications are

made accordingly. Common modificationsare to alter polymer-to-plasticizer ratio or addition of differentplasticizer/polymer. Experimentationof this type can be best achieved by fractional factorial study.

Ø Materials usedin film coating include film formers, solvents, plasticizers, colourants,opaquant-extenders, surfactant, anti oxidant, etc.

Ø Widely usedfilm formers are Hydroxy Propyl Methyl Cellulose (HPMC),Methyl Hydroxy EthylCellulose (MHEC), Ethyl Cellulose (EC), Hydroxy Propyl Cellulose (HPC),PovidoneÒ (four grades available i.e. K-15, K-30, K-60andK-90), Sodium carboxy methyl cellulose, Polyethylene glycols (PEG) andAcrylate polymers (EudragitÒ, EudragitÒRL, EudragitÒRS, EudragitÒE) are used for film coating. Eudragit®L & S areused for enteric coating.Eudragit®RL, Eudragit®RS, Eudragit®Sare available as organic solution and solid while Eudragit®L andEudragit®E are available as organic, solid or aqueous dispersion.

Ø Quality of filmcan be modified by plasticizer.Commonly used plasticizers include PG, glycerin, low molecular weightPEG, castor oils, etc. Castor oil andspans are more used for organic-solvent based coating solution while PE andPEG are used for aqueous coating.

ØFD & C orD & C certified colourants are used.Lakes are choice for film coating as they give reproducibleresults. Opaspray® (opaque colour concentrate for filmcoating) and Opadry® (complete film coating concentrate) arepromoted as achieving less lot-to-lot variation.

Ø Colourants areexpensive and higher concentration is required. So materials like titanium dioxides,silicates, and carbonates are used to provide more pastel colours andincrease film coverage.

EntericCoating:

Ø Entericcoating is used to protect tablet core from disintegration in the acidenvironment of stomach to prevent degradation of acid sensitive API, preventirritation to stomach by certain drugs, delivery of API into intestine, toprovide a delayed release components for repeat action, etc.

Ø Several kindsof enteric layer systems are available like one layer system and two-layersystem. Polymers used for entericcoating are cellulose Acetate Phthalate (CAP), Acrylates (Eudragit®Land Eudragit®S, Hydroxy Propyl Methyl Cellulose Phthalate(HPMCP50, HPMCP55 & HPMCP 55s) and polyvinyl acetate phthalate

Enteric sugar coating:

Ø Here sealingcoat is modified to comprise one of the enteric polymers in sufficientquantity to pass the enteric test for disintegration. The sub coating and subsequent coatingsteps are then as for conventional sugar coating.

Ø Entericpolymers are capable of forming a direct film in a film coating process. Sufficient weight of enteric polymer has tobe used to ensure an efficient enteric effect.

Ø Enteric coatingcan be combined with polysaccharides, which are enzymatically degraded incolon. For example, Cyclodextrin &Galactomannan.

Controlledrelease coating:

Ø Polymers likemodified acrylates, ethyl cellulose, etc are used for the same.

Problems in tablet manufacture and related remedies

Submitted by Mukesh C Gohel on Sun, 12/06/2009 - 19:54

1.10 Problems In Tablet ManufactureAnd Related RemediesWhat

will you gain?

1.10.1 Introduction

1.10.1.1Capping

1.10.1.2 Lamination / Laminating

1.10.1.3 Chipping

1.10.1.4 Cracking

1.10.1.5 Sticking / Filming

1.10.1.6 Picking

1.10.1.7 Binding

1.10.1.8 Mottling

1.10.1.9 Double impression

1.10.2 Problems andRemedies for tablet coating

1.10.2.1 Blistering

1.10.2.2 Chipping

1.10.2.3 Cratering

1.10.2.4 Picking

1.10.2.5 Pitting

1.10.2.6 Blooming

1.10.2.7 Blushing

1.10.2.8 Colour variation

1.10.2.9Infilling

1.10.2.10Orange peel/Roughness

1.10.2.11

Cracking/Splitting

1.10.1Introduction (62,63)

Anideal tablet should be free from any visual defect or functional defect. Theadvancements and innovations in tablet manufacture have not decreased theproblems, often encountered in the production, instead have increased theproblems, mainly because of the complexities of tablet presses; and/or thegreater demands of quality.

Anindustrial pharmacist usually encounters number of problems duringmanufacturing. Majority of visual defects are due to inadequate fines orinadequate moisture in the granules ready for compression or due to faultymachine setting. Functional defects are due to faulty formulation. Solving manyof the manufacturing problems requires an in–depth knowledge of granulationprocessing and tablet presses, and is acquired only through an exhaustive studyand a rich experience.

Here,we will discuss the imperfections found in tablets along–with their causes andrelated remedies. The imperfections are known as: ‘VISUAL DEFECTS’ and they areeither related to imperfections in any one or more of the following factors:

I. Tableting Process

II. Excipient

III. Machine

Thedefects related to Tableting Process are as follows:

i)CAPPING: It isdue air-entrapment in the granular material.

ii) LAMINATION: It is due air-entrapment in the granularmaterial.

iii) CRACKING: It is due to rapid expansion of tabletswhen deep concave punches are used.

The defects related to Excipient are as follows:

iv) CHIPPING: It is due to very dry granules

v) STICKING

vi) PICKING

vii) BINDING

These problems (v, vi, vii) are due tomore amount of binder in the granules or wet granules.

Thedefect related to more than one factor:

viii) MOTTLING: Itis either due to any one or more of these factors:

Dueto a coloured drug, which has different colour than the rest of the granularmaterial? (Excipient- related); improper mixing of granular material(Process-related); dirt in the granular material or on punch faces; oil spotsby using oily lubricant.

Thedefect related to Machine

ix) DOUBLE IMPRESSION: It is due to free rotation of thepunches, which have some engraving on the punch faces.

Further,in this section, each problem is described along-with its causes and remedieswhich may be related to either of formulation (granulation) or of machine(dies, punches and entire tablet press).

1.10.1.1 Capping (1,5)

Definition:‘Capping’ is the term used, when the upper or lower segment of the tabletseparates horizontally, either partially or completely from the main body of atablet and comes off as a cap, during ejection from the tablet press, or duringsubsequent 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.

Table.27. The Causes And Remedies Of Capping Related To ‘Formulation’ (Granulation)

Sr. No. CAUSES REMEDIES

1. Large amount of fines inthe granulation

Remove some or all finesthrough 100 to 200 mesh screen

2. Too dry or very lowmoisture content (leading to loss of proper binding action).

Moisten the granulessuitably. Add hygroscopic substance e.g.: sorbitol, methyl- cellulose orPEG-4000.

3. Not thoroughly driedgranules.

Dry the granules properly.

4. Insufficient amount ofbinder or improper binder.

Increasing the mount ofbinder OR

Adding dry binder such aspre-gelatinized starch, gum acacia, powdered sorbitol, PVP, hydrophilicsilica or powdered sugar.

5. Insufficient or improperlubricant.

Increase the amount oflubricant or change the type of lubricant.

6. Granular mass too cold tocompress firm.

Compress at roomtemperature.

Table.28. The Causes And Remedies Of Capping Related To ‘Machine’ (Dies, Punches And Tablet Press)

Sr. No. CAUSES REMEDIES

1. Poorly finished dies Polish dies properly.Investigate other steels or other materials.

2. Deep concave punches orbeveled-edge faces of punches.

Use flat punches.

3. Lower punch remains belowthe face of die during ejection.

Make proper setting oflower punch during ejection.

4. Incorrect adjustment ofsweep-off blade.

Adjust sweep-off bladecorrectly to facilitate proper ejection.

5. High turret speed. Reduce speed of turret(Increase dwell time).

1.10.1.2 Lamination /Laminating (1,5)

Definition:‘Lamination’ is the separation of a tablet into two or more distinct horizontallayers.

Reason:Air–entrapment during compression and subsequent release on ejection.

Thecondition is exaggerated by higher speed of turret.

Table.29. The Causes And Remedies Of Lamination Related To Formulation (Granulation)

Sr. No. CAUSES REMEDIES

1. Oily or waxy materials ingranules

Modify mixing process. Addadsorbent or absorbent.

2. Too much of hydrophobiclubricant e.g.: Magnesium-stearate.

Use a less amount oflubricant or change the type of lubricant.

Table.30. The Causes And Remedies Of Lamination Related To Machine (Dies, Punches And Tablet Press)

Sr. No. CAUSES REMEDIES

1. Rapid relaxation of theperipheral regions of a tablet, on ejection from a die.

Use tapered dies, i.e.upper part of the die bore has an outward taper of 3° to 5°.

2. Rapid decompression Use pre-compression step.Reduce turret speed and reduce the final compression pressure.

1.10.1.3 Chipping (1)

Definition: ‘Chipping’ is defined as the breaking of tablet edges, whilethe tablet leaves the press or during subsequent handling and coatingoperations.

Reason:Incorrect machine settings, specially mis-set ejection take-off.

Table.31. The Causes And Remedies Of Chipping Related To Formulation (Granulation) Are As Follows

Sr. No. CAUSES REMEDIES

1. Sticking on punch faces Dry the granules properlyor increase lubrication.

2. Too dry granules. Moisten the granules toplasticize. Add hygroscopic substances.

3. Too much binding causes chippingat bottom.

Optimize binding, or usedry binders.

Table.32. The Causes And Remedies Of Chipping Related To Machine (Dies, Punches And Tablet Press)

Sr. No. CAUSES REMEDIES

1. Groove of die worn atcompression point.

Polish to open end,reverse or replace the die.

2. Barreled die (center ofthe die wider than ends)

Polish the die to make itcylindrical

3. Edge of punch face turnedinside/inward.

Polish the punch edges

4. Concavity too deep tocompress properly.

Reduce concavity of punchfaces. Use flat punches.

1.10.1.4 Cracking (1)

Definition: Small, fine cracks observed on the upperand lower central surface of tablets, or very rarely on the sidewall arereferred to as ‘Cracks’.

Reason: It is observed as a result ofrapid expansion of tablets, especially when deep concave punches are used.

Table.33. The Causes And Remedies Of Cracking Related To Formulation (Granulation)

Sr. No. CAUSES REMEDIES

1. Large size of granules. Reduce granule size. Addfines.

2. Too dry granules. Moisten the granulesproperly and add proper amount of binder.

3. Tablets expand. Improve granulation. Adddry binders.

4. Granulation too cold. Compress at roomtemperature.

Table.33. The Causes And Remedies Of Cracking Related To Formulation (Granulation)

Sr. No. CAUSES REMEDIES

1. Tablet expands on ejectiondue to air entrapment.

Use tapered die.

2.Deep concavities causecracking while

removing tablets

Use special take-off.

1.10.1.5 Sticking / Filming (1)

Definition: ‘Sticking’ refers to the tablet materialadhering to the die wall.

Filming is a slow form of sticking and is largely due to excess moisturein the granulation.

Reason: Improperly dried or improperly lubricatedgranules.

Table.35. The Causes And Remedies Of Sticking Related To Formulation (Granulation)

Sr. No. CAUSES REMEDIES

1. Granules not driedproperly.

Dry the granules properly.Make moisture analysis to determine

limits.

2. Too little or improperlubrication.

Increase or changelubricant.

3. Too much binder Reduce the amount ofbinder or use a different type of binder.

4. Hygroscopic granularmaterial.

Modify granulation andcompress under controlled humidity.

5. Oily or way materials Modify mixing process. Addan absorbent.

6. Too soft or weak granules. Optimize the amount ofbinder and granulation technique.

Table.36. The Causes And Remedies Of Sticking Related To Machine (Dies, Punches And Tablet Press)

Sr. No. CAUSES REMEDIES

1. Concavity too deep forgranulation.

Reduce concavity tooptimum.

2. Too little pressure. Increase pressure.

3. Compressing too fast. Reduce speed.

1.10.1.6 Picking (1)

Definition:‘Picking’ is the term used when a small amount of material from a tablet issticking to and being removed off from the tablet-surface by a punch face.

Theproblem is more prevalent on the upper punch faces than on the lower ones. Theproblem worsens, if tablets are repeatedly manufactured in this station oftooling because of the more and more material getting added to the alreadystuck material on the punch face.

Reason: Picking is ofparticular concern when punch tips have engraving or embossing letters, as wellas the granular material is improperly dried.

Table.37. The Causes And Remedies Of Picking Related To Formulation (Granulation)

Sr. No. CAUSES REMEDIES

1. Excessive moisture ingranules.

Dry properly the granules,determine optimum limit.

2. Too little or improperlubrication.

Increase lubrication; usecolloidal silica as a ‘polishing agent’, so that material does not cling topunch faces.

3. Low melting pointsubstances, may soften from the heat of compression and lead to picking.

Add high melting-pointmaterials. Use high meting point lubricants.

4. Low melting pointmedicament in high concentration.

Refrigerate granules andthe entire tablet press.

5. Too warm granules whencompressing.

Compress at roomtemperature. Cool sufficiently before compression.

6. Too much amount of binder. Reduce the amount ofbinder, change the type or use dry binders.

Table.38. The Causes And Remedies Of Picking Related To Machine (Dies, Punches And Tablet Press)

Sr. No. CAUSES REMEDIES

1. Rough or scratched punchfaces.

Polish faces to highluster.

2. Embossing or engravingletters on punch faces such as B, A, O, R, P, Q, G.

Design lettering as largeas possible.

Plate the punch faces withchromium to produce a smooth and non-adherent face.

3. Bevels or dividing linestoo deep.

Reduce depths andsharpness.

4. Pressure applied is notenough; too soft tablets.

Increase pressure tooptimum.

1.10.1.7 Binding (1)

Definition:‘Binding’ in the die, is the term used when the tablets adhere, seize or tearin the die.

Afilm is formed in the die and ejection of tablet is hindered. With excessivebinding, the tablet sides are cracked and it may crumble apart.

Reason:Binding is usually due to excessive amount of moisture in granules, lack oflubrication and/or use of worn dies.

Table.39. The Causes And Remedies Of Binding Related To   Formulation (Granulation)

Sr. No. CAUSES REMEDIES

1. Too moist granules andextrudes around lower punch.

Dry the granules properly.

2. Insufficient or improperlubricant.

Increase the amount oflubricant or use a more effective lubricant.

3. Too coarse granules. Reduce granular size, addmore fines, and increase the quantity of lubricant.

4. Too hard granules for thelubricant to be effective.

Modify granulation. Reducegranular size.

5. Granular material veryabrasive and cutting into dies.

If coarse granules, reduceits size.

Use wear-resistant dies.

6. Granular material toowarm, sticks to the die.

Reduce temperature.

Increase clearance if itis extruding.

Table.40. The Causes And Remedies Of Binding Related To Machine (Dies, Punches And Tablet Press)

Sr. No. CAUSES REMEDIES

1. Poorly finished dies. Polish the dies properly.

2. Rough dies due toabrasion, corrosion.

Investigate other steelsor other materials or modify granulation.

3. Undersized dies. Toolittle clearance.

Rework to proper size.

Increase clearance.

4. Too much pressure in thetablet press.

Reduce pressure. OR

Modify granulation.

1.10.1.8 Mottling (1)

Definition: ‘Mottling’ is the term used to describean unequal distribution of colour on a tablet, with light or dark spotsstanding out in an otherwise uniform surface.

Reason: One cause of mottling may be acoloured drug, whose colour differs from the colour of excipients used forgranulation of a tablet.

Table.41. The Causes And Remedies Of Mottling

Sr. No. CAUSES REMEDIES

1. A coloured drug used alongwith colourless or white-coloured excipients.

Use appropriatecolourants.

2. A dye migrates to thesurface of granulation while drying.

Change the solvent system,

Change the binder,

Reduce drying temperatureand

Use a smaller particlesize.

3. Improperly mixed dye,especially during ‘Direct Compression’.

Mix properly and reducesize if it is of a larger size to prevent segregation.

4. Improper mixing of a Incorporate dry colour

coloured binder solution. additive during powder blending step, then add fine powdered adhesives suchas acacia and tragacanth and mix well and finally add granulating liquid.

1.10.1.9 Doubleimpression (1)

Definition: ‘Double Impression’ involves only thosepunches, which have a monogram or other engraving on them.

Reason: At the moment of compression,the tablet receives the imprint of the punch. Now, on some machines, the lowerpunch freely drops and travels uncontrolled for a short distance before ridingup the ejection cam to push the tablet out of the die, now during this freetravel, the punch rotates and at this point, the punch may make a newimpression on the bottom of the tablet, resulting in ‘Double Impression’.

If the upper punch is uncontrolled, it can rotateduring the short travel to the final compression stage and create a doubleimpression.

Table.42. The Causes And Remedies Of Double Impression

Sr. No. CAUSE REMEDIES

1. Free rotation of eitherupper punch or lower punch during ejection of a tablet.

-Use keying in tooling, i.e. inseta key alongside of the punch, sothat it fits the punch and prevents punch rotation.

-Newer presses have anti-turning devices, whichprevent punch rotation.

1.10.2 Problems and remedies fortablet coating

1.10.2.1 Blistering (1,64)

Definition:It is local detachment of film from the substrate forming blister.

Reason:Entrapment of gases in or underneath the film due to overheating either duringspraying or at the end of the coating run.

Table.43. The Cause And Remedy Of Blistering

Sr. No. CAUSE REMEDY

1. Effect of temperature onthe strength, elasticity and adhesion of the film.

Use mild drying condition.

1.10.2.2 Chipping (1,64)

Definition:It is defect where the film becomes chipped and dented, usually at the edges ofthe tablet.

Reason:Decrease in fluidizing air or speed of rotation of the drum in pan coating.

Table.44. The Cause And Remedy Of Chipping

Sr. No. CAUSE REMEDY

1.High degree of attritionassociated with the coating process.

 

Increase hardness of thefilm by increasing the molecular weight grade of polymer.

1.10.2.3 Cratering (1,64)

Definition:It is defect of film coating whereby volcanic-like craters appears exposing thetablet surface.

Reason:The coating solution penetrates the surface of the tablet, often at the crownwhere the surface is more porous, causing localized disintegration of the coreand disruption of the coating.

Table.45. The Causes And Remedies Of Cratering

Sr. No. CAUSES REMEDIES

1.Inefficient drying.

 Use efficient and optimumdrying conditions.

2. Higher rate of applicationof coating solution.

Increase viscosity ofcoating solution to decrease spray application rate.

1.10.2.4 Picking (1,64)

Definition:It is defect where isolated areas of film are pulled away from the surface whenthe tablet sticks together and then part.

Reason: Conditions similar to cratering that producesan overly wet tablet bed where adjacent tablets can stick together and thenbreak apart.

Table.46. The Causes And Remedies Of Picking

Sr.

No.CAUSE REMEDY

1. Inefficient drying. Use optimum and efficientdrying conditions or increase the inlet air temperature.

2. Higher rate of applicationof coating solution

Decrease the rater ofapplication of coating solution by increasing viscosity of coating solution.

1.10.2.5 Pitting (1,64)

Definition:It is defect whereby pits occur in the surface of a tablet core without anyvisible disruption of the film coating.

Reason:Temperature of the tablet core is greater than the melting point of thematerials used in the tablet formulation.

Table.47. The Cause And Remedy Of Pitting

Sr. No. CAUSE REMEDY

1. Inappropriate drying(inlet air ) temperature

Dispensing with preheatingprocedures at the initiation of coating and modifying the drying (inlet air)temperature such that the temperature of the tablet core is not greater thanthe melting point of the batch of additives used.

1.10.2.6 Blooming (1,64)

Definition:It is defect where coating becomes dull immediately or after prolonged storageat high temperatures.

Reason:It is due to collection on the surface of low molecular weight ingredientsincluded in the coating formulation. Inmost circumstances the ingredient will be plasticizer.

Table.48. The Cause And Remedy Of Blooming

Sr. No. CAUSE REMEDY

1.High concentration and lowmolecular weight of plasticizer.

 

Decrease plasticizerconcentration and increase molecular weight of plasticizer.

1.10.2.7 Blushing (1,64)

Definition:It is defect best described as whitish specks or haziness in the film.

Reason:It is thought to be due to precipitated polymer exacerbated by the use of highcoating temperature at or above the thermal gelation temperature of thepolymers.

Table.49. The Causes And Remedies Of Blushing

Sr. No. CAUSES REMEDIES

1. High coating temperature Decrease the drying airtemperature

2. Use of sorbitol informulation which causes largest fall in the thermal gelation temperature ofthe Hydroxy Propyl Cellulose, Hydroxy Propyl Methyl Cellulose, MethylCellulose and Cellulose ethers.

Avoid use of sorbitol withHydroxy Propyl Cellulose, Hydroxy Propyl Methyl Cellulose, Methyl Celluloseand Cellulose ethers.

1.10.2.8 Colour variation (1,64)

Definition:A defect which involves variation in colour of the film.

Reason:Alteration of the frequency and duration of appearance of tablets in the sprayzone or the size/shape of the spray zone.

Table.50. The Cause And Remedy Of Colour Variation

Sr. No. CAUSE REMEDY

1. Improper mixing, unevenspray pattern, insufficient coating, migration of soluble dyes-plasticizersand other additives during drying.

Go for geometric mixing,reformulation with different plasticizers and additives or use mild dryingconditions.

1.10.2.9 Infilling (1,64)

Definition:It is defect that renders the intagliations indistinctness.

Reason: Inability of foam, formed by airspraying of a polymer solution, to break.The foam droplets on the surface of the tablet breakdown readily due toattrition but the intagliations form a protected area allowing the foam toaccumulate and “set”. Once the foam hasaccumulated to a level approaching the outer contour of the tablet surface, normalattrition can occur allowing the structure to be covered with a continuousfilm.

Table.51. The Cause And Remedy Of Infilling

Sr. No. CAUSE REMEDY

1. Bubble or foam formationbecause of air spraying of a polymer solution

Add alcohol or use spray nozzlecapable of finer atomization.

1.10.2.10 Orange peel/Roughness (1,64)

Definition:It is surface defect resulting in the film being rough and nonglossy. Appearance is similar to that of an orange.

Reason: Inadequate spreading of the coatingsolution before drying.

Table.52. The Causes And Remedies Of Orange Peel/Roughness

Sr. No. CAUSES REMEDIES

1. Rapid Drying Use mild drying conditions

2. High solution viscosity Use additional solvents todecrease viscosity of solution.

1.10.2.11 Cracking/Splitting (1,64)

Definition:It is defect in which the film either cracks across the crown of the tablet(cracking) or splits around the edges of the tablet (Splitting)

Reason: Internal stress in the film exceedstensile strength of the film.

Table.53. The Cause And Remedy Of Cracking/Splitting

Sr. No. CAUSE REMEDY

1. Use of higher molecularweight polymers or polymeric blends.

Use lower molecular weightpolymers or polymeric blends. Alsoadjust plasticizer type and concentration.

KeyPhrases

Ø During tabletmanufacture, an industrial pharmacist usually encounters many problems.Solving these problems requires an in-depth knowledge of tablet-formulationas well as machine-operating processes.

Ø Capping andLamination are the defects arising as a result of air-entrapment in thegranular material.

Ø Chipping is adefect related arising due to very dry granules.

Ø Cracking isdue to rapid expansion of tablets, when

deep concave punches are used.

Ø Sticking,Picking and Binding are the imperfections related to more amount of binder ingranules.

Ø Mottling is animperfection arising due to more than one factor: a coloured drug, dirt ingranules or the use of an oily lubricant.

Ø Double-Impressionis related to a machine defect: it is caused by the free rotation of punchesthat have some engraving on the punch-faces.

Coating defects:

Ø Blistering isrelated to entrapment of gases in or underneath the film due to overheatingeither during spraying or at the end of the coating run. Use of mild drying conditions can solve thisproblem.

Ø Chipping isrelated to higher degree of attrition associated with the coatingprocess. Increase in hardness of thefilm by increasing the molecular weight grade of polymer can solve thisproblem.

Ø Cratering isrelated to penetration of the coating solution into the surface of thetablet, often at the crown where the surface is more porous, causinglocalized disintegration of the core and disruption of the coating. Decrease in spray application rate and useof optimum and efficient drying conditions can solve this problem.

Ø Pitting isdefect in which temperature of the tablet

core is greater than the meltingpoint of the materials used in tablet formulation. Dispensing with preheating procedures atthe initiation of coating and modifying the drying (inlet air) temperaturecan solve this problem.

Ø Blooming ordull film is generally because of higher concentration and lower molecularweight of plasticizer. So use lowerconcentration and higher molecular grade of plasticizer.

Ø Blushing/Whitishspecks/Haziness of the film is related to precipitation of polymerexacerbated by the use of high coating temperature at or above the thermalgelation temperature of the polymers.

Ø Colourvariation is because of improper mixing, uneven spray pattern, insufficient coatingor migration of soluble dyes during drying.Geometric mixing, mild drying conditions and reformulation withdifferent plasticizers can solve this problem.

Ø Infilling isbecause of bubble/foam formation during air spraying of a polymersolution. Addition of alcohol or useof spray nozzle capable of finer atomization can solve this problem.

Ø Orangepeel/Roughness is related to inadequate spreading of the coating solutionbefore drying. So decrease inviscosity of coating solution can counter this defect.

Ø Cracking isseen when internal stresses in the film exceeds tensile strength of the

film. This is common with highermolecular weight polymers or polymeric blends. So use lower molecular weight polymers orpolymeric blends.

Quality Control tests for tablets

Submitted by Mukesh C Gohel on Sun, 12/06/2009 - 19:55

1.11Quality Control Tests for TabletsWhatwill you gain?

1.11.1 Official Standardsas per I.P. / B.P. / U.S.P.

1.11.2 Non – compendialstandards

1.11.3 In – Process Quality Control

1.11.1 Official Standardsas per I.P. / B.P. / U.S.P. (65-67)

Table: 54. Comparison Of Different Pharmacopoeial Quality Control Tests

PHARMACOPOEIAS TYPE OF TABLET TESTS TO BE PERFORMED

BRITISH PHARMACOPOEIA

For all tabletsContent of activeingredients

Disintegration

Uniformity of content

Labeling

Uncoated tabletDisintegration test

Uniformity of weight

Effervescent tabletDisintegration test

Uniformity of weight

Coated tabletDisintegration test

Uniformity of weight

Gastro resistant tablet Disintegration test

Modified release tablet Uniformity of weight

Tablet for use in mouth Uniformity of weight

Soluble tabletDisintegration test

Uniformity of weight

Dispersible tabletDisintegration test

Uniformity of dispersion

Uniformity of weight

INDIAN PHARMACOPOEIA

Uncoated tabletUniformity of containercontent

Content of activeingredient

Uniformity of weight

Uniformity of content

Disintegration test

Enteric coated tablet Disintegration test

Dispersible tabletUniformity of dispersion

Disintegration

Soluble tablet Disintegration

Effervescent tabletDisintegration/Dissolution / Dispersion

test

UNITED STATES Physical tests Bulk density /Tapped

PHARMACOPOEIA applicableto tablet formulation

density of powder

Powder fineness

Loss on drying

Disintegration test

Tablet friability

Dissolution test

Drug release testing

Uniformity of dosage form

Container permeation test

Labeling of inactiveingredients

1.11.2 Non – compendialstandards (2,13)

Measurementof mechanical properties is not covered pharmacopoeial monograph. There arealso a number of tests frequently applied to tablets for which there are nopharmacopoeial requirement but will form a part of a manufacturer’s own productspecification.

I.Hardnesstests/ Crushing strength

The test measures crushing strength property definedas the compressional force applied diametrically to a tablet which justfractures it. Among a large number of measuring devices, the most favored onesare Monsanto tester, Pfizer tester, and Strong cobb hardness tester. All aremanually used. So, strain rate depends on the operator. Heberlein Schleuniger,Erweka, Casburt hardness testers are motor driven.

II.Friability(Official in USP)

The tablet may well be subjected to a tumblingmotion. For example, Coating, packaging, transport, which are not severe enoughto break the tablet, but may abrade the small particle from tablet surface. Toexamine this, tablets are subjected to a uniform tumbling motion for specifiedtime and weight loss is measured. Roche friabilator is most frequently used forthis purpose.

Tests for coated tablets

I. Water vapor permeability

II. Film tensilestrength

III.Coated tabletevaluations:

i)Adhesion testwith tensile-strength tester: Measuresforce required toe peel the film fromthe tablet surface

ii)Diametral crushing strength of coated tablet: Tablet hardness testers are used. This test gives information on the relativeincrease in crushing strength provided by the film and the contribution made bychanges in the film composition

iii)Temperature and humidity may cause film defects. Hence studies are to be carried out

iv)Quantification of film surface roughness, hardness,& colour uniformity. Visual inspection or instruments are used. Resistanceof coated tablet on a white sheet of paper.Resisilient films remain intact, & no colour is transferred to thepaper; very soft coating are readily “erased” from the tablet surface to thepaper

1.11.3 In – Process Quality Control (13)

The control of the tableting process in production isconcerned with the following :

I. Weightof tablet – Single pan electric balance.

II. Crushingstrength – Controls friability and disintegration time.

III. Tabletthickness – Very thick tablet affect packaging particularly into blisters.

IV.Disintegration time.

V. Friability

Asa part of Current Good Manufacturing Practice (cGMP), the production run ismonitored under control chart. At regular interval (10 – 15minutes) theoperator must sample specified number of tablets, weigh them individually,check thickness, crushing strength and all the properties as mentioned above.The process can be automated and interfaced with printer. Such data promotesprocess improvement.

Key Phrases

ØUSP mentionssome of the quality control tests to be performed before the powder iscompressed. e.g., powder fineness, density. etc.

ØFriability isofficial test as per USP.

ØAt regularinterval (10 – 15minutes) during the course of manufacturing the operatormust sample specified number of tablets for testing.

Tablet:Problems in tablet manufacturingFrom Pharmpedia

Next Page: Quality control tests for tabletsPrevious Page: Tablet coating

Contents[hide]

1 Introduction o 1.1 Capping o 1.2 Lamination / Laminating o 1.3 Chipping o 1.4 Cracking o 1.5 Sticking / Filming o 1.6 Picking o 1.7 Binding o 1.8 Mottling o 1.9 Double impression

2 Problems and remedies for tablet coating o 2.1 Blistering o 2.2 Chipping o 2.3 Cratering o 2.4 Picking o 2.5 Pitting o 2.6 Blooming o 2.7 Blushing o 2.8 Colour variation o 2.9 Infilling o 2.10 Orange peel/Roughness o 2.11 Cracking/Splitting

3 Key Phrases

Introduction

(62,63)

An ideal tablet should be free from any visual defect or functional defect. The advancements and innovations in tablet manufacture have not decreased the problems, often encountered in the production, instead have increased the problems, mainly because of the complexities of tablet presses; and/or the greater demands of quality.

An industrial pharmacist usually encounters number of problems during manufacturing. Majority of visual defects are due to inadequate fines or inadequate moisture in the granules ready for compression or due to faulty machine setting. Functional defects are due to faulty formulation. Solving many of the manufacturing problems requires an in–depth knowledge of granulation processing and tablet presses, and is acquired only through an exhaustive study and a rich experience.

Here, we will discuss the imperfections found in tablets along–with their causes and related remedies. The imperfections are known as: ‘VISUAL DEFECTS’ and they are either related to imperfections in any one or more of the following factors:

I. Tableting Process

II. Excipient

III. Machine

The defects related to Tableting Process are as follows:

i) CAPPING: It is partial or complete separation of the top or bottom of tablet due air-entrapment in the granular material.

ii) LAMINATION: It is separation of tablet into two or more layers due to air-entrapment in the granular material.

iii) CRACKING: It is due to rapid expansion of tablets when deep concave punches are used.

The defects related to Excipient are as follows:

iv) CHIPPING: It is due to very dry granules.

v) STICKING: It is the adhesion of granulation material to the die wall

vi) PICKING: It is the removal of material from the surface of tablet and its adherance to the face of punch.

vii) BINDING

These problems (v, vi, vii) are due to more amount of binder in the granules or wet granules.

The defect related to more than one factor:

viii) MOTTLING: It is either due to any one or more of these factors: Due to a coloured drug, which has different colour than the rest of the granular material? (Excipient- related); improper mixing of granular material (Process-related); dirt in the granular material or on punch faces; oil spots by using oily lubricant.

The defect related to Machine

ix)DOUBLE IMPRESSION: It is due to free rotation of the punches, which have some engraving on the punch faces.

Further, in this section, each problem is described along-with its causes and remedies which may be related to either of formulation (granulation) or of machine (dies, punches and entire tablet press).

Capping

(1,5)

‘Capping’ 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.

TABLE.27. THE CAUSES AND REMEDIES OF CAPPING RELATED TO ‘FORMULATION’ (GRANULATION)

Sr. No. CAUSES REMEDIES

1. Large amount of fines in the granulation

Remove some or all fines through 100 to 200 mesh screen

2.Too dry or very low moisture content (leading to loss of proper binding action).

Moisten the granules suitably. Add hygroscopic substance e.g.: sorbitol, methyl- cellulose or PEG-4000.

3. Not thoroughly dried granules. Dry the granules properly.

4. Insufficient amount of binder or improper binder.

Increasing the mount of binder OR

Adding dry binder such as pre-gelatinized starch, gum acacia, powdered sorbitol, PVP, hydrophilic silica or powdered sugar.

5. Insufficient or improper lubricant.

Increase the amount of lubricant or change the type of lubricant.

6. Granular mass too cold to compress firm. Compress at room temperature.

TABLE.28. THE CAUSES AND REMEDIES OF CAPPING RELATED TO ‘MACHINE’ (DIES, PUNCHES AND TABLET PRESS)

Sr. No.

CAUSES REMEDIES

1. Poorly finished dies Polish dies properly. Investigate other steels or other materials.

2. Deep concave punches or beveled-edge faces of punches. Use flat punches.

3. Lower punch remains below the face of die during ejection.

Make proper setting of lower punch during ejection.

4. Incorrect adjustment of sweep-off blade.

Adjust sweep-off blade correctly to facilitate proper ejection.

5. High turret speed. Reduce speed of turret (Increase dwell time).

Lamination / Laminating

(1,5)

Definition: ‘Lamination’ is the separation of a tablet into two or more distinct horizontal layers.

Reason: Air–entrapment during compression and subsequent release on ejection.

The condition is exaggerated by higher speed of turret.

TABLE.29. THE CAUSES AND REMEDIES OF LAMINATION RELATED TO FORMULATION (GRANULATION)

Sr. No.

CAUSESREMEDIES

1. Oily or waxy materials in granules Modify mixing process. Add adsorbent or absorbent.

2.Too much of hydrophobic lubricant e.g.: Magnesium-stearate.

Use a less amount of lubricant or change the type of lubricant.

TABLE.30. The Causes and Remedies of Lamination related to MACHINE (Dies, Punches and Tablet Press)

Sr. No.

CAUSES REMEDIES</ b>

1.Rapid relaxation of the peripheral regions of a tablet, on ejection from a die.

Use tapered dies, i.e. upper part of the die bore has an outward taper of 3° to 5°.

2. Rapid decompressionUse pre-compression step. Reduce turret speed and reduce the final compression pressure.

Chipping

(1)

Definition: ‘Chipping’ is defined as the breaking of tablet edges, while the tablet leaves the press or during subsequent handling and coating operations.

Reason: Incorrect machine settings, specially mis-set ejection take-off.

TABLE.31. THE CAUSES AND REMEDIES OF CHIPPING RELATED TO FORMULATION (GRANULATION) ARE AS FOLLOWS

Sr. No.

CAUSES REMEDIES

1. Sticking on punch faces Dry the granules properly or increase lubrication.

2. Too dry granules. Moisten the granules to plasticize. Add hygroscopic substances.

3. Too much binding causes chipping at bottom. Optimize binding, or use dry binders.

TABLE.32. THE CAUSES AND REMEDIES OF CHIPPING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS)

Sr. No.

CAUSES REMEDIES

1. Groove of die worn at compression point.

Polish to open end, reverse or replace the die.

2. Barreled die (center of the die wider than ends) Polish the die to make it cylindrical

3. Edge of punch face turned inside/inward. Polish the punch edges

4. Concavity too deep to compress properly.

Reduce concavity of punch faces. Use flat punches.

Cracking

(1)

Definition: Small, fine cracks observed on the upper and lower central surface of tablets, or very rarely on the sidewall are referred to as ‘Cracks’.

Reason: It is observed as a result of rapid expansion of tablets, especially when deep concave punches are used.

TABLE.33. THE CAUSES AND REMEDIES OF CRACKING RELATED TO FORMULATION (GRANULATION)

Sr. No. CAUSES REMEDIES

1. Large size of granules. Reduce granule size. Add fines.

2. Too dry granules. Moisten the granules properly and add proper amount of binder.

3. Tablets expand. Improve granulation. Add dry binders.

4. Granulation too cold. Compress at room temperature.

TABLE.34. THE CAUSES AND REMEDIES OF CRACKING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS)

Sr. No. CAUSES REMEDIES

1. Tablet expands on ejection due to air entrapment. Use tapered die.

2.

Deep concavities cause cracking while

removing tablets Use special take-off.

Sticking / Filming

(1)

Definition: ‘Sticking’ 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.

TABLE.35. THE CAUSES AND REMEDIES OF STICKING RELATED TO FORMULATION (GRANULATION)

Sr. No.

CAUSES REMEDIES

1. Granules not dried properly.

Dry the granules properly. Make moisture analysis to determine limits.

2. Too little or improper lubrication. Increase or change lubricant.

3. Too much binder Reduce the amount of binder or use a different type of binder.

4. Hygroscopic granular material.

Modify granulation and compress under controlled humidity.

5. Oily or way materials Modify mixing process. Add an absorbent.

6. Too soft or weak granules. Optimize the amount of binder and granulation technique.

TABLE.36. THE CAUSES AND REMEDIES OF STICKING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS)

Sr. No. CAUSES REMEDIES

1. Concavity too deep for granulation. Reduce concavity to optimum.

2. Too little pressure. Increase pressure.

3. Compressing too fast. Reduce speed.

Picking

(1)

Definition: ‘Picking’ 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 than on the lower ones. The problem worsens, if tablets are repeatedly manufactured in this station of tooling because of the more and more material getting added to the already stuck material on the punch face.

Reason: Picking is of particular concern when punch tips have engraving or embossing letters, as well as the granular material is improperly dried.

TABLE.37. THE CAUSES AND REMEDIES OF PICKING RELATED TO FORMULATION (GRANULATION)

Sr. No.

CAUSES REMEDIES

1. Excessive moisture in granules. Dry properly the granules, determine optimum limit.

2. Too little or improper lubrication. Increase lubrication; use colloidal silica as a ‘polishing agent’, so that material does

not cling to punch faces.

3.Low melting point substances, may soften from the heat of compression and lead to picking.

Add high melting-point materials. Use high meting point lubricants.

4. Low melting point medicament in high concentration.

Refrigerate granules and the entire tablet press.

5. Too warm granules when compressing.

Compress at room temperature. Cool sufficiently before compression.

6. Too much amount of binder. Reduce the amount of binder, change the type or use dry binders.

TABLE.38. THE CAUSES AND REMEDIES OF PICKING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS)

Sr. No.

CAUSES REMEDIES

1. Rough or scratched punch faces. Polish faces to high luster.

2.Embossing or engraving letters on punch faces such as B, A, O, R, P, Q, G.

Design lettering as large as possible.

Plate the punch faces with chromium to produce a smooth and non-adherent face.

3. Bevels or dividing lines too deep. Reduce depths and sharpness.

4. Pressure applied is not enough; too soft tablets. Increase pressure to optimum.

Binding

(1)

Definition: ‘Binding’ in the die, is the term used when the tablets adhere, seize 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 it may crumble apart.

Reason: Binding is usually due to excessive amount of moisture in granules, lack of lubrication and/or use of worn dies.

TABLE.39. THE CAUSES AND REMEDIES OF BINDING RELATED TO FORMULATION (GRANULATION)

Sr. No.

CAUSES REMEDIES

1. Too moist granules and extrudes around lower punch. Dry the granules properly.

2. Insufficient or improper lubricant.

Increase the amount of lubricant or use a more effective lubricant.

3. Too coarse granules. Reduce granular size, add more fines, and increase the quantity of lubricant.

4. Too hard granules for the lubricant to be effective. Modify granulation. Reduce granular size.

5. Granular material very abrasive and cutting into dies.

If coarse granules, reduce its size.

Use wear-resistant dies.

6. Granular material too warm, sticks to the die.

Reduce temperature.

Increase clearance if it is extruding.

TABLE.40. THE CAUSES AND REMEDIES OF BINDING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS)

Sr. No.

CAUSES REMEDIES

1. Poorly finished dies. Polish the dies properly.

2. Rough dies due to abrasion, corrosion.

Investigate other steels or other materials or modify granulation.

3. Undersized dies. Too little clearance.

Rework to proper size.

Increase clearance.

4. Too much pressure in the tablet press.

Reduce pressure. OR

Modify granulation.

Mottling

(1)

Definition: ‘Mottling’ is the term used to describe an unequal distribution of colour on a tablet, with light or dark spots standing out in an otherwise uniform surface.

Reason: One cause of mottling may be a coloured drug, whose colour differs from the colour of excipients used for granulation of a tablet.

TABLE.41. THE CAUSES AND REMEDIES OF MOTTLING

Sr. No.

CAUSES REMEDIES

1.A coloured drug used along with colourless or white-coloured excipients.

Use appropriate colourants.

2.A dye migrates to the surface of granulation while drying.

Change the solvent system,

Change the binder,

Reduce drying temperature and

Use a smaller particle size.

3.Improperly mixed dye, especially during ‘Direct Compression’.

Mix properly and reduce size if it is of a larger size to prevent segregation.

4. Improper mixing of a coloured binder solution.

Incorporate dry colour additive during powder blending step, then add fine powdered adhesives such as acacia and tragacanth and mix well and finally add granulating liquid.

Double impression

(1)

Definition: ‘Double Impression’ involves only those punches, which have a monogram or other engraving on them.

Reason: At the moment of compression, the tablet receives the imprint of the punch. Now, on some machines, the lower punch freely drops and travels uncontrolled for a short distance before riding up the ejection cam to push the tablet out of the die, now

during this free travel, the punch rotates and at this point, the punch may make a new impression on the bottom of the tablet, resulting in ‘Double Impression’.

If the upper punch is uncontrolled, it can rotate during the short travel to the final compression stage and create a double impression.

TABLE.42. THE CAUSES AND REMEDIES OF DOUBLE IMPRESSION

Sr. No.

CAUSE REMEDIES

1.Free rotation of either upper punch or lower punch during ejection of a tablet.

-Use keying in tooling, i.e. inset a key alongside of the    punch, so that it fits the punch and prevents punch rotation.

-Newer presses have anti-turning devices, which prevent punch rotation.

Problems and remedies for tablet coating

Blistering

(1,64)

Definition: It is local detachment of film from the substrate forming blister.

Reason: Entrapment of gases in or underneath the film due to overheating either during spraying or at the end of the coating run.

TABLE.43. THE CAUSE AND REMEDY OF BLISTERING

Sr. No. CAUSE REMEDY

1. Effect of temperature on the strength, elasticity and adhesion of the film.

Use mild drying condition.

Chipping

(1,64)

Definition: It is defect where the film becomes chipped and dented, usually at the edges of the tablet.

Reason: Decrease in fluidizing air or speed of rotation of the drum in pan coating.

TABLE.44. THE CAUSE AND REMEDY OF CHIPPING

Sr. No. CAUSE REMEDY

1.

High degree of attrition associated with the coating process.

 

Increase hardness of the film by increasing the molecular weight grade of polymer.

Cratering

(1,64)

Definition: It is defect of film coating whereby volcanic-like craters appears exposing the tablet surface.

Reason: The coating solution penetrates the surface of the tablet, often at the crown where the surface is more porous, causing localized disintegration of the core and disruption of the coating.

TABLE.45. THE CAUSES AND REMEDIES OF CRATERING

Sr. No. CAUSES REMEDIES

1.

Inefficient drying.

  Use efficient and optimum drying conditions.

2. Higher rate of application of coating solution.

Increase viscosity of coating solution to decrease spray application rate.

Picking

(1,64)

Definition: It is defect where isolated areas of film are pulled away from the surface when the tablet sticks together and then part.

Reason: Conditions similar to cratering that produces an overly wet tablet bed where adjacent tablets can stick together and then break apart.

TABLE.46. THE CAUSES AND REMEDIES OF PICKING

Sr.

No. CAUSE REMEDY

1. Inefficient drying. Use optimum and efficient drying conditions or increase the inlet air temperature.

2. Higher rate of application of coating solution

Decrease the rater of application of coating solution by increasing viscosity of coating solution.

Pitting

(1,64)

Definition: It is defect whereby pits occur in the surface of a tablet core without any visible disruption of the film coating.

Reason: Temperature of the tablet core is greater than the melting point of the materials used in the tablet formulation.

TABLE.47. THE CAUSE AND REMEDY OF PITTING

Sr. No. CAUSE REMEDY

1.Inappropriate drying (inlet air ) temperature

Dispensing with preheating procedures at the initiation of coating and modifying the drying (inlet air) temperature such that the temperature of the tablet core is not greater than the melting point of the batch of additives used.

Blooming

(1,64)

Definition: It is defect where coating becomes dull immediately or after prolonged storage at high temperatures.

Reason: It is due to collection on the surface of low molecular weight ingredients included in the coating formulation. In most circumstances the ingredient will be plasticizer.

TABLE.48. THE CAUSE AND REMEDY OF BLOOMING

Sr. No. CAUSE REMEDY

1.

High concentration and low molecular weight of plasticizer.

 

Decrease plasticizer concentration and increase molecular weight of plasticizer.

Blushing

(1,64)

Definition: It is defect best described as whitish specks or haziness in the film.

Reason: It is thought to be due to precipitated polymer exacerbated by the use of high coating temperature at or above the thermal gelation temperature of the polymers.

TABLE.49. THE CAUSES AND REMEDIES OF BLUSHING

Sr. No. CAUSES REMEDIES

1. High coating temperature Decrease the drying air temperature

2.

Use of sorbitol in formulation which causes largest fall in the thermal gelation temperature of the Hydroxy Propyl Cellulose, Hydroxy Propyl Methyl Cellulose, Methyl Cellulose and Cellulose ethers.

Avoid use of sorbitol with Hydroxy Propyl Cellulose, Hydroxy Propyl Methyl Cellulose, Methyl Cellulose and Cellulose ethers.

Colour variation

(1,64)

Definition: A defect which involves variation in colour of the film.

Reason: Alteration of the frequency and duration of appearance of tablets in the spray zone or the size/shape of the spray zone.

TABLE.50. THE CAUSE AND REMEDY OF COLOUR VARIATION

Sr. No. CAUSE REMEDY

1.

Improper mixing, uneven spray pattern, insufficient coating, migration of soluble dyes-plasticizers and other additives during drying.

Go for geometric mixing, reformulation with different plasticizers and additives or use mild drying conditions.

Infilling

(1,64)

Definition: It is defect that renders the intagliations indistinctness.

Reason: Inability of foam, formed by air spraying of a polymer solution, to break. The foam droplets on the surface of the tablet breakdown readily due to attrition but the intagliations form a protected area allowing the foam to accumulate and “set”. Once the foam has accumulated to a level approaching the outer contour of the tablet surface, normal attrition can occur allowing the structure to be covered with a continuous film.

TABLE.51. THE CAUSE AND REMEDY OF INFILLING

Sr. No. CAUSE REMEDY

1. Bubble or foam formation because of air spraying of a polymer solution

Add alcohol or use spray nozzle capable of finer atomization.

Orange peel/Roughness

(1,64)

Definition: It is surface defect resulting in the film being rough and nonglossy. Appearance is similar to that of an orange.

Reason: Inadequate spreading of the coating solution before drying.

TABLE.52. THE CAUSES AND REMEDIES OF ORANGE PEEL/ROUGHNESS

Sr. No. CAUSES REMEDIES

1. Rapid Drying Use mild drying conditions

2. High solution viscosity Use additional solvents to decrease viscosity of solution.

Cracking/Splitting

(1,64)

Definition: It is defect in which the film either cracks across the crown of the tablet (cracking) or splits around the edges of the tablet (Splitting)

Reason: Internal stress in the film exceeds tensile strength of the film.

TABLE.53. THE CAUSE AND REMEDY OF CRACKING/SPLITTING

Sr. No. CAUSE REMEDY

1.Use of higher molecular weight polymers or polymeric blends.

Use lower molecular weight polymers or polymeric blends.  Also adjust plasticizer type and concentration.

Key Phrases During tablet manufacture, an industrial pharmacist usually

encounters many problems. Solving these problems requires an in-depth knowledge of tablet-formulation as well as machine-operating processes.

Capping and Lamination are the defects arising as a result of air-entrapment in the granular material.

Chipping is a defect related arising due to very dry granules.

Cracking is due to rapid expansion of tablets, when deep concave punches are used.

Sticking, Picking and Binding are the imperfections related to more amount of binder in granules.

Mottling is an imperfection arising due to more than one factor: a coloured drug, dirt in granules or the use of an oily lubricant.

Double-Impression is related to a machine defect: it is caused by the free rotation of punches that have some engraving on the punch-faces.

Coating defects:

Blistering is related to entrapment of gases in or underneath the film due to overheating either during spraying or at the end of the coating run. Use of mild drying conditions can solve this problem.

Chipping is related to higher degree of attrition associated with the coating process. Increase in hardness of the film by increasing the molecular weight grade of polymer can solve this problem.

Cratering is related to penetration of the coating solution into the surface of the tablet, often at the crown where the surface is more porous, causing localized disintegration of the core and disruption of the coating. Decrease in spray application rate and use of optimum and efficient drying conditions can solve this problem.

Pitting is defect in which temperature of the tablet core is greater than the melting point of the materials used in tablet formulation. Dispensing with preheating procedures at the initiation of coating and modifying the drying (inlet air) temperature can solve this problem.

Blooming or dull film is generally because of higher concentration and lower molecular weight of plasticizer. So use lower concentration and higher molecular grade of plasticizer.

Blushing/Whitish specks/Haziness of the film is related to precipitation of polymer exacerbated by the use of high coating temperature at or above the thermal gelation temperature of the polymers.

Colour variation is because of improper mixing, uneven spray pattern, insufficient coating or migration of soluble dyes during drying. Geometric mixing, mild drying conditions and

reformulation with different plasticizers can solve this problem.

Infilling is because of bubble/foam formation during air spraying of a polymer solution. Addition of alcohol or use of spray nozzle capable of finer atomization can solve this problem.

Orange peel/Roughness is related to inadequate spreading of the coating solution before drying. So decrease in viscosity of coating solution can counter this defect.

Cracking is seen when internal stresses in the film exceeds tensile strength of the film. This is common with higher molecular weight polymers or polymeric blends. So use lower molecular weight polymers or polymeric blends