Tablet Formulation

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Pharma Times - Vol 41 - No. 4 - April 2009 21 Abstract Tablet is the most preferred oral dosage form, due to many advantages it offers to formulators as well as physicians and patients. However, the process of manufacturing tablets is complex. Hence, careful consideration has to be given to select right process, and right excipients to ultimately give a robust, high productivity and regulatory compliant product of good quality. Tablet Formulation Design And Manufacture: Oral Immediate Release Application Jayesh Parmar & Manish Rane Colorcon Asia Pvt. Limited Introduction Tablets are solid dosage forms containing medicinal substances with or without suitable diluents. They are the most widely preferred form of medication both by pharmaceutical manufacturer as well as physicians and patients. They offer safe and convenient ways of active pharmaceutical ingredients (API) administration with excellent physicochemical stability in comparison to some other dosage forms, and also provide means of accurate dosing. They can be mass produced with robust quality controls and offer different branding possibilities by means of colored film coating, different shapes, sizes or logos. The objective of this review article is to provide a comprehensive overview of the tablet core manufacturing process with emphasis on oral immediate release formulations, along with common excipients used. Types of Tablet The tablet dosage form is a versatile drug delivery system. Different types of tablet formulations are available, which could be broadly classified based on: (1) route of administration such as tablets for oral delivery, sublingual delivery, buccal delivery, rectal delivery or vaginal delivery, and (2) formulation characteristics such as immediate release tablets, effervescent tablets, melt-in-mouth or fast dissolving tablets, delayed release or extended release tablets. In all the cases, the general manufacturing process, machinery used for preparation of tablets and materials used are similar. The process of manufacturing a robust tablet dosage form and consistently maintain its quality is a key challenge to all formulators. Hence the manufacturing process and formulation components take pivotal importance. Tablet Manufacturing Tablets are compressed powders and their manufacturing is a complex, multistep process. The ultimate aim of these compressed solids is to easily disperse in gastrointestinal fluid, aid in complete absorption of API and, at the same time, offer stability to the formulation. The tablet manufacturing process can be broadly classified as granulation (wet granulation or dry granulation) and direct compression. Granulation is an agglomeration process to improve the flow, density and compressibility of particulate material by size enlargement and densification. Granulation can be achieved by the use of binder solution (wet granulation) or dry binder (dry granulation). Wet granulation is often chosen over dry granulation because of dust elimination, single pot processing, uniformity of API content (low dose API) and obtaining predictable granulation end point determination. Examples of wet granulation methods include fluid bed, high shear, pelletization techniques, such as extrusion- spheronization, spray drying, etc. The quality of this solid oral dosage form is, as a general rule, primarily governed by the physicochemical properties of the powder/ granulation from which the tablets are composed. Dry granulation (roll compaction or slugging) involves the compaction of powders at high pressures into large, often poorly formed tablets or compacts. These compacts are then milled and screened to form a granulation of the desired particle size. The advantage of dry granulation is the elimination of heat and moisture in the processing. Dry granulations can be produced by extruding powders between hydraulically-operated rollers to produce thin cakes that are subsequently screened or milled to give the desired granule size. Direct compression avoids many of the problems associated with wet and dry granulations. However, the inherent physical properties of the individual filler materials are highly critical, and minor variations can alter flow and compression characteristics, so as to make them unsuitable for direct compression. Excipients are now available that allow production of tablets at high speeds without prior granulation steps. These directly compressible excipients consist of special physical forms of substances, such as lactose, sucrose, dextrose, or cellulose, which possess the desirable properties of fluidity and compressibility. Some of the most widely used direct compression fillers are cellulose derivatives (e.g. microcrystalline cellulose), saccharides (e.g. lactose and mannitol), mineral salts (e.g. dicalcium phosphate, calcium carbonate), and partially pregelatinzed starch (Starch 1500®). Table 1 provides the advantages and limitations of different table manufacturing methods. Tablet Components Tablet dosage form is composed of two main ingredients: (1) API and, (2) inactive ingredients also termed as excipients. The different physicochemical properties of API and manufacturing process selected dictates addition of different types of excipients, depending on the specific function they provide to aid in manufacture of tablets, efficacy and stability of the product. Active Pharmaceutical Ingredients API play a very important role in selecting the excipients, method of manufacture, size of tablet, etc. Some of the important characteristics of API, which influence the tablet performance are listed in Table 2. Article Email: [email protected] [email protected]

Transcript of Tablet Formulation

Pharma Times - Vol 41 - No. 4 - April 2009 21

AbstractTablet is the most preferred oral dosage form, due to many advantages it offers to formulators as well as physicians and patients.However, the process of manufacturing tablets is complex. Hence, careful consideration has to be given to select right process,and right excipients to ultimately give a robust, high productivity and regulatory compliant product of good quality.

Tablet Formulation Design And Manufacture:Oral Immediate Release ApplicationJayesh Parmar & Manish RaneColorcon Asia Pvt. Limited

IntroductionTablets are solid dosage forms

containing medicinal substances with orwithout suitable diluents. They are the mostwidely preferred form of medication both bypharmaceutical manufacturer as well asphysicians and patients. They offer safe andconvenient ways of active pharmaceuticalingredients (API) administration withexcellent physicochemical stability incomparison to some other dosage forms, andalso provide means of accurate dosing. Theycan be mass produced with robust qualitycontrols and offer different brandingpossibilities by means of colored film coating,different shapes, sizes or logos.

The objective of this review article is toprovide a comprehensive overview of thetablet core manufacturing process withemphasis on oral immediate releaseformulations, along with common excipientsused.

Types of TabletThe tablet dosage form is a versatile

drug delivery system. Different types oftablet formulations are available, which couldbe broadly classified based on: (1) route ofadministration such as tablets for oraldelivery, sublingual delivery, buccal delivery,rectal delivery or vaginal delivery, and (2)formulation characteristics such asimmediate release tablets, effervescenttablets, melt-in-mouth or fast dissolvingtablets, delayed release or extended releasetablets. In all the cases, the generalmanufacturing process, machinery used forpreparation of tablets and materials used aresimilar. The process of manufacturing arobust tablet dosage form and consistentlymaintain its quality is a key challenge to allformulators. Hence the manufacturingprocess and formulation components takepivotal importance.

Tablet ManufacturingTablets are compressed powders and

their manufacturing is a complex, multistepprocess. The ultimate aim of thesecompressed solids is to easily disperse ingastrointestinal fluid, aid in completeabsorption of API and, at the same time, offerstability to the formulation.

The tablet manufacturing process canbe broadly classified as granulation (wetgranulation or dry granulation) and directcompression. Granulation is anagglomeration process to improve the flow,density and compressibility of particulatematerial by size enlargement anddensification. Granulation can be achievedby the use of binder solution (wet granulation)or dry binder (dry granulation). Wetgranulation is often chosen over drygranulation because of dust elimination,single pot processing, uniformity of APIcontent (low dose API) and obtainingpredictable granulation end pointdetermination. Examples of wet granulationmethods include fluid bed, high shear,pelletization techniques, such as extrusion-spheronization, spray drying, etc. The qualityof this solid oral dosage form is, as a generalrule, primarily governed by thephysicochemical properties of the powder/granulation from which the tablets arecomposed. Dry granulation (roll compactionor slugging) involves the compaction ofpowders at high pressures into large, oftenpoorly formed tablets or compacts. Thesecompacts are then milled and screened toform a granulation of the desired particle size.The advantage of dry granulation is theelimination of heat and moisture in theprocessing. Dry granulations can beproduced by extruding powders betweenhydraulically-operated rollers to produce thincakes that are subsequently screened ormilled to give the desired granule size.

Direct compression avoids many of theproblems associated with wet and drygranulations. However, the inherent physicalproperties of the individual filler materials arehighly critical, and minor variations can alterflow and compression characteristics, so asto make them unsuitable for directcompression. Excipients are now availablethat allow production of tablets at highspeeds without prior granulation steps.These directly compressible excipientsconsist of special physical forms ofsubstances, such as lactose, sucrose,dextrose, or cellulose, which possess thedesirable properties of fluidity andcompressibility.

Some of the most widely used directcompression fillers are cellulose derivatives(e.g. microcrystalline cellulose), saccharides(e.g. lactose and mannitol), mineral salts(e.g. dicalcium phosphate, calciumcarbonate), and partially pregelatinzed starch(Starch 1500®). Table 1 provides theadvantages and limitations of different tablemanufacturing methods.

Tablet ComponentsTablet dosage form is composed of two

main ingredients: (1) API and, (2) inactiveingredients also termed as excipients. Thedifferent physicochemical properties of APIand manufacturing process selected dictatesaddition of different types of excipients,depending on the specific function theyprovide to aid in manufacture of tablets,efficacy and stability of the product.

Active Pharmaceutical Ingredients

API play a very important role inselecting the excipients, method ofmanufacture, size of tablet, etc. Some of theimportant characteristics of API, whichinfluence the tablet performance are listedin Table 2.

Article

Email: [email protected]@colorcon.com

Pharma Times - Vol 41 - No. 4 - April 200922

ExcipientsPharmaceutical excipients can be

defined as any substance other than theactive API or pro-API that has beenappropriately evaluated for safety and isincluded in API delivery system to either;

1. Aid processing of the system duringmanufacture or

2. Protect, support or enhance stability,bioavailability or patient acceptability or

3. Assist in product identification or4. Enhance any other attribute of the

overall safety and effectiveness of theAPI product during storage or use(Blecher, L., 1995).

Ideally all the excipients must bechemically inert, non-hygroscopic,compatible with API, regulatory compliant,non-toxic, have acceptable taste and beinexpensive. The pharmaceutical industryuses many different types of excipients,which can be classified as primary excipientsbased on their functionality or as secondaryexcipients based on the way they are used.

Primary excipients - This includes;fillers (diluents), binders, disintegrants,lubricants, glidants. They comprise the majorpart of a formulation and hold the key to itssuccess.

Table 1 : Tablet manufacturing methods - advantages and limitations

Method Advantages Limitations

Direct compression Simple, economical process. Not suitable for all API,No heat or moisture, so good generally limited to lowerfor unstable compounds. dose compounds.

Segregation potential.Expensive excipients.

Wet granulation Robust process suitable for Expensive: time and energy most compounds. consuming process.Imparts flowability to Specialized equipmenta formulation. required.Can reduce elasticity problems. Stability issues for moistureCoating surface with hydrophilic sensitive and thermolabile polymer can improve wettability. API with aqueousBinds API with excipient, thus granulation.reducing segregation potential.

Wet granulation Suitable for moisture sensitive Expensive equipment.(non-aqueous) API. Needs organic facility.

Vacuum drying techniques can Solvent recovery issues.remove/reduce need for heat. Health and environment

issues.

Dry granulation Eliminates exposure to moisture Dusty procedure.(slugging or roll and drying. Not suitable for allcompaction) compounds.

Slow process.

Table 2: Effect of different physicochemical properties of API on the formulation

Property of API Effects on tablet formulation Examples of API

Dose Low dose may have content uniformity effects. Misoprostol, ramipril - low dose.High dose may result in direct physical impact of the API on tablet Metformin, paracetamol - high dose.roperties.

Solubility Low solubility of API may dictate the choice of manufacturing process Nifedipine, gliclazide have low solubility.from dissolution point of view. A wet granulation is the preferred methodwith such API.

Melting point Low melting point of API may result in sticking problems or Ibuprofen (M.P. ~ 560 C) is known tosoft tablets during compression. cause tablet punch sticking.

Particle size Lower particle size of API may be important for higher solubility and Celecoxib, Albendazole.dissolution. However, this may give rise to capping problem in tablets.

pKa It dictates the pH level at which ionization takes place and subsequent Aspirin, meloxicam exhibit bettersolubilization. Acidic API having pKa (3-5) will solubilize at higher pH. solubility in basic pH.

Flow properties Poor flow of API may lead to loss of tablet hardness and weight variation Paracetamol bulk powder has poor flow.issues. This may restrict the formulator to use granulation techniques or Hence needs to be granulated for tablethigher levels of lubricants/glidants to impart the flow, which may preparation.adversely affect dissolution and compaction.

Bulk density Density plays a significant role in the blend uniformity of API along Glucosamine sulphate has high bulk with other excipients. In general, for a high density API, the diluent density, whereas Chondroitin sulphateselected should have high density and vice-versa in order to avoid has low bulk density.segregation issues in a directly compressible formulation.

Moisture content High moisture content of API may result in sticking issues during Ampicillin trihydrate formulation oftencompression of tablets. cause tablet punch sticking problem.

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Secondary excipients - This includes; film coating, colors, flavors, sweeteners, wetting agents. These excipients are responsible forappearance and performance.

DiluentsDiluent is added to formulation to increase the bulk volume of the active and hence the size of the tablet suitable for handling. The

selection of the diluent will depend on the type of processing and plasticity of materials to be used. In general, a direct-compression formulationwill require a diluent with good flow and compaction properties. Table 3 lists some of the commonly used diluents.

Property of API Effects on tablet formulation Examples of API

Hygroscopicity Highly hygroscopic API may result in problems such as tablet punch Divalproex sodium and L-Carnitine.sticking. Careful selection of manufacturing process, low humidityconditions in processing area become critical for such API.

Polymorphism Certain API exhibit polymorphic forms, which may have differences Desloratadine, Clopidogrelin solubility, chemical stability or bioavailability. The polymorphic trans formation may occur during manufacturing process due to application or generation of heat or presence of moisture.

Degradation Certain API are unstable to heat or moisture or light. Formulating Nifedipine is photosensitive.profile such API into tablets may be challenging. Rabeprazole is sensitive to heat and

moisture.

Excipient Certain API may be incompatible with specific excipients and may Aspirin is incompatible withcompatibility limit their selection. Excipient compatibility testing would help in magnesium stearate, Primary amine

selecting right excipient. based API's are incompatible withLactose (due to Malliard's reaction)

Compactability Good ability to compact renders ease in direct compression of Acetaminophen has poor ability totablets. Certain API's, however, have poor ability to compact and compact, whereas Aspirin is good. hence granulation techniques may be required as a meansof formulation velopment.

Diluent Advantages Limitations Comments

Lactose Lactose deforms by brittle fracture. Lactose intolerance. Available as anhydrous andLess sensitive to Mg. stearate Bovine derived. monohydrate; anhydrous materialover blending. Abrasive - requires high levels used for direct compression dueLess sensitive to press speed. of lubricant. to superior compressibility.Granulation does impart some May brown on aging/Maillardplastic nature to the end product. reaction.Good compressibility. Slowest dissolving sugar -Soluble in water. formulations need adequateMany different grades available. disintegrant.

Spray dried forms may containamorphous material.

Mannitol Non-hygroscopic. Very abrasive. Requires high levels It is not a reducing sugar and can bePartly soluble in water. of lubricant. substituted for lactose (lactose notNon reactive. Can cause punch filming/ picking. acceptable in certain markets).Negative heat of solution - Potential laxative effect at high dose. 10 - 90% usage level.cooling mouth feel. Expensive.Many grades available. Has both plastic and brittle nature

depending on grade.

MCC Highly compactable. Insoluble. Very popular.Has some disintegrant properties The wet massing process and the Used at concentrations of 20 - 90%.due to wicking properties. drying of the granules can lead to Plastically deforming.Non-abrasive. a considerable decrease inInert. compaction properties.Can be used in roller compaction Incompatible with strong oxidizingand extrusion/ spheronization. agents.Variety of particle size, moisture Disintegrant should be used incontent and bulk density is formulations.available.

Table 3: List of most commonly used tablet diluents

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Diluents form a major portion of most of the tablet formulationsdue to newer high potency API's. The moisture content, morespecifically water activity coefficient of such diluents, may influenceAPI stability since many API are prone to degradation by hydrolysis.In general, moisture content may indicate hydrate form or tightlybound water molecule of crystallization, or surface-bound or surface-absorbed water on the excipient. The bound water may not causehydrolysis of sensitive API, but free- or surface- absorbed water maybe responsible for hydrolysis of sensitive API. This free water istermed as water activity coefficient. Figure 1 gives loss on drying(LOD) and water activity coefficient of some commonly used filler.Lactose, for instance, has low LOD, but very high water activitycoefficient. On the other hand, Starch 1500 has very high LOD, butvery low water activity coefficient. Hence, for API such as Aspirin orRanitidine that undergo hydrolysis, Starch 1500 provides stableformulation, whereas lactose or plain microcrystalline cellulose leadsto higher impurity levels on stability (Cunnigham CR 2001).

Today pharmaceutical companies increasingly use high speedtablet press for faster and higher productivity. For such high speed

tablet press, key process and corresponding diluent knowledge hasbecome important. Use of combination of diluents with synergisticproperties or co-processed excipients, such as StarCap 1500®, co-processed starch excipient, are gaining significance in thepharmaceutical industry. Figure 2 shows impact of tablet pressspeed on the tablet breaking force (hardness) when compressed atincreasing compression pressure. It can be seen that formulationwith combination of MCC + Starch 1500 gives low yet acceptablehardness of tablets when compressed at higher speeds and at highcompression pressures. This also means that the disintegration timeis not affected for tablets compressed at higher compression pressure

Diluent Advantages Limitations Comments

Sucrose Sucrose serves as a dry binder Powdered sucrose is a cohesive solid. Sucrose is also available as invert(2-20% w/w) or as a bulking agent Tablets that contain large amounts sugar, compressible sugar and and sweetener in chewable tablets of sucrose may harden over time to as sugar spheres.and lozenges. give poor disintegration.Crystalline sucrose is free flowing.

Partial Has better compaction properties For direct compression, it may be Can be used up to 75% inpregelatinized than native starch. advantageous to combine partial wet granulation.starch Partial gelatinization improves pregelatinized starch with MCC or Can be used up to 50% in

binding yielding, improved granule lactose in a 1:1 ratio for enhancing direct compression.strength and enhanced tablet tablet hardness. Globally accepted.hardness.Multifunctional - acts as binder anddisintegrants.Self lubricant and reducesrequirement of lubricants.

Dicalcium Excellent flow properties. Practically insoluble in water, soluble Not used extensively inphosphate Ability to compact is good and in acid but not alkali. wet granulations.

independent of machine speed. Not recommended for use with Deforms by brittle fracture.Less susceptible to Mg. stearate poorly soluble API. Used up to 50%.over-blending. Loses water of crystallization at Available in milled and Non-hygroscopic. elevated temperatures. unmilled forms.

Can "trap" API under a cone or heap in a dissolution vessel.Abbrasive - can cause accelerated tooling and machine wear.

Figure 1: Water activity Vs Moisture content of some commonlyused fillers.

Figure 2: Effect of Press Speed on Hardness of tablets compressedat different compression pressures.

Formula 3 contains: Dicalcium Phosphate Dihydrate(Emcompress®, 49.75%) +Microcrystalline Cellulose (Avicel® PH102, 50%) + Magnesium Stearate (0.25%)

Formula 4 contains: Partially Pre-gelatinized Starch (Starch 1500®,49.75%) +Microcrystalline Cellulose (Avicel® PH 102, 50%) +Magnesium Stearate (0.25%)

Wat

er a

ctiv

ity a

w

Mos

iture

con

tent

Tabl

et B

read

ing

For

ce (

kp)

Compression Force (KN)

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as shown in Figure 3 (Colorcon technicaldata sheet). This property is important fordirect compression based formulations thatneed low friability, high hardness yetacceptable disintegration time at areasonable compression force.

BinderBinder is added during granulation step

to an API-filler mixture to ensure thatgranules and tablets can be formed with the

required mechanicalstrength. Duringcompaction, the bindersprovide the cohesivebinding and deformationc h a r a c t e r i s t i c snecessary for theformation of tablets.Table 4 l ists somecommonly used bindersin the pharmaceuticalindustry with theirtypical concentrations,advantages andlimitations.

Before tableting,the powder mixture isgranulated simply byadding water, hydro-

alcoholic mixture or an organic solvent toform liquid bridges followed by the dryingprocess. This granulation process results inpowders of larger particle size and that aremore free-flowing for tablet production. Themost common method of adding binders isas a solution in the granulating fluid. It isalso possible to add polymers, such aspartially pregelatinized starch (e.g. Starch1500), polyvinyl pyrrolidone (PVP) andhydroxypropyl methylcellulose (HPMC), aspowders and use water as the granulating

agent in normal equipment or using fluid bedequipment. When the granulate dries, thecrystallization of any solids that had dissolvedin the liquid will form solid bonds betweenthe particles. Inclusion of granulating agentsor binders to increase granule strength isnecessary. Granulating agents are usuallyhydrophilic polymers that have cohesiveproperties that both aid the granulationprocess and impart strength to the driedgranulate. The binder may vary thedisintegration and dissolution and finalperformance of the tablet. Binders form filmson the surface of the granules, which canaid in the wetting of hydrophobic API.However, if added at too great aconcentration, the films can form viscous gelson the granule surface and may retarddissolution. Dry addition of binder is alsopossible in direct compression.

Starch paste has been widely used asa binder. Starch paste is formed when starchgrains are heated in water causing therupture of the grains and release of the watersoluble components. The paste is preparedby suspending the starch in water and thenadding boiling water with stirring. Paste iscooled before adding to the powder, whichon standing increases in viscosity andbecomes an important property to control.Pregelatinized starch is an advanced, more

Table 4: List of some most commonly used binders

Binders Typical Advantages Limitationsconcentration

used (%)

Native starch paste 5 - 25 Good binding ability. Time consuming process, highvariability in preparation ofstarch paste.

Pregelatinized starch 5 - 10 Cold water soluble, so easier to prepare Only functions as a binder. than starch. The formulations with pregelatinized

starch require separatedisintegrating agents.

Partially 5 - 15 Acts as binder and also as disintegrant. Different suppliers have differentpregelatinized Acts as a multifunctional agent. gelatinization level. starch

Polyvinylpyrrolidone 2 - 8 Available in range of molecular Gives harder tablets upon stabilityweight/ viscosities. prolonging the disintegration timeSoluble in water and ethanol. and dissolution of the active.

Hydroxypropyl 2 - 8 It is soluble in different solvent systems May give hard granules especially ifmethylcellulose and suitable for both aqueous, binder concentration and kneading

non-aqueous or hydro-alcoholic solvents. time is increased, during highCan be used for modulation of shear granulation.API release.Number of viscosity grades available for granulation.

Methylcellulose 1 - 5 Good binder. May give hard granules, especiallySmall concentration required for if binder concentration andeffective binding. kneading time is increased,Number of viscosity grades available for during high shear granulation.granulation.

Dis

inte

grat

ion

Tim

e (m

in)

Compression Force (KN)

Figure 3: Effect of Press Speed on disintegration time (min) oftablets compressed at different compression pressures.

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user-friendly version than native starchpaste, since this material may beincorporated as a dry powder and granulatedwith water. It is also possible to prepareslurry and use it as a granulating agent. Anext generation product is partiallypregelatinized starch. This product offersdisintegrant property along with bindingcapacity. Level of gelatinization is a key toproduct performance.

PVP is a versatile binder used assolution in water, ethanol or hydro-alcoholicmixture, or added dry to powder blends andgranulated with water. One disadvantagewith PVP is that it tends to reduce theviscosity of granulations and makes thedetermination of the granulation end pointmore difficult with certain type ofinstrumentation. The tablet produced withPVP as binder also increases disintegrationtime and retards the API release over time.HPMC is soluble in both water and ethanol,and it is versatile and inert material.Generally, lower viscosity grades arepreferred for wet granulation.

DisintegrantDisintegrant is included in the

formulation to ensure that the tablet breaksup into small fragments in contact with liquid.Figure 4 shows influence of disintegratingagent on disintegration time of tablets.

Tablets must have sufficient strength towithstand the stresses of subsequentmanufacturing operations, such as thecoating, packaging, and distribution process.However, once the tablet is taken by thepatient, it must break up rapidly to ensurerapid dissolution of the active ingredient in

immediate release preparations. Toovercome the cohesive strength producedby the compression process, and to breakdown the tablet into the primary particles asrapidly as possible, disintegrants are addedto the tablet formulations. The positioning

of disintegrants withinthe intra- and extra-granular portions ofgranulated formulationscan affect their wateruptake anddisintegration time.Table 5 gives list ofsome disintegrantscommonly used in tabletformulations.

Starch was the firstdisintegrant used intablet manufacture. Thecompaction properties ofmany disintegrants,including native starch,are not satisfactory anduse of highconcentration can alsoreduce tablet strength.Recent trend inpharmaceutical industryis towards use of

powerful disintegrating agents(superdisintegrants), such as croscarmellosesodium, sodium starch glycolate,crospovidone and certain ion exchangeresins, which display excellent disintegrationactivity at low concentrations than nativestarches. Major limitations of thesesuperdisintegrants are relatively high costand hygroscopic nature, which couldnegatively affect the stability of moisturesensitive API (if the packaging does notprovide adequate protection from theenvironment). Figure 5 depicts the moisturevapor sorption graph for differentdisintegrants (Cunnigham CR, 1999).Superdisintegrants, such as crospovidone,sodium starch glycollate and croscarmellosesodium, in general, have high moisturesorption tendency., Therefore, sometimesunsuitable for formulations containingmoisture sensitive or hygroscopic API.Higher concentration of suchsuperdisintegrants also causes problemsduring aqueous film coating, often giving riseto orange peel effect to the coating.

Most pharmacopeias include a disintegrationtest which can be applied to tablets and thedetailed monograph is given in thepharmacopeias.

Table 5 - List of some most commonly used disintegrants

TypicalDisintegrant Concentation Comments

used (%)

Native Starch 5 - 10 Probably works by wicking; swelling minimal atbody temperature.

Partially 5 - 10 Amylose part of partially pregelatinizedpregelatinized starch causes swelling and gives disintegrantstarch action.

MCC 10 - 25 Strong wicking action; loses disintegrant actionwhen highly compressed.

Insoluble ion 2 - 10 Strong wicking tendencies with someexchange swelling action. resings

Sodium starch 2 - 8 Free flowing powder that swells rapidly on contactglycolate with water.

Croscarmellose 1 - 5 Swells on contact with water.sodium

Gums such as < 5 Swells on contact with water; forms viscous gelsagar, guar gum, that can retard dissolution, thus limitingxanthan gum, etc concentration that can be used.

Alginic acid, 4 - 6 Swells like gums, but forms less viscous gels thansodium alginate guar gum, xanthan, etc.

Crospovidone 1 - 5 High wicking activity.

Figure 4: Effect of different disintegrants on the physical propertiesof Hydrochlorthiazide tablets

(Tablet are composed of Hydrochlorthiazide, DicalciumPhosphate, Lactose spray dried, magnesium Stearate anddisintegrants)

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Figure 5: Moisture uptake isotherms for powders of different disintegrating agents.

% W

eigh

t C

hang

e

% Relative Humidity at 25 deg. C

Crospovidone

Socium starch glycolate

Crosslinked CMC

Starch 1500

LubricantLubricants are used in formulations to

aid in smooth ejection of tablet from diecavity, prevent sticking of powder on punchfaces (anti-adherence), reduce interparticlefriction during compression and, to improveflow of powder blend on the machine andinto the die cavity. For a robust formulation,careful consideration has to be given inselecting right type, concentration, order andduration of mixing of lubricant in theformulation. Lubricants can be furtherclassified into three types based on theirdetailed functionality: (1) glidant, whichenhance flow property of powder blend byovercoming powder cohesiveness, (2) anti-adherent, which reduce the friction betweenthe tablet punch faces and tablet punches,and (3) die wall lubricant, which reduce thefriction between the tablet surface and thedie wall during and after compaction toenable easy ejection of the tablet. Die-walllubricants can be divided into two classes:fluid and boundary lubricants. Fluid lubricantswork by separating moving surfacescompletely with a layer of lubricant. Theseare typically mineral oils or vegetable oils,and they may be either added to the mix orapplied directly to the die-wall by means ofwicked punches. The oily lubricants maygive a mottled tablet appearance due touneven distribution, poor powder flow dueto their tacky nature, and reduced tabletstrength. Boundary lubricants work byforming a thin solid film at the interface ofthe die and the tablet. Metallic stearates arethe most widely used boundary lubricants.

Talc is traditionally one of the mostcommonly used glidants, having theadditional benefit of being an excellent anti-

adherent. The level of talc that can be addedto a formulation is restricted by itshydrophobic nature; too high levels resultingin decreased wetting of the tablet and asubsequent reduction in the rate ofdissolution. Fumed silicon dioxides areperhaps the most effective glidants. Theseare materials with very small (10 nm)spherical particles that act as dividingcohesive particles to provide their glidantproperties. They are available in a numberof grades with a range of hydrophobic andhydrophilic forms, and are commerciallyavailable under diverse brand names. Starchhas also been used as a glidant. The use oflarge amounts of starch can also aid thedisintegration properties. Table 6 gives listof some commonly used lubricants in thetablet formulations.

Anti-adherentAnti-adherent causes reduction in

adhesion of powder to punch faces and thus

Table 6 - List of some commonly used lubricants in tablet formulations

TypicalDisintegrant Concentation Comments

used (%)

Glidant

Talc 1 - 5 Fine, crystalline powder, widely used as lubricantand diluent

Fumed silicon dioxide 0.1 - 0.5 Has small particle size and large surface area forgood flowability; used for adsorbent, anti-tackingagent, disintegrant and glidant.

Native starch 1 - 10 Native starch powder is used as glidant and alsoas disintegrant.

Sodium lauryl sulfate 0.2 - 2 Anionic surfactant, lubricant and wetting agent.

Boundary lubricants

Magnesium stearate 0.2 - 2 Hydrophobic, variable properties between suppliers.

Calcium stearate 0.5 - 4 Hydrophobic.

Sodium stearyl fumarate 0.5 - 2 Less hydrophobic than metallic stearates, partiallysoluble.

Polyethylene glycol 2 - 20 Soluble, poorer lubricant activity than fatty 4000 & 6000 acid ester salts.

Sodium lauryl sulfate 1 - 3 Soluble, also acts as wetting agent.

Magnesium lauryl sulfate 1 - 3 Acts as wetting agent.

Sodium benzoate 2 - 5 Soluble.

Fluid lubricants

Light mineral oil 1 - 3 Hydrophobic, can be applied to either formulationor tooling.

Hydrogenated 1 - 5 Hydrophobic, used at higher concentrations asvegetable oil controlled release agents.

Stearic acid 0.25 - 2 Hydrophobic.

Glyceryl behenate 0.5 - 4 Hydrophobic, also used as controlled release agent.

Pharma Times - Vol 41 - No. 4 - April 200928

helps in preventing sticking. These materialsdo not influence ejection force or residualforce. Thus they are most often used incombination with other lubricants to improveoverall performance during compaction.

Magnesium stearate, a boundary walllubricant, readily forms a thin film on the die-wall surface. This results in reduction inpowder ability to form strong compacts. Also,due to hydrophobic nature, it can hinderdisintegration and dissolution performanceof tablets. When formulation containsdisintegrating agents, the addition of lubricantshould be at the end of the mixing process.If both lubricant and disintegrant are addedtogether, then lubricant may form ahydrophobic film around the disintegrating

agent and ultimately result in prolonging disintegration time.Formulation containing high concentration of magnesium stearatemay result in tablets of reduced hardness, even if the compressionforce is increased. Figure 6 gives the effect of different concentrationof magnesium stearate on the breaking force of Hydrochlorthiazidetablets (Cunnigham CR, 2000). As the concentration of magnesiumstearate increased from 0.25% to 1.0% the tablet breaking forcereduced. The effect increased as a function of the compressionforce. However, when stearic acid was used, at even 1%concentration, the tablets produced were increased with compressionpressure.

Also, higher concentration of magnesium stearate can retardthe dissolution of API due to its hydrophobic nature. Figure 7 givesthe effect of magnesium stearate on release profile ofHydrochlorthiazide.

Many pharmaceutical companies use combination of talc andstearic acid or talc and hydrogenated vegetable oils as an alternativeto magnesium stearate. However, the major limitation to suchcombinations is high concentration required to give good lubricantproperties in comparison to magnesium stearate.

The level of a lubricant required in a tablet is formulationdependent and can be optimized using an instrumented tabletingmachine. It should be remembered that the requirements forlubrication and anti-adherent may be very different when tabletpresses are run at laboratory scale and at production scale. Nosingle lubricant provides all the balanced functionality of eachindividual class of lubricant.

Other excipientsCertain excipients, like anti-oxidants and surfactants, are used

only in situations where they are expressly needed to ensure thestability or performance of the product.

Excipient selectionThe selection of excipients is influenced by range of interrelated

factors, both objective and subjective. All the factors, like properties

Tablets contained Hydrochlorthiazide, Dicalcium Phosphate, Lactose,Starch 1500®, MCC, lubricant.

Figure 6: Effect of different concentrations of lubricants on the tabletbreaking force

Figure 7: Effect of Magnesium Stearate on Dissolution ofHydrochlorthiazide

Properties of excipientsStablity (chemical & physical)HygroscopicCompatibleParticle sizeAvailabilityCostRegulatory acceptance

Properties of drugDoseSolubility/ pKaParticle Size/ ShapeMelting Point/ ThermalStabilityFlow PropertiesDensities

Manufacturing processrequirementDirect compressionWet granulationFluid bed granulationSpray dryingExtrusion &spheronizationOther novel process

Selection of excipients for

solid oraldosage forms

Desired release characteristicsImmediate releaseSustained releaseModified release

Figure 8: Factors affecting the selection of excipients.

Compression Force (KN)

Tabl

et B

read

ing

For

ce (

kp)

Pharma Times - Vol 41 - No. 4 - April 2009 29

of API and excipients, desired release

characteristics and even manufacturing

process, play an important role in making a

decision [Figure 8]. For example, the choice

of manufacturing method depends on the

infrastructure available with the company,

associated cost and may be personal

preference or experience. It also depends

on the dose of API and its physicochemical

properties. And finally, suitability and

availability of excipient also play an important

role. In the present scenario, even quality of

service offered by supplier, batch-to-batch

uniformity of product, regulatory acceptance,

are also important parameters to be

considered.

Bibliography AndReferences

Blecher, L., Excipients - The important

components, Pharm. Process., 1995, 12

(1), pg 6 - 7.

Cunnigham C. R. and Scattergood L. K.,

Optimizating lubricant usage in a direct

compression hydrochlorthiazide

formulation containing a plastically

deforming excipient, AAPS, October

2000.

Cunnigham C. R. and Scattergood L. K.,

Evaluation of partially pregelatinized

starch in comparison with

superdisintegrants in a direct

compression hydrochlorthiazide

formulation, AAPS, October 1999.

Colorcon Technical Data Sheet, Dibasic

calcium phosphate replacement with

Starch 1500® in a direct compression

formula.

Cunnigham C. R. and Scattergood L. K.,

The effect of Starch 1500® on the

stability of aspirin tablets stored under

accelerated conditions, AAPS, October

2001.

Cunnigham C. R. and Scattergood L. K.,

Use of Starch 1500® to improve the

uniformity of a low dose direct

compression chlorpheniramine

formulation, AAPS, October 2000.

Rowe RC, Sheskey PJ, Owen SC (Ed.),

Pharmaceutical Excipients.

Pharmaceutical Press and American

Pharmacists Association, Fourth edition,

2005.

Kottke, M. K. and E. M. Rudnic, chapter

10 - Tablet dosage form in Modern

Pharmaceutics, Ed. Banker GS, Rhodes

C, Marcel Dekker Inc., 2002.

Cunnigham, C. R. and Scattergood, L.

K., Fluid bed granulation of

Acetaminophen: Effect of key process

variables on granule and tablet

characteristics, AAPS, October 1999.

Do N., Farrel T., Control of dissolution

rate of immediate release tablets

containing Starch 1500® with a

combination of different types and

grades of Methocel™, AAPS, Nov.

2006.

Kadtare A, Chaubal M, Excipient

Development for Pharmaceutical,

Biotechnology, and API Delivery

Systems, Informa Healthcare, USA,

2006.

UK company Paraytec has introduced

a new instrument designed to allow

formulation scientists to visualise - in real

time - what is happening at a tablet surface

when it dissolves.

The new device - called the ActiPix

Dissolution Imager - was introduced to the

marketplace at Pittcon on March 9 and could

make it easier for drug developers to develop

controlled-release medications.

Paraytec says the instrument offers

formulation scientists an alternative to "high-

cost, complex techniques such as terahertz

spectroscopic imaging and magnetic

resonance imaging "as they investigate the

release of active compounds from dosage

forms.

The ActiPix Dissolution Imager is "a

powerful tool that can reduce the time it takes

Real-time analysis of tablet surfacesPhil Taylor

a drug to come to market, thereby offering

significant potential gains in earnings,"

according to a Paraytec statement.

Tablet holder enables accurate analysis

The instrument combines a specially

designed tablet holder and Paraytec's ActiPix

D-100 UV area imager. The holder is placed

inside the ActiPix D-100 which enables real

time recording and review of data. When

liquid flows over the surface of the

formulation, release of the active ingredient

can be quantitatively monitored directly at the

tablet surface.

"It is important ... to understand the

mechanism of drug release behaviour, as this

regulates the performance of many solid

pharmaceutical dosage formulations," said

Paraytec.

The ActiPix D-100 instrument has been

used in a number of other applications in the

pharmaceutical industry, including enzyme

assays and protein sizing. Paraytec has also

been developing the technology for in-line

testing in bioprocessing, for example by

quantifying protein aggregation.

Paraytec spun of from University of York

Paraytec was spun out from the

University of York to develop a series of

instruments based on miniaturised

ultraviolet-visible (UV-vis) absorbance

detectors and capillary-based fluid handling

technology.

UV absorbance detection is a laboratory

technique widely employed to characterise

and determine the levels of substances which

dissolve in water and other liquids, with light

absorbed at different wavelengths in the

ultra-violet region indicating different

compounds.