1.5.

1 Excipient and their functionalities

(13-15)

Excipient means any component other than the active pharmaceutical ingredient(s) intentionally added to the formulation of a dosage form. Many guidelines exist to aid in selection of non toxic excipients such as IIG (Inactive Ingredient Guide), GRAS (Generally Regarded As Safe), Handbook of Pharmaceutical Excipients and others. While selecting excipients for any formulation following things should be considered wherever possible: keep the excipients to a minimum in number minimize the quantity of each excipients and multifunctional excipients may be given preference over unifunctional excipients. Excipients play a crucial role in design of the delivery system, determining its quality and performance. Excipients though usually regarded as nontoxic there are examples of known excipient induced toxicities which include renal failure and death from diethylene glycol, osmotic diarrhoea caused by ingested mannitol, hypersensitivity reactions from lanolin and cardiotoxicity induced by propylene glycol. Excipients are chosen in tablet 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 Diluents or Fillers FUNCTION Diluents make the required bulk of the tablet when the

drug dosage itself is inadequate to produce tablets of adequate weight and size. Binders or Granulating agents or Adhesives Binders are added to tablet formulations to add cohesiveness to powders, thus providing the necessary bonding to form granules, which under compaction form a cohesive mass or a compact which is referred to as a tablet. A disintegrant is added to most tablet formulations to facilitate a breakup or disintegration of the tablet when placed in an aqueous environment. Antifrictional Agents Lubricants Lubricants are intended to reduce the friction during tablet formation in a die and also during ejection from die cavity. Antiadherents are added to reduce sticking or adhesion of any of the tablet granulation or powder to the faces of the punches or to the die wall. Glidants are intended to promote the flow of tablet granulation or powder mixture from hopper to the die cavity by reducing friction between the particles. MISCELLANEOUS Wetting agents Wetting agents are added to tablet formulation to aid water uptake during

Disintegrants

Antiadherents

Glidants

disintegration and assist drug dissolution. Dissolution retardants Dissolution retardants as the name suggest, retards the dissolution of active pharmaceutical ingredient(s). Dissolution enhancers as the name suggest, enhance the dissolution rate of active pharmaceutical ingredient(s). Adsorbents are capable of retaining large quantities of liquids without becoming wet; this property of absorbent allows many oils, fluid extracts and eutectic melts to be incorporated into tablets. Buffers are added to provide suitable micro environmental pH to get improved stability and / or bioavailability. Antioxidants are added to maintain product stability, they act by being preferentially oxidized and gradually consumed over shelf life of the product. Chelating agents are added to protect against autoxidation; they act by forming complexes with the heavy metal ions which are often required to initiate oxidative reactions. Preservatives are added to tablet formulation in order to prevent the growth of

Dissolution enhancers

Adsorbents

Buffers

Antioxidants

Chelating agents

Preservatives

micro-organisms. Colours Colours are added to tablet formulation for following purposes: to disguise off colour drugs, product identification and for production of more elegant product. Flavours are added to tablet formulation in order to make them palatable enough in case of chewable tablet by improving the taste. Sweeteners are added to tablet formulation to improve the taste of chewable tablets.

Flavours

Sweeteners

Key Phrases Tablet formulations are usually designed to satisfy following criteriaPatient acceptability; accuracy and uniformity of drug content; manufacturability; optimal drug dissolution and stability. Excipients are any component other than active pharmaceutical ingredient(s) intentionally added to the formulation of a dosage form. Excipients play a crucial role in design of the delivery system, determining its quality and performance. 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?

1.5.2.1 Introduction 1.5.2.2 Classification 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 tablet handling during manufacture and to achieve targeted content uniformity, the tablet size should be kept above 2-3 mm and weight of tablet above 50 mg. Many potent drugs have low dose (for e.g. diazepam, clonidine hydrochloride) in such cases diluents provide the required bulk of the tablet when the drug dosage itself is inadequate to produce tablets of adequate weight and size. Usually the range of diluent may vary from 5-80%. Diluents are also synonymously known as fillers. Diluents are often added to tablet formulations for secondary reasons 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 tablet as per die capacity No matter for what purpose they (diluents) are added they must meet certain basic criteria for satisfactory performance in tablet dosage form. They are as follows: Diluent should not react with the drug substance and moreover it should not have any effect on the functions of other excipients, it should not have any physiological or pharmacological activity of its own, it should have consistent physical and chemical characteristics, it should neither promote nor contribute to segregation of the granulation or powder blend to which they are added, it should be able to be milled (size reduced) if necessary in order to match the particle size distribution of the active pharmaceutical ingredient, it should neither support microbiological growth in the dosage form nor contribute to any microbiological load, it should neither adversely affect the

dissolution of the product nor interfere with the bioavailability of active pharmaceutical ingredient, it should preferably be colourless or nearly so.
1.5.2.2 Classification of diluents
(16,17)

Tablet diluents 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 function as binders during wet granulation process. Whereas when used in direct compression system, they serve as the diluent. The inorganic diluents, do not exhibit binding properties when used in wet granulation and direct compression. Tablet diluent or filler may also be classified on the basis of their solubility in water as soluble and insoluble. Table.3. Classification Of Diluents Based On Their Solubility INSOLUBLE TABLET FILLERS OR DILUENTS Starch Powdered cellulose Microcrystalline cellulose Calcium phosphates, etc. Selection of diluent should be done after considering properties of diluent such as: Compactibility, flowability, solubility, disintegration qualities, hygroscopicity, lubricity and stability.
1.5.2.2.1 Organic diluents
(1,17-20)

SOLUBLE TABLET FILLERS OR DILUENTS Lactose Sucrose Mannitol Sorbitol, etc.

Carbohydrates

Sugar and Sugar alcohols Lactose -lactose monohydrate, spray dried lactose and anhydrous lactose are widely used as diluent. Characteristics of -Lactose monohydrate (hydrous) Lactose monohydrate is not directly compressible and therefore it is suitable for use in wet granulation. It has poor flow properties. -lactose monohydrate is water soluble. It produces a hard tablet and the tablet hardness increases on storage. Disintegrant is usually needed in lactose containing tablets. Drug release rate is usually not affected. It is usually unreactive, except for discoloration when formulated with amines and alkaline materials (i.e. browning or maillard reaction). It contains approximately 5% moisture and hence is a potential source of instability especially with moisture sensitive drugs. It is inexpensive. It is commercially available under the trade name of: Pharmatose and Respitose manufactured by DMV International. Characteristics of Lactose spray dried

It is directly compressible diluent. It exhibits free flowing characteristics. It needs high compression pressures in order to produce hard tablets. Its compressibility is adversely affected if dried below 3% moisture. It has high dilution potential. It is more prone to darkening in the presence of excess moisture, amines and other compounds due to the presence of a furaldehyde. Usually, neutral or acid lubricant should be used when spray dried lactose is employed. Expensive compared to anhydrous and hydrous lactose. It is commercially available as Spray Process 315 manufactured by Foremost Farms USA. Characteristics of Lactose anhydrous Lactose anhydrous is a directly compressible diluent. It does not exhibit free flowing property. It can pick up moisture at elevated humidity as a result of which changes in tablet dimensions may occur. It does not undergo a maillard reaction to the extent shown by spray dried lactose, although this may occur in some cases to a slight degree.

It is inexpensive. It is commercially available as Pharmatose DCL 21 manufactured by DMV Pharma. Starch Characteristics of Compressible Starch (Pregelatinized) It is a directly compressible diluent. It has better flow compared to unmodified starch. It also shows high compressibility as the aggregated granules undergo plastic deformation on compression. It possesses good binding properties. It also possesses disintegrant activity. It requires high pressure in order to produce a hard tablet. For good flow, it requires a flow promoter. It is prone to softening when combined with large amounts of magnesium stearate. It is commercially available under the trade name of Starch 1500 LMmanufactured by Colorcon. Sucrose Characteristics of Sucrose or sugar It requires high machine pressures, especially in cases with over wetted

granulations. It is water soluble. It possesses good binding properties. It is slightly hygroscopic. It is inexpensive. It produces gritty mouth feel (i.e., it is not free from grittiness). It is a calorie contributor and is cariogenic. Mannitol Characteristics of Mannitol Mannitol a sugar alcohol is an optical isomer of Sorbitol. It exhibits poor flow properties. It requires high lubricant content. It is probably the most expensive sugar used as a tablet diluent and is water soluble. It is widely used in chewable tablets because of its negative heat of solution, its slow solubility and its mild cooling sensation in mouth. It can be used in vitamin formulation, where moisture sensitivity may create a problem. It is comparatively non hygroscopic.

It is free from grittiness. It possesses low caloric value and is noncariogenic. It is commercially available under the brand name ParteckM manufactured by EMD Chemicals .Other commercial products are Pearlitol and Mannogem. Sorbitol Characteristics of Sorbitol Sorbitol is often combined with mannitol formulations in order to reduce diluent cost. It is highly compressible diluent and is water soluble. It is hygroscopic in nature. It has good mouth feel and sweet cooling taste. It is free from grittiness. It possesses low caloric value and is noncariogenic. It is commercially available as Sorbifin and Neosorb . Poorly absorbed sugar alcohols such as Sorbitol and mannitol can decrease small intestinal transit time. Therefore absorption may be altered for the drugs that are preferentially absorbed from this region. Celluloses
21) (1,17,

derPowoP eolluleeo

Characteristics of Powdered cellulose Powdered cellulose products consist of finely divided amorphous and crystalline -cellulose particles. Powdered cellulose may be used alone or together with other fillers such as lactose, calcium phosphates, dextrans and others. It possesses poor compressibility and exhibits poor flow properties. It has poor binding properties and low dilution potential. It is water insoluble. It possesses some degree of inherent lubricity. It is inexpensive. It is commercially available under the trade name of ElcemaG-250 manufactured by Degussa Corporation. Microcrystalline cellulose Characteristics of Microcrystalline cellulose Microcrystalline cellulose (MCC) is highly compressible and is perhaps the most widely used direct-compression tablet diluent. Hard tablets, at low compression pressures, are usually obtained when MCC is used as tablet diluent. It undergoes plastic deformation on compression and hence it is more sensitive to lubricants. It exhibits fair flowability. It exhibits binding

properties. It also possesses disintegrant activity and thus promotes fast tablet disintegration. It is water insoluble. MCC is expensive. Silicified MCC (SMCCProsolv) provides increased compactibility, enhanced flow and improved uniformity compared to MCC (Avicel manufactured by FMC Biopolymer) SMCC is more suitable for cohesive poorly compressible ingredients in direct compression formulation. Other commercial product is Emcocel manufactured by Penwest Pharmaceutical Co.
1.5.2.2.2 Inorganic diluents
(17,22)

Calcium phosphates The calcium phosphates, here includes, the dihydrate and 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 compression diluents in tablet formulation. Bulk density of calcium phosphates is higher than that of organic fillers. They are used extensively in vitamin and mineral preparations. Dibasic calcium phosphate dihydrate is also commonly known as dicalcium phosphate, calcium hydrogen phosphate dihydrate and secondary calcium phosphate dihydrate. Dibasic calcium phosphate is available commercially under the trade name Di-Tab (manufactured by Rhone-Poulenc) and Emcompress (Manufactured by E.Mendell Co.).An anhydrous form of dibasic calcium phosphate is available commercially under the trade name A-Tab (manufactured by Rhone-Poulenc). Fujicalin, a novel commercially available free flowing spherically granulated dicalcium phosphate anhydrous (SGDCPA) for direct tableting was compared with directly compressible dicalcium phosphate dihydrate (DCPD) and it was found that SGDCPA exhibited same good flowability and better compactibility. Whereas in contrast

to DCPD, SGDCPA exhibited significant uptake of moisture when exposed to relative humidity exceeding 70 %.Tribasic calcium phosphate is also commonly referred as tricalcium phosphate, tricalcium orthophosphate and hydroxyapatite. Tribasic calcium phosphate is available under the trade name Tri-Tab. Characteristic of Calcium Phosphates They are directly compressible and are characterized by brittle fracture on compression during tableting process. Hard tablets are produced when calcium phosphates are used as diluents. They exhibit good flow properties. They are non hygroscopic. They are inexpensive. They are abrasive in nature and hence can cause wear of tablet tooling. Sometimes their alkalinity is a major source of drug instability.
1.5.2.2.3 Co-processed diluents
(17,23)

Co-processing means combining two or more materials by an appropriate process. The products so formed are physically modified in such a special way that they do not loose their chemical structure and stability. Now a days direct compression technique has been one of the well-accepted methods of tablet manufacture. An extensive range of materials from various sources have been developed and marketed as directly compressible diluents such as lactose, starch, cellulose derivatives, inorganic substance, polyalcohols, and sugar-based materials. In addition to the development of directly compressible excipients by modifying just a single substance, co-processing of two or more components has been applied to produce composite particles or co-processed excipients. The composite particles or co-processed

excipients are introduced in order to provide better tableting properties than a single substance or the physical mixture. Table.4. List Of Co-Processed Excipients Used To Achieve Better Tableting Properties TRADE NAME Fast Flo lactose MANUFACTURER Foremost Whey Products DESCRIPTION It is spray processed lactose which is a mixture of crystalline -lactose monohydrate and amorphous lactose. 75% lactose and 25% MCC (MicroCrystalline Cellulose) 93% -lactose monohydrate, 3.5% polyvinylpyrrolidone, and 3.5% crospovidone. Ingredient Technology Sucrose 95-97%, invert sugar 3-4% and magnesium stearate 0.5% Sucrose 97% and modified dextrins 3% Sucrose 90-93% and invert sugar 7-10%. Dextrose 93-99% and maltose 1-7% Calcium sulfate 93% and vegetable gum 7%

Microcellac

Ludipress

Nu-Tab

Di-Pac

Amstar Corp.

Sugartab

E.Mendell Co. Inc.

Emdex

E.Mendell Co. Inc.

Cal-Tab

Ingredient Technology

Cal-Carb

Ingredient Technology Ingredient Technology

Calcium carbonate 95% and maltodextrins 5% Calcium carbonate (minimum) 90% and Starch, NF (maximum) 9%

Calcium 90

Key Phrases Diluents make the required bulk of the tablet when the drug dosage itself is inadequate to produce tablets of adequate weight and size. Diluents are often added to tablet formulations for secondary reasons like to provide better tableting properties. Tablet diluents or fillers can be divided into following categories: i) Organic materials ii) Inorganic materials iii) Co-processed diluents Tablet diluents or fillers may also be classified on the basis of their solubility in water as soluble diluent and insoluble diluent. Microcrystalline cellulose (MCC) is perhaps the most widely used directcompression tablet filler. Co-processing means combining two or more materials by an appropriate process. The composite particles or co-processed excipients are introduced to provide better tableting properties than a single substance or the physical mixture. 1.5.3 Binders ( Adhesives, Granulating agent) What will you gain? 1.5.3.1 Why to go for Granulation? 1.5.3.2 Granulation Processes

1.5.3.3 Types of Binders 1.5.3.4 Direct compression (DC) Binders 1.5.3.5 Mechanism of granule formation 1.5.3.6 Near Infrared (NIR) spectroscopy : A tool for granulation end point measurement 1.5.3.7 Factors to be considered in Granulation 1.5.3.8 Evaluation tests for Binders/Granules Binder is one of an important excipient to be added in tablet formulation. In simpler words, binders or adhesives are the substances that promotes cohesiveness. It is utilized for converting powder into granules through a process known as Granulation. Granulation is the unit operation by which small powdery particles are agglomerated into larger entities called granules.
1.5.3.1 Why to go for Granulation?
(24)

Powders/Granules intended for compression into tablets must possess two essential properties : flow property and compressibility. Flow property/Fluidity is required to produce tablets

of a consistent weight and uniform strength. Compressibility is required to form a stable, intact compact mass when pressure is applied. These two objectives are obtained by adding binder to tablet formulation and then proceeding for granulation process. Granules so formed should possess acceptable flow property and compressibility. Some drugs exhibit poor fluidity and compressibility. In such cases binders have to be added for improving flow property and compressibility. Other reasons for Granulation process are to improve appearance, mixing properties, to avoid dustiness, to densify material, to reduce segregation, in general to either eliminate undesirable properties or to improve the physical and chemical properties of fine powders.
1.5.3.2 Granulation Processes
(24)

The standard methods frequently used today in tablet manufacturing are granulation and direct compression. Granulation technique includes wet granulation and dry granulation/slugging methods wherein binders are added in solution/suspension form and in dry form respectively. In Direct Compression, binders possessing direct compressibility characteristics are used. Binder when used in liquid form gives better binding action as 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 Methyl Cellulose Ethyl Cellulose Hydroxy Propyl Methyl Cellulose ( HPMC) Hydroxy Propyl Cellulose Sodium Carboxy Methyl Cellulose Polyvinyl Pyrrolidone (PVP)

Sucrose

Acacia

Liquid glucose

Tragacanth

Gelatin

Starch Paste Pregelatinized Starch

Alginic Acid Cellulose

Polyethylene Glycol (PEG) Polyvinyl Alcohols Polymethacrylates

Table.6. Commonly Used Binders BINDER CATEGORY Partially Pregelatinized Maize Starch Hydroxy Propyl Methyl MANUFACTURER

Starch 1500

Colorcon

Methocel

Dow Chemicals

Cellulose Wolff-Cellulosics Natural Starch and Chemical Company BASF Company BASF Company BASF Company

Walocel HM

Hydroxy Propyl Methyl Cellulose

Luvitec Luvicross Luvicaprolactam

Polyvinylpyrrolidone Polyvinylpyrrolidone Polyvinylcaprolactam

Table.7. Characteristics Of Commonly Used Binder BINDER SPECIFIED CONCENTRATION 5-25%w/w

COMMENTS
- Freshly prepared starch paste is used as a binder. - Its method of preparation is very crucial.

Starch Paste

Pregelatinized Starch (PGS) [Partially and Fully PGS]

5-10%w/w (Direct Compression) 5-75%w/w (Wet Granulation )

- It is starch that have been processed chemically and/or mechanically to rupture all or part of the granules in the presence of water and subsequently dried. It contains 5% free amylose, 15% free amylopectin and 80% unmodified starch. - Obtained from maize, potato or rice starch.

- It is multifunctional excipient used as a tablet binder, diluent, disintegrant and flow aid. - They enhance both flow and compressibility and can be used as binders in Direct Compression as well as Wet Granulation. - High purity PGS allow simplified processing as they swell in cold water and therefore reduce time/costs compared with traditional starch paste preparation. Hydroxypropyl Methyl Cellulose (HPMC) 2-5%w/w - Comparable to Methyl Cellulose. - Used as a binder in either wet or dry granulation processes. 0.5-5%w/w - Soluble in both water and alcohol. - Used in wet granulation process. - It is also added to powder blends in the dry form and granulated in situ by the addition of water, alcohol or hydroalcoholic solution.

Polyvinyl Pyrrolidone (PVP)

- Valuable binder for chewable tablets. - The drug release is not altered on storage. Polyethylene Glycol (PEG) 6000 10-15%w/w - Used as a meltable binder. - Anhydrous granulating agent where water or alcohol cannot be used . - It may prolong disintegration time when concentration is 5% or higher - It improves the plasticity of other binders.
1.5.3.4 Direct compression (DC) Binders
(29)

Due to ease of manufacture, product stability and high efficiency, the use of Direct Compression for tableting has increased. For Direct Compression, directly compressible binders are required which should exhibit adequate powder compressibility and flowability. Direct Compression binders should be selected on the basis of compression behavior, volume reduction under applied pressure and flow behavior in order to have optimum binding performance. The choice and selection of binders is extremely critical for Direct Compression tablets. Table.8. Commonly Used Dc Binders Dc Binder Avicel (PH 101) SMCC (50) UNI-PURE(DW) MCCa SMCCb Partially PGSc Class Manufacturer FMC Corporation Penwest Pharmaceutical National Starch

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

DC Lactose DI TAB

DC lactose anhydrous Quest International Group 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 TAB> SMCC(50) > DC Lactose , UNI PURE(DW) > Avicel (PH 101) > UNI PURE(LD) UNI PURE(LD) > SMCC(50) , Avicel(PH 101) > UNI PURE(DW) , DC Lactose > DI TAB UNI PURE(LD) > SMCC(50) > UNI PURE(DW) > Avicel(PH 101) > DC Lactose > DI TAB

Compressibility

Crushing Strength

1.5.3.5 Mechanism of granule formation (30) Granules are formed in three stages: Nucleation: Here, the particles adhere due to liquid bridges which are the initiation step of Granulation. These adhered particles play a role of nucleus for further enlargement of granules. Transition: Enlargement of nucleus takes place by two possible mechanisms. Individual particle adhere to the nucleus or two or more nuclei combine among themselves. Ball growth or enlargement of the granule:

Ball growth occurs either by Coalescence or Breakage or Abrasion Transfer or Layering. In Coalescence a larger granule is formed when two or more granules are united. In Breakage granules break and the fragments of granule adhere to other granules. This forms a layer of material over intact granules. In Abrasion Transfer granule material are abraded through attrition by the agitation of granule bed and abraded material adheres to other granules resulting into enlarged granules. In layering particles adheres to the already formed granules increasing their size. 1.5.3.6 Near Infrared (NIR) spectroscopy : A tool for granulation end point measurement (31) NIR Spectroscopy is applicable for monitoring of wet granulation process when impeller torque method cannot be applied. Watano et al determined the granulation end point using agitated fluidized bed where in IR moisture sensor was installed. The properties of the wet mass obtained from NIR are independent of granulator equipment variables such as impeller design. Even the powder blending efficiency in the dry mixing phase can be monitored inline by NIR. NIR spectroscopy could be an excellent tool 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 the API & other tablet components. This is traditionally found by choosing appropriate stability study design. Currently Differential Scanning Calorimetry (DSC) is used to ascertain compatibility. Characteristics of drugs and other excipients The drugs characteristics like its compressibility, particle size, surface area, porosity, hydrophobicity, solubility in binder are important while fixing a granulation process. The drug that exhibits poor compressibility requires

the use of a strong binder (liquid glucose, sucrose, etc.) while the drugs that exhibit good compressibility can be successfully handled using a weak binder ( starch paste etc.,). Fine and porous particles requires higher amount of liquid binder as compared to coarse particles. Hydrophilic drug/excipients exhibiting absorption characteristics require higher volume of binder as compared to hydrophobic drug/excipients. The granule quality (size , friability) is governed by the solubility of the drug in the granulation solution. Spreading of Binder Spreading of binder/granulation solution on the powder blend is of paramount importance in successful granulation. A binder that spreads easily on particles is superior as compared to that which shows poor wetting quality. HPMC is a superior binder for paracetamol as compared to PVP. Type and quantity of Binder

The uniformity of the particle size, hardness, disintegration and compressibility of the granulation depends on type and quantity of binder added to formulation. As for example hard granulations results due to stronger binder or a highly concentrated binder solution which require excessive compression force during tableting. On the other hand, fragile granulations results due to insufficient quantity of binder which segregates easily. Larger quantities of granulating liquid produce a narrower particle size range and coarser and hard granules i.e. The proportion of fine granulates particle decreases. Therefore the optimum quantity of liquid needed to get a given particle size should be known in order to keep a batch to batch variations to a minimum. Temperature and Viscosity The temperature and viscosity of binder is also important. Fluid (less viscous) binder exhibit good spreading behavior. Method of Addition of Binder The method of addition of binder is also important. PVP can be used as solution as a binder or it may be dry blended with powders

and later activated by adding water. Distribution of binder is favored if it is dispersed instead of pouring it. Mixing Time The mixing time also determines quality of granules. If the wet massing time is higher (resulting into hard granules), the tablets may fail the dissolution test in certain cases since drug release from hard granules is altered. Material of Construction of Granulator The material of construction of granulator determines the volume of binder required as well as granule size distribution. Any vessel wall which are wetted easily by binder demands the need of higher volume of binder. As for example vessel wall made up of Stainless Steel require higher volume of binder as compared to vessel made up of plastics (PMMA Polymethylmethacrylate

and PTFE Polytetrafluoroethylene i.e. Teflon). In case of PMMA and PTFE due to high contact angle, all granulating liquid is forced immediately into the powder bed and gives narrow particle size distribution. While in case of steel, due to less contact angle liquid layer formed on the wall surface which in turn causes inhomogeneous distribution of liquid over the powder bed resulting into broader granule size. Type of Granulator Fluidized Bed Granulator produces porous granules as compared to High Shear Granulators. Process Variables Higher degree of densification of the granules results due to higher impeller speed as well as longer wet massing time. And also there is tendency of agglomeration since liquid saturation increases. Consequently, impeller speed and wet massing time affect the granule size. Apparatus Variables

The apparatus variables in High Shear Mixer have a larger effect on granule growth than in Fluidized Bed Granulators because the shear forces are dependent on the mixer construction. The size and shape of the mixing chamber, impeller and chopper vary in different High Shear Mixers. Impeller Movement Adhesion of wetted mass to the vessel is less if impeller movement is helical. This gives 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 by proper construction of the impeller or by coating the vessel with Polytetrafluoroethylene i.e. Teflon.
1.5.3.8 Evaluation tests for Binders/Granules
(1)

Compactness, physical and chemical stability, rapid production capability, efficacy are some of the characteristics that make tablet a ruling dosage form. These characteristics depend on the quality of granules from which it is made. The characteristics of granules produced are affected by formulation and process variables. So it becomes essential to evaluate the granule characteristics to monitor its suitability for tableting. Particle Size and Particle Size Distribution The particle size of granules affect the average tablet weight, tablet weight variation, disintegration time, granule friability,

granulation flowability and the drying rate kinetics of wet granulations. Therefore the effects of granule size and size distribution on the quality of tablet should be determined by formulator. The methods usually adopted for measurement of particle size and particle size distribution includes Microscopy, Sieving, Conductivity test. Surface Area Surface area of the drug effects upon dissolution rate especially in cases where drug have limited water solubility. The two most common methods for surface area determination are Gas Adsorption and Air Permeability. Density Granule density, True Density, Bulk Density may influence compressibility, tablet porosity, flow property, dissolution and other properties. Higher compression load is required in case of dense and hard granules which in turn increases the tablet disintegration and drug dissolution times. Density is usually determined by pycnometer. % Compressibility Compressibility is the ability of

powder to decrease in volume under pressure. Compressibility is a measure that is obtained from density determinations. % Compressibility = (Tapped density Bulk density/Tapped density)*100 Compressibility measures gives idea about flow property of the granules as per CARRS Index which is as follows : Table.10. Carrs Index % Compressibility 5 15 12 16 18 21 23 28 28 35 35 38 > 40 Flow Properties It is very important parameter to be measured since it affects the mass of uniformity of the dose. It is usually predicted from Hausner Ratio and Flow Description Excellent Good Fair Poor Poor Very Poor Extremely Poor

Angle Of Repose Measurement. Hausner Ratio = Tapped Density / Bulk Density Table.11. Hausner Ratio HAUSNER RATIO TYPE OF FLOW Good Flow Moderate Poor Flow

Less than 1.25 1.25 1.5 More than 1.5 Angle of Repose () is the maximum angle between the surface of a pile of powder and horizontal plane. It is usually determined by Fixed Funnel Method and is the measure of the flowability of powder/granules.

= tan-1 (h / r) where, h = height of heap of pile r = radius of base of pile Table.12.Angle Of Repose () ANGLE OF REPOSE < 25 Excellent TYPE OF FLOW

25 30 30 40 > 40

Good Passable Very Poor

Friability Friability is important since it affects in particle size distribution of granules affecting compressibility into tablet, tablet weight variation, granule flowability. Friability is determined carrying out Tumbler Test or using Friability Tester ( Roche Friabilator ) and % loss is determined. Moisture Content It affects the granule flowability, compressibility as well as the stability of moisture sensitive drug and therefore should be determined to evaluate the quality of granule.

Key Phrases Binders are added in tablet formulation to have required flow property and compressibility of powders. Wet Granulation, Dry Granulation/Slugging, Direct Compression are major granule manufacturing methods. Direct Compression Binders are more efficient than conventional binders. Pregelatinized Starch is used as multifunctional excipient: tablet binder (wet granulating agent as well as direct compression binder), diluent, disintegrant and flow aid. Polyethylene Glycol used as meltable binder. Granules are formed in three stages: Nucleation, Transition and Ball Growth. NIR a tool for granulation end point measurement and is better than torque impeller method. Compatibility of binder with API and other excipients, characteristics of binder, process variables, and apparatus variables affects the quality of granules. Granules have to be evaluated in order to measure its suitability for tableting. 1.5.4 Disintegrants What will you gain? 1.5.4.1 Introduction 1.5.4.2 Mechanism of tablet disintegrants

1.5.4.3 Methods of addition of disintegrants 1.5.4.4 Types of disintegrants 1.5.4.5 Factors affecting disintegration
1.5.4.1 Introduction

Bioavailability of a drug depends in absorption of the drug, which is affected by solubility of the drug in gastrointestinal fluid and permeability of the drug across gastrointestinal membrane. The drugs solubility mainly depends on physical chemical characteristics of the drug. However, the rate of drug dissolution is greatly influenced by disintegration of the tablet. The drug will dissolve at a slower rate from a nondisintegrating tablet due to exposure of limited surface area to the fluid. The disintegration test is an official test and hence a batch of tablet must meet the stated requirements of disintegration. Disintegrants, an important excipient of the tablet formulation, are always added to tablet to induce breakup of tablet when it comes in contact with aqueous fluid and this process of desegregation of constituent particles before the drug dissolution occurs, is known as disintegration process and excipients which induce this process are known as disintegrants. The objectives behind addition of disintegrants are to increase surface area of the tablet fragments and to overcome 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 by one or more of the mechanisms listed below:I.By capillary action II.By swelling III.Because of heat of wetting IV.Due to disintegrating particle/particle repulsive forces V.Due to deformation VI.Due to release of gases VII.By enzymatic action By Capillary Action Disintegration by capillary action is always the first step. When we put the tablet into suitable aqueous medium, the medium penetrates into the tablet and replaces the air adsorbed on the particles, which weakens the intermolecular bond and breaks the tablet into fine particles. Water uptake by tablet depends upon hydrophilicity of the drug /excipient and on tableting

conditions. For these types of disintegrants maintenance of porous structure and low interfacial tension towards aqueous fluid is necessary which helps in disintegration by creating a hydrophilic network around the drug particles. By Swelling Perhaps the most widely accepted general mechanism of action for tablet disintegration is swelling Tablets with high porosity show poor disintegration due to lack of adequate swelling force. On the other hand, sufficient swelling force is exerted in the tablet with low porosity. It is worthwhile to note that if the packing fraction is very high, fluid is unable to 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) When disintegrants with exothermic properties gets wetted, localized stress is generated due to capillary air expansion, which helps in disintegration of tablet. This explanation, however, is limited to only a few types of disintegrants and can not describe the action of most modern disintegrating agents. Due to disintegrating particle/particle repulsive forces

Another mechanism of disintegration attempts to explain the swelling of tablet made with non-swellable disintegrants. Guyot-Hermann has proposed a particle repulsion theory based on the observation that nonswelling particle also cause disintegration of tablets. the electric repulsive forces between particles are the mechanism of disintegration and water is required for it. Researchers found that repulsion is secondary to wicking. Due to deformation Hess had proved that during tablet compression, disintegranted particles get deformed and these deformed particles get into their normal structure when they come in contact with aqueous media or water. Occasionally, the swelling capacity of starch was improved when granules were extensively deformed during compression. This increase in size of the deformed particles produces a break up of the tablet. This may be a mechanism of starch and has only recently begun to be studied

Figure.18. Disintegration By Deformation And Repulsion Due to release of gases Carbon dioxide released within tablets on wetting due to interaction between bicarbonate and carbonate with citric acid or tartaric acid. The tablet disintegrates due to generation of pressure within the tablet. This

effervescent mixture is used when pharmacist needs to formulate very rapidly dissolving tablets or fast disintegrating tablet. As these disintegrants are highly sensitive to small changes in humidity level and temperature, strict control of environment is required during manufacturing of the tablets. The effervescent blend is either added immediately prior to compression or can be added in to two separate fraction of formulation. By enzymatic reaction Here, enzymes presents in the body act as disintegrants. These enzymes destroy the binding action of binder and helps in disintegration Table.13. Disintegrating Enzymes ENZYMES Amylase Protease Cellulase Starch Gelatin Cellulose and its derivatives Sucrose BINDER

Invertase

1.5.4.3 Methods of addition of disintegrants The method of addition of disintegrants is also a crucial part. Disintegrating agent can be added 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 disintegrant requires) facilitates breakup of tablets to granules and the intragranular addition of disintegrants produces further erosion of the granules to fine particles.
1.5.4.4 Types of disintegrants (34,40-42)

Starch Starch was the first disintegrating agent widely used in tablet manufacturing. Before 1906 potato starch and corn starch were used as disintegrants in tablet

formulation. However, native starches have certain limitations and have been replaced by certain modified starches with specialized characteristics. The mechanism of action of starch is wicking and restoration of deformed starch particles on contact with aqueous fluid and in doing so release of certain amount of stress which is responsible for disruption of hydrogen bonding formed during compression. Lowenthal & Wood proved that the rupture of the surface of a tablet employing starch as disintegrant occurs where starch agglomerates were found. The conditions best suited for rapid tablet disintegration are sufficient number of starch agglomerates, low compressive pressure and the presence of water. The concentration of starch used is also very crucial part. If it is below the optimum concentration then there are insufficient channels for capillary action and if it is above optimum concentration then it will be difficult to compress the tablet. Pregelatinized starch Pregelatinized starch 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 To have a high swelling properties and faster disintegration, starch is modified by carboxy methylation followed by cross linking, which is available in market as cross linked starch. One of them is SODIUM STARCH GLYCOLATE. Even low substituted carboxymethyl starches are also marketed as Explotab and Primojel. Mechanism of action of this modified starches are rapid and extensive swelling with minimum gelling. And its optimum concentration is 4-6 %. If it goes beyond its limit, then it produces viscous and gelatinous mass which increases the disintegration time by resisting the breakup of tablet. They are highly efficient at low concentration because of their greater swelling capacity. Table.14. List Of Disintegrants DISINTEGRANTS CONCENTRATION SPECIAL COMMENTS

IN GRANULES(%W/W) Starch USP 5-20 Higher amount is required, poorly compressible Lubricant properties and directly compressible Purified wood cellulose Acts by swelling Acts by swelling Sodium starch glycolate, superdisintegrant. Crosslinked PVP Ion exchange resin -

Starch 1500 Avicel(PH 101, PH 102) Solka floc Alginic acid Na alginate Explotab Polyplasdone(XL) Amberlite (IPR 88) Methyl cellulose, Na CMC, HPMC AC-Di-Sol

5-15 10-20

5-15 1-5 2.5-10 2-8 0.5-5 0.5-5 5-10

1-3 2-4

Direct compression Wet granulation Created insitu in effervescent tablet

Carbon dioxide

Cellulose and its derivatives

Sodium carboxy methylcellulose (NaCMC and CARMELLOSE sodium) has highly hydrophilic structure and is soluble in water. But when it is modified by internally crosslinking we get modified crosslinked cellulose i.e. Crosscarmellose sodium which is nearly water insoluble due to cross linking. It rapidly swells to 4-8 times 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 by wicking action. The moisture breaks the hydrogen bonding between adjacent bundles of MCC. It also serves as an excellent binder and has a tendency to develop static charges in the presence of excessive moisture content. Therefore, sometimes it causes separation in granulation. This can be partially overcome by drying the cellulose to remove the moisture. Alginates Alginates are hydrophilic colloidal substances which has high sorption capacity. Chemically, they are alginic acid and salts of alginic acid. Alginic acid is insoluble in water, slightly acidic in reaction. Hence, it should be used in only acidic or neutral granulation. Unlike starch and MCC, alginates do not retard flow and can be successfully used with ascorbic acid, multivitamin formulations and acid salts of organic bases. Ion-exchange resin Ion exchange resin (Ambrelite IPR-88) has highest water uptake capacity than other disintegrating agents like starch and Sodium CMC. It has tendency to adsorb certain drugs. Miscellaneous This miscellaneous category includes disintegrants like surfactants, gas producing disintegrants and hydrous aluminium silicate. Gas producing disintegrating agents is used in soluble tablet, dispersible tablet and effervescent tablet. PolyplasdoneXL and PolyplasdoneXL10 act by wicking, swelling and possibly some deformation recovery. PolyplasdoneXL do not reduce tablet hardness,

provide rapid disintegration and improved dissolution. Polyplasdone as disintegrating agent has small particle size distribution that impart a smooth mouth feel to dissolve quickly. Chewable tablet does not require addition of disintegrant. Superdisintegrants As days passes, demand for faster disintegrating formulation is increased. So, pharmacist needs to formulate disintegrants i.e. Superdisintegrants which are effective at low concentration and have greater disintegrating efficiency and they are more effective intragranularly. But have one drawback that it is hygroscopic therefore not used with moisture sensitive drugs. And this superdisintegrants act by swelling and due to swelling pressure exerted in the outer direction or radial direction, it causes tablet to burst or the accelerated absorption of water leading to an enormous increase in the volume of granules to promote disintegration.

Figure.19. Mechanism of superdisintegrants by swelling Table.15. List Of Superdisintegrants SUPERDISINTEGRANTS EXAMPLE OF MECHANISM OF ACTION -Swells 4-8 folds in < 10 seconds. -Swelling and wicking both. SPECIAL COMMENT -Swells in two dimensions. -Direct compression or granulation

Crosscarmellose Ac-Di-Sol Nymce ZSX Primellose Solutab

Crosslinked cellulose

Vivasol Crosspovidone Crosspovidon M Kollidon Polyplasdone Crosslinked PVP -Swells very little and returns to original size after compression but act by capillary action -Swells 7-12 folds in <30 seconds

-Starch free -Water insoluble and spongy in nature so get porous tablet

Sodium starch glycolate Explotab Primogel

Crosslinked starch

-Swells in three dimensions and high level serve as sustain release matrix -Promote disintegration in both dry or wet granulation -Does not contain any starch or sugar. Used in nutritional products.

Alginic acid NF Satialgine

Crosslinked alginic acid

-Rapid swelling in aqueous medium or wicking action

Soy polysaccharides Emcosoy

Natural super disintegrant

Calcium silicate

-Wicking action -Highly porous, -light weight -optimum concentration is between 2040%

1.5.4.5 Factors affecting disintegration

Effect of fillers

(43,44)

The solubility and compression characteristics of fillers affect both rate and mechanism of disintegration of tablet. If soluble fillers are used then it may cause increase in viscosity of the penetrating fluid which tends to reduce effectiveness of strongly swelling disintegrating agents and as they are water soluble, they are likely to dissolve rather than disintegrate. Insoluble diluents produce rapid disintegration with adequate amount of disintegrants. Chebli and cartilier proved that tablets made with spray dried lactose (water soluble filler) disintegrate more slowly due to its amorphous character and has no solid planes on which the disintegrating forces can be exerted than the tablet made with crystalline lactose monohydrate. Effect of binder As binding capacity of the binder increases, disintegrating time of tablet increases and this counteract the rapid disintegration. Even the concentration of 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 any other ingredient in the tablet formulation. When the mixture is mixed, lubricant particles may adhere to the surface of the other particles. This hydrophobic coating inhibits the wetting and consequently tablet disintegration. Lubricant has a strong negative effect on the water uptake if tablet contains no disintegrants or even high concentration of slightly swelling disintegrants. On the contrary, the disintegration time is hardly affected if there is some strongly swelling disintegrants are present in the tablet. But there is one exception like sodium starch glycolate whose effect remains unaffected in the presence of hydrophobic lubricant unlike other disintegrants. Effect of surfactants Table.16. The Effects Of Various Surfactants

Surfactant Sodium lauryl sulfate

Remarks Good-various drugs Poor - various drugs

Polysorbate 20 Polysorbate 40 & 60 Polysorbate 80 Tweens Poly ethylene glycol

Good Poor Good Poor Poor

(Good decrease in disintegration time, Poor increase in disintegration time) Sodium lauryl sulphate increased absorption of water by starch or had a variable effect on water penetration in tablets. Surfactants are only effective within certain concentration ranges. Surfactants are recommended to decrease the hydrophobicity of the drugs because the more hydrophobic the tablet the greater the disintegration time. Aoki and fukuda claimed that disintegration time of granules of water-soluble drugs did not seem to be greatly improved by the addition of nonionic surfactant during granulation , but the desired effect of a surfactant appeared when granule were made of slightly soluble drugs. The speed of water penetration was increased by the addition of a surfactant. Key Phrases Disintegrants are added to tablet to induce breakup when it comes in contact with aqueous fluid.

 Disintegration by capillary action or by swelling is the major mechanism for disintegrants. Disintegrant can be added intragranular or extragranular or at both stages. Superdisintegrants have greater efficiency at low concentration and hence, their demand is increasing day by day. 1.5.5 Antifrictional Agents What will you gain? 1.5.5.1 Lubricants 1.5.5.1.1 Classification of lubricants 1.5.5.1.1.1 Water Insoluble Lubricants 1.5.5.1.1.2 Water Soluble Lubricants 1.5.5.2 Antiadherents 1.5.5.3 Glidants
1.5.5.1 Lubricants(4,16)

Lubricants are the agents that act by reducing friction by interposing an intermediate layer between the tablet constituents and the die wall during compression and ejection. Solid lubricants, act by boundary mechanism, results from the adherence of the polar portions of molecules with long carbon chains to the metal surfaces to the die wall. Magnesium stearate is an example of boundary lubricant. Other is hydrodynamic mechanism i.e. fluid lubrication where two moving surfaces are separated by a finite and continuous layer of fluid lubricant. Since adherence of solid lubricants to the die wall is more than that of fluid lubricants, solid lubricants are more effective and more frequently used. Since primarily 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 hydrophobic lubricants are added to a granulation, they form a coat around the individual particles (granules), which may cause an increase in the disintegration time and a decrease in the drug dissolution rate. Presence of lubricants may results in a less cohesive and mechanically weaker tablet because it may interfere with the particle particle bonding. Surface area is important parameter for deciding lubricant efficiency. Lubricants with high surface area are more sensitive to changes in mixing time than lubricant with low surface area. Therefore lubricant mixing time should be kept minimum. Tooling used to compress the tablet is important for deciding type and level of lubricant used. Additional lubricant is often added to the tablet formulations that are to be compressed with curved face punches. Further, the amount of lubricant increases as the particle size of the granulation decreases but its concentration should not exceed to 1% for producing maximum flow rate. Lack of adequate lubrication produces binding which can results in tablet machine strain and can lead to damage of lower punch heads, lower cam track, die seats and the tooling itself. And it may also yield tablets with scratched edges and are often fractured at the top edges. With excessive binding the tablet may be cracked and fragmented by ejection.
1.5.5.1.1 Classification of lubricants

Lubricant are classified according to their water solubility i.e. water insoluble and water soluble. Selection of lubricant is depends partly on mode of administration, type of tablet, desired disintegration and dissolution properties, physicochemical properties of granules or powder and cost.
1.5.5.1.1.1 Water Insoluble Lubricants

Water insoluble lubricants are most effective and used at reduced concentration than water soluble lubricants. Since these lubricants function by coating ,

their effectiveness is related with their surface area, extent of particle size reduction, time, procedure of addition and length of mixing. Table.17. List Of Insoluble Lubricants INSOLUBLE LUBRICANTS CONCENTRATION COMMENTS Reduce tablet strength; prolong disintegration; widely used. Insoluble but not hydrophobic; moderately effective. Both lubricant and binder; Dispersion problem; inferior to stearates

Stearates(Magnesium Stearate, Calcium Stearate, 0.25 -1 Sodium stearate)

Talc

1 -2

Sterotex Waxes Stearowet Glyceryl behapate(Compritol888) Liquid paraffin

0.25 1 1-5 1-5 1-5

Up to 5

1.5.5.1.1.2 Water Soluble Lubricants

Water Soluble Lubricants are used when a tablet is completely soluble or when unique disintegration and dissolution characteristics are required. Tablet containing soluble lubricant shows higher dissolution rate than tablet with insoluble lubricants. Physical mixture of this lubricant i.e. SLS or MLS with stearates can lead to the best compromise in terms of lubricity, tablet strength and disintegration. Table.18. List Of Soluble Lubricants WATER SOLUBLE LUBRICANTS CONCENTRATION RANGE (%W/W)

Boric acid Sodium benzoate Sodium oleate Sodium acetate Sodium Lauryl sulfate (SLS) Magnesium lauryl sulfate (MLS)
1.5.5.2 Antiadherents
(4, 16)

1 5 5 5 15

1-2

Some material have strong adhesive properties towards the metal of punches and dies or the tablet formulation containing excessive moisture which has tendency to result 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) Talc 15 COMMENT Lubricant with excellent antiadherents properties Lubricant with excellent antiadherents properties Does not give satisfactory results due to small surface area. Cab-O-Sil and Syloid

Cornstarch

3 10

Colloidal silica

0.1 0.5

DL-Leucine

3 10

Water soluble lubricant; excellent antiadherents properties Antiadherents with water soluble lubricant Antiadherents with water insoluble lubricant

Sodium lauryl sulfate Stearates

1.5.5.3 Glidants

<1

<1
(4, 16)

GLIDANTS are added to the formulation to improve the flow properties of the material which is to be fed into the die cavity and aid in particle rearrangement within the die during the early stages of compression. If the flow properties are extremely poor then glidants are ineffective and consideration of force free mechanisms may be necessary. Starch is a popular glidant because it has additional 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 a glidant which is superior to starch; its concentration should be limited because it has retardant effect on dissolution-disintegration profile. Silaceous material like colloidal silica i.e. syloid, pyrogenic silica (0.25%), hydrated sodium silioaluminate (0.75%) are also successfully used to induce flow. Glidants act by interposing their particles between those of material and lower the overall interparticulate friction of the system by virtue of their reduced adhesive tendencies. Similar to lubricants, they are required at the surface of feed particles and they should be in fine state of division and appropriately incorporated in the mixture. Key Phrases Lubricants are added to reduce the friction during compression. Antiadherents

avoid sticking to die walls and picking by punches. Glidants improve the flow property of material/granules. 1.5.6 Miscellaneous Excipients What will 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 formulation aid water uptake and thereby enhancing disintegration and assisting in drug dissolution. Incorporation of anionic surfactant like Sodium Lauryl Sulphate (SLS) is known to enhance the dissolution.It has been established that SLS improves permeation of drug through biological membrane since it destroys the path through which drug has to pass and thus minimizing the path length for the drug to travel. Wetting agents are mainly added when hydrophobic drug is to be formulated into tablet. SLS, Sodium diisobutyl sulfosuccinate are used as wetting agent in tablet formulation.
1.5.6.2 Dissolution Retardants

Dissolution Retardants are incorporated into tablet formulation only when controlled release of drug is required. Waxy materials like stearic acid and their esters can be used as dissolution retardants.
1.5.6.3 Dissolution Enhancers

They are the agents that alter the molecular forces between ingredients to enhance the dissolution of solute in the solvent. Fructose, Povidone, Surfactants are used as dissolution enhancer.
1.5.6.4 Adsorbents
(4)

Adsorbents are the agents that can retain large quantities of liquids. Therefore liquids like Vitamin E can be incorporated into tablets by addition of adsorbents .Most commonly used adsorbents in pharmaceuticals are anhydrous calcium phosphate, starch, magnesium carbonate, bentonite, kaolin, magnesium silicate, magnesium oxide and silicon dioxide. Generally the liquid to be adsorbed is first mixed with the adsorbent prior to incorporation into the formulation. Silicon dioxide when added 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 a change in pH may cause significant alteration in stability. Most commonly used buffering agent in tablet formulation includes sodium bicarbonate, calcium carbonate, and sodium citrate.
1.5.6.6 Antioxidants

Antioxidants are added in tablet formulation to protect drug from undergoing oxidation. Antioxidants undergo oxidation in place of drug or they block the oxidation reaction or they act as synergists to other antioxidants. Chelators may also act as antioxidant. Most commonly used antioxidants include ascorbic acid and their esters , alpha-tocopherol , ethylene diamine tetra acetic acid , sodium metabisulfite , sodium bisulfite , Butylated Hydroxy Toluene (BHT) , Butylated Hydroxy Anisole (BHA) , citric acid , and tartaric acid .
1.5.6.7 Chelating Agents

Chelating agents tend to form complexes with trace amount 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 used chelators.

1.5.6.8 Preservatives

Preservatives may be a part of tablet formulation in order to prevent the growth of microorganisms in tablet formulation. Parabens like methyl, propyl, benzyl, butyl p-hydroxy benzoate are used as preservatives.
1.5.6.9 Colourants(1, 4,16)

Colourants neither contribute to therapeutic activity nor do they improve product bioavailability or stability but are incorporated into tablets for purposes like to facilitate identification of similar looking products with in a product line to avoid mix ups, to facilitate identification of products of similar appearance that exist in the lines of different manufacturers, to overcome colour change on aging, disguising of off-colour drugs, for brand image in the market, to enhance the aesthetic appearance of the product to have better patient acceptance. Most widely used colourants are dyes and lakes which are FD & C and D & C approved. Dyes are generally applied as solution especially in the granulating agent. Lakes are usually employed as dry powders for colouring. In general, direct compression tablets are coloured with lakes because no granulation step is used. Natural colourants can be used and generally they do not require the FDA certification before use in drug products. One of the important advantage in using lakes is reduced risk of interaction between the drug and other ingredients as well as colour development is rapid which reduces processing time .While employing wet granulation , care should be taken to prevent colour migration during drying . In any coloured tablet, the formulation should be checked for resistance to colour changes on exposure to light. Reflectance Spectrophotometry, Tristimulus Colourimetric Measurements and Microreflectance Photometer used to measure the colour uniformity and gloss on a tablet surface. Table.20. Some Commonly Used Pharmaceutical Colourants (Synthetic) FD & C COLOUR Red 3 Red 40 Erythrosine Allura red AC COMMON NAME

Yellow 5 Yellow 6 Blue 1 Blue 2 Green 3

1.5.6.10 Flavours(1,4)

Tartrazine Sunset Yellow Brilliant Blue Indigotine Fast Green

Flavors are commonly used to improve the taste of chewable tablets as well as mouth dissolved tablets. Flavors are incorporated either as solids (spray dried flavors) or oils or aqueous (water soluble) flavors. Solids that is dry flavors are easier to handle and generally more stable than oils. Oil is usually added at the lubrication step because of its sensitivity to moisture and their tendency to volatilize when heated during drying. It may also be adsorbed onto an excipient and added during the lubrication process. The maximum amount of oil that can be added to granulation without affecting tableting characteristics is 0.5 to 0.75 %w/w. aqueous flavors are less used because of its instability on aging.
1.5.6.11 Sweeteners(1,4,45)

Sweeteners are added primarily to chewable tablets. Table.21. Some Of The Sweeteners Used In Tablet Formulation NATURAL SWEETENERS Mannitol Lactose Sucrose Dextrose ARTIFICIAL SWEETENERS

Saccharin Cyclamate Aspartame

Saccharin is 500 times sweeter than sucrose. Its major disadvantages are that it has a bitter aftertaste and is carcinogenic. Even cyclamate is carcinogenic

.Aspartame is about 180 times sweeter than sucrose. The primary disadvantage of aspartame is its lack of stability in the presence of moisture. When aspartame is used with hygroscopic components, it will be necessary to determine its stability under conditions in which the product can adsorb atmospheric moisture. Aspartame is available in market under the brand Nutrasweetmanufactured and marketed by Nutrasweet Company.