Tablet.pdf

Tablet Introduction 1. Why do we need to convert an active pharmaceutical ingredient into a suitable dosage form? 2. What is a tablet? 3. Advantages and disadvantages of tablet as a dosage form 4. Key Wards Why do we need to convert an active pharmaceutical ingredient into a suitable dosage form? Active pharmaceutical compounds (drugs) are used for the treatment of a disease or for prophylactic purpose. An Active Pharmaceutical Ingredient (API) may exist in solid, liquid or semisolid form. The API and excipients are suitably processed in pharmaceutical industry to convert them into dosage forms such as tablet, capsule, suspension, solution. What is a tablet? It is a solid dosage form each containing a unit dose of one or more medicament/s. Tablets are solid, flat or biconvex discs prepared by compressing a drug or a mixture of drugs with or without suitable excipients. Advantages of tablet as a dosage form -

1. Large scale manufacturing is feasible in comparison to other dosage forms. Therefore, economy can be achieved

2. Accuracy of dose is maintained since tablet is a solid unit dosage form 3. Tailor made release profile can be achieved 4. Longer expiry period and minimum microbial spillage owing to lower moisture content 5. As tablet is not a sterile dosage form, stringent environmental conditions are not required in the tablet

department 6. Ease of packaging (blister or strip) and easy handling over liquid dosage form 7. Easy to transport in bulk 8. Organoleptic properties (taste, appearance and odor) are best improved by coating of tablet 9. Product identification is easy and markings done with the help of grooved punches and printing with

edible ink 10. Different types of tablets are available like buccal, floating, colon targeting, effervescent, dispersible,

soluble, and chewable, etc 11. In composition to parenterals dosage form, a doctor or a nurse is not required for administration i.e. self

administration is possible 12. In comparison to capsules, tablets are more tamperproof

Disadvantages of tablet as a dosage form - 1. It is difficult to convert a high dose poorly compressible API into a tablet of suitable size for human use 2. Difficult to formulate a drug with poor wet ability, slow dissolution into a tablet 3. Slow onset of action as compared to parenterals, liquid orals and capsules 4. The amount of liquid drug (e.g. Vitamin E, Simethicone) that can be trapped into a tablet is very less 5. Difficult to swallow for kids, terminally ill and geriatric patients 6. Patients undergoing radiotherapy cannot swallow tablet

Key Wards Reasons to go for dosage form i) To control organoleptic properties ii) Achieve desired therapeutic level of drug Types of tablets With advancement in technology and increase in awareness towards modification in standard tablet to achieve better acceptability as well as bioavailability, newer and more efficient tablet dosage forms are being developed.

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VARIOUS TYPES OF TABLETS - ORAL TABLETS FOR INGESTION - TABLETS USED IN THE ORAL CAVITY - TABLETS ADMINISTERED BY OTHER ROUTES - TABLETS USED TO PREPARE SOLUTION ORAL TABLETS FOR INGESTION 1 Standard compressed tablet2 Multiple compressed tablets I. Compression coated tablet II. Layered tablet III. Inlay tablet3 Modified Release tablet4 Delayed action tablet5 Targeted tablet I. Floating tablet II. Colon targeting tablet6 Chewable tablets7 Dispersible tablets These tablets are meant to be swallowed intact along with a sufficient quantity of potable water. Exception is chewable tablet. Over 90% of the tablets manufactured today are ingested orally. This shows that this class of formulation is the most popular world wide and the major attention of the researcher is towards this direction. TABLETS USED IN THE ORAL CAVITY 1 Lozenges and troches2 Sublingual tablets3 Buccal tablets4 Dental cones5 Mouth dissolved tablet The tablets under this group are aimed release API in oral cavity or to provide local action in this region. The tablets under this category avoids first-pass metabolism, decomposition in gastric environment, nauseatic sensations and gives rapid onset of action. The tablets formulated for this region are designed to fit in proper region of oral cavity TABLETS ADMINISTERED BY OTHER ROUTES 1 Vaginal tablet2 Implants These tablets are administered by other route except for the oral cavity and so the drugs are avoided from passing through gastro intestinal tract. These tablets may be inserted into other body cavities or directly placed below the skin to be absorbed into systemic circulation from the site of application TABLETS USED TO PREPARE SOLUTION 1. Effervescent tablet2. Hypodermic tablet3. Soluble tablet The tablets under this category are required to be dissolved first in water or other solvents before administration or application. This solution may be for ingestion or parenteral application or for topical use depending upon type of medicament used. www.pharmatechbd.blogspot.com

KEY When two or more active pharmaceutical ingredients are needed to be administered simultaneously and they are incompatible, the best option for the formulation pharmacist would be to formulate multilayered tablet. When we need to release the medicament slowly for long time duration after administration of a single tablet we go for modified release formulation. When we need to release the API at a specific site in the elementary tract, targeted drug delivery is a preferred option. Dispersible tablets disintegrate either rapidly in water, to form a stabilized suspension, or disperse instantaneously in the mouth to be swallowed without the aid of water Sublingual tablet is designed to dissolve in small quantity of saliva and used when immediate action within few minutes is desired. Buccal tablet is most often used when replacement hormonal therapy is to be administered. Implants are inserted into subcutaneous tissue by surgical procedures where they are very slowly absorbed over a period of a month or a year Tablets Formulation Excipients and their functionalitiesDiluentsBindersDisintegrantsAntifrictional AgentsMiscellaneous Excipients Excipients are chosen in tablet formulation to perform a variety of functions like

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

2. For enhancing patient acceptance (flavors, colourants may be added) 3. For providing aid in product identification (colourants may be added) 4. For Optimizing or modifying drug release (disintegrants, hydrophilic polymers, wetting agents,

biodegradable polymers may be added) 5. For enhancing stability (antioxidant, UV absorbers may be added)

EXCIPIENT Diluents or Fillers Binders or Granulating agents or Adhesives Disintegrants Lubricants Antiadherents Glidants MISCELLANEOUS Wetting agents Dissolution retardants Dissolution enhancers Adsorbents Buffers Antioxidants Chelating agents


Preservatives Colours Flavours Sweeteners Excipients and their functions Diluents or Fillers 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. Disintegrants A disintegrant is added to most tablet formulations to facilitate a breakup or disintegration of the tablet when placed in an aqueous environment. Lubricants Lubricants are intended to reduce the friction during tablet formation in a die and also during ejection from die cavity. Antiadherents 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 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. Wetting agents Wetting agents are added to tablet formulation to aid water uptake during disintegration and assist drug dissolution. Dissolution retardants Dissolution retardants as the name suggest, retards the dissolution of active pharmaceutical ingredient(s). Dissolution enhancers Dissolution enhancers as the name suggest, enhance the dissolution rate of active pharmaceutical ingredien(s). Adsorbents 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 Buffers are added to provide suitable micro environmental pH to get improved stability and / or bioavailability. Antioxidants Antioxidants are added to maintain product stability, they act by being preferentially oxidized and gradually consumed over shelf life of the product.


Chelating agents 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 Preservatives are added to tablet formulation in order to prevent the growth of micro organisms Colors Colors are added to tablet formulation for following purposes: to disguise off color drugs, product identification and for production of more elegant product. Flavors Flavors are added to tablet formulation in order to make them palatable enough in case of chewable tablet by improving the taste. Sweeteners Sweeteners are added to tablet formulation to improve the taste of chewable tablets Tablet formulations are usually designed to satisfy following criteria-Patient 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, colors, flavors, sweeteners Diluents 1 Introduction 2 Classification of diluents 2.1 Organic diluents 2.2 Inorganic diluents 2.3 Co-processed diluents 2.4 Key Phrases Introduction 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 Diluent Must Meet Certain Basic Criteria

Diluent should not react with the drug substance 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 colorless or nearly so Classification of Diluents Tablet diluents or fillers can be divided into following categories: www.pharmatechbd.blogspot.com

i)Organic materials - Carbohydrate and modified carbohydrates. ii) Inorganic materials Calcium phosphates and others. iii) Co-processed Diluents. Addition of Diluent 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 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. 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. Disintegrants 1 Introduction 2 Mechanism of tablet disintegrants 3 Methods of addition of disintegrants 4 Types of disintegrants 4.1 Starch 4.2 Pregelatinized starch 4.3 Modified starch 4.4 Cellulose and its derivatives 4.5 Microcrystalline cellulose (MCC) 4.6 Alginates 4.7 Ion-exchange resin 4.8 Miscellaneous 4.9 Superdisintegrants 5 Factors affecting disintegration 5.1 Effect of fillers 5.2 Effect of binder 5.3 Effect of lubricants 5.4 Effect of surfactants 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. 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


Disintegrating Mechanism The tablet breaks to primary particles by the mechanisms listed below:- By capillary action By swelling Because of heat of wetting Due to disintegrating particle/particle repulsive forces Due to deformation Due to release of gases By enzymatic action 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. 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. Heat of wetting (air expansion) Disintegrating particle/particle repulsive forces Deformation Release of gases Enzymatic reaction

When disintegrants with exothermic properties gets wetted, localized stress is generated due to capillary air expansion, which helps in disintegration of tablet.

Another mechanism of disintegration attempts to explain the swelling of tablet made with non swellable disintegrants.

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.

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.

Enzymes presents in the body act as disintegrants. These enzymes destroy the binding action of binder and helps in disintegration. DISINTEGRATING ENZYMES ENZYME Amylase Protease Cellulase Invertase BINDER Starch Gelatin Cellulose and its derivatives Sucrose Disintegrants Addition 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. Types of disintegrants Starch Pregelatinized starch Modified 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. The mechanism of action of starch is wicking and restoration of deformed starch particles on contact with aqueous fluid. The concentration of starch used is also very crucial part B. 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. C. Starch is modified by carboxy methylation followed by cross linking, which is available in market as cross linked starch. EX-SODIUM STARCH GLYCOLATE Mechanism of action of this modified starches are rapid and extensive swelling with minimum gelling. And its optimum concentration is 4-6 %. DISINTEGRANTS LIST Other Disintegrants A. Cellulose and its derivatives B. Microcrystalline cellulose (MCC) C. Alginates D. Ion-exchange resin E. Miscellaneous * 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 * 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. * 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 * Ion exchange resin (AmbreliteIPR-88) has highest water uptake capacity than other disintegrating agents like starch and Sodium CMC. * The 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. Super-disintegrants 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. One drawback that it is hygroscopic therefore not used with moisture sensitive drugs. 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. SUPERDISINTEGRANTS Factors affecting disintegration Fillers Effect Binders Effect Lubricants Effect Sarfactants Effect


1. The fillers affect both rate and mechanism of disintegration of tablet. Insoluble diluents produce rapid disintegration with adequate amount of disintegrants. 2. 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. 3. Lubricants are hydrophobic and they are usually used in smaller size than any other ingredient in the tablet formulation 4. Surfactants are recommended to decrease the hydrophobicity of the drugs the more hydrophobic the tablet the greater the disintegration time. Key Wards 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. Selection of diluent Organic diluents Carbohydrates Sugar and Sugar alcohols Lactose- -lactose monohydrate, spray dried lactose and anhydrous lactose are widely used as diluent Characteristics of -Lactose monohydrate 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. 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. 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. 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 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. Sorbitol Characteristics of Sorbitol 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. Cellulose Powdered cellulose Characteristics of Powdered cellulose 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. Microcrystalline Cellulose Characteristics of Microcrystalline cellulose 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.


Inorganic diluents 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. Dibasic calcium phosphate is available commercially under the trade name (Manufactured byDi-Tab Emcompress An anhydrous form of dibasic calcium phosphate is available commercially under the trade name A-Tab 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 %. 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. Co-processed diluents Co-processing means combining two or more materials by an appropriate process 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. LIST OF CO-PROCESSED EXCIPIENTS USED TO ACHIEVE BETTER TABLETING PROPERTIES Key WARDS 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 direct-compression 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 Binders


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 Contents 1 Why to go for Granulation? 2 Granulation Processes 3 Types of Binders 3.1 Direct compression (DC) Binders 3.2 Mechanism of granule formation 3.3 Near Infrared (NIR) spectroscopy : A tool for granulation end point measurement 3.4 Factors to be considered in Granulation 3.4.1 Compatibility 3.4.2 Characteristics of drugs and other excipients 3.4.3 Spreading of Binder 3.4.4 Type and quantity of Binder 3.4.5 Temperature and Viscosity 3.4.6 Method of Addition of Binder 3.4.7 Mixing Time 3.4.8 Material of Construction of Granulator 3.4.9 Type of Granulator 3.4.10 Process Variables 3.4.11 Apparatus Variables 3.4.12 Impeller Movement 3.5 Evaluation tests for Binders/Granules 3.5.1 Particle Size and Particle Size Distribution 3.5.2 Surface Area 3.5.3 Density 3.5.4 % Compressibility 3.5.5 Flow Properties 3.5.6 Friability 3.5.7 Moisture Content 3.6 Key Phrases Granulation Flow property or 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. Granulation Granulation process are *To improve appearance, * To improve 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. Granulation Processes Granulation technique includes wet granulation and dry granulation/slugging wherein binders are added in solution/suspension form and in dry form respectively. In Direct Compression, binders possessing direct compressibility characteristics are used.


Types of Binders CLASSIFICATION OF BINDERS COMMONLY USED BINDERS CHARACTERISTICS OF COMMONLY USED BINDER Direct compression (DC) Binders 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 To ease of manufacture, product stability and high efficiency directly compressible binders are used COMMONLY USED DC BINDERS CHARACTERISTICS OF DC BINDERS Flow Behavior --DI TAB > SMCC(50) > DC Lactose , UNI PURE(DW) > Avicel (PH 101) > UNI PURE(LD) Compressibility --UNI PURE (LD) > SMCC (50), Avicel (PH 101) > UNI PURE (DW), DC Lactose > DI TAB CRUSHING STRENGTH--UNI PURE (LD) > SMCC (50) > UNI PURE (DW) > AVICEL (PH 101) > DC Lactose &gt DITAB Formation Of Granule Mechanism Mainly the granules are forms in three mechanisms: Nucleation Transition Ball growth or enlargement of the granule 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. Granulation Factors to be Considered- Compatibility Characteristics of drugs and other excipients Spreading of Binder Type and quantity of Binder Temperature and Viscosity Method of Addition of Binder Mixing Time Material of Construction of Granulator Type of Granulator Process Variables Apparatus Variables


Impeller Movement Evaluation tests for Binders/Granules Particle Size and Particle Size Distribution Surface Area Density % Compressibility 18. Friability 19. Moisture Content Compressibility, particle size, surface area, porosity, hydrophobicity, solubility in binder are important while fixing a granulation process.

1. The drug that exhibits poor compressibility requires the use of a strong binder (liquid glucose, sucrose, etc.)

2. Hydrophilic drug/excipients exhibiting absorption characteristics require higher volume of binder as compared to hydrophobic drug/excipients.

3. Spreading of binder/granulation solution on the powder blend is of paramount importance in successful granulation. HPMC is a superior binder for paracetamol as compared to PVP.

4. The uniformity of the particle size, hardness, disintegration and compressibility of the granulation depends on type and quantity of binder added to formulation.

5. Hard granulations results due to stronger binder or a highly concentrated binder solution . 6. Fragile granulations results due to insufficient quantity of binder which segregates easily. 7. Larger quantities of granulating liquid produce a narrower particle size range and coarser and hard

granules . The temperature and viscosity of binder is also important. 1. Fluid (less viscous) binder exhibit good spreading behavior. 2. The method of addition of binder is also important. 3. The mixing time also determines quality of granules. 4. The material of construction of granulator determines the volume of binder 5. Fluidized Bed Granulator produces porous granules as compared to High Shear Granulators. Higher degree of densification of the granules results due to higher impeller.

1. The apparatus variables in High Shear Mixer have a larger effect on granule growth than in Fluidized Bed Granulators.

2. The characteristics of granules produced are affected by formulation and process variables. 3. 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 . 4. Surface area of the drug effects upon dissolution rate. 5. Granule density, True Density, Bulk Density may influence compressibility, tablet porosity, flow

property, dissolution and other Properties. 6. Compressibility is the ability of powder to decrease in volume under pressure.

Antifrictional Agents Contents 1 Lubricants 1.1 Classification of lubricants 1.1.1 Water Insoluble Lubricants 1.1.2 Water Soluble Lubricants 2 Antiadherents 3 Glidants 4 Key Phrases Lubricants


Definition- 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.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. Minimum Lubrication Time 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. Additional lubricant is often added to the tablet formulations that are to be compressed with curved face punches. 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 Lubricants Classification Lubricant are classified according to their water solubility -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. Water Insoluble And Water Soluble Lubricants Example INSOLUBLE LUBRICANTS Example SOLUBLE LUBRICANTS Antiadherents Prevent sticking to punches and die walls EX- Talc, magnesium stearate and corn starch Talc Corn-starch Colloidal silica DL-Leucine Sodium lauryl sulfate Stearates Glidants 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. Starch is a popular glidant because it has additional value of disintegrant. Talc is superior to starch Talc has retardant effect on dissolution- disintegration profile. Similar to lubricants 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. Key Wards 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. Miscellaneous Excipients Contents A.Wetting AgentsB. Dissolution RetardantsC. Dissolution Enhancers D. AdsorbentsE. Buffers F. Antioxidants G.Chelating AgentsH.Preservatives I. ColourantsJ.Flavours K.SweetenersL.Key Phrases 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 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. 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. Dissolution enhancer 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. Adsorbents are the agents that can retain large quantities of liquids. Liquids like Vitamin E can be incorporated into tablets by addition of adsorbents Ex-anhydrous calcium phosphate, starch, magnesium carbonate, bentonite, kaolin, magnesium silicate, magnesium oxide and silicon dioxide. Silicon dioxide ,the liquid glidant and an adsorbent to be adsorbed ,first mixed with the adsorbent prior to incorporation into the formulation. Buffers are added to maintain a required pH since a change in pH may cause significant alteration in stability. Ex-sodium bicarbonate, calcium carbonate, and sodium citrate Antioxidants are added in tablet formulation to protect drug from undergoing oxidation. Ex-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 . Chelating agents tend to form complexes with trace amount of heavy metal ions inactivating their catalytic activity in the oxidation of medicaments Ex-Ethylenediamine tetracetic acid and its salts, Dihydroxy Ethyl Glycine, Citric Acid and Tartaric Acid Preservatives may be a part of tablet formulation in order to prevent the growth of microorganisms Ex-Parabens like methyl, propyl, benzyl, butyl p-hydroxy benzoate Colourants neither contribute to therapeutic activity nor do they improve product bioavailability or stability. Facilitate identification of similar looking products avoid mix ups; to overcome colour change on aging, disguising of off-colour drugs, for brand image in the market , aesthetic appearance of the product Ex- dyes and lakes which are FD & C and D & C approved Lakes are usually employed as dry powders for colouring , they do not require the FDA certification before use in drug products. care should be taken to prevent colour migration during drying , formulation should be checked for resistance to colour changes on exposure to light. SYNTHETIC COLOURANTS used in pharma Flavours & Sweeteners 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. 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. Sweeteners are added primarily to chewable tablets. Saccharin is 500 times sweeter than sucrose, disadvantages are that it has a bitter aftertaste and is carcinogenic. cyclamate is carcinogenic Aspartame is about 180 times sweeter than sucrose. Key Ward -Only FD&C and D&C approved colourants can be incorporated into tablet formulation. Flavours and Sweeteners are one of the important ingredients of chewable and mouth dissolving tablet formulation. Properties of API for tablets formulation Contents 1 High Purity 2 High stability 3 Good compatibility with excipients 4 Optimum bulk powder properties 5 Optimum and Uniform particle size-particle size distribution 6 Spherical shape 7 Good flowability 8 Optimum moisture content 9 Good compressibility 10 Absence of static charge on surface 11 Good organoleptic properties 12 Miscellaneous points 13 Key Phrases High Purity -API has to be in pure form otherwise impurities can catalyze series of chemical reactions, e.g. in case of hydrocortisone impurity of cupric ion causes oxidation of ketone functional group. High stability- The API should be stable against photolysis, oxidation, hydrolysis, etc. to keep the formulation a simple one. Compatibility with excipients- There should not be any kind of interaction between excipient and API. Bulk Powder Properties Prevent segregation. Have optimum size tablet particularly for low potency-low density API. Have good flow. Uniform particle sizedistribution Spherical shape Good flowability Optimum moisture content Good compressibility Absence of static charge on surface Good organoleptic properties Miscellaneous API should have uniform particle size and close particle size distribution to confirm- Uniformity of content, Uniformity of weight, Disintegration time, Granule friability, Drying rate kinetics of wet granulation, Flowability, Compressibility,


Stability, Dissolution, Bioavailability Spherical shape & Good flowability The shape of particles decides flowability. Spherical shaped particles exhibit good flow as compared to needle shaped particles. Flow is important for having uniformity of weight and uniformity of drug content Improving Flowability : *Addition of glidants *Addition of fines *By wet granulation *By densification with help of slugging Moisture Content Moisture Content in not only in API but also in Granules is of prime important. i) Total lack of moisture results into brittle tablet. ii) Moisture affects flow, which in turn affects uniformity of content. iii) High amount of moisture gives stickiness, which will affect compaction. iv) Picking/sticking may be observed. Moisture content can be controlled by: i) Use of anhydrous salts. ii) Use of non-aqueous solvent. iii) Optimum drying time. iv) Addition of finely powdered adsorbent like magnesium oxide. Compressibility The API should exhibit good compressibility, It depends upon its intrinsic nature- a. Elasticity Intrinsic nature of particle can be changed by- i) Wet massing ii) Pre-compression iii) Plastic tabulating matrix (micro crystalline cellulose)Elastic material is less suitable for direct compression. b. Plasticity The crushing strength is dependent on the time that tablet spends in a die. Changing the turret speed can change dwell time. Plastic materials may exhibit viscoelastic deformaiton c. Brittle fracture A particle fractures into small particles on application of pressure in a die. Brittle fracture also promotes tableting. Surface Static Charge Absence of Surface Static Charge is important because- Affects uniformity of dose and weight variation During mixing it may cause segregation and lead to non-uniformity of content if API and excipients are charged. Charged API may adhere to feed frame and result into serious damage to tablet equipment. Organoleptic Properties Many API are unpalatable and unattractive in their natural form. In such cases, tablet formulation require certain care. API has to be checked for colour and taste. Ex- Ranitidine Hydrochloride, Specification says White to pale yellow; pale yellow is a confusing term,varies from men to man.Where it is darker yellow, a bad smell evolve. Whereas the potency even after degradation shows optimum due to development of colour and imparts in absotbance. Similarly, Albendazole has a bad smell but it is a tablet to chew; therefore, bad smell is a big problem. In tablet formulation these type of things are to be considered, and try to avoid or remove these problem.


Colour-API should be colourless For coloured API, the following steps shall be considered: i) Select appropriate excipient to avoid mottling. ii) Incorporate API in smallest particle size. iii) Incorporate colour in dry form along with binder and activate mixture by addition of water or other activator. iv) Coating can be applied to conceal non- inform colour (sugar coated multivitamin tablet). Taste -Ideally API should have no taste The following taste masking options can be tried: i.) Use of prodrug to decrease API solubility in saliva or to reduce affinity for taste receptor e.g. Chloramphenicol Palmitate. ii) Sugar coating or film coating. iii) Addition of sweeteners like mannitol in cause of fast dissolving tablet or chewable tablet. iv) Use of drug-ion exchange adsorbent in formulation. v) Drug -cyclodextrin complex may exhibit good taste profile and good compressibility as well. Miscellaneous 1. API should not exhibit sublime characteristics 2. Liquid APIs are less suitable for tablet formulation. One of the options is conversion of liquid in pseudosolid Key Wards High Purity to avoid contamination and degradation. High stability against photolysis, oxidation, hydrolysis, etc. Good compatibility with excipients. For example, avoid use of lactose with drugs with primary amine functional group. Optimum bulk powder properties to prevent segregation and to have good flow. Optimum particle size and size distribution to have uniformity of weight, uniformity of content, good flow and compressibility. Spherical shape to avoid interlocking between the particles and thus to aid flow. Good flow to have uniformity of weight and uniformity of drug content. Optimum amount of moisture to avoid problems like brittle tablet, picking/sticking, etc. Good compressibility to have nicely bonded tablet. Absence of static charge on the surface to prevent demixing and damage to tableting equipment by adhering to feed frame. Good organoleptic properties to have better patient acceptance. Miscellaneous: Convert liquid API to pseudosolid e.g. Valproic acid and Sodium valproate, etc. Tablet Manufacturing Operations Contents 1 Introduction 2 Dispensing 3 Sizing 4 Powder blending 5 Granulation 6 Drying 7 Tablet compression 8 Auxiliary Equipments 8.1 Granulation Feeding Device 8.2 Tablet weight monitoring devices 8.3 Tablet Deduster 8.4 Fette machine


9. Packaging 9.1 Key Phrases Introduction The manufacture of tablets is a complex multi- stage process in which the starting materials change their Physical characteristics a number of times before the final dosage form is produced. Tablets can be made by granulation, a process that imparts two primary requisites to formulate: compactibility and fluidity. In making tablet Both wet granulation and dry granulation (slugging and roll compaction) are used. Other unit operation involves are-particle size reduction and sizing, blending, granulation, drying, compaction, and (frequently) coating. Typical Manufacturing Operation Dispensing Dispensing is the first step in any pharmaceutical manufacturing process. Dispensing is one of the most critical steps . Dispensing may be done by purely manual or automated dispensaries with mechanical devices Weighing accuracy, Dust control (laminar air flow booths, glove boxes), during manual handling, Lot control of each ingredient, Material movement into and out of dispensary should be considered during dispensing. Sizing Size Reduction, Milling, Crushing, Grinding, Pulverization) Is An Impotent Step (Unit Operation) Involved In The Tablet Manufacturing In manufacturing of compressed tablet, the mixing or blending is easier and more uniform if the ingredients are approximately of same size. A fine particle size is essential in case of lubricant mixing which provides a greater uniformity of dose. Advantages of size reduction It increases surface area, enhance dissolution rate and hence bioavailability. Improved the tablet-to-tablet content uniformity . Promote better flow of mixture in tablet machine. Improved flow properties of raw materials. Improved colour and/or active ingredient. promote uniform drying. Disadvantages A possible change in polymorphic form of the active ingredient, rendering it less or totally inactive, or unstable. Decrease in bulk density cause flow problem and segregation in the mix. Promote the adsorption of air,by increase in surface area from size reduction cause longer dissolution rate. Dry sizing or milling Machine- Fluid energy mill, Colloidal mill, Ball mill, Hammer mill, Cutting mill, Roller mill, Conical mill. HUA- Blending The powder/granules blending are involved at stage of pre granulation and/or post granulation stage of tablet manufacturing. Each process of mixing has optimum mixing time, mixing speed. A simple tumble blender may use, V blender, Oblicone blender, Container blender, Tumbling blender, Agitated powder blender are some example. Granulation


Following particle size reduction and blending, the formulation may be granulated, which provides homogeneity of drug distribution in blend. Drying Drying is a most important step in the formulation and development of pharmaceutical product. It is important to keep the residual moisture low enough to prevent product deterioration and ensure free flowing properties. The commonly used dryer includes Fluidized bed dryer, Vacuum tray dryer, Microwave dryer, Spray dryer, Freeze dryer, Turbo - tray dryer, Pan dryer, etc. Tablet compression After the preparation of granules ( wet granulation) or Sized slugs (dry granulation) or Mixing of ingredients (direct compression)- granules are compressed to get final product. Tablet may be of different shapes,sizes although they are usually round or oval. Each tablet is made by pressing the granules inside a die by two punches (UPPER-LOWER) Turret & Cams The punches and dies are fixed to a turret that spins round. As it spins, the punches are driven together by two fixed cams - an upper cam and lower cam. The top of the upper punch (the punch head) sits on the upper cam edge .The bottom of the lower punch sits on the lower cam edge. The shapes of the two cams determine the equence of movements of the two punches. This sequence is repeated over and over because the turret is spinning round. Other Necessary Equipment Granulation Feeding Device Mechanized/Force feeder Tablet weight monitoring devices Tablet Deduster Metal Detector Chilling Device for thermolebile product Blister Packing Strip Packing Bottle Packing Key wards Particle size reduction and sizing Blending Granulation Drying, compaction Coating. Tablet The Methods of Manufacture Two main methods are practiced world wide in manufacturing of Pharmaceutical Tablets Direct Compression Wet Granulation

Direct compression Contents 1 Introduction 2 The events that motivates the industry people to use direct compression technique 3 Merits


4 Merits over wet granulation process 5 Demerits 6 Manufacturing steps for direct compression 7 Direct compression Excipients 7.1 An ideal direct compression excipient should possess the following attributes 7.2 Major excipients required in direct compression 7.2.1 Diluents 7.2.2 Binders 7.2.3 Disintegrants 8 Key Wards Introduction Definition: The term direct compression is defined as the process by which tablets are compressed directly from powder mixture of Active Pharmaceutical Ingredients (API) and suitable excipients. No pretreatment of the powder blend by wet or dry granulation procedure is required. The Events Of Motivation For Direct Compression I.Commercial availability of the directly compressible excipients possessing both good compressibility and good flowability. II. Major advances in tablet compression machinery, i) Improved positive die feeding ii) Precompression of powder blend Merits Of DIRECT COMPRESSION Direct compression is more efficient ,involves only dry blending and compaction of API and necessary excipients. Important advantage of direct compression is economical process.Reduced processing time, reduced labor costs, fewer manufacturing steps, and less number of equipments are required, less process validation, reduced consumption of power. Elimination of heat and moisture, thus increasing not only the stability but also the suitability of the process for thermolabile and moisture sensitive APIs. Particle size uniformity. Prime particle dissolution. The chances of batch-to-batch variation are negligible, because the unit operations required for manufacturing processes is fewer. Chemical stability problems for API and excipient would be avoided. Provides stability against the effect of aging which affects the dissolution rates. Demerits of Direct Compression Excipient Related Process Related Problems in the uniform distribution of low dose drugs. High dose drugs having high bulk volume, poor compressibility and poor flowability are not suitable for direct compression. The choice of excipients for direct compression is extremely critical. Direct compression diluents and binders must possess both good compressibility and good flowability. Many active ingredients are not compressible either in crystalline or amorphous forms. Direct compression blends may lead to unblending because of difference in particle size or density of drug and excipients. Similarly the lack of moisture may give rise to static charges, which may lead to unblending. Non-uniform distribution of colour, especially in tablets of deep colours. Capping, lamination, splitting, or layering of tablets is sometimes related to air entrapment during direct compression. When air is trapped, the resulting tablets expand when the pressure of tablet is released, resulting in splits or layers in the tablet. In some cases require greater sophistication in blending and compression equipments. Direct compression equipments are expensive.


Three Steps Operation Milling of drug and excipients. Mixing of drug and excipients. Tablet compression. Excipients For Direct compression- Direct compression excipients mainly include diluents, binders and disintegrants. The success of direct compression formulation is highly dependent on functional behavior of excipients. Expected Characters for Direct Compressible Excipients- *It should have good compressibility. *It should possess good hardness after compression, that is material should not possess any deformational properties; otherwise this may lead to capping and lamination of tablets. *It should have good flowability. *It should be physiologically inert. *It should be compatible with wide range of API. *It should be stable to various environmental conditions (air, moisture, heat, etc.). *It should not show any physical or chemical change in its properties on aging. Cont-- *It should have high dilution potential. i.e. Able to incorporate high amount of API. *It should be colourless, odorless and tasteless. *It should accept colourants uniformity. *It should possess suitable organoleptic properties according to formulation type, that is in case of chewable tablet diluent should have suitable taste and flavor. For example mannitol produces cooling sensation in mouth and also sweet test. *It should not interfere with bioavailability and biological activity of active ingredients. *It should be easily available and economical in cost. Diluents-Selection of direct compression diluent is extremely critical, because the success or failure of direct compression formulation completely depends on characteristics of diluents. Properties of API (particle size and shape, bulk density, solubility), flowability, compressibity . stability (moisture, light, and other environmental factors), Binders- Binders are the agents used to impart cohesive qualities to the powdered material. direct compressible materials are not only free flowingbut also sufficiently cohesive to act as binder. Disintegrants- Disintegrants are the agents Key Wards- advanced technologies to prepare tablets , requires only blending and compression of excipients, economical process , suitable for heat and moisture sensitive API and not suitable for very low and very high dose drugs. Wet granulation 1 Introduction 2 Wet granulation 2.1 Introduction 2.2 Important steps involved in the wet granulation 2.3 Limitation of wet granulation 2.4 Special wet granulation techniques 2.4.1 High shear mixture granulation 2.4.2 Fluid bed granulation 2.4.3 Extrusion and Spheronization 2.4.4 Spray drying granulation 2.5 Lists of equipments for wet granulation 2.6 Current topics related to wet granulation 3 Dry granulation 3.1 Introduction 3.2 Advantages


3.3 Disadvantages 3.4 Steps in dry granulation 3.5 Two main dry granulation processes 3.5.1 Slugging process 3.5.2 Roller compaction 3.6 Formulation for dry granulation 4 Advancement in Granulations 4.1 Steam Granulation 4.2 Melt Granulation / Thermoplastic Granulation 4.3 Moisture Activated Dry Granulation (MADG) 4.4 Moist Granulation Technique (MGT) 4.5 Thermal Adhesion Granulation Process (TAGP) 4.6 Foam Granulation 5 Key Phrases Introduction Definition - Granulation may be defined as a size enlargement process which converts small particles into ically stronger & larger agglomerates. Characteristics of granules- The ideal characteristics of granules include spherical shape, smaller particle size distribution with sufficient fines to fill void spaces between granules, adequate moisture (between 1-2%), good flow, good compressibility and sufficient hardness. Properties of granulation Particle size of the drug and excipients Type of binder (strong or weak) Volume of binder (less or more) Wet massing time ( less or more) Amount of shear applied Drying rate ( Hydrate formation and polymorphism) Steps involved in the wet granulation Wet granulation process simply involves wet massing of the powder blend with granulating liquid, wet sizing and drying. i) Mixing of the drug(s) and excipients ii) Preparation of binder solution iii) Mixing of binder solution with powder mixture to form wet mass. iv) Coarse screening of wet mass using a suitable sieve (6-12 #screens). v) Drying of moist granules. vi) Screening of dry granules through a suitable sieve (14-20 #screen). vii) Mixing of screened granules with disintegrant, glidant, and lubricant. Wet Granulation-Limiting Factors The greatest disadvantage of wet granulation is its cost. It is an expensive process because of labor, time, equipment, energy and space requirements. Loss of material during various stages of processing Stability may be major concern for moisture sensitive or thermo labile drugs Multiple processing steps add complexity and make validation and control difficult An inherent limitation of wet granulation is that any incompatibility between formulation components is aggravated. Wet Granulation Techniques *High shear mixture granulation High shear mixture has been widely used in Pharmaceutical industries for blending and granulation. Blending and wet massing is accompanied by high mechanical agitation by an impeller and a chopper.


Advantages- Short processing time Less amount of liquid binders required compared with fluid bed. Highly cohesive material can be granulated. *Fluid bed granulation Fluid bed granulation is a process by which granules are produced in a single equipment by spraying a binder solution onto a fluidized powder bed. The material processed by fluid bed granulation are finer, free flowing and homogeneous. *Extrusion-spheronization It is a multiple step process capable of making uniform sized spherical particles= Advantages- Ability to incorporate higher levels of active components without producing excessively larger particles. Applicable to both immediate and controlled release dosage form. *Spray drying It is a unique granulation technique that directly converts liquids into dry powder in a single step. This method removes moisture instantly and converts pumpable liquids into a dry powder. Advantages- Rapid process Ability to be operated continuously Suitable for heat sensitive product Special wet granulation techniques High shear mixture granulation High shear mixture has been widely used in Pharmaceutical industries for blending and ranulation. Blending and wet massing is accompanied by high mechanical agitation by an impeller and a chopper. Advantages: 1. Short processing time Less amount of liquid binders required compared with fluid bed. Highly cohesive material can be granulated. ii) Fluid bed granulation Fluidization is the operation by which fine solids are transformed into a fluid like state. Fluid bed granulation is a process by which granules are produced in a single equipment by spraying a binder solution onto a fluidized powder bed. iii) Extrusion-spheronization It is a multiple step process capable of making uniform sized spherical particles. It is primarily used as a method to roduce multi-particulates for controlled release application. Advantages: Ability to incorporate higher levels of active components without producing excessively larger particles. Applicable to both immediate and controlled release dosage form. iv) Spray drying It is a unique granulation technique that directly converts liquids into dry powder in a single step. This method removes moisture instantly and converts pumpable liquids into a dry powder. Advantages: Rapid process Ability to be operated continuously 8. Suitable for heat sensitive product Lists of equipments for wet granulation High Shear granulation: Little ford Lodgie granulator Little ford MGT granulator Diosna granulator Gral mixer Granulator with drying facility:


Fluidized bed granulator Day nauta mixer processor Double cone or twin shell processor Topo granulator Special granulator: Roto granulator Marumerizer Dry granulation Introduction - In dry granulation process the powder mixture is compressed without the use of heat and solvent. It is the least desirable of all methods of granulation. The two basic procedures are to form a compact of material by compression and then to mill the compact to obtain a granules. Advantages The main advantages of dry granulation or slugging are that it uses less equipments and space. For moisture sensitive material For heat sensitive material For improved disintegration since powder particles are not bonded together by a binder Disadvantages It requires a specialized heavy duty tablet press to form slug It does not permit uniform colour distribution as can be achieved with wet granulation where the dye can be incorporated into binder liquid. 3. The process tends to create more dust than wet granulation, increasing the potential contamination. Steps in dry granulation i) Milling of drugs and excipients ii) Mixing of milled powders iii) Compression into large, hard tablets to make slug iv) Screening of slugs v) Mixing with lubricant and disintegrating agent vi) Tablet compression Factors which determine how well a material may slug i) Compressibility or cohesiveness of the mater ii) Compression ratio of powder iii) Density of the powder iv) Machine type v) Punch and die size vi) Slug thickness vii) Speed of compression viii) Pressure used to produce slug Advancement in Granulations Steam Granulation Melt Granulation / Thermoplastic Granulation Moisture Activated Dry Granulation (MADG) Moist Granulation Technique (MGT) Thermal Adhesion Granulation Process (TAGP) Foam Granulation Steam Granulation It is modification of wet granulation. Here steam is used as a binder instead of water. Benefits includes : Higher distribution uniformity, Higher diffusion rate into powders, More favourable thermal balance during drying step,


Steam granules are more spherical, Have large surface area hence increased dissolution rate of the drug from granules, Processing time is shorter therefore more number of tablets are produced per batch, Compared to the use of organic solvent water vapour is environmentally friendly, No health hazards to operators, No restriction by ICH on traces left in the granules, Freshly distilled steam is sterile and therefore the total count can be kept under control, Lowers dissolution rate so can be used for preparation of taste masked granules without modifying availability of the drug. Key Wards In wet granulation process a granulating liquid is used to facilitate the agglomeration process. Wet granulation has been and continues to be the most widely used agglomeration process. Typically wet massing of pharmaceutical powder is carried out in the high shear mixture before wet screening and dried in fluidized bed equipment. In the dry granulation process granulation takes place without utilizing liquid. In this process dry powder particles may be brought together mechanically by compression into slug or by rolled compaction. Steam Granulation, Melt Granulation, MADG, MGT, TAGP, Foam Granulation are some of the new advancements in granulation and show better quality granule formation as compared to conventional granulation methods. Introduction Coated tablets are defined as tablets covered with one or more layers of mixture of various substances such as natural or synthetic resins ,gums ,inactive and insoluble filler, sugar, plasticizer, polyhydric alcohol ,waxes ,authorized colouring material and some times flavoring material . Aspects of tablet coating 1. Therapy i) Avoid irritation of oesophagus and stomach ii) Avoid bad taste iii) Avoid inactivation of drug in the stomach iv) Improve drug effectiveness v) Prolong dosing interval vi) Improve dosing interval vii) Improve patient compliance 2. Technology i) Reduce influence of moisture ii) Avoid dust formation iii) Reduce influence of atmosphere iv) Improve drug stability v) Prolong shelve life 3. Marketing i) Avoid bad taste ii) Improve product identity iii) Improve appearance and acceptability The Basic principle Tablet coating is the application of coating composition to moving bed of tablets with concurrent use of heated air to facilitate evaporation of solvent. INVOLVE i) Insulation which influences the release pattern as little as possible and does not markedly change the appearance.


ii) Modified release with specific requirement and release mechanism adapted to body function in the digestive tract. iii) Colour coating which provides insulation or is combined with modified release coating. Coating Process Type of coating Sugar coating Sugar coating provides a combination of insulation, taste masking, smoothing the tablet core, colouring and modified release. Film Coating------- Film coating is more favored over sugar coating and widely used Sugar Coating Five Separate Operations 1. Sealing/Water proofing: provides a moisture barrier and harden the tablet surface. 2. Subcoating: causes a rapid buildup to round off the tablet edges. 3. Grossing/Smoothing: smoothes out the subcoated surface and increases the tablet size to predetermine dimension. 4. Colouring: gives the tablet its colour and finished size. 5. Polishing: produces the characteristics gloss. Sealcoating Sealcoating is also known as water proofing The tablet cores must be sealed, thoroughly dried and free of all residual solvents, prior to applying any sugar-syrup. The seal coat provides a moisture barrier and hardness the surface of the tablet The sealants are generally water-insoluble polymers Common sealant include :Shellac, Zine, Cellulose acetate phthalate (CAP), Polyvinylacetate phthalate, Hyroxylpropylcellulose, Hyroxypropylmethylcellulose Subcoating Generally two methods are used for subcoating: i)The application of gum based solution followed by dusting with powder and then drying. This routine is repeated until the desired shape is achieved. ii)The application of a suspension of dry powder in gum/sucrose solution followed by drying TYPICAL SUBCOATING SOLUTION DUSTING POWDER FOR SUBCOATING FORMULATION FOR SUBCOATING SUSPENSION Smoothing To increases the tablet size to a predetermined dimension. The smoothing process is specifically for smoothing and filing the irregularity on the surface generated during subcoating. Smoothing usually can be accomplished by the application of a simple syrup solution (approximately 60-70 % sugar solid). Colour coating The successful completion of a sugar coating process is often most critical.


The process and involves the multiple application of syrup solution (60-70 % sugar solid) containing colouring matter. Soluble dyes are used in the sugar coating to achieve the desired colour. Polishing Sugar-coated tablets needs to be polished to achieve a final elegance. Polishing is achieved by applying the mixture of waxes like beeswax, carnubawax, candelila wax or hard paraffin wax to tablets in polishing pan. Film Coating Film coating Process description Definition-Film coating is deposition of a thin film of polymer surrounding the tablet core. Traditionally Conventional pan equipments is used, but now a days more sophisticated equipments are employed to have a high degree of automation and coating time. The drying conditions cause removal of the solvent. The Process Usually spray process is employed in preparation of film coated tablets. Accela cota is the prototype of perforated cylindrical drum providing high drying air capacity. Fluidized bed equipment has made considerable impact where tablets are moving in a stream of air passing through the perforated bottom of a cylindrical column. With a smaller cylindrical insert, the stream of cores is rising in the center of the device together with a spray mist applied in the middle of the bottom. Process Requirements Adequate means of atomizing the spray liquid for application to the tablet core. Adequate mixing and agitation of tablet bed. Sufficient heat input in the form of drying air to provide the latent heat of evaporation of the solvent. Good exhaust facilities to remove dust and solvent is necessary. Formulations Development Why to go for film Coating? Is it necessary to mask objectionable taste, colour and odor? Is it necessary to control drug release? What tablets size, shape, or colour constrains must be placed on the developmental work? Colour, shape and size of final coated tablet are important for marketing. Film Coating Materials Film formers, which may be enteric or nonenteric Solvents Plasticizers Colourants Opaquant-Extenders Miscellaneous coating solution components 1. Film formers Film coating materials should have the following characteristics- i) Solubility in solvent of choice for coating preparation ii) Solubility requirement for the intended use e.g. free water-solubility, slow water-solubility or pH -dependent solubility iii) Capacity to produce an elegant looking product iv) High stability against heat, light, moisture, air and the substrate being coated v) No inherent colour, taste or odor vi) High compatibility with other coating solution additives vii) Nontoxic with no pharmacological activity


viii) High resistance to cracking ix) Film former should not give bridging or filling of the debossed tablet x) Compatible to printing procedure Film Formers Hydroxy Propyl Methyl Cellulose (HPMC) Methyl Hydroxy Ethyl Cellulose (MHEC) Ethyl Cellulose (EC) Hydroxy Propyl Cellulose (HPC) Povidone Sodium carboxy methyl cellulose Polyethylene glycols (PEG) Acrylate polymers -----and so on HPMC-It is available in different viscosity grades. It has solubility characteristic in gastric fluid, organic and aqueous solvent system Advantages -it does not affect tablet disintegration and drug availability, it is cheap, flexible, highly resistant to heat, light and moisture, it has no taste and odor, colour and other additives can be easily incorporated. Disadvantage -when used alone, the polymer has tendency to bridge or fill the debossed tablet surfaces. So mixture of HPMC and other polymers/ plasticizers is used. Methyl Hydroxy Ethyl Cellulose -It is available in wide variety of viscosity grades. It is not frequently used as HPMC because soluble in fewer organic solvents. Ethyl Cellulose -Different viscosity grades are available, insoluble in water and gastric fluids , it is used in combination with water-soluble additives like HPMC and not alone. Povidone -It is available in four viscosity grades i.e. K-15, K-30, K-60 and K-90. Average molecular weight of these grades is 10000, 40000, 160000 and 360000 respectively. K-30 is widely used as tablet binder and in tablet coating. Sodium carboxy methyl cellulose -It is available in medium, high and extra high viscosity grades. It is easily dispersed in water to form colloidal solutions but it is insoluble in most organic solvents and hence not a material of choice for coating solution based on organic solvents. Polyethylene glycols (PEG)-Lower molecular weights PEG (200-600) are liquid at room temperature and are used as plasticizers. High molecular weights PEG (900-8000series) are white, waxy solids at room temperature. Combination of PEG waxes with CAP gives films that are soluble in gastric fluids. Acrylate polymers -EudragitIt is marketed under the name of Eudragit E is freely soluble in gastric fluid up to pH 5 andco-polymer . It is available as organic solution (12.5% in isopropanol/acetone), solid material or 30% aqueous RLdispersion. They produce films for delayed action. Solvents Solvents are used to dissolve or disperse the polymers i) Should be either dissolve/disperse polymer system ii) Should easily disperse other additives into solvent system iii) Small concentration of polymers (2-10%) should not in an extremely viscous solution system creating processing problems iv) Should be colourless, tasteless, odorless, inexpensive, inert, nontoxic and nonflammable v) Rapid drying rate vi) No environmental pollution. Plasticizers Internal or External plasticizing technique is used to modify quality of film. Combination of plasticizer may be used to get desired effect. Concentration of plasticizer is expressed in relation to the polymer being plasticized. Recommended levels of plasticizers range from 1-50 % by weight of the film former.


EX-castor oil, PG, glycerin, lower molecular weight (200-400 series), PEG, surfactants, etc. Colourants Most common colourants in use are certified FD & C or D & C colourants. These are synthetic dyes or lakes. Lakes are choice for sugar or film coating as they give reproducible results. The inorganic materials (e.g. iron oxide) and the natural colouring materials (e.g. anthrocyanins, carotenoids, etc) are also used to prepare coating solution. Homogenous distribution of suspended colourants in the coating solution requires the use of the powdered colourants (

Enteric polymers are capable of forming a direct film in a film coating process. Sufficient weight of enteric polymer has to be used to ensure an efficient enteric effect. Controlled release coating Polymers like modified acrylates, water insoluble cellulose (ethyl cellulose), etc. used for control release coating. Specialized coating Compressed coating the tablet core cannot tolerate organic solvent or water and yet needs to be coated for taste masking or to provide delayed or enteric properties Electrostatic coating A strong electrostatic charge is applied to the substrate. The coating material containing conductive ionic species of opposite charge is sprayed onto the charged substrate. Dip coating Coating is applied to the tablet cores by dipping them into the coating liquid Vacuum film coating Vacuum film coating is a new coating procedure that employs a specially designed baffled pan Equipments Three general types of equipments are available 1.Standard coating pan e.g., Pellegrin pan system Immersion sword system Immersion tube system 2.Perforated pan system e.g.,Accela cota system Hicoater system Glattcoater system Driacoated system 3.Fluidized bed coater Process parameters Air capacity- This value represents the quantity of water or solvent that can be removed during the coating process which depends on the quantity of air flowing through the tablet bed, temperature of the air and quantity of water that the inlet air contains. Coating composition/compound The coating contains the ingredients that are to be applied on the tablet surface and solvents which act as carrier for the ingredients. Tablet surface area It plays an important role for uniform coating. The total surface area for unit weight decreases significantly from smaller to larger tablets. Application of a film with the same thickness requires less coating composition. Equipment efficiency Tablet coaters use the expression coating efficiency a value obtained by dividing the net increase in coated tablet weight by the total nonvolatile coating weight applied to the tablet. Ideally 90-95 % of the applied film coating should be on the tablet surface. Coating efficiency for conventional sugar coating is much less and 60% would be acceptable. Key Wards The sugar coating involves several steps like, sealing, subcoating, colour coating and printing. Sugar coating process yields elegant and highly glossed tablet. Newer techniques utilize spraying systems and varying degree of automation to improve coating efficiency and product uniformity.


Film coating is deposition of a thin film of polymer surrounding the tablet core. Film coating is more favored than sugar coating because weight increase is 2-3%, single stage process, easily adaptable to controlled release, it retains colour of original core, high adaptability to GMP, automation is possible, etc. Accela cota and fluidized bed equipments are widely used for film coating. Basic formula is obtained from past experience or from literature and modifications are made accordingly. Common modifications are to alter polymer-to-plasticizer ratio or addition of different plasticizer/polymer. Experimentation of this type can be best achieved by fractional factorial study. Materials used in film coating include film formers, solvents, plasticizers, colourants, opaquant-extenders, surfactant, anti oxidant, etc. Widely used film formers are Hydroxy Propyl Methyl Cellulose (HPMC),Methyl Hydroxy Ethyl Cellulose (MHEC), Ethyl Cellulose (EC), Hydroxy Propyl Cellulose (four grades available i.e. K15, K-30, K-60and K-90), Sodium(HPC), Povidone carboxy methyl cellulose, Polyethylene glycols (PEG) and Acrylate polymers (Eudragit, EudragitRL, EudragitRS, EudragitE) are used for film coating. EudragitL & S are used for enteric coating. EudragitRL, EudragitRS, EudragitS are available as organic solution and solid while EudragitL and EudragitE are available as organic, solid or aqueous dispersion. Quality of film can be modified by plasticizer. Commonly used plasticizers include PG, glycerin, low molecular weight PEG, castor oils, etc. Castor oil and spans are more used for organic solvent based coating solution while PE and PEG are used for aqueous coating. FD & C or D & C certified colourants are used. Lakes are choice for film coating as they give reproducible results. Opaspray (opaque colour concentrate for film coating) and Opadry (complete film coating concentrate) are promoted as achieving less lot-to-lot variation. Colourants are expensive and higher concentration is required. So materials like titanium dioxides, silicates, and carbonates are used to provide more pastel colours and increase film coverage. Enteric Coating -Enteric coating is used to protect tablet core from disintegration in the acid environment of stomach to prevent degradation of acid sensitive API, prevent irritation to stomach by certain drugs, delivery of API into intestine, to provide a delayed release components for repeat action, etc. Several kinds of enteric layer systems are available like one layer system and two-layer system. Polymers used for enteric coating are cellulose Acetate Phthalate (CAP), Acrylates (EudragitL and EudragitS, Hydroxy Propyl Methyl Cellulose Phthalate (HPMCP50, HPMCP55 & HPMCP 55s) and polyvinyl acetate phthalate Enteric sugar coating Here sealing coat is modified to comprise one of the enteric polymers in sufficient quantity to pass the enteric test for disintegration. The sub coating and subsequent coating steps are then as for conventional sugar coating. Enteric polymers are capable of forming a direct film in a film coating process. Sufficient weight of enteric polymer has to be used to ensure an efficient enteric effect. Enteric coating can be combined with polysaccharides, which are enzymatically degraded in colon. For example, Cyclodextrin & Galactomannan Controlled release coating: Polymers like modified acrylates, ethyl cellulose, etc are used for the same. Tablet Manufacturing Problems in Tablet Contents 1 Introduction 1.1 Capping 1.2 Lamination / Laminating 1.3 Chipping 1.4 Cracking 1.5 Sticking / Filming


1.6 Picking 1.7 Binding 1.8 Mottling 1.9 Double impression 2 Problems and remedies for tablet coating 2.1 Blistering 2.2 Chipping 2.3 Cratering 2.4 Picking 2.5 Pitting 2.6 Blooming 2.7 Blushing 2.8 Colour variation 2.9 Infilling 2.10 Orange peel/Roughness 2.11 Cracking/Splitting 3 Key Phrases Introduction An ideal tablet should be free from any visual defect or functional defect. In Manufacturing technology a lot of advanchment happened in last 50 years,in technoly, in the process and in the materials being used but problems has not been decreased. Demands of Quality have increased in one hand on the other hand the process is a complex one. Manufacturing pharmacist often encounters number of problems during manufacturing. Majority of visual defects are due to inadequate fines or inadequate moisture in the granules ready for compression or due to faulty machine setting. Functional defects are due to faulty formulation. Knowledge of granulation processing and tablet presses may help solving the problems The Imperfections The imperfections or VISUAL DEFECTS may happen for the following factors- Tableting Process Excipient Machine Process Related Defects i) CAPPING: It is due air-entrapment in the granular material. ii) LAMINATION: It is due air-entrapment in the granular material. iii) CRACKING: It is due to rapid expansion of tablets when deep concave punches are used. Excipient Related Defects iv) CHIPPING: It is due to very dry granules v) STICKING vi) PICKING vii) BINDING viii) MOTTLING- more than one factor-Due to a coloured drug, which has different colour than the rest of the granular material? (Excipient- related); improper mixing of granular material (Process-related); dirt in the granular material or on punch faces; oil spots by using oily lubricant. Machine Related Defect ix) DOUBLE IMPRESSION -due to free rotation of the punches.


Causes And Remedies Capping Capping is the term used, when the upper or lower segment of the tablet separates horizontally, either partially or completely from the main body of a tablet and comes off as a cap, during ejection from the tablet press, or during subsequent handling. Reason: Capping is usually due to the airentrapment in a compact during compression, and subsequent expansion of tablet on ejection of a tablet from a die. CAUSES AND REMEDIES OF CAPPING RELATED TO FORMULATION CAUSES AND REMEDIES OF CAPPING RELATED TO MACHINE-DIES, PUNCHES AND TABLET PRESS Lamination / Laminating Definition: Lamination is the separation of a tablet into two or more distinct horizontal layers. Reason: Airentrapment during compression and subsequent release on ejection. The condition is exaggerated by higher speed of turret. CAUSES AND REMEDIES OF LAMINATION RELATED TO FORMULATION (GRANULATION) and Lamination related to MACHINE (Dies, Punches and Tablet Press) Chipping Definition: Chipping is defined as the breaking of tablet edges, while the tablet leaves the press or during subsequent handling and coating operations. Reason: Incorrect machine settings, specially mis-set ejection take-off. CAUSES AND REMEDIES OF CHIPPING RELATED TO FORMULATION (GRANULATION) ARE AS FOLLOWS CAUSES AND REMEDIES OF CHIPPING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS) Cracking Definition: Small, fine cracks observed on the upper and lower central surface of tablets, or very rarely on the sidewall are referred to as Cracks. Reason: It is observed as a result of rapid expansion of tablets, especially when deep concave punches are used. HUA CAUSES AND REMEDIES OF CRACKING RELATED TO FORMULATION (GRANULATION) CAUSES AND REMEDIES OF CRACKING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS) Sticking / Filming Definition: Sticking refers to the tablet material adhering to the die wall. Filming is a slow form of sticking and is largely due to excess moisture in the granulation. Reason: Improperly dried or improperly lubricated granules. CAUSES AND REMEDIES OF STICKING RELATED TO FORMULATION (GRANULATION) CAUSES AND REMEDIES OF STICKING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS) Picking Definition: Picking is the term used when a small amount of material from a tablet is sticking to and being removed off from the tablet-surface by a punch face.

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