Tablets

Tablets By, Mr. Nitin M. Kadam

CONTENT….. Introduction General Properties Advantages Disadvantages Types of Tablets Tablet Additives

Continued…. Formulation Development Preformulation of drugs & additives Introduction to tablet Additives Need of Granulation Mechanisms Manufacturing Processes and Equipments for granulations Advance Granulation Techniques Characterization and Evaluation All about Tablets. All about Tablet Coating

Introduction Definition: Tablet is defined as a compressed unit solid dosage form containing medicaments with or without excipients. According to the Indian Pharmacopoeia, Pharmaceutical tablets are solid, flat or biconvex dishes, unit dosage form, prepared by compressing a drugs or a mixture of drugs, with or without diluents. They vary in shape and differ greatly in size and weight, depending on amount of medicinal substances and the intended mode of administration.

Absorption of drug form tablets

Advantages Greatest dose precision and the least content variability. Cost is lowest of all oral dosage form. Lighter and compact. Easiest and cheapest to package and strip. Easy to swallowing with least tendency for hang-up.

Continued… Sustained release product is possible by various techniques. Objectionable odour and bitter taste can be masked by various techniques. Suitable for large scale production. Greatest chemical and microbial stability over all oral dosage form. Product identification is easy and rapid requiring no additional steps when employing an embossed and/or monogrammed punch face.

Disadvantages Difficult to swallow in case of children and unconscious patients. Some drugs resist compression into dense compacts, owing to amorphous nature, low density character. Drugs with poor wetting, slow dissolution properties, may be difficult to formulate or manufacture as a tablet that will still provide adequate or full drug bioavailability. Bitter testing drugs, drugs with an objectionable odor or drugs that are sensitive to oxygen may require encapsulation or coating. In such cases, capsule may offer the best and lowest cost.

General properties of Tablet dosage forms A tablet should have elegant product identity while free of defects like chips, cracks, discoloration, and contamination. Should have sufficient strength to withstand mechanical shock during its production packaging, shipping and dispensing. Should have the chemical and physical stability to maintain its physical attributes over time. The tablet must be able to release the medicinal agents in a predictable and reproducible manner. Must have a chemical stability over time so as not to follow alteration of the medicinal agents.

Different Types of Tablets (A) Tablets ingested orally: Compressed tablet, e.g. Paracetamol tablet Multiple compressed tablet Delayed release tablet, e.g. Enteric coated Bisacodyl tablet Sugar coated tablet, e.g. Multivitamin tablet Film coated tablet, e.g. Metronidazole tablet Chewable tablet, e.g. Antacid tablet (B) Tablets used in oral cavity: Buccal tablet, e.g. Vitamin-c tablet Sublingual tablet, e.g. Vicks Menthol tablet Troches or lozenges Dental cone

(c) Tablets administered by other route: Implantation tablet Suppositories or Inserts, e.g. Clotrimazole tablet (D) Tablets used to prepare solution: Effervescent tablet, e.g. Dispirin tablet (Aspirin) Dispensing tablet, e.g. Enzyme tablet (Digiplex) Hypodermic tablet Tablet triturates e.g. Enzyme tablet (Digiplex)

Tablet Additives In addition to active ingredients, tablet contains a number of inert materials known as additives or excipients. Different excipients are: Diluent Binder and adhesive Disintegrents Lubricants and glidants Coloring agents Flavoring agents Sweetening agents

Diluents : Diluents are fillers used to make required bulk of the tablet when the drug dosage itself is inadequate to produce the bulk. Secondary reason is to provide better tablet properties such as improve cohesion , to permit use of direct compression manufacturing or to promote flow . A diluents should have following properties: 1. They must be non toxic 2. They must be commercially available in acceptable grade 3. There cost must be low 4. They must be physiologically inert 5. They must be physically & chemically stable by themselves & with the drugs. 6. They must be free from all microbial contamination. 7. They do not alter the bioavailability of drug. 8. They must be color compatible.

Commonly used tablet diluents 1. Lactose-anhydrous and spray dried lactose 2. Directly compressed starch-Sta Rx 1500 3. Hydrolyzed starch-Emdex and Celutab 4. Microcrystalline cellulose-Avicel (PH 101and PH 102) 5. Dibasic calcium phosphate dehydrate 6. Calcium sulphate dihydrate 7. Mannitol 8. Sorbitol 9. Sucrose- Sugartab, DiPac, Nutab 10. Dextrose

2. Binders and Adhesives : These materials are added either dry or in wet- form to form granules or to form cohesive compacts for directly compressed tablet. Example : Acacia, tragacanth- Solution for 10-25% Conc. Cellulose derivatives- Methyl cellulose, HPC, HPMC Gelatin- 10-20% solution Glucose- 50% solution Polyvinylpyrrolidone (PVP)- 2% conc. Starch paste-10-20% solution Sodium alginate Sorbitol

3. Disintegrants : Added to a tablet formulation to facilitate its breaking or disintegration when it contact in water in the GIT. Example: Starch- 5-20% of tablet weight. Starch derivative – Primogel and Explotab (1-8%) Clays- Veegum HV, bentonite 10% level in colored tablet only Cellulose Cellulose derivatives- Ac- Di-Sol (sodium carboxy methyl cellulose) Alginate PVP (Polyvinylpyrrolidone), cross-linked

Superdisintegrants : Swells up to ten fold within 30 seconds when contact water. Example : Crosscarmellose- cross-linked cellulose, Crosspovidone- cross-linked povidone (polymer), Sodium starch glycolate- cross-linked starch. These cross-linked products swell upto 10 fold with in 30 seconds when in contact with water. A portion of disintegrant is added before granulation and a portion before compression, which serve as glidants or lubricant. Evaluation of carbon dioxide in effervescent tablets is also one way of disintegration

4. Lubricant and Glidants : Lubricants are intended to prevent adhesion of the tablet materials to the surface of dies and punches , Glidants are intended to promote flow of granules or powder material by reducing the friction between the particles. Example: Lubricants- Stearic acid, Stearic acid salt - Stearic acid, Magnesium stearate, Talc, PEG (Polyethylene glycols), Surfactants Glidants- Corn Starch – 5-10% conc., Talc-5% conc., Silica derivative - Colloidal silicas such as Cab-O-Sil, Syloid, Aerosil in 0.25-3% conc.

5. Coloring agent: The use of colors and dyes in a tablet has three purposes: (1) Masking of off color drugs (2) Product Identification (3) Production of more elegant product All coloring agents must be approved and certified by FDA. Two forms of colors are used in tablet preparation – FD &C and D & C dyes. These dyes are applied as solution in the granulating agent or Lake form of these dyes. Lakes are dyes absorbed on hydrous oxide and employed as dry powder coloring. Example: FD & C yellow 6-sunset yellow FD & C yellow 5- Tartrazine FD & C green 3- Fast Green FD & C blue 1- Brilliant Blue FD & C blue 2 - Indigo carmine D & C red 3- Erythrosine. D & C red 22 – Eosin Y

6. Flavoring agents: For chewable tablet- flavor oil are used 7. Sweetening agents: For chewable tablets: Sugar, mannitol. Saccharine (artificial): 500 time’s sweeter than sucrose Disadvantage: Bitter aftertaste and carcinogenic Aspartame (artificial) Disadvantage: Lack of stability in presence of moisture.

Granulation Need To prevent segregation of the constituents of the powder mix. To improve the flow properties of the mix To improve the compaction characteristics of the mix Other reasons: Toxic, Slightly hygroscopic, denser. Methods Dry granulation Wet granulation Effect of granulation methodon granule structure.

Granulation technology on large scale by various techniques

Mechanisms of Granulation There are Five Particle Bonding Mechanisms, Adhesion and cohesion forces in the immobile liquid films Interfacial forces in mobile liquid films within the granules Formation of solid bridges after solvent evaporation Attractive forces between solid particles Mechanical interlocking

Adhesion and cohesion forces in immobile liquid films between individual primary powder particles. Interfacial forces in mobile liquid films Solid bridges Partial mellting, Binder hardening, crystalization of dissolved sub. Attractive forces between solid particles Mechanism of granule formation Mechanisms of Granulation

Steps to make powder ready for compression

Granulation Equipments (Granulators) Dry granulator Wet granulator

Effective dose of drug is too high for direct compression Drug is sensitive to heat or moisture or both. Dry granulators: Sluggers Roller Compactors Is used when……

Wet granulators Shear mixer granulator High speed granulator Fluidized bed granulator Spray driers

WET GRANULATION: some equipment…. High Shear Granulator Littleford Lodige Mixer/Granulator Littleford MGT Granulator Diosna Granulator Gral Mixer/Granulator Granulator with Drying Facility Fluidized Bed Granulator Day Nauta Mixer Processor Double cone/Twin Shell Processor Topo Granulator Special Granulator Roto Granulator Marumerizer

Wet granulation equipment shear granulator

SOP Of Shear Mixture Granulator: Mixed powder are fed in to the bowl Granulating liquid is added The moist mass has then transferred to a granulator such as oscillating granulator

Disadvantage Long duration Large number of equipment are needed High material loss Advantage Not very sensitive to the material End point can be determined by inspection

High speed granulator Widely used in pharmaceutical SS mixing bowl containing a three blade main impeller, revolves in horizontal plane, and a three blade auxiliary chopper –revolves vertical or horizontal plane Unmixed powder –in the bowl mixed for few minute with rotating impeller Granulation

Typical Time Sequence Mixing – 2 minutes Granulation – 8 minutes Discharge – 1 minutes Gives more normal PSD with lesser fines. Diosna Mixer / Granulator Rapid Mixer Granulator (RMG) blade chopper

Rapid Mixing Granulator: (RMG)

Advantage Mixing,Massing,Granulation in a single equipment within few minutes Disadvantage End point monitor needed

Designs of FB granulators Top spray Bottom spray Rotating disc granulator Suction Fan Fabric Filter Bag Granulating solution Product Bed Spray Nozzle Air Filter Air Heater

Fluidized Bed Granulator Advantage One unit so saving labour cost, transfer loses and time 2-6 time greater heat transfer than tray dryer Uniform drying….prevent mottling. Process can be automated once parameters optimized Disadvantage Expensive Multiple process variable Filter clocking, demixing, electrostatic charge, solvent explosion

Fluidized Bed Granulator (Industrial Equipment)

Merumizer (spheronizer) Wet mass containing drug , diluents and binder is pass through extruder to get rod shaped segments. Cylinder Screw-feed Extruder Segments are placed in MERUMIZER where they are shaped into sphere by centrifugal and frictional forces produced by rotating plates/blades and form granules Advantage Granules with regular size, shape with lower friability, so less amount of fines.

Other More Specialized Granulators Spray Driers

MELT SOLIDIFICATION A melt granulation process has been investigated which efficiently agglomerates pharmaceutical powders for use in both immediate- and sustained-release solid dosage forms. The process utilizes materials that are effective as granulating fluids when they are in the molten state. Cooling of the agglomerated powders and the resultant solidification of the molten materials completes the granulation process. Both the molten agglomeration and cooling solidification were accomplished in a high shear Collette Gral mixer equipped with a jacketed bowl. Hence, the melt granulation process replaces the conventional granulation and drying operations which use water or alcohol solutions.

Direct Compression Need of other component Large dose- not suitable Small dose-impractical Moderate dose- suitable Directly compressible vehicles Limitations Stratification-poor content uniformity Large dose drugs [30%] Interaction Static charge Equipment and procedures used Screening/Milling * Three Parts * Principle * Operation * Types of Mills

Ball Mill Bench top Model Industrial Model Working Mechanism

Tablet Production Powders intended for compression into tablets must possess two essential properties Powder fluidity The material can be transported through the hopper into the die To produce tablets of a consistent weight Powder flow can be improved mechanically by the use of vibrators, incorporate the glidant Powder compressibility The property of forming a stable, intact compact mass when pressure is applied

Tableting Procedure Filling Compression Ejection

Tablet Compression Machines Hopper for holding and feeding granulation to be compressed Dies that define the size and shape of the tablet Punches for compressing the granulation within the dies Cam tracks for guiding the movement of the punches Feeding mechanisms for moving granulation from the hopper into the dies

Single Punch Machine The compression is applied by the upper punch Stamping press

Upper and Lower Collar Collar locker Single Punch Machine (Tablets)

Multi-station Rotary Presses The head of the tablet machine that holds the upper punches, dies and lower punches in place rotates As the head rotates, the punches are guided up and down by fixed cam tracks , which control the sequence of filling, compression and ejection. The portions of the head that hold the upper and lower punches are called the upper an lower turrets

The portion holding the dies is called the die table The pull down cam (C) guides the lower punches to the bottom, allowing the dies to overfill The punches then pass over a weight-control cam (E) , which reduces the fill in the dies to the desired amount A swipe off blade (D) at the end of the feed frame removes the excess granulation and directs it around the turret and back into the front of the feed frame

The lower punches travel over the lower compression roll (F) while simultaneously the upper punches ride beneath the upper compression roll (G) The upper punches enter a fixed distance into the dies, while the lower punches are raised to squeeze and compact the granulation within the dies After the moment of compression, the upper punches are withdrawn as they follow the upper punch raising cam (H)

The lower punches ride up the cam (I) which brings the tablets flush with or slightly above the surface of the dies The tablets strike a sweep off blade affixed to the front of the feed frame (A) and slide down into a receptacle At the same time, the lower punches re-enter the pull down cam (C) and the cycle is repeated

Although tablet compressing machinery has undergone numerous mechanical modifications over the years, the compaction of materials between a pair of moving punches within a stationary die has remained unchanged The principle modification from earlier equipment has been an increase in production rate which is regulated by Number of tooling sets Number of compression stations Rotational speed of the press

Special adaptations of tablet machines allow for the compression of layered tablets and coated tablets A device that chills the compression components to allow for the compression of low-melting point substances such as waxes i.e. suppositories

Compression Machine Tooling PUNCHES BB Tooling : 5.25” L, BD 0.75”, 1”. B Tooling : LP 3 9/16” D Tooling : Large tablets L 5.25”, BD 1”, 1 ¼ ” HD. DIES OD 0.945” 7/16” RT or 9/16” Cap T OD 1 3/16” – 9/16” RT, 3/3” Cap T

Evaluation of Tablet General Appearance: The general appearance of a tablet, its identity and general elegance is essential for consumer acceptance, for control of lot-to-lot uniformity and tablet-to-tablet uniformity. The control of general appearance involves the measurement of size, shape, color, presence or absence of odor, taste etc. Size & Shape: It can be dimensionally described & controlled. The thickness of a tablet is only variables. Tablet thickness can be measured by micrometer or by other device. Tablet thickness should be controlled within a ± 5% variation of standard value.

Unique identification marking: These marking utilize some form of embossing, engraving or printing. These markings include company name or symbol, product code, product name etc. Organoleptic properties: Color distribution must be uniform with no mottling. For visual color comparison compare the color of sample against standard color. Hardness : Tablet requires a certain amount of strength or hardness and resistance to friability to withstand mechanical shocks of handling in manufacture, packaging and shipping. Hardness generally measures the tablet crushing strength

Different Hardness Tester Erweka Pfizer Schleuniger Monsanto Strong-cobb

6.Friability: Friability of a tablet can determine in laboratory by Roche friabilator. This consist of a plastic chamber that revolves at 25 rpm, dropping the tablets through a Distance of six inches in the friabilator, which is then operate for 100 revolutions. The tablets are reweighed. Compress tablet that lose less than 0.5 to 1.0 % of the Tablet weigh are consider acceptable.

7. Drug Content and Release: Weight Variation test (U.S.P.): T ake 20 tablet and weighed individually. Calculate average weight and compare the individual tablet weight to the average. The tablet pass the U.S.P. test if no more that 2 tablets are outside the percentage limit and if no tablet differs by more than 2 times the percentage limit. (II) Content Uniformity Test: Randomly select 30 tablets. 10 of these assayed individually. The Tablet pass the test if 9 of the 10 tablets must contain not less than 85% and not more than 115% of the labeled drug content and the 10 th tablet may not contain less than 75% and more than 125% of the labeled content. If these conditions are not met, remaining 20 tablet assayed individually and none may fall out side of the 85 to 115% range .

(III) Disintegration Test (U.S.P.): The U.S.P. device to test disintegration uses 6 glass tubes that are 3” long; open at the top and 10 mesh screen at the bottom end. To test for disintegration time, one tablet is placed in each tube and the basket rack is positioned in a 1-L beaker of water, simulated gastric fluid or simulated intestinal fluid at 37 ± 2 0 C such that the tablet remain 2.5 cm below the surface of liquid on their upward movement and not closer than 2.5 cm from the bottom of the beaker in their downward movement. Move the basket containing the tablets up and down through a distance of 5-6 cm at a frequency of 28 to 32 cycles per minute. Floating of the tablets can be prevented by placing perforated plastic discs on each tablet.

According to the test the tablet must disintegrate and all particles must pass through the 10 mesh screen in the time specified. If any residue remains, it must have a soft mass. Disintegration time: Uncoated tablet: 5-30 minutes Coated tablet: 1-2 hours

Dissolution Test (U.S.P.) Two set of apparatus: Apparatus-1: A single tablet is placed in a small wire mesh basket attached to the bottom of the shaft connected to a variable speed motor. The basket is immersed in a dissolution medium (as specified in monograph) contained in a 100 ml flask. The flask is cylindrical with a hemispherical bottom. The flask is maintained at 37±0.5 0 C by a constant temperature bath. The motor is adjusted to turn at the specified speed and sample of the fluid are withdrawn at intervals to determine the amount of drug in solutions.

Apparatus-2: It is same as apparatus-1, except the basket is replaced by a paddle. The dosage form is allowed to sink to the bottom of the flask before stirring. For dissolution test U.S.P. specifies the dissolution test medium and volume, type of apparatus to be used, rpm of the shaft, time limit of the test and assay procedure for. The test tolerance is expressed as a % of the labeled amount of drug dissolved in the time limit.

Problems In Tableting Capping Lamination / Laminating Chipping Cracking Sticking / Filming Picking Binding Mottling Double impression Granule Size and size distribution Poor flow Punch Variation Hardness Variation

CAUSES AND REMEDIES OF CAPPING RELATED TO ‘ FORMULATION’ (GRANULATION) Sr. No. CAUSES REMEDIES 1. Large amount of fines in the granulation Remove some or all fines through 100 to 200 mesh screen 2. Too dry or very low moisture content (leading to loss of proper binding action). Moisten the granules suitably. Add hygroscopic substance e.g.: sorbitol, methyl- cellulose or PEG-4000 3. Not thoroughly dried granules. Dry the granules properly. 4. Insufficient amount of binder or improper binder. Increasing amount of binder OR Adding dry binder such as pre-gelatinized starch, gum acacia, powdered sorbitol, PVP, hydrophilic silica or powdered sugar. 5. Insufficient or improper lubricant. Increase the amount of lubricant or change the type of lubricant. 6. Granular mass too cold to compress firm. Compress at room temperature.

CAUSES AND REMEDIES OF CAPPING RELATED TO ‘ MACHINE’ (DIES, PUNCHES AND TABLET PRESS) Sr. No. CAUSES REMEDIES 1. Poorly finished dies Polish dies properly. Investigate other steels or other materials. 2. Deep concave punches or beveled-edge faces of punches. Deep concave punches or beveled-edge faces of punches. 3. Lower punch remains below the face of die during ejection. Make proper setting of lower punch during ejection. 4. Incorrect adjustment of sweep-off blade. Adjust sweep-off blade correctly to facilitate proper ejection. 5. High turret speed. Reduce speed of turret (Increase dwell time).

Causes and Remedies of Lamination related to MACHINE (Dies, Punches and Tablet Press)] Causes And Remedies Of Chipping Related To Formulation (Granulation) Are As Follows Sr. No. CAUSES REMEDIES 1. Rapid relaxation of the peripheral regions of a tablet, on ejection from a die. Use tapered dies, 2 Rapid decompression Use pre-compression step. Reduce turret speed and reduce the final compression pressure. Sr. No. CAUSES REMEDIES 1. Sticking on punch faces Dry the granules properly or increase lubrication. 2. Too dry granules. Moisten the granules to plasticize. Add hygroscopic substances. 3. Too much binding causes chipping at bottom. Optimize binding, or use dry binders.

CAUSES AND REMEDIES OF CHIPPING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS ) CAUSES AND REMEDIES OF CRACKING RELATED TO FORMULATION (GRANULATION) Sr. No. CAUSES REMEDIES 1. Groove of die worn at compression point. Polish to open end, reverse or replace the die. 2. Barreled die (center of the die wider than ends) Polish the die to make it cylindrical 3. Edge of punch face turned inside/inward. Polish the punch edges 4. Concavity too deep to compress properly. Reduce concavity of punch faces. Use flat punches. Sr. No. CAUSES REMEDIES 1. Large size of granules. Reduce granule size. Add fines. 2. Too dry granules. Moisten the granules properly and add proper amount of binder 3. Tablets expand. Improve granulation. Add dry binders. 4. Granulation too cold. Compress at room temperature

CAUSES AND REMEDIES OF CRACKING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS ) THE CAUSES AND REMEDIES OF STICKING RELATED TO FORMULATION (GRANULATION) Sr. No. CAUSES REMEDIES 1. . Tablet expands on ejection due to air entrapment. Use tapered die. 2. Deep concavities cause cracking while removing tablets Use special take-off Sr. No. CAUSES REMEDIES 1. Granules not dried properly. Dry the granules properly. Make moisture analysis to determine limits. 2. Too little or improper lubrication Increase or change lubricant. 3. Too much binder Reduce the amount of binder or use a different type of binder. 4. Hygroscopic granular material. Modify granulation and compress under controlled humidity. 5. Oily materials Modify mixing process. Add an absorbent. 6. Too soft or weak granules. Optimize the amount of binder and granulation technique.

CAUSES AND REMEDIES OF STICKING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS ) CAUSES AND REMEDIES OF PICKING RELATED TO FORMULATION (GRANULATION) Sr. No. CAUSES REMEDIES 1. Concavity too deep for granulation. Reduce concavity to optimum. 2. Too little pressure. Increase pressure. 3. Compressing too fast. Reduce speed Sr. No. CAUSES REMEDIES 1. Excessive moisture in granules. Dry properly the granules, determine optimum limit. 2. Too little or improper lubrication. Increase lubrication; use colloidal silica as a ‘polishing agent’, so that material does not cling to punch faces. 3. Low melting point substances, may soften from the heat of compression and lead to picking. Add high melting-point materials. Use high meting point lubricants. 4. Low melting point medicament in high concentration. Refrigerate granules and the entire tablet press. 5. Too warm granules when compressing. Compress at room temperature. Cool sufficiently before compression. 6. Too much amount of binder. Reduce the amount of binder, change the type or use dry binders.

CAUSES AND REMEDIES OF PICKING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS) CAUSES AND REMEDIES OF BINDING RELATED TO FORMULATION (GRANULATION) Sr. No. CAUSES REMEDIES 1. Rough or scratched punch faces. Polish faces to high luster. 2. Embossing or engraving letters on punch faces such as B, A, O, R, P, Q, G. Design lettering as large as possible. Plate the punch faces with chromium to produce a smooth and non-adherent face. 3. Pressure applied is not enough; too soft tablets. Increase pressure to optimum. Sr. No. CAUSES REMEDIES 1. Too moist granules and extrudes around lower punch. Dry the granules properly. 2. Insufficient or improper lubricant. Increase the amount of lubricant or use a more effective lubricant 3. Too coarse granules. Reduce granular size, add more fines, and increase the quantity of lubricant. 4. Too hard granules for the lubricant to be effective. Modify granulation. Reduce granular size. 5. Granular material very abrasive and cutting into dies. If coarse granules, reduce its size. Use wear-resistant dies. 6. Granular material too warm, sticks to the die. Reduce temperature.

CAUSES AND REMEDIES OF BINDING RELATED TO MACHINE (DIES, PUNCHES AND TABLET PRESS ) CAUSES AND REMEDIES OF MOTTLING Sr. No. CAUSES REMEDIES 1. Poorly finished dies. Polish the dies properly. 2. Rough dies due to abrasion, corrosion. Investigate other steels or other materials or modify granulation. 3. Undersized dies. Too little clearance. Rework to proper size. Increase clearance. 4. Too much pressure in the tablet press. Reduce pressure. OR Modify granulation. Sr. No. CAUSES REMEDIES 1. A coloured drug used along with colourless or white-coloured excipients. Use appropriate colourants. 2. A dye migrates to the surface of granulation while drying. Change the solvent system, Change the binder, Reduce drying temperature and Use a smaller particle size. 3. Improperly mixed dye, especially during ‘Direct Compression’. Mix properly and reduce size if it is of a larger size to prevent segregation. 4. Improper mixing of a coloured binder solution. Incorporate dry colour additive during powder blending step, then add fine powdered adhesives such as acacia and tragacanth and mix well and finally add granulating liquid.

Tablet Coating Tablet coating objectives. Three Primary components involved in tablet coating Tablet properties Coating process Coating equipment. Parameters of the coating process. Facility and ancillary equipment. Automation in coating processes. Coating compositions

1. Tablet Properties Mechanical and Physical Strength Smooth surface Physical shape Chemical nature of tablet ingredients Hygroscopicity

2. Coating Process Three types of equipments The standard coating pan The perforated coating pan The fluidized bed (Air suspension) coater. These systems based on three basic designs 1. Conventional pan system Depending on drying efficiency Pellegrini system Immersion-sword system Immersion –tube system 2. Perforated pan system Accela-coata Hi-coater systems Driacoater Glatt coater 3. Fluidized bed (Air suspension) system

Convensional pan: 8-60 inches diameter revolving on its horizontal axis. Heated air is directed into the pan and onto the tablet bed surface. Exhausted by means of ducts positioned through the front of the pan Drying efficiency is achieved by, Pellegrini pan : Has a baffled pan and diffuser for uniform distribution of drying air. Enclosed and automated .

2. Immersion-sword system Drying air through perforated metal sword immersed in the tablet bed. Upward flow through bed. Spray onto the bed surface 3. Immersion-tube system Tube immersed in tablet bed Delivers heated air and coating solution through spray built in the tip of tube Flows upward and exhausted by a conventional duct.

Perforated pan system: Perforated drum rotates on its horizontal axis in an enclosed housing. Accela-Coata and Hi-coater system : Drying air is directed in to drum , is passed through bed , and is exhausted through perforations in to drum.

Driacoater : Introduces drying air through hollow perforated ribs located inside periphery of the drum. With rotating pan, ribs dip into bed Drying air passes up through and fluidizes bed Exhaust is from back of the pan Glatt coater : Drying air directed from inside the drum through bed and out an exhaust duct With an optional split-chambered plenum drying air can be directed in the reverse manner Several air flow configurations are possible.

3. Fluidized bed (Air suspension system) Highly efficient Fluidization of tablet bed is achieved in a columnar chamber by the upward flow of drying air. Industrial FBC with bottom spray

Spray application System Two basic types of spray system differ in manner in which atomization of liquid is achieved High-pressure, airless (a) High pressure liquid (250-3000psig) through a small orifice (.009”- .020” id) Degree of automization- fluid pressure, orifice size, viscosity. 2. Low-pressure, air-automized (b) Low pressure liquid (5-50psig) through a large orifice (.020”- .060” id) Degree of automization- fluid pressure, orifice size, viscosity, air pressure, air cap design.

Parameters of Coating Process Rate of coating composition application= Rate of evaporation of volatile solvent Deviation from this results a serious coating problems Mathematical modeling for automated aqueous coating process Inlet A(T 1 ,H 1 )+C 1 (S)+pSA 1 -> E -> A(T 2 ,H 2 )+C 2 +pSA 2 Exhaust Where, A(T,H) = Air capacity, C(S) = Coating Composition, pSA = Tablet surface area, E = Equipment efficiency.

Air Capacity: Quantity of water or solvent removed during coating process Depends on : 1. Quantity of air flow through tablet bed, 2. Temperature of air, 3. water content of inlet air. Coating Composition: Inlet air-heated, exhaust air- cool. Drying of film- rate of application Thin rapidly drying formulations dry quickly on the tablet surface allowing constant application by efficient atomization of coating solution

Tablet surface area: Size and presence of debossed features affects coating conditions Total surface area per unit weight decreases from smaller to larger tablets For same thickness of film, smaller tablets requires more coating composition as compared with larger tablets Size of atomized coating droplets must be smaller and better controlled as the features to be coated become smaller. Equipment efficiency, E: Net increase in coated tablet weight Coating Efficiency, E = -------------------------------------------------------------------- Total nonvolatile coating weight applied to tablets

Facility and Ancillary Equipment Facility should meet to requirement of cGMP Adequate space for equipment, processing, in-process storage Safety requirements depending on nature of solvent- electrical explosion-proofing, specialized ventilation Exhaust air treatment to recover solvent or to prevent entry in to atmosphere Federal EPA defines limits of organic solvents and particulate allowed in atmosphere Aqueous based coating is advantageous Other Equipments Tanks, filters, mixers, mills, jacketed tanks, portable pressure tanks or pumping systems.

Tablet Coating Process Final production step on which quality of product may be judged Sugar Coating Steps involves, Sealing, Subcoating Syruping (Smooting) Finishing Polishing

Seal coating To prevent moisture penetration into tablet core Specially in pan-ladling process in which localized overwetting of portion of tablet bed occur Shellac Affects disintegration and dissolution time due to polymerization on aging Zein Such effect is not reported 2. Subcoating To round the edges and build up size . Subcoating Steps Sticky binder solution Dusting of subcoating powders Drying

3. Syrup (Smoothing/ color) coating To cover and fill in the imperfections in tablet surface caused by subcoating To impart desired color First syrup coat contains some suspended powders i.e. grossing syrups Dilute colorants– tinted base– uniform coating Syrup solution containing dye applied until final size and color are achieved 4. Finishing Final syrup coating step Few clear coats of syrup may be applied 5. Polishing Desired luster is obtained in this final step Clean standard coating pan, canvas-lined coating pans Application of powdered wax or warm solution of waxes in suitable volatile solvent

Film Coating Film coating and sugar coating shares the same equipments and process parameters Two methods, Pan-Pour method Same as that of pan-pour sugar coating Method is relatively slow and relies heavily on skill and technique of operator Aqueous based film coating is not suitable due to localized over-wetting 2) Pan-Spray method Use of automated spraying system

Process Variables To ensure the consistent product quality, certain elements of process need to be controlled regardless of coating pan system The variables to be controlled in pan-spray film coating process are: Pan variables Pan design/ baffling Speed Pan load 2. Process air Air quality Temperature Airflow rate/ volume/ balance 3. Spray variables Spray rate Degree of atomization Spray pattern Nozzle-to-bed distance

Development Of Film Coating Formulations Water vapor permeability Film tensile strength Coated Tablet Evaluation Adhesion test with tensile strength tester Diametral crushing strength of coated tablets Rate of coated tablet disintegration/ dissolution Stability studies Surface roughness, hardness, color uniformity through instrumental mean Visual inspection for coated tablet quality. Qualitative measure of resistance of a coated tablet to abrasion by white paper.

Coating Formula Optimization Modifications in basic formula, To improve adhesion of the coating to the core To decrease bridging of intagliations To increase coating hardness To improve any other property as per need of formulation Common modifications are Changes in polymers-to-plastisizers ratio Addition of different polymers or plstisizers

Material used in Film Coating Should have following attributes; Solubility in solvent Solubility required for intended use Capacity to produce elegant looking product Stability with heat, light, moisture, air, substrate. Essentially no color, taste, odor Compatibility with common coating solution additives Nontoxic , therapeutically inert and ease of application to the particles or tablets Resistance to cracking, and provision of adequate moisture, light, odor, or drug sublimation barrier when desired No bridging or filling of the debossed tablet surfaces by the film former Ease of printing procedures on high-speed equipment

A. Film Formers Classified in Nonenteric and Enteric Materials 1 . Nonenteric Materials HPMC, MHEC, EC, HPC, Povidone, SCMC, PEG, Acrylate Polymers

2. Enteric Materials Reasons for enteric coating Protect acid labile drugs from gastric fluid e.g. enzymes, ATBTs Prevent gastric distress or nausea due to irritation from drug, e.g. Sodium Salicylate To deliver drugs for local action in intestines, e.g. Intestinal antiseptic (Kanamycin) For drugs optimally absorbed in small intestine Provide delayed release component for repeat-action tablets Material should have following properties Resistance to gastric fluids Ready susceptibility or permeability to intestinal fluids Stability with coating composition and drug substrate Stability alone and in coating solution Formation of continuous film Nontoxicity, Low cost Ease of application without special equipments Ability to be printed or to allow film to be applied to debossed tablets

Enteric materials CAP, Acrylate Polymers HPMCP PVAP B. Solvents C. Plasticizers “ Internal ” or “ External ” techniques D. Colorants E. Opaquant-Extenders F. Miscellaneous Coating Solution Components

Quality Control Stability Testing Film Defects Specialized Coatings Compression Coating Electrostatic Coating Dip Coating Vacuum Film Coating

Blistering Chipping Cratering Picking Pitting Blooming Blushing Colour variation Infilling Orange peel/Roughness Cracking/Splitting Problems And Remedies For Tablet Coating

PROBLEMS AND REMEDIES FOR TABLET COATING THE CAUSE AND REMEDY OF BLISTERING Sr. No. CAUSES REMEDIES 1. Effect of temperature on the strength, elasticity and adhesion of the film Use mild drying condition. THE CAUSE AND REMEDY OF CHIPPING 1. High degree of attrition associated with the coating process. Increase hardness of the film by increasing the molecular weight grade of polymer. THE CAUSES AND REMEDIES OF CRATERING 1. Inefficient drying. Use efficient and optimum drying conditions. 2. Higher rate of application of coating solution. Increase viscosity of coating solution to decrease spray application rate. THE CAUSES AND REMEDIES OF PICKING 1. Inefficient drying. Use optimum and efficient drying conditions or increase the inlet air temperature. 2. Higher rate of application of coating solution Decrease the rater of application of coating solution by increasing viscosity of coating solution. THE CAUSE AND REMEDY OF PITTING 1. Inappropriate drying (inlet air ) temperature Dispensing with preheating procedures at the initiation of coating and modifying the drying (inlet air) temperature such that the temperature of the tablet core is not greater than the melting point of the batch of additives used. THE CAUSE AND REMEDY OF BLOOMING 1. High concentration and low molecular weight of plasticizer. Decrease plasticizer concentration and increase molecular weight of plasticizer

THE CAUSES AND REMEDIES OF BLUSHING 1. High coating temperature Decrease the drying air temperatur 2. Use of sorbitol in formulation which causes largest fall in the thermal gelation temperature of the Hydroxy Propyl Cellulose, Hydroxy Propyl Methyl Cellulose, Methyl Cellulose and Cellulose ethers. Avoid use of sorbitol with Hydroxy Propyl Cellulose, Hydroxy Propyl Methyl Cellulose, Methyl Cellulose and Cellulose ethers. THE CAUSE AND REMEDY OF COLOUR VARIATION 1. Improper mixing, uneven spray pattern, insufficient coating, migration of soluble dyes-plasticizers and other additives during drying. Go for geometric mixing, reformulation with different plasticizers and additives or use mild drying conditions. THE CAUSE AND REMEDY OF INFILLING 1. Bubble or foam formation because of air spraying of a polymer solution Add alcohol or use spray nozzle capable of finer atomization. THE CAUSES AND REMEDIES OF ORANGE PEEL/ROUGHNESS 1. Rapid Drying Use mild drying conditions 2. High solution viscosity Use additional solvents to decrease viscosity of solution. THE CAUSE AND REMEDY OF CRACKING/SPLITTING 1. Use of higher molecular weight polymers or polymeric blends. Use lower molecular weight polymers or polymeric blends. Also adjust plasticizer type and concentration.

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