2. TABLETS
ļ± Definition: Compressed or compressed and coated solid unit dosage form, containing medicament(s)
with or without other ingredients (excipients). Tablets are available in various shapes and sizes,
ā¢ Tablets need to be designed interms of formulation and manufacturing methods to achieve desired
physical, chemical and therapeutic properties.
ļ± Formulation:
Apart from medicament other ingredients which are added, called additives/ Excipients.
ā¢ Exicipients in Conventional Tablets:
ā¢ Purpose: To increase bulk for easy handling, ease of manufacturing, to increase dissolution rate, to
improve stability, to increase patient acceptability, for product identification etc.
1. Diluents:
2. Binders and adhesives:
3. Disintegrants:
4. Lubricants and Glidants:
Optional:
5. Colorants:
6. Flavoring agents:
7. Sweeteners:
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3. 1. They must be nontoxic and acceptable to the regulatory agencies in all countries where the product is
to be marketed.
2. They must be commercially available in an acceptable grade.
3. There cost must be acceptably low.
4. They must not be contraindicated by themselves (e.g. sucrose)or because of a component (e.g.
sodium).
5. They must be physiologically inert.
6. They must be physically & chemically stable by themselves & in combination with the drug(s) and other
tablet components. ( e.g. tetracycline drug with calcium phosphate as diluent-reduced bioavailability,
Amine drug bases or salts of alkaline compounds with lactose as diluent along with magnesium
stearate-discoloration of tablet).
7. They must be free from any unacceptable microbiologic āloadā.
8. They must be color compatible (should not produce any off-color appearance).
9. They must not alter the bioavailability of drug(s).
10. If drug product is also classified as food (e.g. vitamin), they must be approved as food additives.
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Tablet Excipients Criteria:
4. 4
ļ± Diluents are fillers used to make up the required bulk of the tablet when the drug dosage itself is
inadequate to produce this bulk.
Secondary reasons:
to provide better tablet properties such as improved cohesion,
to permit use of direct compression manufacturing or
to promote flow.
ļ± Commonly used tablet diluents
1. Lactose, Lactose anhydrous and spray dried lactose
2. Starch (Corn, Maize, potato)
3. Dibasic calcium phosphate dihydrate
4. Calcium sulfate dihydrate
5. Mannitol ā Expensive sugar. Because of slow solubility, cooling effect and pleasant feeling in
mouth, widely used in chewable tablets. Itās non hygroscopic, can be used in moisture sensitive
vitamin formulations. Poor flow property, require high amount of lubricant.
6. Sorbitol- sometimes combined with mannitol to reduce cost. Hygroscopic.
7. Sucrose- not for diabetic.
8. Dextrose-hydrous and anhydrous, can replace some part of spray dried lactose.
Diluents:
5. ļ± Directly compressible diluents:
1. Spray dried lactose - good flow properties, need neutral or acid lubricant( gylceryl
monostearate or stearic acid.
2. Microcrystalline cellulose- AvicelĀ® (Grade PH 101(powder) and PH 102(granules)).
Good flow property. Unique diluent that produce cohesive compact and also act as
disintegrant. Expensive, combined with other diluents.
3. Directly compressible starches-Sta Rx 1500Ā®- free flowing, as diluent, binder &/or
disintegrant.
4. Hydrolyzed starches-EmdexĀ® and CelutabĀ®- free flowing, sweet, can replace mannitol
in chewable tablet. May increase tablet hardness.
5. Sucrose based- Sugartab Ā®, DiPac Ā®, Nutab Ā®
ļ± Type of diluent to be used depends on type of drug and method of manufacture.
ā¢ For e.g. Hydrate forms of Dibasic calcium phosphate and Calcium sulfate possess low concentration of
unbound moisture and low affinity for atmospheric moistureā¦can be used for water-sensitive drug.
ā¢ Anhydrous lactose doesnāt undergo Maillard reaction with amine drugs but itās hygroscopic, require
moisture proof packaging.
ā¢ For wet granulation method, hydrous form of lactose is generally used.
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6. ļ± These materials are added either dry or in liquid form during wet granulation to form granules or to
promote cohesive compacts for directly compressible tablets.
ļ± Examples:
ā¢ Acacia, tragacanth- Natural gums, used in solutions of 10-25% Conc. Alone or in combination. More
effective in solution form.
Disadvantages: Variable composition and Microbial contamination, wet granules should be dried quickly.
ā¢ Gelatin: Used in combination with acacia. More consistent than acacia and tragacanth.
ā¢ Starch paste-Most commonly used granulating agent. Translucent paste. Pregelatinized starch.
ā¢ Liquid glucose(i.e.50% solution in water): Similar to (50-74%)sucrose solutions. Low cost adhesives.
ā¢ Sorbitol.
ā¢ Modifies natural polymer: Sodium Alginate and alginate derivatives,
ā¢ Cellulose derivatives- Methyl cellulose, Hydroxy propyl methyl cellulose, Hydroxy propyl cellulose are
common binders. Dry form for direct compression. HPC in alcoholic solution as anhydrous adhesive.
Ethyl Cellulose may be used only as an alcoholic solution but retard disintegration.
ā¢ Polyvinylpyrrolidone (PVP)-Synthetic polymer. May be used in either aqueous or alcoholic solution. Also
as dry binder.
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Binders and Adhesives:
7. ļ± A disintegrant is added to most tablet formulations to facilitate a breakup or disintegration of the tablet
when it contacts fluid in the GIT.
ā¢ Mechanism: Drawing water/fluid into the tablet, swelling, and causing the tablet to burst apart into
fragments of drug which subsequently get dissolved for the attainment of drug bioavailability.
ļ± Most commonly used disintegrants:
ā¢ Starch :Used in conc. of 5 to 20 % of tablet weight) , low cost.
ā¢ Starch derivative (substituted carboxymetyl starchesā PrimogelĀ® and ExplotabĀ® (Used in lower conc. of
1-8%, usually 4 % as optimum conc.)
ā¢ Pregelatinized starches are also used usually in a 5 % conc.
ā¢ Clays- Veegum HV and bentonite have been used at about a 10% level.
Limited to colored tablets only, as clays produce an off-white appearance. Less effective as disintegrants
than some of the newer modified polymers and starches.
ā¢ Alginates.
ā¢ Cellulose derivatives- Micro crystalline cellulose.
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Disintegrants:
8. ļ±SUPERDISINTEGRANTS:
ā¢ Examples:
ā¢ Crosscarmellose: Ac- Di-SolĀ® (cross linked sodium carboxy methyl cellulose), effective in low conc.
ā¢ Crosspovidone- cross-linked PVP (polymer).
ā¢ Sodium starch glycolate- cross-linked starch.
ā¢ These cross-linked products swells quickly when comes in contact with water.
ļ± Note:
If granulation method of manufacturing: A portion of disintegrant is added before granulation ( which
facilitate granules disintegration) and a portion after granulation (i.e. before compression ) , which
facilitate tablet disintegration into granules.
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9. ļ± Lubricants are intended to reduce the friction during tablet ejection between the walls of the tablet and
the walls of the die cavity. Antiadherents reduce sticking or adhesion of any of the tablet materials to the
faces of the punches or to the die wall.
ā¢ Glidants are intended to promote flow of the tablet granules or powder material by reducing friction
between the particles.
ā¢ Overlapping functions of lubricants, antiadherents and glidants.
ļ± Examples: Lubricants- Stearic acid (Low melting point, less effective than its salts), Stearic acid salts and
derivatives - Calcium stearate and Magnesium stearate are the most commonly used salts.
Talc: Most samples found to contain traces of iron, considered carefully if drug degradation is catalyzed by
iron.
ā¢ Water soluble lubricants: Higher molecular weight PEGs (Polyethylene glycols) and polymeric Surfactants
but less effective.
ļ± Note: Lubrication is basically coating process, the finer the particle size of lubricants, the more effective
lubricant action likely to be.
ā¢ Antiadherents: Most of the lubricants (except water soluble lubricants) also function as antiadherents. E.g.
Talc, magnesium stearate, and starch, starch derivatives, various colloidal silicas.
ā¢ Glidants/flow promoters: Talc at a 5 % concentration, Corn Starch at a 5-10% conc., or colloidal silicas such
as Cab-O-Sil Ā®, Syloid Ā®, or Aerosil Ā® in 0.25-3% concentrations.
ā¢ Waxes and Mineral oils can applied to granules as fine spray but produce oil spots.
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Lubricants and Glidants:
10. ļ± The use of colors and dyes in tablet formulation has three purposes:
(1) Masking of off-color drugs,
(2) Product Identification,
(3) Production of more elegant product.
ļ± Natural vegetable colors are limited and unstable. Synthetic colors are also limited due to decertification.
All coloring agents to be used must be approved and certified by FDA.
ļ± Two forms of colors used in tablet preparation are the FD &C and D & C dyes and the Lake form of these
dyes. Dyes are applied as solutions in the granulating agent. Lakes (Aluminum salts of water soluble dyes
) are dyes that have been absorbed on a hydrous oxide( e.g. Al(OH)3). and usually employed as dry
powders for coloring. Dyes are water soluble. Lakes are water insoluble.
ļ± Precautions: When water soluble dyes- pastel shades should be used as these show the least mottling
from uneven distribution in the final tablet.
ā¢ When wet granulation is employed, care should be taken to prevent color migration during drying.
ā¢ The formulation for colored tablet should be checked for resistance to color changes on exposure to
light.
ļ± Examples: Natural: Carmine(Cochineal), Annatto, Beta carotene, Turmeric, etc.
ļ± Synthetic: FD & C yellow 6 (sunset yellow FCF), FD & C yellow 5 (Tartrazine) , FD & C green 3 (Fast Green),
FD & C blue 1 (Brilliant Blue FCF) , FD & C blue 1 Aluminum lake (Brilliant Blue FCF) FD & C blue 2 ( Indigo
carmine), D & C Green 5, Synthetic Iron Oxides ( black, red and yellow)etc.
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Colorants:
11. ļ± Flavours are usually limited to chewable tablet or other mouth dissolving tablets. Water soluble flavours
are not preferred in tablets because of poor stability.
ļ± Flavor oils are employed in tablets by adding into granulating solvents, are dispersed on clays and other
adsorbents or are emulsified in aqueous granulating solvents.
ļ± Maximum amount of oil allowed is 0.5 to 0.75 %.
ļ± Dry flavours are also available.
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Flavoring agents :
Sweeteners :
ļ± To limit/exclude use of sugar, the use of sweeteners is limited to chewable tablets.
ļ± Examples: Sucrose and sugar derivatives. Mannitol-72% as sweet as sucrose.
ā¢ FDA approved Artificial sweeteners (sugar substitutes):
ā¢ Saccharin (Sugar freeĀ®): Discovered in 1878. 300 times sweetener than sucrose.
Disadvantages: Bitter aftertaste and experimentally found carcinogenic in animals. Experimentally, no harmful
effects on humans were observed with consumption of 5 g saccharin daily over 5 months.
ā¢ Aspartame(NutraSweetĀ®) : 1965. 200 times sweetener than sucrose. No bitter aftertaste.
Disadvantage: Lack of stability in the presence of moisture.
ā¢ Acesulfame K (Sweet OneĀ®): 1967. 600 times sweetener than sucrose.
ā¢ Sucralose (SplendaĀ®): 1976. 600 times sweetener than sucrose.
ā¢ Neotame
ā¢ Natural low-calorie sweetener, Stevia ( Steviol Glycosides from leaves of Stevia rebaudiana. plant): Approved
in 2015 by FSSAI (Food Safety and Standards Authority of India). 200-400 times sweetener than sucrose.
12. ļ± Materials intended for compaction into a tablet must possess two characteristics: Fluidity and
compressibility.
ā¢ Fluidity: Good flow properties( smooth and uniform flow of tablet materials) are essential for the
transport of the material through the hopper, into and through the feed frame, and into the dies.
Therefore granulation is the process attempts to improve flow of powder materials by forming sphere
like aggregates called āgranulesā. Powder/granules flow can be improved mechanically by the use of
vibrators, force feeders or by incorporating the glidant in the tablet formulation.
ļ± Powder compressibility : Compressibility is the property of forming a stable, compact mass when
pressure is applied. Granulation converts powder with poor adhesion into aggregates capable of
compaction.
ļ± Granules properties: Size, Size distribution, shape, surface are, density, strength and friability, flow
properties(can be indicated by Angle of repose, compressibility Index, Hopper flow rate), compaction
force. These properties affect the tablet average weight, tablet weight variation, hardness, disintegration
time, dissolution rate, drying rate of wet granules, compression force required.
ļ± Depending on the formulation ingredients and powder properties, tablets can be manufactured by any of
three basic methods.
ā¢ Direct compression
ā¢ Wet granulation
ā¢ Dry granulation/Compression granulation/slugging
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Manufacturing of Tablets:
15. ļ± There are few crystalline substances may be compressed directly but majority of the drugs and other
formulation components may interfere with direct compressibility. However, the use of compressible
diluents with moderate-dose drugs makes, this process the most preferred method of tablet
manufacture.
ļ± Advantages:
ā¢ 1. Most economic method as it involves fewer processing steps & equipments, low labor input,
ā¢ 2. A dry process, suitable for moisture sensitive drugs,
ā¢ 3. Tablets produced by this method generally show with good dissolution profile.
ļ± Limitations:
1. Difference in particle size and density between formulation components may lead to stratification
which may result in poor content uniformity of the drug in tablets particularly with low dose drugs.
2. Direct compression of non-compressible large- dose drugs, require large amount of diluents and
resultant tablet would be costly and difficult to swallow.
3. Not suitable for high dose, poorly compressible drugs.
4. Because of dry nature of this method, static charge buildup can occur on the drugs during
processing which may prevent uniform distribution of drug in the formulation.
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Direct Compression
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ļ± This method has been used for many years and is a valuable technique when the effective dose of a drug is
too high for direct compression, and the drug is sensitive to heat, moisture or both which restricts wet
granulation.
ļ± Process:
ā¢ The initial blend of powders is forced into the dies of a large capacity tablet press and is compacted
using flat faced punches, the compacted masses are called slugs, and process is referred as āsluggingā.
ā¢ The slugs are then milled or screened (sometimes slugs are screened, slugged again, and screened again) to
produce granules flowing more uniformly than the original powder blend.
ā¢ Final compression of the granules.
ļ± Slugging is like to increase compression time. Multiple time compression causes a strengthening of the
bonds that hold the tablet together and improves flow of blend.
ļ± On a large scale, compression granulation can also be performed on a roller compactor. Roller compactor is
capable of producing as much as 500 kg/hr of compacted ribbon segments which are equivalent to slugs by
the slugging process, which can be then milled and screened in to granules for final compression.
ļ± Advantages: Minimum equipments and less space compared to wet granulation. Scale-up is easy.
It also eliminates moisture addition and heat application unlike wet granulation.
ļ± Limitations of dry granulation:
1. Dry granulation process generates considerable dust which may cause cross contamination & risk to workers.
2. Tablets produced by this method tend to be softer than those produced by wet granulation.
Dry granulation/Compression granulation:
18. 18
Chilsonator Roller compactor:
Advantages of roller compactor over slugging: Increased production capacity, greater control of compaction
pressure & dwell time, and no need for excessive lubrication of the granules.
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ļ± Wet granulation involves unique processing steps like wet massing of the powder mix, wet sizing or milling and
drying.
ļ± Procedure: After preliminary weighing, screening and mixing, wet mixing/granulation, wet milling, drying, dry
screening, mixing with part of disintegrant, glidant and lubricant, and finally compression.
ļ§ Aqueous solutions are safer than other solvents. Water, 70 % IPA.
ļ± Wet mixing: Wet granulation forms the granules by binding the powders together with an adhesive, instead of
compaction.
ā¢ Method of binder addition: In this technique, binder can be added as a solution, suspension, or slurry in a
granulating solvent or in a dry form, followed by the addition of granulating liquid.
ā¢ Method of addition depends on solubility of binder and on the components of mixture.
ā¢ Powder should be moist rather than wet or pasty, therefore amount of solvent added is limited ( Overly wet mass
dries slowly and forms hard aggregates after drying, which tend to turn to powder during dry milling. If under wetting
then granules would be too soft and friable).
ā¢ When small amount of solvent permissible, dry binder mixing with dry powder and when large quantity of solvent is
require, the binder is usually dissolved in the liquid. Solution of the binder should be fluid enough to disperse easily
in the powder mass.
āŖ The liquid plays a key role in the granulation process. It forms liquid bridges between particles. These surface
tension forces and capillary pressure are responsible for initial granule formation and strength. Uniform mixing of
binder and binder activation must be ensured. Granulation time depends on the wetting properties of the powder
mixture for the granulation fluid used, and the efficiency of the mixer.
Wet granulation:
22. ā¢ End point of wet mixing/granulation can be roughly determined by pressing a portion of the wet mass in the
palm of the hand, if the ball of mass crumbles under moderate pressure, the mass is ready for the next step of
wet screening
ļ± Wet screening converts moist mass into coarse, granular aggregates. Purpose is to further consolidate granules
and to increase surface area to improve drying rate. In some cases and with modern high speed
mixer/granulators, this step may be omitted to save the time
ļ± Drying: To remove granulating solvent or to reduce the moisture content to optimum level.
ā¢ During drying, interparticulate bonds result from fusion or re-crystallization and curing of the binding agent,
with van der Waals forces playing a significant role.
ļ± Dry Screening to the desired size and size distribution of granules.
ļ¶ Safety Precaution: The use of volatile or inflammable solvents for wet granulation creates problems during
drying. Work areas must be well ventilated to reduce direct toxic effects or to keep the solvent vapor
concentration below explosion limits. All equipment should be electrically grounded to prevent spark that could
initiate explosion. Explosion proof motors or explosion-resistant motors may be required.
ā¢ EPA- Environmental Protection Agency norms must be followed for the amount of organic solvent that can be
exhausted into the atmosphere. This may require recovery of solvent and may increase cost of production.
ā¢ Advantages: Better flow properties of granules. Improved compressibility, require low pressure during
compression. Better content uniformity of drug in tablets. Tablets comply further processing of coating. Dust
generation is less, reduces cross contamination & risk to workers.
ļ± Limitations of wet granulation: 1. Time consuming and costly as multiple separate steps and equipments are
involved 2. Not suitable for heat and moisture sensitive drugs. 3. Scale-up is more complicated. 4. Power failure
without back-up battery system during processing may result into loss of batch. 22
23. ā¢ Steam Granulation Technology
ā¢ Moisture Activated Dry Granulation (MADG)
ā¢ Melt Granulation Technology
ā¢ Foamed Binder Technology (FBG)
ā¢ Freeze Granulation Technology
ā¢ Thermal Adhesion Granulation Process (TAG)
ā¢ Reverse-phase Wet Granulation
ā¢ Pneumatic Dry Granulation (P.D.G.)- (Dry Granulation)
ā¢ Advanced Equipments:
ā¢ High shear mixers: e.g. RMG- Rapid Mixer Granulator. Perform Dry mixing, wet mixing and granulation in
one equipment.
ā¢ Fluidized bed granulator: Perform all Dry mixing, wet mixing, granulation and drying in one equipment.
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Novel Granulation Technologies:
24. ā¢ They are unit dosage form and offer the greatest dose precision and the least content variability.
ā¢ Their cost is lowest of all oral dosage forms.
ā¢ Tamperproof dosage form.
ā¢ They are the lightest and compact of all dosage forms.
ā¢ They are Easiest and cheapest to package and ship.
ā¢ Product identification is simplest and cheapest, requiring no additional steps when employing an
embossed or monogrammed punch face.
ā¢ They are easy to swallow with the least tendency for āhang-upā, especially when coated.
ā¢ Tablets can be modified for special release profile, such as delayed release (enteric coated) or sustained
release.
ā¢ They are suitable for large scale production compared to other oral unit dosage forms.
ā¢ They have the best chemical, mechanical and microbiological stability over all oral dosage forms.
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Advantages of tablets over other dosage forms:
25. ā¢ Some drugs resist compression into dense compacts, owing to their amorphous nature or low density
character.
ā¢ Drugs withā¦.
Poor wetting,
Slow dissolution properties,
Large dosages,
Optimum absorption high in the specific part of GIT may be difficult or impossible to formulate and
manufacture as a tablet that will still provide adequate or full drug bioavailability.
ā¢ Bitter tasting drugs, drugs with an objectionable odor, or drugs that are sensitive to oxygen or
atmospheric moisture may require encapsulation of drug prior to compression or tablet coating. In such
cases, capsule may offer the best and lowest cost approach.
ā¢ Difficult to swallow in case of children and unconscious patients.
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Disadvantages of tablets as dosage form:
26. 26
1. The Theory and Practice of Industrial Pharmacy by Leon Lachman, A.lieberman
2. Saccharin deemed ānot hazardousā in United States and abroad Louis Z.G. Touyz, Curr Oncol. 2011 Oct;
18(5): 213ā214. doi: 10.3747/co.v18i5.836
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References: