Notes on "Tablets"

According to the Indian Pharmacopoeia, Pharmaceutical tablets are solid, flat or biconvex dishes, unit dosage form, prepared by compressing a drug or a mixture of drugs, with or without diluents.

• Tablets can be defined as a compressed solid dosage form containing medicaments with or without excipients.


• As they are usually made by compression technology they are also called as "Compressed Tablets."

Advantages of Tablets as a dosage form:

1. Dosage accuracy.


2. Economical.


3. Lighter and compact.


4. Easiest and cheapest for packing and transportation: Again reduces the final cost of the product.


5. Easy to swallow with a little amount of water.


6. Convenient to carry and administer.


7. Release patterns of the drug can be modified from fast release to sustained release.


8. Objectionable odor and bitter taste can be masked by a coating technique.


9. Suitable for large scale production.


10. Greatest chemical and microbial stability overall oral dosage form.

Disadvantages of Tablets as dosage form:

1. Difficult to swallow in case of children and unconscious patients.


2. Some drugs resist compression into dense compacts, owing to amorphous nature and/ low-density character.


3. Drugs with poor wetting, slow dissolution properties, may be difficult to formulate or manufacture as a tablet.


4. Bitter testing drugs, drugs with an objectionable odor or drugs that are sensitive to oxidation or photodegradation may require encapsulation or coating.

Ideal properties for Tablets as dosage form: 

1. A tablet should have elegant look and should be free from manufacturing defects like chipping, cracking, mottling, etc.


2. Should have sufficient strength to withstand mechanical shock during its production packaging, shipping, and handling.


3. Should have the chemical and physical stability.


4. The tablet must be able to release the medicinal agents in a predictable and reproducible manner.

Types of tablets:-

A) Tablets Ingested Orally:-

1. Compressed Tablets.


2. Multiple compressed tablets


3. Multilayered Tablets.


4. Sustained action tablets.


5. Enteric coated tablets.


6. Sugar coated tablets.


7. Film-coated tablets.


8. Chewable tablets.


9. Effervescent tablets.

B) Tablets used in the Oral Cavity:-

1. Buccal tablets.


2. Sublingual Tablets.


3. Lozenges.


4. Dental cones.

C) Tablets administered by other routes:

1. Implantation tablets.


2. Vaginal tablets.

D) Tablets used to prepare solutions:

1. Effervescent tablets.


2. Dispensing tablets.


3. Hypodermic tablets.


4. Tablet triturates.

Tablet Ingredients

• In addition to active ingredients, tablets contain plenty of inert materials known as additives or excipients.


• Different excipients used in tablet manufacturing are:

1. Diluents.


2. Binders and adhesives.


3. Disintegrants.


4. Lubricants and glidants.


5. Colouring agents.


6. Flavoring agents.


7. Sweeteners.

 

1. Diluents:

• Most drugs doses are in milligrams which are not suitable to compress into tablets.


• Diluents are fillers used to make the required bulk of tablets when the drug dosage itself is low to produce the bulk.


• Another reason is to provide better tablet properties like, improve adherence, to allow use of direct compression technique or to promote flow.


• A diluent should have following properties:

1. They must be nontoxic.


2. They must be commercially available in required grades.


3. Economical and easy to obtain.


4. They must be physiologically inert.


5. They must be physically & chemically stable by themselves & in combination with the drugs.


6. They must be free from microbial contamination.


7. They should not alter the bioavailability of the drug.


8. They must be color compatible in the formulation.


9. They should not interfere with absorption of drugs.

• 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 sulfate dihydrate


7. Mannitol


8. Sorbitol


9. Sucrose- Sugartab, DiPac, Nutab


10. Dextrose

• Lactose:


• Most commonly used diluent in tablet formulation.


• It is compatible with most of the drugs, whether it is used in a hydrous or anhydrous form.


• Anhydrous lactose has an advantage over lactose that it does not undergo "Maillard reaction" which is browning & discoloration of the tablet due to the interaction of amine drug with lactose.


• Spray dried lactose in concentration 20-25% of active ingredient is used for direct compression.

 

• Starch:


• Obtained from corn, wheat, potatoes is used as a diluent, binder and as a disitegrant.


• Starch is an inert polysaccharide available abundantly in the plant kingdom.


• Sta-Rx 1500 is free flowing, directly compressible starch used as diluent, binder and /or disintegrating agent.


• Two hydrolyzed starch Emdex and Celutab, which in the combination of 90-92% of dextrose and 3-5% of maltose, are free-flowing and directly compressible.

 

• Sucrose:


• It is used as diluent.


• Some sugar-based diluents are used for direct compression.


• These are:

1. Sugartab: 90-93% sucrose and 7-10% invert sugar


2. DiPac: 97%sucrose and 3% modified dextrin


3. Nu Tab: 95%sucrose & 4% invert sugar with small amount of cornstarch & magnesium stearate.

• Microcrystalline cellulose: (MCC)


• Trade name Avicel is used for direct compression.


• These are of two types: PH101 (Powder) and PH102 (Granules).

• Dibasic calcium phosphate and calcium sulfate


• Used as diluents but reduce the bioavailability of tetracyclines.


• DCP is considered as a good diluent and used commonly in industries.

 

2. Binders and Adhesives:

• These materials are added either in dry or in wet- form to form granules or to form cohesive compacts for the directly compressed tablet.


• Binders keep all granules together after compression and keep tablet intact after compression.


• Deficient addition leads to "Capping."


• Example: Acacia, tragacanth- Solution for 10-25% Conc.


• Cellulose derivatives- Methyl cellulose, Hydroxy propyl methyl cellulose (HPMC), Hydroxy propyl cellulose (HPC).


• Gelatin- 10-20% 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 comes in contact with water.


• e.g.: Starch- 5-20% of tablet weight.


• Starch derivatives – Primogel and Explotab (1-8%).


• Cellulose derivatives- Carboxymethyl Cellulose


• Superdisintegrants:


• Swells up to ten fold within 30 seconds when contact water hence called as superdisintegrants.


• e.g.: Croscarmellose- cross-linked cellulose,


• Crosspovidone- cross-linked povidone (polymer),


• Sodium starch glycolate- cross-linked starch.


• These cross-linked products swell up to 10n fold within 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.


• They reduce inter-particle friction and improve the rate of flow of the granules.


• Glidants are intended to promote flow of granules or powder material by reducing the interparticulate friction.


• Example: Lubricants- Stearic acid, Magnesium stearate, Talc, PEG (Polyethylene glycols), Surfactants.


• Glidants- Corn Starch – 5-10% conc., Talc-5% conc., Silica derivative - Colloidal silicas.

5. Coloring agents:

• The use of colors and dyes in a tablet has three purposes:


• Masking of off-color drugs.


• Product Identification.


• Improve the appearance of the 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 solutions in the granulating agent or Lake form of these dyes.


• Lakes are dyes adsorbed on hydrous oxide and employed as dry powder coloring.


• Example: FD & C yellow 6-sunset yellow, FD & C yellow 5- Tartrazine.

6. Flavoring agents:

• For chewable tablets- flavor oils 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:

• The process of conversion of small powder particles into aggregates is called as granulation.


• It can be discussed under three steps:

1. Weighing of Ingredients:

• All required ingredients are weighed by using a calibrated good quality weighing balance.


• This process is double checked in order to avoid human errors.

1. Mixing the powdered ingredients and excipients:

• It is done to ensure the formation of uniform tablets containing a homogeneous mixture of medicines and excipients.


• The mixing is done in ascending order of weights.

1. Conversion of the mixture in granules:

• The granules are preferred over fine powder to prepare compressed tablets because,

 

Sr.No	Fine Powder	Granules
1	Requires large area for storage	Requires comparatively less area.
2	Loss during operation is more	Less loss during operation.
3	Problem of dusting during operation	Very less dusting during operation
4	Chances of separation of powders during operation because of vibrations of machine separates powders of different densities: results in loss of uniformity of contents.	Even though the size of granules may be big or small contents are always uniform: No loss of uniformity of contents of tablets.
5	Air entrapment during operation may result in capping and breaking during transportation and handling.	Have more knitting power hence form a strong tablet.
6	Can cause sticking, as powder being light blown out of die during compression.	Granules being heavier does not blow out of die during compression and hence doesn’t stick to the machine.
7	Can produce loss of weight uniformity: different powders with different density doesn't flow evenly through the hopper.	Being of uniform size flow evenly and help produce the tablets of uniform weight.

 

METHODS OF GRANULATION:

There are three common methods of granulation

• Wet granulation or Moist Granulation.


• Dry Granulation.


• Direct compression/ Slugging.

Wet Granulation or Moist Granulation:

Raw materials → Weighing → Screening → Wet massing →  Sieving/Milling → Drying → Screening → Mixing → Compression  

• The most common method employed for granulation.


• The medicament is mixed with diluent, binder, a part of disintegrating agent and then, moistened with required quantity of granulating agent to form a coherent mass.


• Formation of coherent mass is a crucial stage, the formation of coherent mass can be confirmed by pressing between thumb and finger, a good coherent mass breaks evenly without sticking to fingers and forming the powder.


• The sticking of coherent mass to wires of mesh shows over moistening while powdering shows less moistening.


• The formed coherent mass is passed through the sieve no. 8 or 10.


• The collected granules are dried at 60° C in a hot air oven.


• Dried granules are passed through sieve no. 20.


• The lubricant, remaining part of the disintegrating agent are added, granules are then ready for compression.

2) Direct compression:

• Processing steps are:  

Raw material →       Weighing → Screening → Mixing → Compression.

• Direct compression consists of compressing tablets directly from powdered materials without modifying physical nature of materials.


• This method is applicable only for crystalline chemicals having good compressible characteristic and flow properties such as Potassium salt (chlorate, chloride, bromide), Sodium chloride, Ammonium chloride, Methenamine etc.


• If necessary, direct compression vehicles can be used which are having good flow and compressible characteristics.


• Commonly used directly compression diluents are MCC (Microcrystalline cellulose (Avicel), lactose, Starch, Sucrose, Dicalcium phosphate, Mannitol for chewable tablets.


• Advantages:


• Low labor inputs.


• A dry process.


• Lesser processing steps


• Disadvantages:


• Stratification may occur due to differences in particle size and bulk density which results poor content uniformity.


• A large dose drug may cause problems in direct compression.


• It requires diluents.


• The tablet becomes large in size which is difficult to swallow and also costly.


• During handling of dry materials static charge may form which may affect uniform distribution of drug.


• Direct compression diluent may interact with the drug. For example, amine drug with Lactose produce discoloration of the tablet.

  3 Dry granulation:

• Processing steps are:

Raw material →         weighing → Screen → Mixing → Slugging →   Milling → Screening → Mixing → Compression

• When tablet ingredients are sensitive to moisture and/or unable to withstand elevated temperature during drying and when the tablet ingredient has insufficient cohesive properties, slugging may be used to form granules.


• This method is referred to as dry granulation.


• This technique is used in preparation of aspirin, aspirin combination, acetophenetidin, thiamine hydrochloride, ascorbic acid, magnesium hydroxide.


• The raw material is first compressed into larger tablets called as "Slugs".


• These slugs are then size reduced to desired size by using Hammer mill.


• The formed granule are finally compressed to get tablets.

Granulation Characteristics

 

• The characteristics of a tablet like compactness, physical and chemical stability, efficacy, rapid production capability depend on the quality of granulation. Granules must possess two characteristics,


• Granules must posses two characteristics, fluidity (ability to flow) and compressibility.


• Good flow properties are essential for the transport of materials through the hopper, feed frame and into dies.


• Tablet materials should be in a physical form that flows smoothly and uniformly.


• The ideal physical form for this purpose is a sphere, which offers minimum contact surface between themselves and with the wall of the machine parts.


• Therefore granulation process improves the flow of powdered materials by forming sphere like aggregates called granules.

Granulation Properties: Following properties should be verified before compression:

• Particle size & shape:


• Particle size of granulation affect the average tablet weight, weight variation, disintegration time, friability, granule flow ability. The methods for determine particle size and size distribution are sieving, and microscopy .


• Surface area: Dissolution of a drug depends on surface area of powder materials or granules. The most common method for determination of surface area is gas


• The most common method for determination of surface area is gas adsorption and air permeability.


• Density: Granule density may influence compressibility, tablet porosity, dissolution and other properties. Generally three types of density arise for granules:
  
  
  
  • True density, Bulk density, Granule density.
  
  
  
  


• True Volume      = Vol. excluding inter & intra granular space


• Bulk Volume      = Vol. including inter & intra granular space


• Granule Volume = Vol. excluding inter granular space but including intra granular space.


• True density can be measured by Mercury, helium displacement method and also using low surface tension liquid like benzene with the help of Pyenometer.


• Bulk density can be measured by taking a known wt. of materials in a graduated measuring cylinder and tapping upto a constant reading.


• Porosity directly related with true density and bulk density.


• Porosity = Total empty space / Bulk volume


• Strength & Friability:


• After formation of granules these are used for tableting.


• Granules are aggregation of component particles that is held together by bonds of infinite strength.


• Measurement of granule strength is estimation of attractive forces seeking to hold the granules together.


• Friability is the ability to formation of fines or fragments.


• Strength can be measure by placing the granules between two anvils (flat face) and force required to break the granules is measured.


• Flow properties: For the movement of granules from hopper to die cavity sufficient flow properties are essential.


• Improper flow cause weight variation of content uniformity. Factors affecting flow properties are:
  
  
  
  • Frictional forces
  
  
  • Surface tension forces
  
  
  • Mechanical forces caused by interlocking of particles of irregular shape
  
  
  • Electrostatic forces
  
  
  • Cohesive or Van der Waals Flow properties of granules can be measure by two methods:
  
  
  
  

• Angle of repose: It is maximum angle between the surface of a pile of powder and horizontal plane, when powders are allowed to flow freely from a certain height.


• It can be measured by fixed funnel and cone method.


• Powder or granulation is allowed to flow through the funnel until the apex of conical pile just touches the tip of the funnel. Measuring the radius (r) and height (h) of pile repose angle can be measured.


• Angle of Repose≤ 30 → Free flowing material Angle of Repose ≥ 40 → Poorly flowing material

• Hopper Flow rate: Granules are allowed to flow from the conical hopper onto a recording balance device and dw/dt is calculated


• Compaction:


• This measure the force applied during compression.


• Tablet presses are instrumented by affixing transducers to measure the forces.


• The signals produced by transducers are converted to digital output by computer.