Tablets

by Tapamoy Chakraborty

A tablet (also known as a pill) is a pharmaceutical oral dosage form (oral solid dosage, or OSD) or solid unit dosage form. Tablets may be defined as the solid unit dosage form of medicament or medicaments with suitable excipients. It comprises a mixture of active substances and excipients, usually in powder form, pressed or compacted from a powder into a solid dose.

Tablets are prepared either by molding or by compression. The excipients can include diluents, binders or granulating agents, glidants (flow aids) and lubricants to ensure efficient tabletting; disintegrants to promote tablet break-up in the digestive tract; sweeteners or flavours to enhance taste; and pigments to make the tablets visually attractive or aid in visual identification of an unknown tablet. A polymer coating is often applied to make the tablet smoother and easier to swallow, to control the release rate of the active ingredient, to make it more resistant to the environment (extending its shelf life), or to enhance the tablet's appearance. Medicinal tablets were originally made in the shape of a disk of whatever color their components determined, but are now made in many shapes and colors to help distinguish different medicines. Tablets are often stamped with symbols, letters, and numbers, which enable them to be identified. Sizes of tablets to be swallowed range from a few millimetres to about a centimetre.

The compressed tablet is the most popular dosage form in use today. About two-thirds of all prescriptions are dispensed as solid dosage forms, and half of these are compressed tablets. A tablet can be formulated to deliver an accurate dosage to a specific site; it is usually taken orally, but can be administered sublingually, buccally, rectally or intravaginally. The tablet is just one of the many forms that an oral drug can take such as syrups, elixirs, suspensions, and emulsions.

Model compounds

The compounds and size fractions were used in the studies: sodium chloride (125-180 µm, 355-500 µm), sodium bicarbonate (raw material, 45-63 µm, 125-180 µm), calcium carbonate (raw material), mannitol (250-425 µm) and dibasic calcium phosphate dihydrate (DCP; 90-180 µm). The different size fractions were obtained by dry sieving (Retsch, Germany). The term compound is used throughout this thesis for materials that are not used as binders.

Binder materials

The binder materials were used in the studies: polyethylene glycol (PEG) 3000, PEG 6000, PEG 10000, PEG 20000, microcrystalline cellulose (MCC), silicified microcrystalline cellulose (SMCC), pregelatinised starch (PGS), polyvinylpyrrolidone (PVP), α-lactose monohydrate (crystalline lactose), partially crystalline lactose and amorphous lactose.

Superdisintegrant

Crosslinked carboxymethyl cellulose sodium (Ac-Di-Sol) was used as superdisintegrant. All powders were stored at 40% relative humidity (RH) (saturated chrome trioxide in water) (Nyqvist, 1983), except partially crystalline and amorphous lactose, which were stored at 0% RH (phosphorus pentoxide), and all were stored at room temperature for at least 48 hours before characterisation, mixing and compaction.

Common excipients used in tablets

Excipient	Function	Examples
Diluents	Provide bulk and enable accurate dosing of potent ingredients	Sugar compounds e.g. lactose, dextrin, glucose, sucrose, sorbitol Inorganic compounds e.g. silicates, calcium and magnesium salts, sodium or potassium chloride
Binders, compression aids, granulating agents	Bind the tablet ingredients together giving form and mechanical strength	Mainly natural or synthetic polymers e.g. starches, sugars, sugar alcohols and cellulose derivatives
Disintegrants	Aid dispersion of the tablet in the gastrointestinal tract, releasing the active ingredient and increasing the surface area for dissolution	Compounds which swell or dissolve in water e.g. starch, cellulose derivatives and alginates, crospovidone
Glidants	Improve the flow of powders during tablet manufacturing by reducing friction and adhesion between particles. Also used as anti-caking agents.	Colloidal anhydrous silicon and other silica compounds
Lubricants	Similar action to glidants, however, they may slow disintegration and dissolution. The properties of glidants and lubricants differ, although some compounds, such as starch and talc, have both actions.	Stearic acid and its salts (e.g. magnesium stearate)
Tablet coatings and films	Protect tablet from the environment (air, light and moisture), increase the mechanical strength, mask taste and smell, aid swallowing, assist in product identification. Can be used to modify release of the active ingredient. May contain flavours and colourings.	Sugar (sucrose) has now been replaced by film coating using natural or synthetic polymers. Polymers that are insoluble in acid, e.g. cellulose acetate phthalate, are used for enteric coatings to delay release of the active ingredient.
Colouring agents	Improve acceptability to patients, aid identification and prevent counterfeiting. Increase stability of light-sensitive drugs.	Mainly synthetic dyes and natural colours. Compounds that are themselves natural pigments of food may also be used.

Common examples of adverse reactions to excipients

Excipient	Function	Caution in practice
Tartrazine	Colouring agent	Reported cases of hypersensitivity, and hyperkinetic activity in children
Aspartame	Sweetener	Caution in patients with phenylketonuria
Benzalkonium chloride	Preservative	Bronchoconstriction (nebuliser solutions) and ocular toxicity (soft contact lens solutions)
Sodium metabisulphite	Antioxidant	Hypersensitivity, including bronchospasm and anaphylaxis, are reported for all sulphites
Propyl gallate	Antioxidant	Contact sensitivity and skin reactions
Lactose	Tablet filler	Caution in patients with galactosaemia, glucose-galactose malabsorption syndrome, or lactase deficiency
Sesame oil	Oil (injections)	Hypersensitivity reactions reported
Lanolin (wool fat)	Emulsifier (topical products)	Skin hypersensitivity reactions, caution in patients with known sensitivity

Diluents: Diluents are fillers used to make up the volume of tablet if tablet is inadequate to produce the volume. Diluents used as disintegrants in dispersible and orally disintegrating tablet.

Example: Lactose, Spray dried lactose, Micro crystalline cellulose (Avicel 101 and 102), Pvpk30 (Pearlitol SD200 and 25C), Sorbitol, Dibasic calcium phosphate dehydrate, Calcium sulphate dehydrate etc.

Binders: Binders are used as binding agent in tablets; it provides cohesive strength to powdered materials. Binders are added in both dry and wet form to form granules.

Example: Gelatin, glucose, Lactose, cellulose derivatives-Methyl cellulose, Ethyl cellulose, Hydroxy propylmethyl cellulose,Hydroxy propyl cellulose, starch, Poly vinyl pyrrolidone (Povidone), Sodium alginate, Carboxymethylcellulose, Acacia etc.

Lubricants: Used to reduce the friction between die wall and tablet, prevent adhesion of tablet to dies and punches. Helps in easy ejection of tablets from die cavity. Classified in to 2 types.

Example: Insoluble- Stearic acid, Magnesium stearate, Calcium stearate, Talc, Paraffin.
Soluble- Sodium lauryl sulphate, Sodium benzoate, PEG 400, 600,8000 etc.

Glidants: Helps in free flowing of granules from hopper to die cavity. Minimize friction between particles.
Example: Colloidal Silicon dioxide (Aerosil), Cornstarch, Talc etc.

Anti-adherents: These are added to prevent adhesion of tablet material to punches and dies.
Example: Talc

Anti-adherent: Prevent sticking of tablet to dies and punches.

Superdisintegrants: When they come in contact with water in oral cavity/GIT break down in to small particles.

Example: Croscarmellose sodium (Ac-di-sol),Crospovidone (Polyplasdone), and Sodium starch glycollate, Starch etc.

List of Diluent

1. Microcrystalline Cellulose [trade name: Avicel 101, 102, 200; Celex, MCC Sanaq],

2. Powdered Cellulose [5–40% for wet granulation and 10–30% for dry granulation]

3. Anhydrous Lactose

4. Lactose Monohydrate

5. Spray-Dried Lactose,

6. Mannitol [preferable for chewable tablet]

7. Starch

8. Pregelatinized Starch

9. Maize Starch

10. Corn Starch

11. Sorbitol

12. Sucrose

13. Compressible Sugar (20–60% for chewable tablets)

14. Confectioner’s Sugar (10–50%)

15. Sugar Spheres

16. Dextrates

17. Dextrin

18. Dextrose

19. Calcium Phosphate, Dibasic, Anhydrous

20. Calcium Carbonate

21. Maltose

22. Maltodextrin

23. Kaolin

24. Calcium Phosphate, Dibasic, Dihydrate

25. Tribasic Calcium Phosphate,

26. Calcium Sulfate

27. Cellaburate

28. Calcium Lactate

29. Cellulose Acetate

30. Silicified Microcrystalline Cellulose,

31. Cellulose Acetate

32. Corn Syrup

33. Pregelatinized Starch and Corn Starch

34. Corn Syrup Solids

35. Erythritol (30.0–90.0%)

36. Ethylcellulose (1.0–3.0%)

37. Ethyl Acrylate and Methyl Methacrylate Copolymer Dispersion

38. Fructose

39. Isomalt

40. Alpha-Lactalbumin

41. Lactitol

42. Magnesium Carbonate (direct compression ≤45)

43. Magnesium Oxide

44. Methacrylic Acid and Ethyl Acrylate Copolymer

45. Methacrylic Acid and Methyl Methacrylate Copolymer

46. Polydextrose

47. Sodium Chloride (Capsule diluent 10–80%)

48. Simethicone

49. Pregelatinized Modified Starch

50. Starch, Pea

51. Hydroxypropyl Pea Starch

52. Starch, Pregelatinized Hydroxypropyl Pea

53. Potato Starch

54. Starch, Hydroxypropyl Potato

55. Pregelatinized Hydroxypropyl Potato Starch,

56. Starch, Tapioca

57. Wheat Starch

58. Starch Hydrolysate, Hydrogenated

59. Pullulan

60. Talc (Tablet and capsule diluent 5.0–30.0%)

61. Amino Methacrylate Copolymer

62. Trehalose

63. Xylitol

List of Binder used

1. Polyvinylpyrrolidone is also known as Povidone, [grade: Povidone K-15, K-30, K-60, K-90 (trade name: Kollidon®)]

2. Copovidone (2.0 – 5.0 % in direct compression and 2.0 – 5.0% in wet granulation)

3. Carbomer (0.75 – 3.0%)

4. Corn Starch and Pregelatinized Starch (Commercially known as STARCH 1500)

5. Pregelatinised starch (5-10%)

6. Carboxymethylcellulose Sodium, Carmellose Sodium (1.0–6.0%)

7. Hypromellose/ hydroxypropyl methylcellulose (HPMC), Methocel (2-5%)

8. PEG (Polyethylene Glycol)

9. Hydroxyethyl Cellulose

10. Hydroxypropyl Cellulose (2.0 – 6.0%)

11. Hydroxyethylmethyl Cellulose

12. Calcium carboxymethylcellulose/ Calcium cellulose glycolate /Carmellosum calcium (5-15%)

13. Guar Galactomannan/ Guar Gum (up to 10.0%)

14. Ethylcellulose

15. Chitosan Hydrochloride

16. Dextrin

17. Low-Substituted Hydroxypropyl Cellulose

18. Hydroxypropyl Starch

19. Ceratonia (0.15 – 0.75 %)

20. Inulin

21. Magnesium Aluminum Silicate (2.0 – 10.0%)

22. Maltodextrin (2–40% for direct compression and 3–10% for wet granulation)

23. Methylcellulose (1.0–5.0%)

24. Dextrates

25. Polyethylene Oxide (5.0 – 85.0%)

26. Povidone (0.5 – 5.0%)

27. Sodium Alginate (1.0 – 3.0%)

28. Starch (3–20% w/w usually 5–10%)

29. Liquid Glucose (5.0 – 10.0%)

30. Sucrose (2–20% dry granulation and 50–67% wet granulation)

31. Compressible sugar (5–20% as a dry binder in tablet formulations)

32. Zein (30% for wet granulation)

33. Gelatin (1–3% for wet mix)

34. Polymethacrylates (10–35 % for dry mix and 15–35 % as a solution and 4.5–10.5% w/w solids)

35. Sorbitol (2–10% for wet mix)

36. Glucose (2–25% for wet mix)

37. Sodium alginate (1–3% for wet mix)

38. Zein

39. Acacia (1.0 – 5.0%)

List of Disintegrants used

1. Crospovidone (commercial name- Kollidon CL) (2–5%)

2. Croscarmellose Sodium (Commercial name Ac-Di-Sol, Primellose) (10–25% in capsules and 0.5–5.0% in tablets) Croscarmellose sodium at concentrations up to 5% w/w may be used as a tablet disintegrant. 2% w/w is used in direct compressed tablets and 3% w/w in wet-granulation processed tablets.)

3. Low-Substituted Hydroxypropyl Cellulose

4. Sodium Starch Glycolate (Commercial name Primogel, Explotab) (2-8%, Optimum concentration is about 4%, although 2% is sufficient in many cases).

5. Chitosan Hydrochloride

6. Corn Starch and Pregelatinized Starch

7. Calcium Alginate & Calcium Sodium Alginate (<10%)

8. Docusate Sodium (≈ 0.5%)

9. Microcrystalline Cellulose (5–15%)

10. Hydroxypropyl Starch

11. Magnesium Aluminum Silicate (2-10%)

12. Methylcellulose (2.0–10.0%)

13. Sodium Alginate (2.5–10%)

14. Starch (3–25% w/w)

15. Pregelatinised Starch (5–10%)

16. Calcium carboxymethylcellulose / calcium cellulose glycolate / carmellosum calcium (1–15%)

17. Powdered Cellulose (5–20%)

List of lubricants used

1. Magnesium stearate

2. Magnesium silicate

3. Calcium stearate

4. Sodium Lauryl Sulphate

5. Sodium Stearyl Fumarate

6. Magnesium Lauryl Sulphate

7. Stearic Acid

8. Calcium Stearate

9. Glyceryl Behenate

10. Behenoyl Polyoxylglycerides

11. Glyceryl Dibehenate

12. Lauric Acid

13. Glyceryl Monostearate

14. Glyceryl Tristearate

15. Myristic Acid

16. Palmitic Acid

17. Poloxamer

18. Polyethylene Glycol

19. Polyethylene Glycol 3350

20. Polysorbate 20

21. Polyoxyl 10 Oleyl Ether

22. Polyoxyl 15 Hydroxystearate

23. Polysorbate 40

24. Polyoxyl 20 Cetostearyl Ether

25. Polyoxyl 40 Stearate

26. Polysorbate 60

27. Polysorbate 80

28. Potassium Benzoate

29. Sodium Benzoate

30. Sorbitan Monolaurate

31. Sorbitan Monooleate

32. Sodium Stearate

33. Sorbitan Monopalmitate

34. Sorbitan Monostearate

35. Zinc Stearate

36. Sorbitan Sesquioleate

37. Sorbitan Trioleate

38. Talc

List of glidant used

1. Colloidal Silicon Dioxide (trade name: Aerosil 200/ Cab-o-sil)

2. Talc

3. Tribasic Calcium Phosphate

4. Calcium Silicate

5. Cellulose, Powdered

6. Magnesium Oxide

7. Sodium Stearate

8. Magnesium Silicate

9. Silica, Dental-Type

10. Magnesium Trisilicate

11. Hydrophobic Colloidal Silica

List of coloring agents used

1. Caramel

2. Ferric Oxide

3. Titanium Dioxide

4. Ferrosoferric Oxide

5. Aluminum Oxide

6. FD & C Red #40 /Allura Red AC

7. Amaranth

8. FD & C Blue #1 /Brilliant Blue FCF

9. Canthaxanthin

10. Carmine

11. Carmoisine (Azorubine)

12. Curcumin (Tumeric)

13. FD & C Red #3 /Erythrosine

14. Fast Green FCF

15. Green S (Lissamine Green)

16. D & C Red #30 /Helendon Pink

17. FD & C Blue #2 /Indigo Carmine

18. Iron Oxide Black

19. Iron Oxide Red

20. D & C Red #7 / Lithol Rubin BK

21. Patent Blue V

22. D & C Red #28 / Phloxine B

23. Iron Oxide Yellow

24. D & C Red #27 / Phloxine O

25. Ponceau 4R (Cochineal Red A)

26. Quinoline Yellow WS

27. D & C Yellow #10

28. Riboflavin (Lactoflavin)

29. FD & C Yellow #5 /Tartrazine

30. FD & C Yellow #6 / Sunset Yellow FCF

List of Flavoring agent used

1. Vanillin

2. Peppermint flavor powder

3. Berry flavor powder

4. Strawberry flavor powder

5. Orange flavor powder

6. Lemon flavor powder

7. Orange essence

8. Ethyl Maltol (It has a flavor and odor 4–6 times as intense as maltol)

9. Eucalyptus Oil

10. Isobutyl Alcohol

11. Sodium Succinate

12. Adipic Acid

13. Almond Oil

14. Anethole

15. Benzaldehyde

16. Denatonium Benzoate

17. Ethyl Acetate

18. Ethyl Vanillin

19. Ethylcellulose

20. Fructose

21. Fumaric Acid

22. l-Glutamic Acid, Hydrochloride

23. Lactitol

24. Leucine

25. Malic Acid

26. Maltol

27. Menthol / Racementhol (Tablets 0.2–0.4%)

28. Methionine

29. Methyl Salicylate

30. Monosodium Glutamate

31. Peppermint Oil

32. Strawberry flavor, liquid

33. Peppermint Spirit

34. Racemethionine

35. Rose Oil

36. Rose Water, Stronger

37. Sodium Acetate

38. Sodium Lactate Solution

39. Tartaric Acid

40. Thymol

41. Fumaric Acid

42. Inulin

43. Isomalt

44. Neohesperidin Dihydrochalcone

List of sweetening agent used

1. Sucralose

2. Saccharin Sodium

3. Neotame

4. Sucrose

5. Acesulfame Potassium

6. Aspartame

7. Aspartame Acesulfame

8. Corn Syrup

9. Corn Syrup Solids

10. Dextrates

11. Dextrose

12. Dextrose Excipient

13. Erythritol

14. Fructose

15. Galactose

16. Glucose

17. Glycerin

18. Inulin

19. Invert Sugar

20. Isomalt

21. Lactitol

22. Maltitol

23. Maltose

24. Mannitol

25. Saccharin

26. Saccharin Calcium

27. Sorbitol

28. Starch Hydrolysate, Hydrogenated

29. Sugar, Compressible

30. Sugar, Confectioner’s

31. Tagatose

32. Trehalose

33. Xylitol

Surfactant used

1. Behenoyl Polyoxylglycerides

2. Polysorbate 20

3. Polysorbate 40

4. Docusate Sodium

5. Polysorbate 60

6. Polysorbate 80

7. Benzalkonium Chloride

8. Caprylocaproyl Polyoxylglycerides

9. Cetylpyridinium Chloride

10. Lauroyl Polyoxylglycerides

11. Linoleoyl Polyoxylglycerides

12. Octoxynol 9

13. Oleoyl Polyoxylglycerides

14. Poloxamer

15. Polyoxyl 10 Oleyl Ether

16. Polyoxyl 15 Hydroxystearate

17. Nonoxynol 9

18. Polyoxyl 20 Cetostearyl Ether

19. Polyoxyl 40 Stearate

20. Pullulan

21. Polyoxyl Lauryl Ether

22. Polyoxyl Stearyl Ether

23. Sodium Lauryl Sulfate

24. Sorbitan Monolaurate

25. Sorbitan Monooleate

26. Polyoxyl Stearate

27. Sorbitan Monopalmitate

28. Sorbitan Monostearate

29. Stearoyl Polyoxylglycerides

30. Sorbitan Sesquioleate

31. Sorbitan Trioleate

32. Tyloxapol

List of Release-Modifying Agents used

1. Carbomer Copolymer

2. Shellac

3. Carbomer Homopolymer

4. Hypromellose

5. Carbomer Interpolymer

6. Carboxymethylcellulose Sodium

7. Carrageenan

8. Cellaburate

9. Ethylcellulose

10. Glyceryl Monooleate

11. Starch, Pregelatinized Modified

12. Glyceryl Monostearate

13. Guar Gum

14. Hydroxypropyl Betadex

15. Hydroxypropyl Cellulose

16. Polyethylene Oxide

17. Polyvinyl Acetate Dispersion

18. Sodium Alginate

19. Starch, Pregelatinized

20. Xanthan Gum

21. Alginic Acid

List of Coating materials

List of Preservatives materials

Preservative	Class	Concentration in preparations (in %)
Preservative	Class	Oral	Parenterals	Opthalmic/ Nasal	Ointments and creams
Methyl Paraben	Amino aryl acid esters	0.25	0.01-0.5	0.1	0.001-0.2
Ethyl Paraben		0.1-0.25	0.01-0.5	0.1	0.001-0.2
Propyl Paraben		0.5-0.25	0.005-0.02	0.1	0.001-0.2
Butyl Paraben		0.1-0.4	0.015	0.1	0.001-0.2
Benzyl Alcohol	Alkyl/ aryl alcohols	3.0	0.5-10
Chlorobutanol	Alkyl/ aryl alcohols	0.5	0.25-0.5	0.5	0.5
Phenol	Phenols	0.1-0.5	0.065-0.02		0.25-0.5
Meta cresol		0.15-0.3	0.1-0.25		0.1-0.3
Chloro cresol		0.2	0.1-0.18		0.1-0.3
Benzoic acid	Alkyl/aryl acids	0.1-0.2
Sorbic acid	Alkyl/aryl acids	0.1-0.2
Thiomersal	Organic mercurials	0.1	0.01	0.01	0.01
Phenylmercuric nitrate	Organic mercurials	0.002-0.1	0.002	0.004	0.002
Bronopol	Diols	0.01-0.1
Propylene Glycol	Diols	15-30
Benzylkonium Chloride	Quatenary Ammonium Compounds	0.002-0.02	0.01	0.004-0.02	0.01
Benzethonium Chloride	Quatenary Ammonium Compounds	0.01-0.02	0.01	0.004-0.01	0.01

Area required for manufacture of tablets

Tablet Manufacturing Equipment/ Machines

Common equipment used in pharmaceutical tablet manufacturing include:

1. Size reduction equipment/ communition equipment e.g., hammer mill, vibration mill, roller mill, pin mill, fluidized energy mill, end-runner mill, edge-runner mill, cutter mill and ball mill.

2. Weighing balance/ balances e.g., bulk weighing balance (weighs in kilogram), electronic weighing balance (weighs in grams and milligrams).

3. Mixing equipment e.g., pneumatic mixers (air-mix mixer or air-driven mixer), diffusion/ tumbling mixers (e.g., V-blender, double cone blender, cubic mixer, drum blender), convective mixers (e.g., ribbon blenders, orbiting screw mixers, horizontal high-intensity blenders, planetary blenders, diffusion mixer with intensifier bar/agitator, Forberg blenders, horizontal double arm mixers, vertical high-intensity mixer).

4. Granulators e.g., rotating shape granulators, mechanical agitator granulators (e.g., ribbon or paddle blender, sigma blade mixer, planetary mixer, orbiting screw mixers), high-shear granulator, fluidized bed granulator, dry granulator etc.

5. Dying equipment e.g., spray dryer, rotary dryer, fluidized bed dryer etc.

6. Tabletting machine – single punch tablet press and multi-station/ rotary tablet press (e.g., High-speed rotary tablet machines and multi-layer rotary tablet machines).

7. Quality control equipment e.g., disintegration equipment (Manesty single unit disintegrating apparatus or Erweka multiple unit disintegrating apparatus), USP Dissolution Tester, Tablet Hardness Tester, Tablet Thickness Tester, Tablet Friability Testers etc.

8. Coating and polishing machines for coated tablets e.g., standard coating pan, perforated pan, fluidized bed/ Air suspension coating system etc.

9. Packaging machines e.g., blister packaging machines, strip packing machine, aluminium foil packaging machine, etc.

Tablet Manufacturing Equipment continues to improve in both production speed and uniformity of the tablets compressed.

Steps Involved In Tablet Formulation/ Procedure for Manufacturing Tablets

1. Dispensing: Each ingredient in the tablet formula is weighed and accurately dispensed as per dose. This is one of the critical steps in any type of formulation process and should be done under technical supervision.

2. Sizing: Formulation ingredients must be in finely divided form, otherwise, size reduction should be carried out for better flow property and easy mixing.

3. Powder blending: Powders are mixed using a suitable blender to obtain a uniform and homogeneous powder mix. The drug substance and excipients are mixed in geometric dilution.

4. Granulation: Here small powder particles are gathered together into layers, and permanent aggregates to render them into free-flowing states.

5. Drying and dry screening: Screened wet granules need to be dried for a particular time period in tray dry or fluid bed dryer at controlled temperature not exceeding 55⁰C. Dried granules are screened through the appropriate mesh screen.

6. Tablet compression: This step involves the compression of granules into a flat or convex, round, oblong, or unique shaped, scored or unscored tablets; engraved with an identifying symbol and/ or code number using tablet press.

7. Coating: Tablets and granules are coated if there is need to mask the unpleasant taste/odour of some drug substance or to increase the aesthetic appeal of uncoated tablets as well as to modify the release or control the release of drug substance from tablets. This is achieved by enclosing or covering the core tablet or granules with coating solutions.

Some of the steps above are skipped depending on the manufacturing process used during tablet formulation.

Techniques/ Methods Used in Tablet Formulation

Tablets are commonly manufactured by

1. Wet granulation

2. Dry granulation or

3. Direct compression.

One important requirement is that the drug mixture flows freely from the hopper of the tabletting machine into the dies to enable high-speed compression of the powder mix into tablets.

Flowchart of wet granulation process

A stepwise summary of the manufacturing steps used in the manufacture of tablets by the wet granulation method are listed below.

1. Weighing, milling and mixing of the APIs with powdered excipients (excluding the lubricant)

2. Preparation of binder solution

3. Mixing of binder solution with powders to form a damp mass

4. Screening the dampened powder into pellets or granules (wet screening) using 6- to 12-mesh screen

5. Drying of moist granules

6. Sizing the granulation by dry screening using 14- to 20-mesh screen

7. Mixing of the dried granules with lubricant and disintegrants

8. Compression of granules into tablets.

Tablets manufactured by wet granulation exhibit sufficient mechanical properties to be subsequently exposed to other unit operations, e.g. film coating.

Manufacture of tablets by dry granulation method

The formation of granules by compacting powder mixtures into large pieces or compacts which are subsequently broken down or sized into granules (often referred to as dry granulation, double compression or pre-compression) is a possible granulation method which, however, is not widely used in the manufacture of tablets. This method is used when tablet excipients have sufficient inherent binding properties. The procedure can also be used as a means to avoid exposure of drug substances to elevated temperatures (during drying) or moisture. Double compression method eliminates a number of steps but still includes weighing, mixing, slugging, dry screening, lubrication, and compression of granules into tablets. Compaction for the dry granulation process is generally achieved either by slugging or roller compaction.

Slugging

In this method, the powder mix is compressed into a soft large flat tablet (about 1 inch in diameter) using a tablet press that is capable of applying high stress. Following this, the slugs are broken by hand or milled using conventional milling equipment to produce granules of the required size. Lubricant is added in the usual manner, and the granules then compressed into tablets. Aspirin is a good example of where slugging is satisfactory. Other materials, such as aspirin combinations, acetaminophen, thiamine hydrochloride, ascorbic acid, magnesium hydroxide, and other antacid compounds, may be treated similarly.

Roller Compaction

Results similar to those accomplished by the slugging process are also obtained with powder compactors. In roller compaction method, the formulation ingredients are mixed and are passed between high-pressure (oppositely) rotating rollers that compress the powder at 1 to 6 tons of pressure. The compacted material is then milled to a uniform granule size and compressed into tablets after the addition of a lubricant. The roller compaction method is often preferred to slugging. Excessive pressures that may be required to obtain cohesion of certain materials may result in a prolonged dissolution rate.

Flowchart of dry granulation process

A stepwise summary of the manufacturing steps used in the manufacture of tablets by the dry granulation method are listed below.

1. Weighing and Milling of formulation ingredients (drug substance and excipients)

2. Mixing of milled powders.

3. Compression of mixed powders into slugs.

4. Milling and sieving of slugs.

5. Mixing with disintegrant and lubricant.

6. Compression into tablets.

Manufacture of tablets by direct compression method

As its name implies, direct compression involves direct compression of powdered materials into tablets without modifying the physical nature of the materials itself. The technology involved in this method assumes great importance in the tablet formulations, because it is often the cheapest means, particularly in the production of generics that the active substance permits. Direct compression avoids many of the problems associated with wet and dry granulations. Its successful application in tablet formulation rests on two fundamental issues:

1. The availability of suitable excipients

2. The availability of suitable machinery.

Flowchart of direct compression process

A stepwise summary of the manufacturing steps used in the manufacture of tablets by the dry granulation method are listed below.

1. Milling of therapeutic agent and excipients

2. Mixing of milled powders, disintegrants and lubricants

3. Compression into tablets.

It is worth noting that tablets produced by direct compression are often softer than their counterparts that have been produced by wet granulation and therefore they may be difficult to film-coat.

Comparison of various steps used in different methods of tablet manufacturing processes

Tablets defects/ special problem in compressing tablet process

· Weight variation (granule size and size distribution)

· Poor mixing

· Poor flow

· Capping and lamination

· Picking of tablets

· Chipping and splitting

· Sticking

· Embossing/print defect

· Layered tablet splitting/layer not clearly defined

· Low hardness/ low mechanical strength of tablets/ soft tablets

· Variable hardness/ hardness variation

· Mottling

· Punch variation

· Double impression

· Presence of hairs/fibre on tablet surface

· Black spot/stain

Types of Tablets

Tablets are classified according to their route of administration or function. The following are the 5 main classification groups.

1. Tablets ingested orally

1.1. Compressed tablets
1.2. Multiple compressed tablets

i) Multilayered tablets

ii) Inlay tablets
1.3. Sustained action tablets
1.4. Enteric coated tablets
1.5. Sugar coated tablets
1.6. Film coated tablets
1.7. Chewable tablets

2. Tablets used in the oral cavity

2.1. Buccal tablets
2.2. Sublingual tablets
2.3. Lozenge tablets and torches
2.4. Dental cones

3. Tablets administered by other routes
3.1. Implantation tablets
3.2. Vaginal tablets

4. Tablets used to prepare solutions
4.1. Effervescent tablets

5. Molded tablets or tablet triturates (TT)
5.1. Dispensing tablets (DT)
5.2. Hypodermic tablets (HT)

* Compressed tablets^1,2,3:
These tablets are uncoated and made by compression of granules. These tablets are usually intended to provide rapid disintegration and drug release. These tablets after swallowing get disintegrated in the stomach, and its drug contents are absorbed in the gastrointestinal tract and distribute in the whole body.

* Multiple compressed tablets^2,3:
These tablets are prepared to separate physically or chemically incompatible ingredients or to produce repeat action prolonged action products. To avoid incompatibility, the ingredients of the formulation except the incompatible materials are compressed into a tablet then incompatible substances along with necessary excipients are compressed tablet.

* Multilayered tablets³:
These tablets consist of two or more layer of materials compressed successively in the same tablets. The color of each layer may be the same or different. The tablets having layers of different colors are known as "multicolored tablets".

* Inlay Tablet^3,4:
A type of layered tablet in which instead the core tablet being completely surrounded by coating, top surface is completely exposed. While preparation, only the bottom of the die cavity is filled with coating material and core is placed upon it. When compression force is applied, some coating material is displaced to form the sides and compress the whole tablet. It has some advantages over compression coated tablets:
i) Less coating material is required.
ii) Core is visible, so coreless tablets can be easily detected.
iii) Reduction in coating forms a thinner tablet and thus freedom from capping of top coating.

* Sustained action tablets^4,5:
These tablets are used to get a sustained action of medicament. These tablets when taken orally release the medicament in a sufficient quantity as and when required maintaining the maximum effective concentration of the drug in the blood throughout the period of treatment.

* Enteric-coated tablets^4,5:
These are compressed tablets meant for administration by swallowing and are designed to bypass the stomach and get disintegrated in the intestine only. These tablets are coated with enteric coated polymer to have release within the intestine.eg: tablets containing anthelmentics and amoebicides.

* Immediate release tablets^2,3,5:
The mechanisms for release of drug from modified-release dosage forms are more complex and variable than those associated with immediate release dosage forms. According to BCS (Bio pharmaceutics classification system), there are three major factors that govern the rate and extent of drug absorption of immediate release (IR) solid oral dosage forms: dissolution rate, solubility and intestinal permeability. For IR dosage forms containing active pharmaceutical ingredients (APIs) showing high solubility, high intestinal permeability and rapid dissolution, a waiver from performing bioequivalence studies (bio waiver) can be scientifically justified.

Tablet Ingredients⁴ :
In addition to active ingredients, tablet contains a number of inert material known as additives or excipients. Different excipients are:⁴

*    Diluents
* Binder and adhesive
*    Disintegrants
*    Lubricants and glidants
*    Colouring agents
*    Flavouring agents
*    Sweetening agents

Excipients present in a formulation must meet certain criteria; few such criteria are listed below.
* They must be nontoxic & acceptable by all countries.
* They must be physiologically inert.
* Cost must be low.
* They must be physically & chemically stable.
* They must be free from any unacceptable microbiological load.
* They must be colour compatible.

Quality Control Tests for Tablets

Tablets are solid drug delivery system prepared by compressing a single dose of one or more active drug substance(s) with some additives/ pharmaceutical excipients. They may be circular, oblong, oval, triangular or cylindrical in shape and flat-, round-, concave- or convex-faced with straight or bevelled edges.

In tablet formulation development and during manufacturing of tablet dosage forms, a number of quality control tests are performed to ensure that tablets produced meet the requirements as specified in official compendium and conventional requirements established by the industries over the years. These tests can be grouped into two broad categories namely:

1. Pharmacopoeial or Official tests

2. Non-pharmacopoeial or Non-official tests

Pharmacopoeial or Official tests

They are called official tests because the test methods are described in official compendia such as the British Pharmacopoeia, American Pharmacopoeias etc. They are standardized test procedures which have clearly stated limits under which compressed tablets could be accepted. These tests include:

1. Content of Active Ingredient/ Absolute drug content test

2. Uniformity of Weight

3. Uniformity of Content

4. Disintegration time test

5. Dissolution test

These tests are traditionally concerned with the content and the in vitro release of the active ingredient. It must be emphasized that what is presented here should by no means replace what are presented on each of the tests in official compendia.

Content of Active Ingredient

This is determined from a sample of 20 tablets which should be randomly selected from a batch of tablets. The tablets are weighed together and are crushed in a mortar with a pestle.

An amount equivalent to the theoretical content of each tablet or the average of the crushed tablets is weighed out in an analytical balance. The weighed powder is dispersed in a solvent in which the active drug is freely soluble or in a solvent prescribed in the individual drug monograph.

This is filtered and an aliquot of the resultant filtrate is subjected to the stipulated assay procedures. The assay procedures are usually given in the individual drug monograph.

Analysis of the active drug is usually carried out using spectrophotometry or High-Performance Liquid Chromatography (HPLC). The formulation scientist must be familiar with Beer-Lambert’s law. This could be found in relevant analytical textbooks.

Uniformity of Weight/ Weight variation test

The test for uniformity of weight is performed by weighing individually 20 tablets randomly selected from a tablet batch and determining their individual weights. The individual weights are compared with the average weight.

The sample complies with USP standard if no more than 2 tablets are outside the percentage limit and if no tablet differs by more than 2 times the percentage limit.

Coated tablets are exempted from these requirements but must conform to the test for content uniformity.

Uniformity of Content

Content uniformity test was developed to ensure content consistency of active drug substances within a narrow range around the label claim in dosage units. This test is crucial for tablets having a drug content of less than 2 mg or when the active ingredient comprises less than 2% of the total tablet weight.

By the USP method, 30 tablets are randomly selected, 10 of these tablets are assayed individually according to the method described in the individual monograph. Unless otherwise stated in the monograph, the requirements for content uniformity are met if the amount of active ingredient in nine (9) of the ten (10) tablets lies within the range of 85% to 115% of the label claim. The tenth tablet may not contain less than 75% or more than 125% of the labelled drug content.

If one or more dosage units do not meet these criteria, the remaining 20 tablets are assayed individually and none may fall outside of the 85% to 115% range for the batch to be accepted.

Various factors are responsible for the variable content uniformity in tablets. This may include:

i. Tablet weight variation.

ii. Uneven distribution of the drug in the powder or granules

iii. Segregation of the powder mixture or granulation during formulation processes

Disintegration Time Test

For tablets, the first important step towards drug dissolution is breakdown of the tablets into granules or primary powder particles, a process known as disintegration. All USP tablets must pass a test for disintegration, which is conducted in vitro using a disintegration test apparatus.

The apparatus consists of a basket-rack assembly containing six open-ended transparent tubes of USP-specified dimensions, held vertically upon a 10-mesh stainless steel wire screen.

During testing, a tablet is placed in each of the six tubes of the basket, and through the use of a mechanical device, the basket is raised and lowered in a bath of fluid (e.g. water, or as prescribed in the individual drug monograph) at 29 to 32 cycles per minute, the wire screen always below the level of the fluid. For most normal release tablets, the time permitted is 15 minutes.

Tablets are said to have disintegrated if no fragments (other than fragments of coating) remains on the screen, or if particles remain, they are soft without an unwetted core. Chewable tablets are not required to comply with the test.

Research has established that one should not automatically expect a correlation between disintegration and dissolution. However, since the dissolution of drug from the fragmented tablet appears to control partially or completely the appearance the drug in the systemic circulation, disintegration is still used as a guide by the formulator in the preparation of an optimum tablet formula and as an in-process control test to ensure batch to batch uniformity.

Factors affecting disintegration of tablets include:

i. Medium used

ii. Temperature of the test media

iii. Operator’s experience

iv. Nature of the drug

v. The diluent used in the formulation

vi. The type and concentration binder used

vii. Type and amount of disintegrant used including method of incorporation.

viii. The presence of excessive lubricants and overly mixed lubricants

ix. Compressional force used.

Dissolution Test

This test measures the amount of time required for a given percentage of the drug substance in a tablet to go into solution under a specified set of conditions. It is intended to provide a step toward the evaluation of the physiological availability of the drug substances.

In vitro dissolution test is performed using a variety of equipment/apparatus. The British Pharmacopoeia recommends three types of apparatus – the rotating basket, the rotating paddle and the flow-through cell. The static-basket magnetic stirrer assembly can also be used for this test.

The rotating paddle method is generally more discriminatory than the basket method. The flow-through cell method is very useful particularly for

a. Poorly soluble active constituents (can use large volume to achieve sink conditions)

b. Enteric-coated products (can easily change between different pH fluids)

c. Modified release products.

d. The dissolution medium for each drug is available in the individual drug monograph. For basic drugs, acidic media are used (e.g. 0.1 M hydrochloric acid) while alkaline media are used for acidic drugs (e.g. alkaline buffers). For drugs with non-ionizing molecules, water is recommended.

e. Dissolution rate test is performed at 37 ± 1 ^oC. Samples are removed from the dissolution chamber at periodic intervals and analyzed for drug content using a spectrophotometer. Dissolution samples removed for assay should be filtered to remove particles of drugs present, and to exclude tablet excipients that might otherwise interfere with the assay. Non-absorbent filter papers are recommended.

f. Most commonly, the results of dissolution tests are expressed in terms of the time required to release some percentage of labelled amount of drug from the dosage form. This approach is reported to be particularly useful for quality control purposes once the dissolution characteristics of a drug and dosage form are well understood.

For tablet dosage form design purposes, and for critical product comparison, however, the time required for substantially complete 80 to 90% release or amount released versus time profiles are the most desired approach.

While in vitro dissolution experiment may not correlate perfectly with in vivo bioavailability, the concept of dissolution efficiency proposed by Kahn and Rhodes could be employed to assess the most probable in vivo performance of a tablet formulation.

Dissolution test is not designed to measure the efficacy or safety of the tablet being tested. Both the effectiveness and safety of a specific dosage form must be demonstrated, initially, by means of appropriate in vivo studies and clinical evaluation.

Various factors can affect the dissolution of a drug; they are classified under three categories as follows:

1. Physiochemical properties of the drug

a. Polymorphic form: A metastable form of a solid has higher solubility and dissolution compared to its stable counterpart.

b. Particle size: The smaller the particle size of a solid, the larger the particle surface area and the higher the dissolution.

c. Salt form: A salt form of a drug has a higher aqueous solubility compared to its conjugate acid or base, as well as higher dissolution.

d. Hydrates versus anhydrates: The anhydrous form shows higher dissolution than hydrates due to their solubility differences.

2. Factors related to tablet manufacturing

a. The amount and type of binder can affect the hardness, disintegration, and dissolution of tablets.

b. The method of granulation, granule size, and size distribution can affect tablet dissolution.

c. The concentration and type of disintegrants used, as well as the method of their addition, can affect disintegration and dissolution.

d. Compression load can influence density, porosity, hardness, disintegration, and dissolution of tablets.

3. Factors related to method of dissolution study

a. Composition of the dissolution medium, pH, ionic strength, viscosity.

b. Type of dissolution equipment.

c. Temperature of the medium

d. Volume of dissolution medium

e. Intensity of agitation

f. Sink or nonsink conditions (under a sink condition, the concentration of the drug should not exceed 10 – 15 % of its maximum solubility in the dissolution medium in use).

g. Sensitivity of analytical method used to determine drug concentration in the release medium.

Non-Pharmacopoeial or Non-Official Tests

These are tests that are performed on tablets and which are not listed in official compendia and concern a variety of quality attributes that need to be evaluated, such as the porosity of tablets, hardness or crushing strength test, friability test, tensile strength determination, thickness test etc.

Some of these tests have no officially set limits for acceptance or rejection and thus may vary from manufacturer to manufacturer and from formulation to formulation.

Tablet Hardness or Crushing Strength Test

This measures the degree of force (in kilograms, pounds, or in arbitrary units) needed to fracture a tablet. Besides the concentration of binders used and the compression force, the hardness of a tablet depends on

i. The characteristics of the granules to be compressed e.g., hardness and deformation under load.

ii. The type and concentration of lubricant used and

iii. The space between the upper and lower punches at the time of compression.

The crushing strength of tablets is usually checked using Monsanto or Stokes hardness tester, Strong-Cobb hardness tester and the Pfizer crushing strength tester. All are manually used. So, strain rate depends on the operator.

Currently, electrically driven hardness testers such as those manufactured by SOTAX, Key, Van Kel, Erweka, Dr Schleuniger Pharmatron etc., are widely used to measure crushing strength of tablets.

These equipment eliminate the operator variability encountered with manual hardness testers. Newer equipment with printers are also available.

A force of about 4 kg is considered the minimum requirement for a satisfactory tablet. Measurement is usually carried out using a minimum of ten tablets.

It has been found that a linear relationship exists between crushing strength and the logarithm of compressional force, except at high forces.

The strength of a cylindrical flat-faced tablet can be expressed as a tensile strength (T_s). This can be calculated as follows:

Where F is the force needed to fracture a cylindrical flat-faced tablet of thickness t along its diameter D.

Friability Test

This measures the resistance of tablets or granules to abrasion or fracture. The idea behind this test is to mimic the kind of forces, caused by phenomena such as collisions and sliding of tablets towards each other, which a tablet is subjected to during coating, packaging, handling, and shipping.

A minimum of 20 tablets are dedusted, weighed and subjected to a uniform tumbling motion for a specified time. They are then dedusted and reweighed.

The measure of abrasion/ friability loss is usually expressed as percentage loss in weight. It is calculated from the equation:

The test is rejected if any tablet caps, laminates or breaks up in course of the test. As a rule of thumb, a maximum weight loss of not more than 1% generally is considered acceptable for most pharmaceutical products. Values of up to 2% or above have been reported in direct compression formulations.

The friability of tablets may be influenced by moisture content. Chewable tablets show a high friability weight loss compared to conventional compressed tablets. A number of instruments are available for friability tests but the most popular and most reliable is the Roche Friabilator.

Tablet Thickness

Tablet thickness is determined by the diameter of the die, the amount of fill permitted to enter the die cavity, the compaction characteristics of the fill material, and the force or pressure applied during compression. To manufacture tablets of uniform thickness during and between batch productions for the same formulation, care must be exercised to employ the same factors of fill, die, and pressure.

The degree of pressure affects not only thickness but also hardness of the tablet; hardness is perhaps the more important criterion since it can affect disintegration and dissolution. Thus, for tablets of uniform thickness and hardness, it is doubly important to control pressure. Tablet thickness also becomes an important characteristic in packing operations and in counting of tablets using filling equipment which uses the uniform thickness of the tablets as a counting mechanism.

https://www.researchgate.net/publication/360156539_Tablets_preparation_Excipients_and_Tests#fullTextFileContent

pHarmaVa