Tablets

TAblets: Types, Formulation, Manufacturing and Evaluation

1. T ABLE T S NARESH GORANTLA M.Pharm .., ( Ph.D ) Asso . Professor, Balaji college of Pharmacy, Ananthapuramu

2. INT R ODUCTION Tablet is defined as a compressed 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 drug or a mixture of drugs, with or without diluents.

3. advantages : They are unit dosage form and offer the greatest capabilities of all oral dosage form for the 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. Sustained release product is possible by enteric coating.

4. Objectionable odour and bitter taste can be masked by coating technique. 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.

5. Disadvantages : Difficult to swallow in case of children and U nconscious patients. Some drugs resist compression into dense compacts, owing to amorphous nature, low density character. Drugs with poor wetting, slow dissolution properties, optimum absorption high in GIT 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.

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

7. Tablets administered by other route: Implantation tablet Vaginal tablet, e.g. Clotrimazole tablet (D) Tablets used to prepare solution: 1. Effervescent tablet, e.g. Disprin tablet ( A spirin) 2. Dispensing tablet, e.g. Enzyme tablet (Digiplex) Hypodermic tablet Tablet triturates e.g. Enzyme tablet (Digiplex)

8. FORMULATION OF Tablet s 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 Colouring agents Flavoring agents Sweetening agents

9. EXCIEPIENTS- functions Impart weight, accuracy, & volume(its allow accuracy of dose) Improve solubility Increase stability Enhance bioavailability Modifying drug release Assist product identification Increase patient acceptability Facilitate dosage form design

10. 1. Diluent: 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 h a v e manu f act ur i n g o r t o p r omo t e fl o w . A dilue n t should following properties: They must be non toxic They must be commercially available in acceptable grade There cost must be low They must be physiologically inert They must be physically & chemically stable by themselves & in combination with the drugs. They must be free from all microbial contamination. They do not alter the bioavailability of drug. They must be color compatible.

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

12. 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, Hydroxy propyl methyl cellulose, Hydroxy propyl cellulose Gelatin- 10-20% solution Glucose- 50% solution Polyvinylpyrrolidone (PVP)- 2% conc. Starch paste-10-20% solution Sodium alginate Sorbitol

13. 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

14. Superdisintegrants: Swells up to ten fold within 30 seconds when contact water. Example: Crosscarmellose- cross-linked Crosspovidone- cross-linked povidone (polymer), cellu l o s e, Sod i um s t a r ch gl yc ol a t e - c r o s s- lin k ed st a r ch. The s e c r os s - lin k ed p r oduct s s w ells with i n 3 se c ond s when in c o n t a ct w i th water. A portion of disintegrant is added before granulation and a portion before compression, which serve as glidants or lubricant .

15. 4. Lubricant and Glidants: Lubricants are intended to prevent adhesion of the tablet materials to the surface of dies and punches, reduce inter particle friction and may improve the rate of flow of the tablet granulation. 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.

16. 5. Coloring agent: The use of colors and dyes in a tablet has three purposes: Masking of off color drugs Product Identification 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

17. Flavoring agents: For chewable tablet- flavor oil are used 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.

18. The following steps are involved in the manufacturing of Tablets : Weighing of the ingredients. Mixing the powdered ingredients and excipients. Converting the mixed ingredients into granules . Compression of granules to prepare tablets. Manufacturing of tablets

19. Granules are aggregations of fine particles of powders in a mass of about spherical shape.

20. To prevent segregation of the constituents of the powder m ix . To improve the flow properties of the mix. To improve the compression characteristics of the mix. To reduce caking of hygroscopic materials on storage. As granules are denser than the parent powder mix, occupy less volume per unit weight. Easy for storage . Why we prepare granules when we have powders.?

21. Granulation to Prevent Segregation

22. Some of the available methods in the industrial field for the preparation of granules: Dry Granulation Wet granulation 3. Direct compression Methods of Granulation

23. GRANULATION methods

24. Dry Granulation Dry granulation methods, powder particles are aggregated under high pressure. The dry granulation process is use to form granules without using liquid solution because the product to be granulated may be sensitive to moisture and heat. Two method are used for dry granulation . Slugging Roller compaction

25. 1 . SLUGGING The powders is forced into the dies of a large capacity tablet press and is compacted by means flat and faced punches , the compacted mass is called Slugs and the process is called to as a Slugging. The resulting slugs are milled to yield granules.

26. 2. ROLLER COMPACTION This method is used for dry granulation on large scale on a specially designed machine called roller compactor. In this method powders is compressed in a roller compactor forming a sheet or large pieces that are broken down into a tablet granulation.

27. ROLLER COMPACTORS

28. Wet granulation Wet granulation involves the massing of a mix of dry primary powder particles using a granulating fluid. The fluid contain a solvent which must be volatile so that it can be removed by drying. Typically liquid include water, ethanol or isopropanol either alone or in combination. primary advantages of water are that: it is non-flammable, which means that expensive safety precautions not be taken.

29. Method of wet granulation Mixing :-The first stage in the wet granulation process is often a dry mixing stage in which the active component is mixed with a diluents. The purpose of the mixing stage is to ensure that the powder blend and hence the resulting tablets are homogeneous in content. Granulation :- Granulation is a unit operation in which mixed powders are simultaneously mixed with a suitable fluid, e.g. water, isopropanol or ethanol.

30. DRYING :- After the process of granulation, the product exists as a wet mass from which the liquid must be removed. Water is usually removed by evaporation for which energy is needed. SEIVING :- When the drying process is complete, it is likely that the product will have cohered into relatively large masses, especially if tray drying has been used. The dried material is therefore passed through a sieve (usually 250– 700 mm) to break up aggregates and to give a relatively uniformly sized granules.

31. MIXING OF ADDITIVES :- A second mixing stage now follows in which several important ingredients of the formulation are added. Glidant :- To increase flow of material during manufacturing processes Lubricant :- To avoid sticking with wall of dyes. Disintegrating agent:- To disintegrate in GIT tract.

32. Stages in tablet formation "Compaction cycle“ 1- Die filling. 2- Tablet formation. 3- Tablet ejection.

33. 1- Die filling: Flow of powders (or granules) of the drug and excipients from a hopper into the die. The die is closed at its lower end by the lower punch. 2- Tablet formation: The upper punch descends powder and enters the die and the powder is compressed until a tablet is formed. Lower punch may be stationary or moving upward in the die. After maximum applied force is reached, the upper punch leaves the die by moving upward. 3- Tablet ejection: The lower punch rises up until its tip reaches the die top. The tablet is subsequently removed by a pushing device.

34. Compression machines The various type of machines used for this purpose, are: Single punch tablet machine which may be hand operated or electrically operated Multi-punch tablet machine Rotary tablet machine Dry cota tablet machine

35. SINGLE PUNCH TABLET MACHINE Hopper shoe Lower punch Upper punch Capacity regulator : To adjust the position of lower punch to accommodate the required qty. of granules by the die. Ejection regulator Die Driving wheel

36. MULTI-PUNCH TABLET MACHINE In a multi-punch tablet machine there are 2 to 12 dies on a big platform. The working of this machine similar to that of a single punch machine but in this machine one stroke as many tablets are compressed .

37. ROTARY TABLET MACHINE It is used in large scale production unit . In this machine 1200 tablets are prepared in one minute . There are 70 sets of dies & punches . A rotary tablet machine has a circular rotating head, carrying a number of punch & dies assembles. There is uniform filling of the die . In that compression of granules takes place as the upper & the lower punches pass between a pair of rollers.

38. DRYCOTA TABLET MACHINE Th e ma c hine i s use d f or manuf a cturi n g o f mu l ti - compressed, multi-coloured & press coated tablets. In this machine two rotary machines work simultaneously. Th e c o r e table t i s p r epa r ed i n o n e machi n e w hich is transferred to the second machine for compress coating.

39. Working of compression machines Machines built to compress tablets consist of: 1- Hopper: for holding granulations for compressing. 2- Feed frame: for distributing the materials into the dies. 3- Dies: for controlling the size and the shape of the tablet. 4- Punches: for compressing the granulations within the dies. 5- Cam tracks for guiding the movement of the punches.

40. Compression cycle Granules from hopper empty in the feed frame (A) containing several interconnected compartments. These compartments spread the granulation over a wide area to provide time for the dies (B) to fill . 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)

41. 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 a chute into a receptacle At the same time, the lower punches re-enter the pull down cam (C) and the cycle is repeated

42. Official tests: Size and shape and appearance of tablet. Content of active ingredient. Uniformity of weight/weight variation test Disintegration . Dissolution . Unofficial tests: Hardness test. Friability EVALUATION OF TABLETs

43. 1 .GENERAL APPEARANCE : The general appearance of a tablet is essential for consumer acceptance. it involves: Size & Shape : Tablet thickness should be controlled within a ± 5% variation of standard value. Unique identification marking: These markings include company name or symbol, product code, product name etc. Organoleptic properties: Color distribution must be uniform in comparison with the color of the standard.

44. weigh randomly 20 tablets individually in a batch. Determine the average weight of 20 tablets. Compare individual tablet weight to average weight 2.WEIGHT VARIATION TEST: As per I.P. , If the tablet weight is, < 80mg , % deviation allowed up to 10% 80-250mg , % deviation allowed up to 7.5% > 250mg , % deviation allowed up to 5% If any of the tablet deviates, another 10 tablets are selected from the same batch and the procedure is repeated. Of 30 tablets , not more than 1 tablet should deviate.

45. It is used to ensure that every tablet contains the amount of drug substance intended with little variation. Procedure: 10 tablets are assayed, 9 tablets should have % limit of 85-115%. If more than 1 tablet deviates from 85-115%, Another 20 tablets are assayed Not more than 1 tablet should have the % limit of 75-125% 3.Content uniformity test:

46. 4 .Disintegration test: Disintegration is the breakdown of tablet crust into finely divided particulate matter or into granules once the tablet is exposed to the gastric fluids . Type of tablets Time Of disintegration uncoated conventional tablets 15min sugar coated tablets 60 min . film coated tablets 30 min

47. For Uncoated tablets: Start the disintegration test on 6 tablets, if one or two tablets from the 6 tablets fail to disintegrate completely within 30min, repeat the same test on another 12 tablet. N LT 16 tablets should disintegrate completely within the time and if more than two tablets (from the 18) fail to disintegrate, the batch must be rejected. For Coated tablets: Put the tablet in the apparatus in water or 0.1 N HCl for 30min at 37 o C (according to the U.S.P). So 16 tablets from the 18 must completely disintegrate within the time. If two or more tablets do not disintegrate within the time the batch is rejected. For Enteric coated tablets: Put in simulated gastric fluid for two hours (emptying time) Put in phosphate buffer (PH 6.8) for one hour. If one or two tablets fail to disintegrate repeat on 12 tablets. So 16 tablets should disintegrate. If more than two tablets fail to disintegrate, reject the batch.

48. 5 . Dissolution Test (U.S.P.): It is the solubilization of the drug or active moiety in to the dissolution media. Different types of dissolution apparatus: Apparatus -I-Rotating Basket type. Apparatus -II- Rotating Paddle type. Apparatus-3-Reciprocating cylindrical type. Apparatus-4-Flow through cell. Apparatus-5-Paddle over disk. Apparatus-6-Cylindrical apparatus. Apparatus-7-Reciprocating disc apparatus .

49. Method: Place 1000 ml of water into the vessel. Place the specified number of tablets in the dry basket and set the apparatus. Start the motor and adjust the temperature and rotation speed to 36.5◦c to 37.5◦c and 100 rpm or as given in monograph. Withdraw the sample after specified time intervals. Filter and determine the amount of active ingredient present in it by the method given in the monograph. Acceptance criteria: S1= 6 tablets are taken Acceptable: If all of the tablets are not less than Q ±5% If S1 fails, S2=S1+6 tablets are taken Acceptable: If average of 12 tablets is ≥Q and no tablet is less than Q-15% If S2 fails, S3= 12+12 tablets are taken Average of 24 ≥ Q% not more than 2 tablets should be less than Q-15% and None should be less than Q-25%

50. It is defined as the force required to break a tablet in a diametric compression . Tablet requires a certain amount of strength or hardness and resistance to friability to withstand mechanical shocks of handling in manufacture, packaging and shipping Types of hardness testers used. Monsanto hardness tester . Strong cob tester. Pfizer tester. For, Conventional tablets hardness : 2.5- 5 kg/cm 2 Dispersible/ chewable tablets hardness: 2.25- 2.5 kg/cm 2 Extended release tablets hardness : 5- 7.5 kg/cm 2 6 . Hardness test:

51. The instrument used is Roche friabilator. It consists of a drum having 280-290mm diameter with a thickness of 30mm. A drum is mounted on a horizontal axis of a drive motor. Drum is operated at a speed of 25rpm . & Allowed revolutions for each tablet is 100. Allowable range: loss 0.5 - 1% weight 7 . Friability test:

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