TABLETS- Coated & uncoated tablet, various modified release tablets

A detailed study on tablets, , definition, advantages, disadvantages, excipients, method of preparation, types, method of preparation, defects of coated and uncoated tablets, quality control test for tablet, various modified tablets clasfication with brief introduction, examples, advantage and disadvantages

1. TABLETS By: Ms. Ashiya Najfath Assistant Professor PA College of Pharmacy

2. DEFINITION Tablets are the solid dosage form containing medicament or medicaments, usually circular in shape and may be flat or biconvex. Tablets are prepared by the compression method and are hence called the ‘Compressed Tablets’.

3. ADVANTAGES OF TABLETS: The tablets are easy to be administered. They are easy to be dispensed. These are more stable dosage form. They maintain the accuracy of dosage. Bitter and nauseous substances can be given easily in tablet form after giving a suitable coating to the tablets. They are the lightest and the most compact of all dosage forms.

4. 7. Of all the dosage form, tablets are easiest and the cheapest as regard packing and transport. 8. They are better suited to a large scale production as compared with any other unit oral dosage form. 9. These are an economical dosage form. 10. They have longer expiry period due to lower moisture content. 11. They are more temper proof in comparison to capsule.

5. DISADVANTAGES OF TABLETS: Some drugs resist compression into tablet form due to their amorphous nature or low density character. Bitter tasting drugs, drugs with objectionable odour or drugs that the sensitive to oxygen or atmospheric moisture may require encapsulation or a special type of coating which may increase the cost of the finished tablets. Drugs with poor wetting and slow dissolution properties are difficult to convert into tablets which provide full drug bioavailability. The tablets cannot be used in case of emergency cases, because the rate at which active ingredient reaches the site to be treated slow. Bioavailability of some drugs may be low due to poor absorption from the gastric tract.

6. MANUFACTURING OF COMPRESSED TABLETS Steps involved are: Preparation of granules for compression Weighing the ingredients Mixing – powdered ingredients + excipients Converting the mixed ingredients into granules Compression of granules into tablets Coating Quality control

7. EXCIPIENTS Diluents The diluent is needed in the formulation of a tablet, when the quantity of medicament in each tablet is very small and it is not possible to make a good tablet. The commonly used diluents are lactose, sucrose, sodium chloride, dextrose and starch, mannitol, sorbitol . 2. Granulating agents These are used to convent the fine powder into granules. A granulating agent provided proper moisture to convert fine powder into damp mass, which after passing through a sieve of suitable number forms granules. The various granulating agents used are water, alcohol, mucilage of starch, mucilage of acacia, mucilage of tragacanth , gelatin solution, iso -propyl alcohol, acetone etc.

8. 3. Binding agents These are used in granulation to provide proper strength to the granules, in order to keep the tablet intact after compression. The various binding agents used are gum acacia powder, gum tragacanth , gelatin, sucrose, methyl cellulose etc. 4. Disintegrating agents The substances which are added in the tablet formulation to ensure disintegrating of the tablets into smaller particles when swallowed are called Disintegrating Agents. Ex: potato starch methyl cellulose, bentonite 5. Lubricants These are added to improve the appearance tablets, flow properties of granules and to prevent the sticking of the materials to the dies and punches. e.g. talc, magnesium stearate and calcium stearate

9. 6. Adsorbents These substances are used to adsorb volatile nil, liquid extract and tincture etc. which are included in the formulation of tablets. The commonly used adsorbents are magnesium carbonate, kaolin and starch. 7. Colouring agents, Flavouring agents and Sweetening agents. Colours of approved, certified F.D. and C dyes are used. The colours are used to improve the elegance of the tablet. Flavouring agent is dissolved in organic solvent and the solution is sprayed on the granules. Sweetening agents are used to improve the taste of tablets.

10. Preparation of granules: Granulation is a technique of particle enlargement by agglomeration. It is one of most significant unit operations in the production of tablets. During this process, small fine or coarse particles are converted into large agglomerates called granules. Generally , granulation begins after initial dry mixing of the powder ingredients along with the drug so that a uniform distribution of each ingredient throughout the powder mixture is achieved. Granules prepared in the making tablets have particle size in the range or 0.2-4.0 mm. G ranulation is categorized into two types, namely, dry granulation and wet granulation. Granulation technologies like roller compaction, spray drying, supercritical fluid, low/high shear mixing, extrusion/ spheronization and fluid bed granulation have been used for preparation of various tablets.

11. 1. Wet granulation

12. 2. Dry granulation

13. Compression of granules into tablets Single punch tablet machine Multipunch tablet machine Rotary tablet machine Dry cota machine

14. Single punch tablet machine It consists of the following major parts: Hopper shoe: T o supply the granules to the die and remove the tablet after its compression. Lower punch Upper punch Capacity regulator: To accommodate the required quantity of granule by the die. Ejection regulator: To adjust the position of lower punch, so that its highest position is at par with surface of the die. die

15. Manufacturing defects in tablets Capping: Partial or complete removal of top or bottom portion of the tablet Picking and sticking: In picking material is removed or picked up by the upper punch from the upper surface of the tablet. In sticking , material sticks to the wall of the die. Mottling: Unequal distribution of colour on the surface of colored tablets. Weight variation Hardness variation Double impression

16. Coating It is done by the following process: Pan coating Press coating

17. COATED TABLETS: Tablet coating is a process of applying film of materials on the surface of pharmaceutical tablets to achieve special benefits . The amount of coating on the surface of a tablet is critical to the effectiveness of the oral dosage form. Tablets are usually coated in horizontal rotating pans with the coating solution sprayed onto the free surface of the tablet bed. When a coating solution is applied to a batch of tablets, the surfaces of the tablets get covered with a tacky polymeric film. The tablets are then allowed to dry using suitable means and the film eventually forms a non-sticky dry surface. Tablet coating is relatively costly process. It is tedious and time-consuming process that requires the expertise of highly skilled technician.

18. The objectives of tablet coating include: I mproving aesthetic quality by incorporating special colours M ask the disagreeable odour , colour or taste O ffer product stability through physical/chemical protection control and sustain the release of the drug incorporate two or more incompatible drugs protect an acid-labile drug from the gastric environment increase mechanical strength of tablets. Types of machines used to coat tablets: standard coating pan perforated coating pan fluidized bed coater.

19. Types of Coated Tablets: Sugar coated tablets: A sugar-coated tablet is coated with sugar to disguise the taste. Sugar coating offers a sweet coat mainly made from polysaccharides and sucrose – to mask bitter taste. It also offers a sweet aroma especially on foul smelling pills like fish supplements. Examples: Hyoscine butylbromide Sugar Coated Tablet (Sanofi), Ibuprofen Sugar Coated Tablet (Bristol), Premarin 0.625 mg Sugar Coated Tablet (Pfizer), etc.

20. Method: Sugar coating is done by the pan coating method . It is one of the oldest arts to mask the unpleasant flavours and tastes of medicaments, but nowadays sugar coating of tablets is done for improving its aesthetic value. The various stages in the sugar coating process are: Sieving Sealing Subcoating Syrup coating Finishing Polishing

21. Sieving: The tablets to be coated are shaken in a suitable sieve to remove the fine powder or broken pieces of tablets. Sealing: Sealing is done to ensure that a thin layer of water proof materials , such as, shellac or cellulose acid phthalate is deposited on the surface of the tablets. The shellac or cellulose acid phthalate is dissolved in alcohol or acetone and its several coats are given in a coating pan. A coating pan is made of copper or stainless steel . The pan is rotated with the help of an electric motor . There is an arrangement of hot air to be supplied inside the coating pan. The speed of the pan is adjusted in such a way that the tablets remain separated from each in the pan. Nowadays it is possible to do the sealing of tablets by fluidised bed coating or by spraying techniques.

22. Subcoating In subcoating several coats of sugar and other materials , such as , gelatin, acacia etc. are given to round off tablets and to help in building up the tablet size. After each addition of the syrup, dusting powder ( mixture of starch, talc and powdered acacia ) is sprinkled. The dusting powder does not allow the tablets to stick together. The alternative addition of syrup and dusting powder is repeated until a coating of the required thickness is produced . Towards the end of the process, warm syrup without dusting powde r is used to obtain a smooth surface . Syrup coating This is done to give sugar coats, opacity and colour to the tablets. Colouring materials and opacifying agents are also added to the syrup. The process of coating is repeated until uniform coloured tablets are obtained.

23. Finishing Three to four coats of syrup are applied in rapid succession without dusting powder and cold air is circulated to dry each coat. T his forms a hard smooth coat. Polishing Beeswax is dissolved in volatile organic solvent and a few coats of it are given. The finished tablets are transferred to a polishing pan which is made of canvas cloth. The polishing pan is rotated at a suitable speed so that the wax coated tablets are rubbed on the canvas cloth. This gives a proper shining to the tablets.

24. Film coated tablets A film-coated tablet is covered with a thin layer of resins, polymers and/or plasticizers capable of forming a film. The coating gives aesthetic look and improves the taste of the pill . Spraying is used to create an even film around a tablet. Examples: Metformin Film Coated Tablet ( Wockhardt ), Atenolol Film Coated Tablet ( Teva ), Atorvastatin Film Coated Tablet ( Milpharm ), etc . Enteric coated tablets It is designed to temporarily withstand attack by stomach acid , so that it does not dissolve in the stomach but allows release of the medication in the intestine . Enteric coating provides a gastric acid resistant coat for the tablets that have ingredients sensitive to stomach acid . If a drug from tablet is to be absorbed in the small intestine, there is a need for the tablet to withstand gastric acid and reach the targeted area in the lower part of GIT where there is no acidity and is absorbed slowly. Examples : Omeprazole Magnesium Enteric-Coated Tablet (Glow Sun India), Aspirin Enteric-Coated Tablet ( Teva ), etc.

25. Gelatin coated tablets Gelatin-coated tablets are compressed tablets coated with either one or two-toned colour gelatin. Gelatin is a natural binding, coating and disintegration agent used to create the gel cap, a capsule-shaped tablet as the outer covering. It produces a tablet rich in protein with lustrous appearance and a pleasant mouth feel. Examples: Famtac Gelatin Coated Tablet (Abbott Healthcare), GlucosaFamotidine Gelatin Coated Tablet (Universal Drug), etc. Compression coated tablets Compression coated tablet covers bitter or unpleasant substance and mottled appearance, or provide a barrier for a substance irritating to the stomach or one inactivated by gastric juice. Most drugs that are compression-coated contain two materials separated into two parts. The outer coat is typically a water-soluble sugar compound that dissolves after swallowing. The internal core usually contains an enteric coating that allows for a second drug to release during a later digestive stage . Examples: Sumatriptan Succinate Tablet (Glaxo), Glipizide Tablet (Care Formulation Lab ), etc.

26. Coating process 3 requiremnets : Tablet quality : Tough enough, must be consistent in porosity and hardness as well as must be free of dust. Construction of coater: Comprises of a coating pan, a spraying system, an air handling unit, a dust collector, and the controls. Coating operation: Involves loading batch of dedusted and preheated tablets into the coating pan, spraying coating solution and its distribution and drying.

27. Defects in tablet coating Blistering: L ocal detachment of film from the substrate Cratering : It is defect of film coating whereby volcanic-like craters appears on the tablet which in turn results in the exposure of the tablet's surface. Picking: I solated areas of film are pulled away from the surface when the tablet sticks together or when part of the film sticks to the pan Pitting: It is defect whereby pits (deformation) occur in the surface of a tablet core without any visible signs of disruption of the film coating. Blooming : It is defect where coating becomes dull immediately or after prolonged storage at high temperatures. Blushing : It is haziness or appearance of white specks in the tablet film.

28. 7. Colour variation : It involves variation in colour of the tablet film within a batch. 8. Infilling: It is defect that renders the intagliations indistinctness 9. Orange peel: It is surface defect resulting in the film being rough and matt. 10 . Cracking/Splitting: It is defect in which the film either cracks across the crown of the tablet or splits around the edges of the tablet. 11. Bridging: It occurs when the coating fills in the lettering or logo on the tablet surface. 12 . Scuffing: Scuffing involves the generation of gray-to-black marks on the surface of white (or lightly coloured ) film-coated tablets. 13 . Twinning: This twinning is used when two or more tablets stick together.

29. UNCOATED TABLETS The main objective of the tablet formulation design is to deliver orally correct amount of drug in the proper form over proper time and at desired location, so as to have suitable chemical integrity protected at the point of its action. The physical design and complete chemical makeup of the tablet can have a profound effect on the efficiency of the drug being administered. In general, the, usually in powder form. tablet =mixture of drug(s) + excipients A tablet is usually a composed of 5-10% of the drug , 80% of fillers, disintegrants , lubricants, glidants , and binders; and other compounds which ensure easy disintegration, disaggregation, and dissolution of the tablet in the stomach or the intestine.

30. EXAMPLE OF UNCOATED TABLET FORMULATION Acetylsalicylic Acid (ASA) is a non-steroidal anti-inflammatory drug that inhibits platelet aggregation. Procedure: All ingredients except PRU® are blended for 15 minutes. PRU ® is added and the powder mixture is mixed for another 3 minutes. Now the powder mixture is ready for direct compression. Equipment used is tablet press and turbula mixer, tablet diameter is 25 mm with biplane shape. The instruments used for quality control testing include tablet hardness tester, friability tester, disintegration test apparatus, dissolution test apparatus and spectrophotometer

31. Quality control of tablets Shape of tablets. A ppearance Content of active ingredient in tablets Uniformity of weight Disintegration test for tablets Dissolution test for tablets Mechanical strength Friability test

32. Shape of tablets: In the pharmacopoeia the shape of a tablet is defined as circular with flat or convex faces. 2. Appearance: Uncoated tablets: When a broken section is examined under a lens, either a relatively uniform texture (single-layer tablets) or a stratified structure (multi-layer tablets) is seen. There should be no signs of coating. Coated tablets: Have a smooth and often colored surface.

33. 3. Content of active ingredient in tablets: The amount of active ingredient in tablet is determined by doing the assay as stated in the monograph. Generally 20 tablets or such other number as may be indicated in the monograph are used in the assay . Where 20 tablets cannot be obtained, a smaller number, which must not be less than 5, may be used.

34. 4. Uniformity of weight It is desirable that every individual tablet in a batch should be uniform in weight , but small variation may occur. Weigh 20 tablets selected at random and determine their average weight . Not more than 2 of the individual weights may deviate from the average weight by more than the percentage deviation given in the Table 14-3 and none should deviate by more than twice that percentage . 5. Uniformity of content Percentage of medicament is calculated by doing assay for a particular drug, the method of which is given in the pharmacopoeia against its monograph .

35. 6. Disintegration test for tablet Disintegration of a tablet means to break the tablet into smaller particles after swallowing. The time required to disintegrate the tablet is called ‘‘Disintegration Time’’. The rate of disintegration depends upon the type of the tablet . In general, Pharmacopoeia prescribed a limited of 15 mts. for most of the tablets, unless otherwise indicated in the monograph. The disintegration test apparatus as per I.P. specification is used and it consists of: A rigid basket-rack assembly supporting six cylindrical glass tubes. These tubes are held vertically by two superimposed transparent plastic plates with six holes having the same diameter as the tubes

36. The upper and lower plates are held in position by vertical metal rods at the periphery and a metal rod in the centre of the upper plate for attachment to a mechanical device. The assembly should be raised and lowered between 28 to 32 times per minute in the liquid at 37°C. The tablets are kept immersed in the liquid within the tubes by means of cylindrical guides discs. The assembly is suspended in the liquid medium in a 1000 ml beaker. The beaker may be filled in such a way that the wire mesh at the highest point is at least 25 mm below the surface of the liquid and its lowest point is at least 25 mm above the bottom of the beaker. A separate method is used for each type of tablet .

37. 7. Dissolution test The test is done for measuring the amount of time required for a given percentage of the drug substance in a tablet to go into solution under specified condition in vitro. Method: Place 1000 ml of water which should be free from dissolved air and previously warmed to 36.5° to 37.5° C into the vessel. Place the specified number of tablets in the dry basket. Set the apparatus. Start the motor and adjust the rotation speed to 100 rpm or as directed in the monograph. Withdraw the stated volume of solution from the vessel after 45 minutes or after the time specified in the monograph. Filter and determine the amount of active ingredient present in it by the method given in the monograph.

38. Repeat the complete operation 4 times. The tablets pass the test if for each of the five tablets, the amount of active ingredient in solution is not less than 70 per cent of the stated amount. No re-testing is allowed.

39. 8. Mechanical strength The Pharmacopoeia has not fixed any standard for the mechanical strength or hardness of tablets. The following devices are commonly used by manufacturers to find out the mechanical strength of tablets: a. Monsanto hardness tester b. Pfizer tablet hardness tester

40. 9. Friability test Normally during the course of compression of tablets a sufficient pressure is applied on the granules, so that the tablets can withstand the wear and tear during transportation and handling. Friability test is performed to evaluate the ability of the tablet to withstand wear and tear in packing, handling and transporting. The apparatus used to perform this test is known as " Friabilator ".

41. The apparatus consists of a plastic chamber, which is divided into two parts and it revolves at a speed of 25 r.p.m . Twenty tablets are weighed and placed in the plastic chamber. The chamber is rotated for 4 minutes or 100 revolutions. During each revolution the tablet falls from a distance of 6 inch. The tablets are removed for the chamber after 100 revolutions and weighed . Loss in weight indicates the friability . The tablets are considered to be of good quality if the loss in weight is less than 0.8%.

42. VARIOUS MODIFIED TABLETS: The term modified tablet is used to describe products that alter the timing and/or the rate of release of the drug. Modified tablets are designed to release their medication in controlled manner, at pre-determined rate, duration and location in the body to achieve and maintain optimum therapeutic blood levels of drug. These dosage forms have been developed to deliver drug to the part of the body where it will be absorbed, to simplify dosing schedules, and to assure that concentration of drug is maintained over an appropriate time interval. ADVANTAGES: L ess frequent administration M ore reproducible dispersion throughout the gastrointestinal tract R eduction in drug release variations Improved bioavailability.

43. a. Sustained Release Tablets: Sustained drug release systems include any drug delivery system that achieves slow release of drug over an extended period of time . Sustained release tablet is unit solid dosage form through which drug is administered to a patient at a given rate to maintain a certain concentration of the administered drug over a specific time period into the patient’s body while reducing possible side effects . These tablets provide actual therapeutic control that would be temporal (time related), spatial (site related) or both. The performance of a drug administered as a sustained release tablets depends upon its release from the formulation and movement within the body during its passage to the site of action. It can either release part of drug (loading dose) immediately or in small amounts (maintenance dose) after administration.

44. Advantages: i . Reduced drug concentration fluctuations in the body ii. Reduction in drug dose iii. Improved patient compliance iv. Safety of drugs Limitations: i . Chance of dose dumping ii. High cost of production iii. Difficulty in dose retrieval iv. Need for additional patient education v. Reduced potential for accurate dose adjustment.

45. The desired biopharmaceutical properties of a drug to be used in sustained release tablets includes- molecular weight, aqueous solubility, apparent partition coefficient, pKa and ionization at physiological pH, stability and route of administration. The formulation strategies for oral sustained release tablets includes- Diffusion sustained release, Dissolution sustained release, pH dependent system, Altered density system, Osmotic pump system and Ion exchange system. Examples: Acebrophylline Sustained Release Tablet ( Jantec ), Paracetamol Sustained Release Tablets (Aspire Remedies Pvt Ltd.), Indapamide Sustained Release Tablets IP (Care Formulations Lab), etc.

46. b. Extended-Release Tablets: Extended-release (ER) tablet is a dosage form that allows at least a two-fold reduction in dosing frequency as compared to an immediate release (conventional) tablet. They also differ from immediate release tablets which release content within few minutes of ingestion. ER tablets slowly release drug into the body over a period of time, usually 12 hours and are only taken once or twice a day. ER tablets may also known as controlled release (CR), sustained release (SR), time release (TR), long acting (LA), extra time (XT), extra long (XL), delayed release (DR), enteric coated (EC), modified release (MR), sustained action (SA) and continuous control (CC).

47. Advantages : L ess frequent dosing F ewer side effects L ess fluctuations in blood levels C omplete absorption, potential to improved patient compliance and convenience I ncreased stability I mproved bioavailability Disadvantages: Slower onset of action and comparatively high cost. ER tablets may show side effects that may remain for a much longer period of time. The higher drug load in these tablets may cause loss of integrity of the release characteristics. The size of ER tablet may cause difficulties in ingestion or transit through gut. The drug release rates are affected by presence of food in GIT. Sometimes the target tissue is exposed to constant amount of drug over extended period resulting in drug tolerance.

48. ER tablets should be taken as prescribed and should not be crushed, splited or chewed . Results in an overdose if crushed or chewed . Air or moisture can change the effectiveness of ER tablets, so it is important to store them in sealed bottles and in a dry place . Altering the original form of an ER tablets can make it less effective. Examples : Divalproex Sodium Extended Release Tablet ( Synko Healthcare Limited), Carvedilol Phosphate Extended Release Tablet (Ace Kinetics), Ranolazine Extended Release Tablet (Taj Generics), Venlafaxine Extended Release Tablet (Talent Health care).

49. c. Fast Dissolving Tablets: Fast dissolving tablets (FDT) are solid dosage forms designed to dissolve in saliva remarkably faster , within a few seconds (usually less than 60 sec.), and those are real fast dissolving tablets. FDTs disintegrate rapidly in saliva without the need to take water and are commonly used for the pediatric and geriatric patients who have difficulties such as fear of choking while swallowing them with water or have difficulties in chewing them. FDTs can also be known as orally disintegrating or dispersible tablets (ODTs), mouth melting tablets (MMTs) or mouth dissolving tablets (MDTs), immediate release (IR) tablets. Mouth dissolving tablets are formulated by use of super disintegrants like Croscarmellose sodium, sodium starch glycolate and crospovidone or by maximizing pore structure of the tablets by freeze drying and vacuum drying.

50. Advantages : No need of water to swallow tablet E asy administration to pediatric, elderly and mentally disabled patients A ccurate dosing F aster dissolution and absorption of the drug offering rapid onset of action, I ncreased bioavailability R educed first pass metabolism I mproved safety Disadvantages : I ts mechanical strength. highly porous, soft molded metrics or compressed with low compressional pressure, are friable and brittle which make them difficult to handle . Bad taste/ odour drugs are difficult to formulate as FDT. Several of the FDT are hygroscopic and thus cannot maintain its physical integrity under normal humidity condition and thus requires specialized package. Dryness of the mouth due to decreased saliva production may hamper dissolution, rate of absorption from the saliva solution and overall bioavailability.

51. The bioavailability of some drugs may be increased by formulating them as FDT due to absorption of drugs in oral cavity and also due to pregastric absorption of saliva containing dispersed drugs that pass down into the stomach. Moreover, the amount of drug that is subjected to first pass metabolism is reduced as compared to conventional tablets. Techniques used for production include freeze drying, tablet moulding , and spray drying, sublimation, direct compression and mass extrusion . Examples : Piroxicam Fast Dissolving Tablet (Pfizer), Rizatriptan Fast Dissolving Tablet (Merck and Co), Ondensetron (Glaxo Wellcome ), Rofecoxib Fast Dissolving Tablet (Torrent), Montelukast (Ranbaxy),

52. d. Double Layered Tablets: Double-layer tablets (DLT), often called Bilayer tablets , are controlled (gradual) release formulations that have a combination of two or more drugs in a single tablet. DLT technology separates two incompatible drugs in which one layer is immediate release as a loading dose , and the second layer is controlled/sustained release as a maintenance dose. Two incompatible drugs can also be formulated into a bilayer tablet by adding an inert intermediate layer . These tablets make it easier for patients , because they can reduce the number of daily doses required , to simplify dosage regimens. In DLT, compressing separate layers of each drug minimizes the area of contact between two layers . An additional intermediate layer of inert material may also be included to ensure the layers don't make contact .

53. Advantages : D ose precision and the least content variability. They are lighter and compact E asiest and cheapest to package and strip E asy to swallow with least tendency for hang-up, can mask objectionable odour and bitter taste and are suitable for large scale production. It has greatest chemical and microbial stability. Disadvantages : DLT manufacturing is more expensive than single-layer tableting such as high tablet press costs, slow operation in bilayer mode and more time spent on formulation development, analysis, and validation. L ayer separation I nsufficient hardness I naccurate individual layer weight control cross contamination between the layers

54. DLTs are prepared by single-sided tablet press, double-sided tablet press and bilayer tablet press with displacement monitoring. Examples: Glimipride & Metformin Hydrochloride (SR) Bilayer Tablets ( Angiolife Healthcare), Diclofenac Potassium Paracetamol Double Layer Tablet ( Angiolife Healthcare), Tramadol, Acetaminophen Bilayer Tablet (Taj Pharma), Amlodipine Besilate Metoprolol Succinate Bilayer Tablets, etc.