Tablets

It is a solid unit dosage from of medicament is administered orally.

1. TABLETS Mr. Sagar Kishor Savale [Department of Pharmaceutics] [email protected] 2015 - 016 Department of Pharmacy (Pharmaceutics) | Sagar savale 1 10/07/2016 Sagar Kishor Savale

2. INTRODUCTION 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. 2 10/07/2016 Sagar Kishor Savale

3. Definition according to the BP Tablets are dosage forms that are circular in shape with either flat or convex faces and prepared by compressing the medicament or mixture of medicaments usually with added substances Tablets are now the most popular dosage form ( 70% of all ethical pharmaceutical preparations produced) 3 10/07/2016 Sagar Kishor Savale

4. 4 10/07/2016 Sagar Kishor Savale

5. Tableting machine Click to figure video was started 5 10/07/2016 Sagar Kishor Savale

6. Click to figure video was started 6 10/07/2016 Sagar Kishor Savale

7. The Advantages of the Tablet dosage form 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. 7 10/07/2016 Sagar Kishor Savale

8. 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. 8 10/07/2016 Sagar Kishor Savale

9. Disadvantages of Tablet dosage form are : Difficult to swallow in case of children and unconscious 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. 9 10/07/2016 Sagar Kishor Savale

10. Different types of Tablets (A) Tablets ingested orally: 1. Compressed tablet, e.g. Paracetamol tablet 2. Multiple compressed tablet 3. Repeat action tablet 4. Delayed release tablet, e.g. Enteric coated Bisacodyl tablet 5. Sugar coated tablet, e.g. Multivitamin tablet 6. Film coated tablet, e.g. Metronidazole tablet 7. Chewable tablet, e.g. Antacid tablet (B) Tablets used in oral cavity: 1. Buccal tablet, e.g. Vitamin-c tablet 2. Sublingual tablet, e.g. Vicks Menthol tablet 3. Troches or lozenges 4. Dental cone 10 10/07/2016 Sagar Kishor Savale

11. (c) Tablets administered by other route: 1. Implantation tablet 2. Vaginal tablet, e.g. Clotrimazole tablet (D) Tablets used to prepare solution: 1. Effervescent tablet, e.g. Dispirin tablet (Aspirin) 2. Dispensing tablet, e.g. Enzyme tablet ( Digiplex ) 3. Hypodermic tablet 4. Tablet triturates e.g. Enzyme tablet ( Digiplex ) 11 10/07/2016 Sagar Kishor Savale

12. 10/07/2016 Sagar Kishor Savale 12 TYPES OF TABLETS COMPRESSED TABLETS In addition to the medicinal agent or agents, compressed tablets usually contain a number of pharmaceutical adjuncts, including the following: Diluents or fillers : which add the necessary bulk to a formulation to prepare tablets of the desired size. Binders or adhesives : which promote adhesion of the particles of the formulation, allowing a granulation to be prepared and maintaining the integrity of the final tablet.

13. 10/07/2016 Sagar Kishor Savale 13 Disintegrants or disintegrating agents : which promote breakup of the tablets after administration to smaller particles for ready drug availability. Antiadherents, glidants, lubricants, or lubricating agents : which enhance the flow of the material into the tablet dies, minimize wear of the punches and dies, prevent fill material from sticking to the punches and dies, and produce tablets with a sheen. Miscellaneous adjuncts: such as colorants and flavorants. After compression, tablets may be coated with various materials as described later. Tablets for oral, buccal, sublingual, or vaginal administration may be prepared by compression.

14. 10/07/2016 Sagar Kishor Savale 14 MULTIPLY COMPRESSED TABLETS Multiply compressed tablets are prepared by subjecting the fill material to more than a single compression. The result may be a multiple-layer tablet or a tablet within a tablet, the inner tablet being the core and the outer portion being the shell. .

15. 10/07/2016 Sagar Kishor Savale 15 Layered tablets are prepared by initial compaction of a portion of fill material in a die followed by additional fill material and compression to form two-layered or three- layered tablets, depending on the number of separate fills. Each layer may contain a different medicinal agent, separated for reasons of: chemical or physical incompatibility staged drug release for the unique appearance of the layered tablet. Usually, each portion of fill is a different color to produce a distinctive-looking tablet. In preparation of tablets within tablets, special machines are required to place the preformed core tablet precisely within the die for application of surrounding fill material.

16. 10/07/2016 Sagar Kishor Savale 16 SUGARCOATED TABLETS Compressed tablets may be coated with a colored or an uncolored sugar layer. The coating is water soluble and quickly dissolves after swallowing. The sugarcoat protects the enclosed drug from the environment and provides a barrier to objectionable taste or odor. The sugarcoat also enhances the appearance of the compressed tablet and permits imprinting of identifying manufacturer’s information. Among the disadvantages to sugarcoating tablets are the time and expertise required in the coating process and the increase in size, weight, and shipping costs. Sugarcoating may add 50% to the weight and bulk of the uncoated tablet.

17. 10/07/2016 Sagar Kishor Savale 17 FILM-COATED TABLETS Film-coated tablets are compressed tablets coated with a thin layer of a polymer capable of forming a skin-like film. The film is usually colored and has the advantage over sugarcoatings in that it is: more durable less bulky less time- consuming to apply. By its composition, the coating is designed to rupture and expose the core tablet at the desired location in the gastrointestinal tract.

18. 10/07/2016 Sagar Kishor Savale 18 GELATIN-COATED TABLETS A recent innovation is the gelatin-coated tablet. The innovator product, the gelcap, is a capsule- shaped compressed tablet that allows the coated product to be about one-third smaller than a capsule filled with an equivalent amount of powder.

19. 10/07/2016 Sagar Kishor Savale 19 ENTERIC-COATED TABLETS Enteric-coated tablets have delayed-release features. They are designed to pass unchanged through the stomach to the intestines, where the tablets disintegrate and allow drug dissolution and absorption and/or effect. Enteric coatings are employed when the drug substance: is destroyed by gastric acid or is particularly irritating to the gastric mucosa or when bypass of the stomach substantially enhances drug absorption.

20. 10/07/2016 Sagar Kishor Savale 20 BUCCAL AND SUBLINGUAL TABLETS Buccal and sublingual tablets are flat, oval tablets intended to be dissolved in the buccal pouch ( buccal tablets ) or beneath the tongue ( sublingual tablets ) for absorption through the oral mucosa.

21. 10/07/2016 Sagar Kishor Savale 21 They enable oral absorption of drugs that are destroyed by the gastric juice and/or are poorly absorbed from the gastrointestinal tract. Buccal tablets are designed to erode slowly, whereas those for sublingual use (such as nitroglycerin) dissolve promptly and provide rapid drug effects. Lozenges or troches are disc-shaped solid dosage forms containing a medicinal agent and generally a flavoring substance in a hard candy or sugar base. They are intended to be slowly dissolved in the oral cavity, usually for local effects, although some are formulated for systemic absorption.

22. 10/07/2016 Sagar Kishor Savale 22 CHEWABLE TABLETS Chewable tablets, which have a smooth, rapid disintegration when chewed or allowed to dissolve in the mouth, have a creamy base, usually of specially flavored and colored mannitol. Chewable tablets are especially useful for administration of large tablets to children and adults who have difficulty swallowing solid dosage forms.

23. 10/07/2016 Sagar Kishor Savale 23 EFFERVESCENT TABLETS Effervescent tablets are prepared by compressing granular effervescent salts that release gas when in contact with water. These tablets generally contain medicinal substances that dissolve rapidly when added to water. The “bubble action” can assist in breaking up the tablets and enhancing the dissolution of the active drug.

24. 10/07/2016 Sagar Kishor Savale 24 MOLDED TABLETS Certain tablets may be prepared by molding rather than by compression. The resultant tablets are very soft and soluble and are designed for rapid dissolution.

25. 10/07/2016 Sagar Kishor Savale 25 TABLET TRITURATES Tablet triturates are small, usually cylindrical, molded or compressed tablets containing small amounts of usually potent drugs. Today, only a few tablet triturate products are available commercially, with most of these produced by tablet compression. Since tablet triturates must be readily and completely soluble in water, only a minimal amount of pressure is applied during their manufacture. A combination of sucrose and lactose is usually the diluent. The few tablet triturates that remain are used sublingually, such as nitroglycerin tablets. Pharmacists also employ tablet triturates in compounding. For example, triturates are inserted into capsules or dissolved in liquid to provide accurate amounts of potent drug substances.

26. 10/07/2016 Sagar Kishor Savale 26

27. 10/07/2016 Sagar Kishor Savale 27 HYPODERMIC TABLETS Hypodermic tablets are no longer available in the United States. They were originally used by physicians in extemporaneous preparation of parenteral solutions. The required number of tablets was dissolved in a suitable vehicle, sterility attained, and the injection performed. The tablets were a convenience, since they could be easily carried in the physician’s medicine bag and injections prepared to meet the needs of the individual patients. However, the difficulty in achieving sterility and the availability of prefabricated injectable products, some in disposable syringes, have eliminated the need for hypodermic tablets.

28. 10/07/2016 Sagar Kishor Savale 28

29. 10/07/2016 Sagar Kishor Savale 29 DISPENSING TABLETS Dispensing tablets are no longer in use. They might better have been termed compounding tablets because the pharmacist used them to compound prescriptions; they were not dispensed as such to the patient.

30. 10/07/2016 Sagar Kishor Savale 30 IMMEDIATE-RELEASE TABLETS Immediate-release tablets are designed to disintegrate and release their medication with no special rate-controlling features, such as special coatings and other techniques.

31. 10/07/2016 Sagar Kishor Savale 31 EXTENDED-RELEASE TABLETS Extended-release tablets (sometimes called controlled-release tablets) are designed to release their medication in a predetermined manner over an extended period.

32. 10/07/2016 Sagar Kishor Savale 32

33. 10/07/2016 Sagar Kishor Savale 33 VAGINAL TABLETS Vaginal tablets, also called vaginal inserts , are uncoated, bullet-shaped or ovoid tablets inserted into the vagina for local effects. They contain : antibacterials for the treatment of nonspecific vaginitis caused by Haemophilus vaginalis antifungals for the treatment of vulvovaginitis candidiasis caused by Candida albicans and related species.

34. 10/07/2016 Sagar Kishor Savale 34 INSTANTLY DISINTEGRATING OR DISSOLVING TABLETS Instant-release tablets (rapidly dissolving tablets, or RDTs) are characterized by disintegrating or dissolving in the mouth within 1 minute, some within 10 seconds Tablets of this type are designed for children and the elderly or for any patient who has difficulty in swallowing tablets. They liquefy on the tongue, and the patient swallows the liquid. A number of techniques are used to prepare these tablets, including: Lyophilization soft direct compression These tablets are prepared using very water- soluble excipients designed to wick water into the tablet for rapid disintegration or dissolution. They have the stability characteristics of other solid dosage forms.

35. 10/07/2016 Sagar Kishor Savale 35 The original fast-dissolving tablets were molded tablets for sublingual use. They generally consisted of active drug and lactose moistened with an alcohol–water mixture to form a paste. The tablets were then molded , dried , and packaged . For use, they were simply placed under the tongue to provide a rapid onset of action for drugs such as nitroglycerin. Also, they have been used for drugs that are destroyed in the gastrointestinal tract, such as testosterone, administered sublingually for absorption to minimize the first-pass effect.

36. 10/07/2016 Sagar Kishor Savale 36 These RDTs are more convenient to carry and administer than an oral liquid. There are no standards that define an RDT, but one possibility is dissolution in the mouth within approximately 15 to 30 seconds; anything slower would not be categorized as rapidly dissolving. Packaging They are generally packaged in cards or bubble-type packaging with each individual tablet in its own cavity.

37. 10/07/2016 Sagar Kishor Savale 37 Not withstanding these advantages, there are a number of disadvantages and difficulties associated with formulating RDTs, including: drug loading taste masking friability manufacturing costs stability of the product

38. 10/07/2016 Sagar Kishor Savale 38 COMPRESSED TABLETS The physical features of compressed tablets are well known: Round, oblong or unique in shape thick or thin large or small in diameter flat or convex unscored or scored in halves, thirds, or quadrants engraved or imprinted with an identifying symbol and/or code number coated or uncoated colored or uncolored one, two, or three layered.

39. 10/07/2016 Sagar Kishor Savale 39 Tablet diameters and shapes are determined by the die and punches used in compression. The less concave the punches, the flatter the tablets; conversely The more concave the punches the more convex the resulting tablets. Punches with raised impressions produce recessed impressions on the tablets Punches with recessed etchings produce tablets with raised impressions or monograms. Monograms may be placed on one or on both sides of a tablet, depending on the punches

40. 10/07/2016 Sagar Kishor Savale 40

41. Tablet Ingredients In addition to active ingredients, tablet contains a number of inert materials known as additives or excipients. Different excipients are: 1. Diluent 2. Binder and adhesive 3. Disintegrents 4. Lubricants and glidants 5. Colouring agents 6. Flavoring agents 7. Sweetening agents 41 10/07/2016 Sagar Kishor Savale

42. EXCIEPIENTS- functions Impart weight, accuracy, & volume(its allow acccuracy of dose) Improve solubility Increase stability Enhance bioavailability Modifying drug release Assist pdt identification Increase patient acceptability Facilitate dosage form design 42 10/07/2016 Sagar Kishor Savale

43. Excipient functions 43 10/07/2016 Sagar Kishor Savale

44. 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 manufacturing or to promote flow. A diluent should have following properties: 1. They must be non toxic 2. They must be commercially available in acceptable grade 3. There cost must be low 4. They must be physiologically inert 5. They must be physically & chemically stable by themselves & in combination with the drugs. 6. They must be free from all microbial contamination. 7. They do not alter the bioavailability of drug. 8. They must be color compatible. 44 10/07/2016 Sagar Kishor Savale

45. Commonly used tablet diluents 1 . Lactose-anhydrous and spray dried lactose 2. Directly compressed starch- Sta Rx 1500 3. Hydrolyzed starch- Emdex and Celutab 4. Microcrystalline cellulose- Avicel (PH 101and PH 102) 5. Dibasic calcium phosphate dehydrate 6. Calcium sulphate dihydrate 7. Mannitol 8. Sorbitol 9. Sucrose- Sugartab, DiPac, Nutab 10. Dextrose 45 10/07/2016 Sagar Kishor Savale

46. 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 46 10/07/2016 Sagar Kishor Savale

47. 47 10/07/2016 Sagar Kishor Savale

48. 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 48 10/07/2016 Sagar Kishor Savale

49. 49 10/07/2016 Sagar Kishor Savale

50. 4. Superdisintegrants: Swells up to ten fold within 30 seconds when contact water. Example: Crosscarmellose - cross-linked cellulose, Crosspovidone - cross-linked povidone (polymer), Sodium starch glycolate- cross-linked starch. These cross-linked products swells with in 30 seconds when in contact with water. A portion of disintegrant is added before granulation and a portion before compression, which serve as glidants or lubricant. 50 10/07/2016 Sagar Kishor Savale

51. 5. 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. 51 10/07/2016 Sagar Kishor Savale

52. 6. Coloring agent: The use of colors and dyes in a tablet has three purposes: (1) Masking of off color drugs (2) Product Identification (3) 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 52 10/07/2016 Sagar Kishor Savale

53. 7. Flavoring agents: For chewable tablet- flavor oil are used 8. 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. 53 10/07/2016 Sagar Kishor Savale

54. 9. Wetting Agents Water molecules attract each other equally in all directions. Water molecules on the surface, however, can only be pulled into the bulk water by water molecules underneath, since there are no water molecules to pull in the opposite direction. The surface tension of water is strong enough to support the weight of tiny insects such as water striders. The surface tension in action can be visualized by placing a small drop of alcohol on a thin layer of water. Alcohol with lower surface tension mixes with water causing reduction in the surface tension in the local region. Owing to the higher surface tension of water in the neighbor, water is pulled from the alcohol dropped region into the neighbor, and this leads to the formation of a dry spot in the middle of the water layer. 54 10/07/2016 Sagar Kishor Savale

55. API Filler Mixing of granulation blend Granulation Binder(s) Preparation of binder solution Drying Milling LOD Disintegrant screening screening Initial Blending lubricant screening Final Blending Compression Solvent Film coating agent Preparation Film Coating of Tablets Packaging and Labelling Weight Hardness Friability Flow Chart 55 10/07/2016 Sagar Kishor Savale

56. Lactose Non-reactive in anhydrous or hydrous form Hydrous form undergoes maillard reaction leading to browning and discoloration of certain drugs, hence anhydrous form is preferred. But anhydrous form picks up moisture when exposed to humidity. In wet granulation, hydrous lactose of two varieties are used 60-80 mesh (coarse) and 80-100 mesh (regular) grade. Lactose formulation show good release. Low cost diluent. But may discolor in presence of amine drug bases or salts of alkaline compounds 56 10/07/2016 Sagar Kishor Savale

57. Spray dried lactose Lactose is placed in aqueous solution, removed impurities and spray dried Mixture of large alpha monohydrate crystals and spherical aggregates of smaller crystals Good flowability but less compressibility Poor dilution potential Less compressibility upon initial compaction Problem of browning due to contamination of 5-hydroxyfurfural which was accelerated in the presence of basic amine drugs and catalyzed by tartarate , citrate and acetate ions 57 10/07/2016 Sagar Kishor Savale

58. Fast-Flow lactose (early 1970s) Spherical aggregates of microcrystals lactose monohydrate Held together by a higher concentration of glass (amorphous lactose) Much more compressible Highly fluid Non hygroscopic Tablets are three to four times harder than regular spray dried Tabletose : aggromerate form of lactose More compressible than spray dried but less compressible than Fast Flo lactose 58 10/07/2016 Sagar Kishor Savale

59. Starch Can be corn, wheat or potato source USP grade of starch has poor flow & compression characteristics Also has high moisture content between between 11 & 14 %. Specially dried starches also have standard moisture level of 2-4% Therefore used in wet granulation 59 10/07/2016 Sagar Kishor Savale

60. Sta 1500: Intact starch grains and ruptured starch grains that have been partially hydrolyzed and subsequently aggromerated Free flowing, self lubricating, containing slightly high MC (10 %) Due to which does not form hard compacts Dilution potential is minimal, not generally used as filler-binder but as filler disintegrant Retains the disintegrant properties of starch without increasing the fluidity and compressibility of the total formulation Flow promoters like colloidal silicon dioxide is needed. Lubricants tend to dramatically soften tablets containing high concentrations of Starch 1500 60 10/07/2016 Sagar Kishor Savale

61. Dextrose 90-92% dextrose, 3-5% maltose and the remainder higher glucose polysaccharides Available both anhydrous and a hydrate product Excellent compressibility and good flow Contain 8-10% moisture and may increase hardness after compression Largest particle size, therefore blending problem may occur Cerelose is also avilable 61 10/07/2016 Sagar Kishor Savale

62. Stages of pharmaceutical manufacturing API Excipients Primary Packaging Secondary Packaging API Finished Product Starting Materials (Chemicals) 62 10/07/2016 Sagar Kishor Savale

63. Drug product manufacture Dosage Form Wet granulation milling blending Fluid Bed Dryer lubrication tableting coating imprinting Process combines the drug and excipients into the dosage form Excipients API crystallization filtration oven drying Dry granulation / milling Direct compression 63 10/07/2016 Sagar Kishor Savale

64. Tableting methods 64 10/07/2016 Sagar Kishor Savale

65. Manufacturing Methods 65 10/07/2016 Sagar Kishor Savale

66. Powders intended for compression into tablets must possess two essential properties Powder fluidity or flowability The material can be transported through the hopper into the die To produce tablets of a consistent weight Powder flow can be improved mechanically by the use of vibrators, incorporate the glidant Powder compressibility The property of forming a stable, intact compact mass when pressure is applied is called powder compressibility Easily mixed with other particles Homogenous colouring etc Friction and adhesion properties 66 10/07/2016 Sagar Kishor Savale

67. Slugging (dry granulation) Blend is forced into dies of large capacity tablet press and compacted using flat faced punches. compacted masses are called slugs and process is called slugging. c. Slugs milled or screened to produce good free flowing granules for compression. 67 10/07/2016 Sagar Kishor Savale

68. Dry compaction/Roller compaction On a large scale compression granulation can also be performed on a roller compactor. Granulation by dry compaction can also be achieved by passing powders between two rollers that compact the material at pressure of up to 10 tons per linear inch. Materials of very low density require roller compaction to achieve a bulk density sufficient to allow encapsulation or compression. One of the best examples of this process is the densification of aluminum hydroxide. Roller compactor is capable of producing as much as 500 kg/hr of compacted ribbon like materials which can be then screened and milled in to granules for compression . 68 10/07/2016 Sagar Kishor Savale

69. Limitations of dry granulation 1- Dry granulation often produces a higher percentage of fines or non compacted products, which could compromise the quality or create yield problems for the tablet. 2- It requires drugs or excipients with cohesive properties. 69 10/07/2016 Sagar Kishor Savale

70. Wet granulation The most popular method (over 70% ) Granulation is done To prevent segregation of the constituents of the powder blend. To improve flowability of the powder mixture. To improve the compaction characteristics of the powder mixture due to better distribution of the binder within the granules. To improve homogeneity and thus ensure content uniformity Wet granulation is a process of using a solution binder to the powder mixture. The amount of liquid can be properly managed; overwetting = the granules to be too hard, underwetting =too soft and friable. Aqueous solutions are safer than other solvents. 70 10/07/2016 Sagar Kishor Savale

71. Procedure of Wet Granulation Step 1: Weighing and Blending Step 2: wet granulate prepared by adding the binder solution Step 3 : Screening the damp mass into pellets or granules (6-8mesh) Step 4 : Drying the granulation in thermostatically controlled ovens Step 5 : Dry screening: Step 6 : Mixing with other ingredients: A dry lubricant, antiadherent and glidant is added to the granules either by dusting over the spread-out granules or by blending with the granules. Dry binder, colorant or disintegrant may be also added in this step. Step 7 : Tableting : Last step in which the tablet is fed into the die cavity and then compressed. 71 10/07/2016 Sagar Kishor Savale

72. Single punch machine Multi-station rotary presses The head of the tablet machine that holds the upper punches, dies and lower punches in place rotates As the head rotates, the punches are guided up and down by fixed cam tracks, which control the sequence of filling, compression and ejection. The portions of the head that hold the upper and lower punches are called the upper and lower turrets The portion holding the dies is called the die table 72 10/07/2016 Sagar Kishor Savale

73. 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) 73 10/07/2016 Sagar Kishor Savale

74. 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 74 10/07/2016 Sagar Kishor Savale

75. 75 10/07/2016 Sagar Kishor Savale

76. 76 10/07/2016 Sagar Kishor Savale

77. The principle modification from earlier equipment has been an increase in production rate which is regulated by Number of tooling sets Number of compression stations Rotational speed of the press High speed rotary machine Multirotary machine 77 10/07/2016 Sagar Kishor Savale

78. 78 10/07/2016 Sagar Kishor Savale

79. 79 10/07/2016 Sagar Kishor Savale

80. 80 10/07/2016 Sagar Kishor Savale

81. Processing problems Capping is the partial or complete separation of the top or bottom crowns of a tablet from the main body of the tablet. Lamination is separation of a tablet into two or more distinct layers. Both of these problems usually result from air entrapment during processing. Picking is removal of a tablet’s surface material by a punch. Sticking is adhesion of tablet material to a die wall. These two problems result from excessive moisture or substances with low melting temperatures in the formulation 81 10/07/2016 Sagar Kishor Savale

82. Mottling is an unequal color distribution on a tablet, with light or dark areas standing on otherwise uniform surface. This results from use of a drug with a color different from that of the tablet excipients or from a drug with colored degradation products. Weight variation-granule size distribution, poor fiow,punch variation Hardness variation Double impression-monograms or engraving on punch 82 10/07/2016 Sagar Kishor Savale

83. Background 83 10/07/2016 Sagar Kishor Savale

84. 84 10/07/2016 Sagar Kishor Savale

85. 10/07/2016 Sagar Kishor Savale 85 Tablets Defects Capping Lamination Sticking & Picking Hardness variation Chipping Splitting Erosion Thickness variation Black Spots Double Impressions

86. 10/07/2016 Sagar Kishor Savale 86 Capping

87. 10/07/2016 Sagar Kishor Savale 87 Lamination

88. 10/07/2016 Sagar Kishor Savale 88

89. 10/07/2016 Sagar Kishor Savale 89 Sticking & Picking

90. 10/07/2016 Sagar Kishor Savale 90

91. The Causes and Remedies of Capping related to ‘Formulation’ 91 10/07/2016 Sagar Kishor Savale

92. The Causes and Remedies of Capping related to ‘Machine’ 92 10/07/2016 Sagar Kishor Savale

93. The Causes and Remedies of Lamination related to ‘Formulation’ 93 10/07/2016 Sagar Kishor Savale

94. The Causes and Remedies of Lamination related to ‘Machine’ 94 10/07/2016 Sagar Kishor Savale

95. The Causes and Remedies of Chipping related to ‘Formulation’ 95 10/07/2016 Sagar Kishor Savale

96. The Causes and Remedies of Chipping related to ‘Machine’ 96 10/07/2016 Sagar Kishor Savale

97. The Causes and Remedies of Cracking related to ‘Formulation’ 97 10/07/2016 Sagar Kishor Savale

98. The Causes and Remedies of Cracking related to ‘Machine’ 98 10/07/2016 Sagar Kishor Savale

99. The Causes and Remedies of Sticking related to ‘Formulation’ 99 10/07/2016 Sagar Kishor Savale

100. The Causes and Remedies of Sticking related to ‘Machine’ 100 10/07/2016 Sagar Kishor Savale

101. The Causes and Remedies of Picking related to ‘Formulation’ 101 10/07/2016 Sagar Kishor Savale

102. The Causes and Remedies of Picking related to ‘Machine’ 102 10/07/2016 Sagar Kishor Savale

103. The Causes and Remedies of Binding related to ‘Formulation’ 103 10/07/2016 Sagar Kishor Savale

104. The Causes and Remedies of Binding related to ‘Machine’ 104 10/07/2016 Sagar Kishor Savale

105. The Causes and Remedies of Mottling 105 10/07/2016 Sagar Kishor Savale

106. The Causes and Remedies of Double Impression 106 10/07/2016 Sagar Kishor Savale

107. 10/07/2016 Sagar Kishor Savale 107 Tablet coating

108. 10/07/2016 Sagar Kishor Savale 108 Objectives of Coating/why coating Reduce influence of atmosphere Mask: taste odor & color of drug Control or Modify drug Release: CR, SR ……. Protect drug against GI environment : Enteric coating Avoid irritation of esophagus and stomach Incompatibility: Drug & drug Improve elegance : color imprinting & patient acceptance Increases the mechanical strength of the core tablet To prevent direct contact with the drug substance

109. 10/07/2016 Sagar Kishor Savale 109 Types of coating processes The main types are used in the pharmaceutical industry today Coating Functional coating Non Functional coating - Sugar coating Compression coating

110. 10/07/2016 Sagar Kishor Savale 110 The main steps involved in the coating of tablets are as follows: The tablets (or granules) are placed within the coating apparatus and agitated. The coating solution is sprayed on to the surface of the tablets. Warm air is passed over the tablets to facilitate removal of the solvent from the adsorbed layer of coating solution on the surface of the tablets. When the solvent has evaporated, the tablets will be coated with the solid component of the original coating solution.

111. 10/07/2016 Sagar Kishor Savale 111

112. 10/07/2016 Sagar Kishor Savale 112

113. 10/07/2016 Sagar Kishor Savale 113 Sugar coating • Description of tablets: Smooth, rounded and polished to a high gloss. • Process: Multistage process involving 6 separate operations

114. 10/07/2016 Sagar Kishor Savale 114 Sugar coating Sealing tablet core: application of a water impermeable polymer such as Shellac, cellulose acetate phthalate and polyvinyl acetate phthalate, which protects the core from moisture, increasing its shelf life. Sub coating After the tablets are waterproofed if needed, three to five subcoats of a sugar-based syrup are applied. This bonds the sugar coating to the tab- let and provides rounding. The sucrose and water syrup also contains gelatin, acacia, or PVP to enhance coating. Smoothing process -remove rough layers formed in step 2 with the application of sucrose syrup. This syrup is sucrose based, with or without additional com- ponents such as starch and calcium carbonate.

115. 10/07/2016 Sagar Kishor Savale 115 Sugar coating Colouring - for aesthetic purposes often titanium based pigments are included. Polishing - effectively polished to give characteristic shine, commonly using beeswax, carnauba wax. Printing -permanent ink for characterization

116. 10/07/2016 Sagar Kishor Savale 116 Film coating Coating tablets, capsules, or pellets by surrounding them with a thin layer of polymeric material. Process : Single stage process, which involves spraying a coating The solution or suspension is sprayed to a rotating tablet bed followed by drying, which facilitates the removal of the solvent leaving behind the deposition of thin film of coating materials around each tablet

117. 10/07/2016 Sagar Kishor Savale 117 Film coating Film coating contains the following; 1. Film forming Polymer 2. Solvent 3. Plasticizer 4. Colourant

118. 10/07/2016 Sagar Kishor Savale 118 F ilm-coating machine

119. 10/07/2016 Sagar Kishor Savale 119 Film forming Polymer

120. 10/07/2016 Sagar Kishor Savale 120 Plasticizer LOW MOLECULAR WEIGHT ORGANIC MOLECULES, CAPABLE OF MODIFYING THE PHYSICAL PROPERTIES OF A POLYMER - Better mechanical properties – Resistance to deformation – Flexible, elastic films (high modulus of elasticity) – Continuous film

121. 10/07/2016 Sagar Kishor Savale 121 Solvent Solvent organic Environmental Safety Financial Solvent residues P. Water Product – Stability

122. 10/07/2016 Sagar Kishor Savale 122 Film-coating solutions may be nonaqueous or aqueous. The nonaqueous solutions contain the following types of materials to provide the desired coating to the tablets: A film former capable of producing smooth, thin films reproducible under conventional coating conditions and applicable to a variety of tablet shapes. Example: cellulose acetate phthalate. An alloying substance providing water solubility or permeability to the film to ensure penetration by body fluids and therapeutic availability of the drug. Example: polyethylene glycol.

123. 10/07/2016 Sagar Kishor Savale 123 A plasticizer to produce flexibility and elasticity of the coating and thus provide durability. Example: castor oil. A surfactant to enhance spreadability of the film during application. Example: polyoxyethylene sorbitan derivatives. Opaquants and colorants to make the appearance of the coated tablets handsome and distinctive. Examples: Opaquant, titanium dioxide; colorant, FD&C or D&C dyes. Sweeteners , flavor s , and aromas to enhance the acceptability of the tablet by the patient. Examples: sweeteners, saccharin; flavors and aromas, vanillin. A glossant to provide luster to the tablets without a separate polishing operation. Example: beeswax. A volatile solvent to allow the spread of the other components over the tablets while allowing rapid evaporation to permit an effective yet speedy operation. Example: alcohol mixed with acetone.

124. 10/07/2016 Sagar Kishor Savale 124 One commercial water-based colloidal coating dispersion called Aquacoat (FMC Corporation) contains a 30% ethyl cellulose pseudolatex. Pseudolatex dispersions have a high solids content for greater coating ability and a relatively low viscosity. The low viscosity allows less water to be used in the coating dispersion, requiring less evaporation and reducing the likelihood that water will interfere with tablet formulation. In addition, the low viscosity permits greater coat penetration into the crevices of monogrammed or scored tablets. A plasticizer may be added to assist in the production of a dense, relatively impermeable film with high gloss and mechanical strength.

125. 10/07/2016 Sagar Kishor Savale 125 A typical aqueous film-coating formulation contains the following: Film-forming polymer (7% to 18%). Examples: cellulose ether polymers such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, and methylcellulose. Plasticizer (0.5% to 2.0%). Examples: glycerin, propylene glycol, polyethylene glycol, diethyl phthalate, and dibutyl subacetate. Colorant and opacifier (2.5% to 8%). Examples: FD&C or D&C lakes and iron oxide pigments. Vehicle (water, to make 100%).

126. 10/07/2016 Sagar Kishor Savale 126 Film coating Sugar coating Film coating Tablet appearance Retains shape of original core Small weight increase of 2-10 % due to coating material logo or ‘break lines’ possible No Wait & size variation Tablet appearance Rounded with high degree of polish Larger weight increase 30-100 % due to coating material Logo or ‘break lines’ are Impossible Wait & size variation within the batch or from batch to batch Sugar coating Process Can be automated Easy training operation Single stage process Less Time Easily adaptable for controlled release allows for functional coatings. Process Difficult to automated Considerable training operation Multi stage process More time Not able to be used for controlled Release

127. 10/07/2016 Sagar Kishor Savale 127 Problems of Film Coating PICKING/ STICKING : small holes pulled in film or small amount of the film flaking from the tablet surface PEELING : the coating peels away from the tablet surface or large amount of the film flaking from the tablet surface

128. 10/07/2016 Sagar Kishor Savale 128 Twinning : two or more tablets that stick together. Common problem with flat or capsule shaped tablets Roughness or orange peel : film not smooth Problems of Film Coating

129. 10/07/2016 Sagar Kishor Savale 129 Problems of Film Coating CRACKING: Torn or cracked films CORE EROSION : loss of material from tablet surface

130. 10/07/2016 Sagar Kishor Savale 130 Problems of Film Coating Color Variation or mottling LOGO BRIDGING : the coating fills in the logo on the tablets

131. 10/07/2016 Sagar Kishor Savale 131 Functional coatings Functional coatings are coatings, which perform a pharmaceutical function Enteric coating Controlled release coating

132. 10/07/2016 Sagar Kishor Savale 132 ENTERIC COATING The technique involved in enteric coating is protection of the tablet core from disintegration in the acidic environment of the stomach by employing pH sensitive polymer , which swell or solubilize in response to an increase in pH to release the drug. Aims of Enteric protection: Protection of active ingredients, from the acidic environment of the stomach. Protection from local irritation of the stomach mucosa. Release of active ingredient in specific target area within gastrointestinal tract.

133. 10/07/2016 Sagar Kishor Savale 133 Among the materials used in enteric coatings are: Pharmaceutical shellac Hydroxypropyl methylcellulose phthalate Polyvinyl acetate phthalate Diethyl phthalate Cellulose acetate phthalate.

134. 10/07/2016 Sagar Kishor Savale 134 FLUID BED COATER

135. 10/07/2016 Sagar Kishor Savale 135

136. 10/07/2016 Sagar Kishor Savale 136 Press coating Press coating process involves compaction of coating material around a preformed core for creating modified-released products involves the compaction of granular materials around preformed tablet core using specially designed tableting equipment. Compression coating is a dry process

137. 10/07/2016 Sagar Kishor Savale 137 COMPRESSION COATING Compared to sugarcoating using pans, compression coating is more uniform and uses less coating material, resulting in tablets that are lighter, smaller, and easier to swallow and less expensive to package and ship.

138. 10/07/2016 Sagar Kishor Savale 138 CHANGES ON SOLID DOSAGE FORM Starting materials Manufacturing process

139. 10/07/2016 Sagar Kishor Savale 139 PACKAGING AND STORING TABLETS Tablets are stored in tight containers, in places of low humidity, and protected from extremes in temperature.

140. 10/07/2016 Sagar Kishor Savale 140 Products that are prone to decomposition by moisture generally are packaged with a desiccant packet. Drugs that are adversely affected by light are packaged in light-resistant containers. With a few exceptions, tablets that are properly stored will remain stable for several years or more.

141. 10/07/2016 Sagar Kishor Savale 141 Upon aging Hardness - The increase in tablet hardness can frequently be attributed to the increased adhesion of the binding agent and other formulative components within the tablet

142. 10/07/2016 Sagar Kishor Savale 142 In tablets containing volatile drugs, such as nitroglycerin , the drug may migrate between tablets in the container, resulting in a lack of uniformity among the tablets. Also, packing materials, such as cotton and rayon, in contact with nitroglycerin tablets may absorb varying amounts of nitroglycerin, reducing potency of the tablets. The USP directs that nitroglycerin tablets be preserved in tight containers, preferably of glass, at controlled room temperature.

143. 10/07/2016 Sagar Kishor Savale 143 Also, migration within tablets can occur resulting in unequal distribution within a single tablet; this can be problematic if the tablet is scored and designed to be broken in half where the two halves may not contain equal portions of the drug. Storage of a container next to a heat source may result in greater loss or movement of the volatile drug in the portion of the bottle closest to the heat.

144. 10/07/2016 Sagar Kishor Savale 144 The USP further directs that nitroglycerin tablets be dispensed in the original unopened container, labeled with the following statement directed to the patient. “Warning: to prevent loss of potency, keep these tablets in the original container or in a supplemental nitroglycerin container specifically labeled as being suitable for nitroglycerin tablets. Close tightly immediately after use” (4).

145. 10/07/2016 Sagar Kishor Savale 145 Pan coating Benefits Mask taste Chemical barrier Controlled release Appearance Critical Parameters Air flow Spray Drum dynamics Rotational speed Fill fraction Air+Moisture Dry Air Rotation Baffle Spray Nozzle Air Flow Inlet Filter Steam Inlet Temperature Inlet Air Outlet Air Outlet Filter Outlet Temperature

146. 10/07/2016 Sagar Kishor Savale 146 OTHER SOLID DOSAGE FORMS FOR ORAL ADMINISTRATION LOZENGES LOLLIPOPS

147. 10/07/2016 Sagar Kishor Savale 147 Chewable tablets Chewable tablets are pleasant-tasting tablets formulated to disintegrate smoothly in the mouth with or without chewing. They are prepared by wet granulation and compression, using only minimal degrees of pressure to produce a soft tablet. Generally, chewable tablets do not contain disintegrants, so patients must be counseled to chew the tablets thoroughly and not swallow them whole.

148. 10/07/2016 Sagar Kishor Savale 148 Mannitol , a white crystalline hexahydric alcohol, is used as the excipient in most chewable tablets. Mannitol is about 70% as sweet as sucrose, with a cool feel in the mouth. Mannitol accounts for 50% or more of the weight of many chewable tablet formulations. Sometimes other sweetening agents, such as: sorbitol lactose dextrose crystalline maltose glucose may be substituted for part or all of the mannitol. Xylitol may be used in the preparation of sugar- free chewable tablets.

149. 10/07/2016 Sagar Kishor Savale 149 Among the types of products prepared as chewable tablets are: antacids (e.g., calcium carbonate) antibiotics (e.g., erythromycin) anti-infective agents (e.g., didanosine) anticonvulsants (e.g., carbamazepine) vasodilators (e.g., isosorbide dinitrate) analgesics (e.g., acetaminophen) various vitamins Cold– allergy combination tablets.

150. 10/07/2016 Sagar Kishor Savale 150 The following is a formula for a typical chewable antacid tablet Aluminum hydroxide 325.0mg Mannitol 812.0mg Sodium saccharin 0.4mg Sorbitol (10% w/v solution ) 32.5mg Magnesium stearate 25.0mg Mint flavor concentrate 4.0mg

151. 10/07/2016 Sagar Kishor Savale 151 QUALITY STANDARDS AND COMPENDIAL REQUIREMENTS In addition to the apparent features of tablets, tablets must meet other physical specifications and quality standards. These include criteria for: Weight Weight variation Content uniformity Thickness Hardness Disintegration Dissolution These factors must be controlled during production (in-process controls) and verified after the production of each batch to ensure that established product quality standards are met

152. 10/07/2016 Sagar Kishor Savale 152 1. Tablet Weight and USP Weight Variation Test The quantity of fill in the die of a tablet press determines the weight of the tablet. The volume of fill is adjusted with the first few tablets to yield the desired weight and content . For example , if a tablet is to contain 20 mg of a drug substance and if 100,000 tablets are to be produced, 2,000 g of drug is included in the formula. After the addition of the pharmaceutical additives, such as the diluent, disintegrant, lubricant, and binder, the formulation may weigh 20 kg, which means that each tablet must weigh 200 mg for 20 mg of drug to be present

153. 10/07/2016 Sagar Kishor Savale 153 Thus, the depth of fill in the tablet die must be adjusted to hold a volume of granulation weighing 200mg. During production, sample tablets are periodically removed for visual inspection and automated physical measurement. The USP contains a test for determination of dosage form uniformity by weight variation for uncoated tablets. In the test, 10 tablets are weighed individually and the average weight is calculated. The tablets are assayed and the content of active ingredient in each of the 10 tablets is calculated assuming homogeneous drug distribution.

154. 10/07/2016 Sagar Kishor Savale 154 Content Uniformity By the USP method, 10 dosage units are individually assayed for their content 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 each dosage unit lies within the range of 85% to 115% of the label claim and the standard deviation is less than 6%. If one or more dosage units do not meet these criteria, additional tests as prescribed in the USP are required.

155. 10/07/2016 Sagar Kishor Savale 155 3. Tablet Thickness The thickness of a tablet is determined by: The diameter of the die The amount of fill permitted to enter the die The compaction characteristics of the fill material The force or pressure applied during compression. To produce 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.

156. 10/07/2016 Sagar Kishor Savale 156

157. 10/07/2016 Sagar Kishor Savale 157 4. Tablet Hardness and Friability It is fairly common for a tablet press to exert as little as 3,000 and as much as 40,000lb of force In production of tablets. Generally, the greater the pressure applied, the harder the tablets , although the characteristics of the granulation also have a bearing on hardness. Certain tablets, such as lozenges and buccal tablets, that are intended to dissolve slowly are intentionally made hard; other tablets, such as those for immediate drug release, are made soft. Tablets should be sufficiently hard to resist breaking during normal handling and yet soft enough to disintegrate properly after swallowing.

158. 10/07/2016 Sagar Kishor Savale 158 Special dedicated hardness testers or multifunctional systems are used to measure the degree of force (in kilograms, pounds, or in arbitrary units) required to break a tablet. A force of about 4kg is considered the minimum requirement for a satisfactory tablet. A tablet’s durability: may be determined through the use of a friabilator . A maximum weight loss of not more than 1% generally is considered acceptable for most products.

159. 10/07/2016 Sagar Kishor Savale 159

160. 10/07/2016 Sagar Kishor Savale 160 5. Tablet Disintegration For the medicinal agent in a tablet to become fully available for absorption, the tablet must first disintegrate and discharge the drug to the body fluids for dissolution. Tablet disintegration also is important for tablets containing medicinal agents (such as antacids and antidiarrheals ) that are not intended to be absorbed but rather to act locally within the gastrointestinal tract. In these instances, tablet disintegration provides drug particles with an increased surface area for activity within the gastrointestinal tract. All USP tablets must pass a test for disintegration, which is conducted in vitro using a testing apparatus. The apparatus consists of a basket and rack assembly containing six open-ended transparent tubes of USP-specified dimensions, held vertically upon a 10-mesh stainless steel wire screen.

161. 10/07/2016 Sagar Kishor Savale 161 Tablets must disintegrate within the times set in the individual monograph, usually 30 minutes , but varying from about 2 minutes for nitroglycerin tablets to up to 4 hours for buccal tablets. If one or more tablets fail to disintegrate, additional tests prescribed by the USP must be performed. Enteric-coated tablets are similarly tested, except that the tablets are tested in simulated gastric fluid for 1 hour, after which no sign of disintegration, cracking, or softening must be seen. They are then actively immersed in the simulated intestinal fluid for the time stated in the individual monograph, during which time the tablets disintegrate completely for a positive test.

162. 10/07/2016 Sagar Kishor Savale 162

163. 10/07/2016 Sagar Kishor Savale 163

164. 10/07/2016 Sagar Kishor Savale 164 6. Tablet Dissolution In vitro dissolution testing of solid dosage forms is important for a number of reasons : It guides formulation and product development toward product optimization. Dissolution studies in the early stages of a product’s development allow differentiation between formulations and correlations identified with in vivo bioavailability data. Consistent in vitro dissolution testing ensures bioequivalence from batch to batch.

165. 10/07/2016 Sagar Kishor Savale 165 The goal of in vitro dissolution testing is to provide insofar as is possible a reasonable prediction of or correlation with the product’s in vivo bioavailability. The system relates combinations of a drug’s solubility (high or low) and its intestinal permeability (high or low) as a possible basis for predicting the likelihood of achieving a successful in vivo–in vitro correlation (IVIVC).

166. 10/07/2016 Sagar Kishor Savale 166 Using this system, drugs are placed into one of four categories as follows: Category I drug (high-solubility and high-permeability) Category II drug, dissolution may be the rate-limiting step for absorption, and an IVIVC may be expected. - dissolution rate is slower than the rate of gastric emptying - Category III drug (In the case of a high-solubility and low- permeability ), permeability is the rate-controlling step, and only a limited IVIVC may be possible. Category IV drug (low solubility and low permeability)  significant problems are likely for oral drug delivery

167. 10/07/2016 Sagar Kishor Savale 167 Tablet disintegration is the important first step to the dissolution of the drug in a tablet. A number of formulation and manufacturing factors can affect the disintegration and dissolution of a tablet, including particle size of the drug substance solubility and hygroscopicity of the formulation type and concentration of the disintegrant binder lubricant manufacturing method particularly the compactness of the granulation compression force used in tableting any in-process variables

168. 10/07/2016 Sagar Kishor Savale 168 COMPRESSED TABLET MANUFACTURE Compressed tablets may be made by three basic methods: wet granulation dry granulation direct compression Most powdered medicinal agents require addition of excipients such as: diluents binders disintegrants Lubricants  to provide the desired characteristics for tablet manufacture and efficacious use.

169. 10/07/2016 Sagar Kishor Savale 169 One important requirement in tablet manufacture is that the drug mixture flows freely from the hopper of the tablet press into the dies to enable high-speed compression of the powder mix into tablets. Granulations of powders provide this free flow. Granulations also increase material density, improving powder compressibility during tablet formation.

170. 10/07/2016 Sagar Kishor Savale 170 Reasons for Granulation To avoid powder segregation To enhance the flow of powder Granules have higher porosity than powders To improve the compressibility of powders. Avoid dustiness , The granulation of toxic materials will reduce the hazard of generation of toxic dust, which may arise during the handling of the powders. Materials, which are slightly hygroscope, may adhere & form a cake if stored as a powder. Granules, being denser than the parent powder mix, occupy less volume per unit weight.

171. 10/07/2016 Sagar Kishor Savale 171 WET GRANULATION Wet granulation is a widely employed method for the production of compressed tablets. The steps required are weighing and blending the ingredients preparing a dampened powder or a damp mass screening the dampened powder or damp mass into pellets or granules drying the granulation sizing the granulation by dry screening adding lubricant and blending forming tablets by compression.

172. 10/07/2016 Sagar Kishor Savale 172 Weighing and Blending Specified quantities of active ingredient, diluent or filler, and disintegrating agent are mixed by mechanical powder blender or mixer until uniform. Fillers include: lactose microcrystalline cellulose starch powdered sucrose calcium phosphate. The choice of filler usually is based on: the experience of the manufacturer with the material its relative cost its compatibility with the other formulation ingredients.

173. 10/07/2016 Sagar Kishor Savale 173 EXAMPLE For example, calcium salts must not be used as fillers with tetracycline antibiotics because of an interaction between the two agents that results in reduced tetracycline absorption from the gastrointestinal tract. Among the fillers most preferred are: lactose , because of its solubility and compatibility , microcrystalline cellulose , because of its easy compaction , compatibility , and consistent uniformity of supply

174. 10/07/2016 Sagar Kishor Savale 174 Disintegrating agents include: croscarmellose corn and potato starches sodium starch glycolate sodium carboxymethylcellulose polyvinylpyrroli -done (PVP) crospovidone cation exchange resins alginic acid other materials that swell or expand on exposure to moisture and effect the rupture or breakup of the tablet in the gastrointestinal tract.

175. 10/07/2016 Sagar Kishor Savale 175 Croscarmellose (2%) and sodium starch glycolate (5%) are often preferred because of their: high water uptake rapid action. One commercial brand of sodium starch glycolate is reported to swell up to 300% of its volume in water When starch is employed, 5% to 10% is usually suitable, but up to about 20% may be used to promote more rapid tablet disintegration. The total amount of disintegrant used is not always added in preparing the granulation.

176. 10/07/2016 Sagar Kishor Savale 176 Preparing the Damp Mass A liquid binder is added to the powder mixture to facilitate adhesion of the powder particles. A good binder results in appropriate tablet hardness and does not hinder the release of the drug from the tablet.

177. 10/07/2016 Sagar Kishor Savale 177 Among binding agents: solutions of povidone, an aqueous preparation of cornstarch (10% to 20%) glucose solution (25% to 50%) molasses methylcellulose (3%) carboxymethyl- cellulose microcrystalline cellulose. If the drug substance is adversely affected by an aqueous binder, a nonaqueous solution, or dry binder, may be used.

178. 10/07/2016 Sagar Kishor Savale 178 The amount of binding agent used is part of the operator’s art; however, the resulting binder–powder mixture should compact when squeezed in the hand. The binding agent contributes to adhesion of the granules to one another and maintains the integrity of the tablet after compression.

179. 10/07/2016 Sagar Kishor Savale 179 Overwetting can result in  granules that are too hard for proper tablet formation Underwetting can result in  tablets that are too soft and tend to crumble. When desired, a colorant or flavorant may be added to the binding agent to prepare a granulation with an added feature.

180. 10/07/2016 Sagar Kishor Savale 180 Screening the Damp Mass into Pellets or Granules The dampened powder granules are screened or the wet mass is pressed through a screen (usually 6 or 8 mesh) to prepare the granules. This may be done by hand or with special equipment that prepares the granules by extrusion through perforations in the apparatus. The resultant granules are spread evenly on large lined trays and dried to consistent weight or constant moisture content.

181. 10/07/2016 Sagar Kishor Savale 181 Drying the Granulation Granules may be dried in thermostatically cotrolled ovens that constantly record the time, temperature, and humidity.

182. 10/07/2016 Sagar Kishor Savale 182 Sizing the Granulation by Dry Screening After drying, the granules are passed through a screen of a smaller mesh than that used to prepare the original granulation. The degree to which the granules are reduced depends on the size of the punches to be used. In general, the smaller the tablet to be produced, the smaller the granules. Screens of 12- to 20-mesh size are generally used for this purpose. Sizing of the granules is necessary so that the die cavities for tablet compression may be completely and rapidly filled by the free-flowing granulation. Voids or air spaces left by too large a granulation result in the production of uneven tablets.

183. 10/07/2016 Sagar Kishor Savale 183 Adding Lubrication and Blending After dry screening, a dry lubricant is dusted over the spread-out granulation through a fine- mesh screen. Lubricants contribute to the preparation of compressed tablets in several ways: They improve the flow of the granulation in the hopper to the die cavity. They prevent adhesion of the tablet formulation to the punches and dies during compression. They reduce friction between the tablet and the die wall during the ejection of the tablet from the machine. They give a sheen to the finished tablet

184. 10/07/2016 Sagar Kishor Savale 184 Among the more commonly used lubricants are: magnesium stearate calcium stearate stearic acid talc, sodium stearyl fumarate . Magnesium stearate is most used. The quantity of lubricant used varies from one operation to another but usually ranges from about 0.1% to 5% of the weight of the granulation.

185. 10/07/2016 Sagar Kishor Savale 185

186. 10/07/2016 Sagar Kishor Savale 186 ALL-IN-ONE GRANULATION METHODS Technologic advances now allow the entire process of granulation to be completed in a continuous fluid bed process , using a single piece of equipment, the fluid bed granulator.

187. 10/07/2016 Sagar Kishor Savale 187 The fluid bed granulator performs the following steps: preblending the formulation powder, including active ingredients, fillers, and disintegrants, in a bed with fluidized air granulating the mixture by spraying onto the fluidized powder bed, a suitable liquid binder, such as an aqueous solution of acacia, hydroxypropyl cellulose, or povidone drying the granulated product to the desired moisture content.

188. 10/07/2016 Sagar Kishor Savale 188

189. 10/07/2016 Sagar Kishor Savale 189 Another method , microwave vacuum processing, also allows the powders to be: mixed wetted agglomerated dried within the confines of a single piece of equipment. The wet mass is dried by gentle mixing, vacuum, and microwave. The use of the microwave reduces the drying time considerably, often by one fourth. The total batch production time is usually in the range of 90 minutes. After adding lubricants and screening, the batch is ready for tablet formation or capsule filling.

190. 10/07/2016 Sagar Kishor Savale 190

191. 10/07/2016 Sagar Kishor Savale 191 Advantages of wet granulation Advantages Reduced segregation of formulation components during storage and/or processing Useful technique for the manufacture of tablets containing low and or high concentrations of therapeutic agent Employs conventional excipients and therefore is not dependent on the inclusion of special grades of excipients

192. 10/07/2016 Sagar Kishor Savale 192 Disadvantages of wet granulation Disadvantages Often several processing steps are required Solvents are required in the process: this leads to a number of concerns: Drug degradation may occur in the presence of the solvent The drug may be soluble in the granulation fluid Heat is required to remove the solvent

193. 10/07/2016 Sagar Kishor Savale 193 DRY GRANULATION By the dry granulation method, the powder mixture is compacted in large pieces and subsequently broken down or sized into granules. For this method, either the active ingredient or the diluent must have cohesive properties. Dry granulation is especially applicable to materials that cannot be prepared by wet granulation because they degrade in moisture or the elevated temperatures required for drying the granules.

194. 10/07/2016 Sagar Kishor Savale 194 Slugging After weighing and mixing the ingredients, the powder mixture is slugged, or compressed, into large flat tablets or pellets about 1 inch in diameter. The slugs are broken up by hand or by a mill and passed through a screen of desired mesh for sizing. Lubricant is added in the usual manner, and tablets are prepared by compression. Aspirin, which is hydrolyzed on exposure to moisture, may be prepared into tablets after slugging.

195. 10/07/2016 Sagar Kishor Savale 195 Roller Compaction Instead of slugging, powder compactors may be used to increase the density of a powder by pressing it between rollers at 1 to 6 tons of pressure. The compacted material is broken up, sized, and lubricated, and tablets are prepared by compression in the usual manner. The roller compaction method is often preferred to slugging. Binding agents used in roller compaction formulations include Methylcellulose hydroxy methylcellulose (6% to 12%), which can produce good tablet hardness and friability.

196. 10/07/2016 Sagar Kishor Savale 196 Advantages of dry granulation These methods are not generally associated with alterations in drug morphology during processing. No heat or solvents are required.

197. 10/07/2016 Sagar Kishor Savale 197 Disadvantages of dry granulation Specialist equipment is required for granulation by roller compaction. Segregation of components may occur mixing. There may be issues regarding powder flow. The final tablets produced by dry granulation tend to be softer than those produced by wet granulation Slugging and roller compaction lead to the generation of considerable dust

198. 10/07/2016 Sagar Kishor Savale 198

199. 10/07/2016 Sagar Kishor Savale 199

200. 10/07/2016 Sagar Kishor Savale 200 DIRECT COMPRESSION TABLETING Some granular chemicals, like potassium chloride, possess free-flowing and cohesive properties that enable them to be compressed directly in a tablet machine without any need of granulation. For chemicals lacking this quality, special pharmaceutical excipients may be used to impart the necessary qualities for the production of tablets by direct compression. These excipients include fillers, such as: spray-dried lactose microcrystals of alpha-monohydrate lactose sucrose–invert sugar–corn starch mixtures microcrystalline cellulose crystalline maltose dicalcium phosphate

201. 10/07/2016 Sagar Kishor Savale 201 Disintegrating agents , such as: direct compression starch sodium carboxymethyl starch cross-linked carboxymethylcellulose fibers cross-linked polyvinylpyrrolidone lubricants , such as: magnesium stearate talc Glidants , such as fumed silicon dioxide

202. 10/07/2016 Sagar Kishor Savale 202 Advantages and disadvantages of direct compression Advantages: Low labour input A dry process Fewest processing steps Disadvantages : Stratification (layers) may occur due to differences in particle size and bulk density which results poor content uniformity. A large dose drug may cause problem in direct compression. It requires diluents. The tablet becomes large in size which is difficult to swallow and also costly. During handling of dry materials static charge may form which may present uniform distribution of drug. Direct compression diluent may interact with the drug. For example, amine drug with Lactose produce discoloration of tablet

203. 10/07/2016 Sagar Kishor Savale 203

204. 10/07/2016 Sagar Kishor Savale 204 WET GRANULATION DRY GRANULATION DIRECT COMPRESSION 1. Milling and mixing of drugs and excipients 1. Milling and mixing of drugs and excipients 1. Milling and mixing of drugs and excipients 2 .Preparation of binder solution 2. Compression into slugs or roll compaction 2. Compression of tablet 3. Wet massing by addition of binder solution or granulating solvent 3. Milling and screening of slugs and compacted powder 4. Screening of wet mass 4. Mixing with disintegrant /lubricant 5. Drying of the wet granules 5. Compression of tablet 6. Screening of dry granules 7. Blending with disintegrant / lubricant and 8. Compression of tablet

205. 10/07/2016 Sagar Kishor Savale 205 Compression process Filling : By gravitational flow (or mechanical conveyors) of powder from hopper via the die table into die. The die is closed at its lower end by the lower punch. Compression: The upper punch descends and enters the die and the powder is compressed until a tablet is formed. During the compression phase, the lower punch can be stationary or can move upwards in the die. After maximum applied force is reached, the upper punch leaves the powder Ejection: During this phase, the lower punch rises until its tip reaches the level of the top of the die. The tablet is subsequently removed from the die and die table by a pushing device.

206. 10/07/2016 Sagar Kishor Savale 206

207. 10/07/2016 Sagar Kishor Savale 207

208. 10/07/2016 Sagar Kishor Savale 208 Tablet compression machine Hopper for holding and feeding granulation to be compressed Dies that define the size and shape of the tablet Punches for compressing the granulation within the dies Cam tracks for guiding the movement of the punches Feeding mechanisms for moving granulation from the hopper into the die Tablet ejector

209. 10/07/2016 Sagar Kishor Savale 209

210. Solid dosage processing Dosage forms Quality factors Excipients Particle properties Processing routes Unit operations Size reduction (milling) Blending Dry granulation (roll compaction) Wet granulation Drying Tablet compaction Coating 210 10/07/2016 Sagar Kishor Savale

211. Models at different scales 211 10/07/2016 Sagar Kishor Savale

212. Product and process functions Product function Product property: Content uniformity, dissolution, flowability, dust formation Particle Properties: Particle size, particle shape, surface characteristics Process function Process parameters: Type of unit operation, operational parameters 212 10/07/2016 Sagar Kishor Savale

213. Particle properties Product property = F( particle properties , formulation) 213 10/07/2016 Sagar Kishor Savale

214. Mean particle size and flowability 214 10/07/2016 Sagar Kishor Savale

215. Size distributions for various powders 215 10/07/2016 Sagar Kishor Savale

216. Powder flow and tablet weight variations 216 10/07/2016 Sagar Kishor Savale

217. Processing routes Fill die Coating, Packaging etc.. Compress Tablet Direct Compression Drug Diluent Glidant Disintegrant Lubricant Mixing Mixing Dry Granulation Disintegrant Glidant Lubricant Drug Diluent Lubricant Mixing Compression Comminution Screening Mixing Mixing Wetting Granulation Drying Screening Mixing Drug Diluent Binder Solvent Disintegrant Glidant Lubricant Wet Granulation Other Routes Fluidized bed granulation Extrusion / rotary granulation Tablet Compression 217 10/07/2016 Sagar Kishor Savale

218. Unit operations Unit Operation Every separate manufacturing step. Unit Dose Operations Determined by what manufacturing steps are needed to combine the active ingredient with other needed ingredients to make a quality finished product. Type of unit operation Dispensing Milling/Screening Blending Granulation Drying Compression Coating Packaging 218 10/07/2016 Sagar Kishor Savale

219. Dispensing One of the most critical steps in pharmaceutical manufacturing manual weighing on a weight scale with material lifting assistance like vacuum transfer and bag lifters automated weighing Issues: dust control (laminar air flow booths, glove boxes) weighing accuracy multiple lots of active ingredient with different assays, moisture and residual solvent content cross contamination 219 10/07/2016 Sagar Kishor Savale

220. Dispensing is the first step in any pharmaceutical manufacturing process. Dispensing is one of the most critical steps in pharmaceutical manufacturing; during this step, the weight of each ingredient i n the mixture is determined according to dose. Issues like: weighing accuracy, dust control (laminar air flow booths, glove boxes), during manual handling, lot control of each ingredient, material movement into and out of dispensary should be considered during dispensing. 220 10/07/2016 Sagar Kishor Savale

221. Raw Material Dispensing Record 221 10/07/2016 Sagar Kishor Savale

222. Considerations Theoretical quantity of API [100% assay (anhydrous) and nil water] = 30 Kg 222 10/07/2016 Sagar Kishor Savale

223. Milling/Screening 223 10/07/2016 Sagar Kishor Savale

224. Particle size reduction The sizing (size reduction, milling, crushing, grinding, pulverization) is an impotent step (unit operation) involved in the tablet manufacturing. In manufacturing of compressed tablet, the mixing or blending of several solid ingredients of pharmaceuticals is easier and more uniform if the ingredients are approximately of same size. Advantages associated with size reduction in tablet manufacture are as follows: i) It increases surface area, which may enhance an actives dissolution rate and hence bioavailability. ii) Improved the tablet-to-tablet content uniformity by virtue of the increased number of particles per unit weight. iii) Improved flow properties of raw materials. iv) Improved colour and/or active ingredient dispersion in tablet excipients . 224 10/07/2016 Sagar Kishor Savale

225. Excessive heat generation can lead to degradation, change in polymorphic form Increase in surface energy can lead to agglomeration May result in excessive production of fines or overly broad particle size distribution 225 10/07/2016 Sagar Kishor Savale

226. Forces in milling Shear (cutting forces) Compression (crushing forces) Impact (high velocity collision) Griffith theory T = Tensile stress Y = Young’s modulus ε = Surface energy c = fault length 226 10/07/2016 Sagar Kishor Savale

227. Milling equipment – screen mills Critical parameters for a conical screen mill Screen Hole Size/Shape Impeller Type Impeller Clearance Speed Evaluate impact on aspirin granulation Particle size reduction Milling time and energy requirements Overall milling performance Milling Work Index = Size reduction / Milling work Milling Time Index = Size reduction / Milling time 227 10/07/2016 Sagar Kishor Savale

228. Screen hole size has largest impact on particle size reduction, milling time and energy requirements Milling work index significantly lower for smaller screen hole sizes Impeller type has largest effect on overall milling performance Impeller clearance not significant at small clearances Milling work index lower at higher mill speeds Deflection of material away from screens 228 10/07/2016 Sagar Kishor Savale

229. Milling equipment – impact mills Significant wear on surfaces Hammer mills Medium to coarse size reduction Peripheral speed 20-50 m/sec Pin mills Peripheral speed up to 200 m/sec Capable of fine grinding Can be used to mill sticky materials 229 10/07/2016 Sagar Kishor Savale

230. Milling equipment – jet mill Superfine to colloid size reduction Can be used for heat sensitive products Different configurations Pancake (spiral) jet mill Fines exit from center Loop/oval jet mill Fines exit from top Opposing jet mills Particles impact each other in opposing jets Fluidized bed jet mill Particles are jetted towards center (low wear on equipment) Fixed/moving target jet mills Particles impact on surface of target (wear can be significant) 230 10/07/2016 Sagar Kishor Savale

231. Milling equipment – stirred media mill Critical parameters Agitator speed Feed rate Size of beads Bead charge Density of beads Design of blades Mill chamber Residence time 231 10/07/2016 Sagar Kishor Savale

232. Mill selection 232 10/07/2016 Sagar Kishor Savale

233. Energy based analysis – ball mill Macroscale energy-size relationships (Chen et al., 2004) Calculate specific energy for a given size reduction Functional form derived from theoretical considerations Rittinger’s model Energy required for particle size reduction is proportional to the area of new surface created Kick’s model Energy required to break a particle is proportional to the ratio of the particle volume before reduction to the volume after reduction 233 10/07/2016 Sagar Kishor Savale

234. Energy based analysis – ball mill Size Reduction of α –Lactose Monohydrate in a Ball Mill 234 10/07/2016 Sagar Kishor Savale

235. Milling/Screening Principle: Mixing or blending is more uniform if ingredients are of similar size 235 10/07/2016 Sagar Kishor Savale

236. Manufacturing Instructions screening 236 10/07/2016 Sagar Kishor Savale

237. Blending 237 10/07/2016 Sagar Kishor Savale

238. Powder Blending The powder/granules blending are involved at stage of pre granulation and/or post granulation stage of tablet manufacturing. Each process of mixing has optimum mixing time and so prolonged mixing may result in an undesired product. So, the optimum mixing time and mixing speed are to be evaluated. Blending step prior to compression is normally achieved in a simple tumble blender. The various blenders used include blender, Oblicone blender, Container blender, Tumbling blender , Agitated powder blender, etc. 238 10/07/2016 Sagar Kishor Savale

239. Blending – diffusion mixing Critical parameters Blender load Blender speed Blending time V-Blender Cross Flow Blender Bin Blender Double Cone Blender 239 10/07/2016 Sagar Kishor Savale

240. Blending – convective mixing Ribbon Blenders Orbiting Screw Blenders Planetary Blenders Horizontal Double Arm Blenders Forberg Blenders Vertical High Intensity Mixers Horizontal High Intensity Mixers Diffusion Mixers with Intensifier/Agitator 240 10/07/2016 Sagar Kishor Savale

241. Blending Blending is the most difficult operation in the manufacturing process since perfect homogeneity is practically impossible due to differences in size, shape and density of particles 241 10/07/2016 Sagar Kishor Savale

242. Mixer and blender 242 10/07/2016 Sagar Kishor Savale

243. Granulation 243 10/07/2016 Sagar Kishor Savale

244. Dry Granulation The dry granulation process is used to form granules without using a liquid solution because the product to be granulated may be sensitive to moisture and heat. Forming granules without moisture requires compacting and densifying the powders. In this process the primary powder particles are aggregated under high pressure. Dry granulation can be conducted under two processes; either a large tablet (slug) is produced in a heavy duty tabletting press or the powder is squeezed between two rollers to produce a sheet of materials (roller compactor, commonly referred to as a chilsonator ). 244 10/07/2016 Sagar Kishor Savale

245. Advantage: A void exposure of the powder to moisture and heat. Used for powders of very low bulk density to ↑ their bulk density. Disadvantage: Tablet disintegration and dissolution may be retarded due to double lubrication and compaction 245 10/07/2016 Sagar Kishor Savale

246. Steps of Dry Granulation • The blend of finely divided powders is forced into the dies of a large capacity tablet press . • Then, compacted by means of flat faced punches (Compacted masses are called slugs and the process is slugging) or roll compactor to produce sticks or sheets . • Slugs or sheets are then milled/screened to produce granules (flow more than the original powder mixture ). 246 10/07/2016 Sagar Kishor Savale

247. Methods of Dry Granulation Slugging technique If a tablet press is used for the compaction process, the term slugging is used. But since particles with a small particle size do not flow well into the die of a tablet press, the results are weight differences from one tablet (slug) to another. This in turn causes large fluctuations in the forces applied onto the individual slugs, with translates in variations of the slug’s mechanical strength. Therefore, the properties of these granulates obtained by milling the slugs cannot be controlled well either. This is one of the main reasons why slugging is hardly used any more as a dry granulation method . 247 10/07/2016 Sagar Kishor Savale

248. B. Roller compaction technique A Roller compactor generally consist of three major units : A feeding system , which conveys the powder to the compaction area between the rolls A compaction unit , where powder is compacted between two counter rotating rolls to a ribbon by applying a force A size reduction unit , for milling the ribbons to the desired particle size. 248 10/07/2016 Sagar Kishor Savale

249. Roll compaction Critical parameters Roll speed and pressure Horizontal and vertical feed speed, deaeration Roll diameter and surface Advantages Improve powder flow Reduce segregation potential No moisture addition, drying 249 10/07/2016 Sagar Kishor Savale

250. Johanson’s theory Slip region Nip region Compressibility Eff. angle of friction Wall angle of friction 250 10/07/2016 Sagar Kishor Savale

251. Eff. angle of friction and peak pressure ( Johanson’s theory) 251 10/07/2016 Sagar Kishor Savale

252. Eff. angle of friction and nip angle ( Johanson’s theory) Eff. Angle of Friction Nip Angle 252 10/07/2016 Sagar Kishor Savale

253. Eff. angle of friction and nip angle ( Johanson’s theory) 253 10/07/2016 Sagar Kishor Savale

254. Effect of lubrication on peak roll pressure 254 10/07/2016 Sagar Kishor Savale

255. 255 10/07/2016 Sagar Kishor Savale Effect of lubrication on nip angle

256. 10/07/2016 Sagar Kishor Savale 256 Effect of entrained air on feeding and discharging

257. 10/07/2016 Sagar Kishor Savale 257 Characterization of flowability Hausner ratio = tapped density / bulk density Excellent 1.05 –1.10 Good 1.11–1.15 Fair 1.15–1.20 Passable 1.21–1.25 Poor 1.26–1.31 Very Poor 1.32–1.37 Extremely Poor 1.38–1.45

258. 10/07/2016 Sagar Kishor Savale 258 Roll compaction and flow properties Soares et al. (2005), Dry granulation and compression of spray dried plant extracts, AAPS PharmSciTech Before Compaction (poor) After Compaction (excellent)

259. 10/07/2016 Sagar Kishor Savale 259 Recent Advances in Granulation Techniques Steam Granulation : Modification of wet granulation; steam is used as a binder instead of water; granules are more spherical and exhibit higher rate of dissolution Melt Granulation / Thermoplastic Granulation : Granulation is achieved by the addition of meltable binder i.e. binder is in solid state at room temperature but melts in the temperature range of 50 – 80˚C [e.g. PEG (water soluble), stearic acid, cetyl or stearyl alcohol (water insoluble)] - drying phase unnecessary since dried granules are obtained by cooling them to room temperature Moisture Activated Dry Granulation (MADG) : Involves distribution of moisture to induce agglomeration – drying time is reduced

260. 10/07/2016 Sagar Kishor Savale 260 Moist Granulation Technique (MGT) : A small amount of granulating fluid is added to activate dry binder and to facilitate agglomeration. Then a moisture absorbing material like Microcrystalline Cellulose (MCC) is added to absorb any excess moisture making drying step unnecessary. Mainly employed for controlled release formulations Thermal Adhesion Granulation Process (TAGP) : Granules are prepared by moisturizing excipient mixtures with very little solvent in a closed system (tumble mixing) with low heating – mainly employed for preparing direct compression formulations Foam Granulation : Binders are added as aqueous foam

261. 10/07/2016 Sagar Kishor Savale 261 Drying Tray dryer Fluid bed dryer

262. 10/07/2016 Sagar Kishor Savale 262 Drying is a most important step in the formulation and development of pharmaceutical product. It is important to keep the residual moisture low enough to prevent product deterioration and ensure free flowing properties. The commonly used dryer includes Fluidized bed dryer, Vacuum tray dryer, Microwave dryer, Spray dryer, Freeze dryer, Turbo - tray dryer, Pan dryer, etc. Drying

263. 10/07/2016 Sagar Kishor Savale 263 • A process of evaporating the liquid contained within aggregates produced by a wet granulation process to a predetermined moisture content  • Accomplished via 1. Tray dryer (direct contact with heating medium) 2. Fluidized bed dryer (indirect contact of the product with the heating medium Drying Process

264. 10/07/2016 Sagar Kishor Savale 264 Drying Purpose: To reduce the moisture level of wet granules What are the problems What are the equipment Why do it Over drying (bone dry) Excess fines Possible fire hazard Direct Heating Static Solids Bed Dryers Direct Heating Moving Solids Bed Dryers Fluid Bed Dryer Indirect Conduction Dryers To keep the residual moisture low enough (preferably as a range) to prevent product deterioration Ensure free flowing properties

265. 10/07/2016 Sagar Kishor Savale 265 Manufacturing Instructions drying Drying SOP No.: LOD: 1.0-2.5% (moisture balance at 105ºC) Date Verified by Performed by Time end Time start Instructions Step √ √ √ √ √ √ √ √ √ √ FBD in let temp 60ºC Damper 80% open for 15 min Damper 50% open after 15 minutes ; LOD ……..% 3.2

266. 10/07/2016 Sagar Kishor Savale 266 Fluid bed drying Air Flow Inlet Filter Condensor Steam Damper Damper Outlet Filter Air Flow Product Temperature Inlet Temperature Outlet Temperature From Granulator To Mill Drying Zone Filter Bag Air Flow Retaining Screein

267. 10/07/2016 Sagar Kishor Savale 267 Single machines utilized for both the wet granulation and drying process in one unit operation. Use Fluid Bed Dryer ( FBD) It is a multiple step process performed in the same vessel to mix, granulate and dry the powders. Combines wetting the powders to for granules &then, drying them in the same piece of equipment. Fluid bed drying

268. 10/07/2016 Sagar Kishor Savale 268 A. Reduced product handling B. Closed process suitable to:  Gentle product handling. Intensive mixing of the solid material. Uniform spraying of all particles in the fluid bed. Uniform, reproducible product quality. Potent compounds Minimizing product/operator exposure Minimizing cross contamination and product loss  Reduced cleaning and overall process time  Reduced equipment and floor space requirements Advantages of Fluid bed drying

269. 10/07/2016 Sagar Kishor Savale 269 Tablet Compaction

270. 10/07/2016 Sagar Kishor Savale 270 Powders intended for compression into tablets must possess two essential properties : Powder fluidity The material can be transported through the hopper into the die to produce tablets of a consistent weight Powder flow can be improved mechanically by incorporate the glidant . Powder compressibility The property of forming a stable, intact compact mass when pressure is applied. Tablet Compaction

271. 10/07/2016 Sagar Kishor Savale 271 The term “direct compression” is defined as the process by which tablets are compressed directly from powder mixture of API and suitable excipients. It involves only two unite operations powder mixing and tableting. Advantages of Direct Compaction: Reduced production time &cost. Product stability can be improved. Faster drug dissolution due to fast disintegration into primary particles. less number of equipment are required, less process validation Elimination of heat and moisture, thus increasing not only the stability but also the suitability of the process for thermo-labile and moisture sensitive API’s. The chances of batch-to-batch variation are negligible, because the unit operations required for manufacturing processes is fewer. Direct compression

272. 10/07/2016 Sagar Kishor Savale 272 Disadvantages of Direct Compaction Large particles must be used → (acceptable flowability and bulk density) Many active ingredients are not compressible either in crystalline or amorphous forms. Needs directly compressible filler that is usually expensive, e.g. microcrystalline cellulose ( Avicel ), spray dried lactose Problems in the uniform distribution of low dose drugs. High dose drugs having high bulk volume, poor flowability and poor compressibility are not suitable for direct compression. For example , Aluminium Hydroxide, Magnesium Hydroxide Non-uniform distribution of colour , especially in tablets of deep colours Direct compression

273. 10/07/2016 Sagar Kishor Savale 273 Design: 1. Hopper for holding and feeding granules or powder to be compressed. 2. Dies that define the size and shape of the tablet. 3. Punches for compressing the granules within the dies. 4. Cam tracks for guiding the movement of the punches. 5. A feeding mechanism for moving granules from the hopper into the dies. Tablet Compression Machine

274. 10/07/2016 Sagar Kishor Savale 274 Die filling Gravitational flow of the powder from hopper via the die table into the die. (The die is closed at its lower end by the lower punch ). Tablet formation The upper punch descends, enters the die, the powder is compressed until a tablet is formed. after maximum applied force is reached, the upper punch leaves the powder i.e. compression phase . Tablet ejection The lower punch rises until its tip reaches the level of the top of the die. The tablet is subsequently removed from the die and die table by a pushing device. Stages of Tablet Formation (Compaction Cycle)

275. 10/07/2016 Sagar Kishor Savale 275 Powders fed into a die Powder compressed between punches Tableting Process

276. 10/07/2016 Sagar Kishor Savale 276 Tablet Presses Single Punch Rotary Press High Speed Rotary Press Multi-layer Rotary Press

277. 10/07/2016 Sagar Kishor Savale 277 Single Punch press Core components: D ie Lower punch Upper punch Single Punch press (Eccentric Press ): B ench-top models that make one tablet at a time (single-station presses) Disadvantages: Production of small batches of tablets (200 tablets per minute).

278. 10/07/2016 Sagar Kishor Savale 278 Rotary Press Rotary Press( Multi station Press): It was developed to increase the output of tablets ( 10 000 tablets per minute ), used for Large scale production. It consists of a number of dies and sets of punches (from 3 up to 60 ). The dies are mounted in a circle in the die table and both the die table & the punches rotate t ogether during operation of the machine. Rotary Press machine

279. 10/07/2016 Sagar Kishor Savale 279 The core components and compression cycle of rotary presses A: upper punch B: die cavity C: die D: lower punch The compression is applied by both the upper punch and the lower punch. The compression cycle of a rotary tablet press

280. 10/07/2016 Sagar Kishor Savale 280 Stage 1: Top punch is withdrawn from the die by the upper cam, Bottom punch is low in the die so powder falls in through the hole and fills the die. Stage 2: Bottom punch moves up to adjust the powder weight-it raises and expels some powder Stage 3: Top punch is driven into the die by upper cam; Bottom punch is raised by lower cam. Both punch heads pass between heavy rollers to compress the powder. Stage 4: Top punch is withdraw by the upper cam. Lower punch is pushed up and expels the tablet. Tablet is removed from the die surface by surface plate Stage 5: Return to stage 1 Compression cycle of rotary presses

281. 10/07/2016 Sagar Kishor Savale 281 Tablet tooling; punches and dies

282. 10/07/2016 Sagar Kishor Savale 282 Caplet Shape Dies Oval Shapes Dies Round Shapes Dies Star Shapes Dies Tablet tooling; punches and dies

283. 10/07/2016 Sagar Kishor Savale 283 Compression Principle: Powder/granules are pressed inside a die and compressed by two punches into required size, shape and embossing What are the problems What are the equipment Why do it Poor flow in hopper Inadequate lubrication Capping, chipping, cracking, lamination, sticking, picking, binding, mottling Double compression Multiple Stations (Rotary) and High Speed Tablet Presses To compress powder into tablets

284. 10/07/2016 Sagar Kishor Savale 284 Manufacturing Instructions compression Balance no.: Vernier Caliper no.: Hardness tester no.: Friability tester no.: Disintegration tester no.: Tooling No. of units Checked by Verified by Upper punch: …mm x …mm oval shaped concave embossed……. 55 Lower punch: …mm x …mm oval shaped concave embossed……. 55 Dies: …mm x ….mm oval shaped 1

285. 10/07/2016 Sagar Kishor Savale 285 Manufacturing Instructions compression Parameter Limit Results Machine speed 20 rpm (15-25 rpm) Wt. of 20 tabs 12.00g + 2 (11.76-12.24g) Theoretical weight/tab 600mg Hardness 25Kg (20-30 Kg) Thickness (av. of 10 tabs) 4.10mm + 0.15mm (3.95 – 4.25mm) Length 10mm + 0.1 mm (9.9 – 10.1 mm) Width 5 mm + 0.1mm (4.9 – 5.1 mm) Disintegration time NMT 15 mins Wt. variation + 3% of Av. Wt. Friability (10 tabs) NMT 1.0% w/w

286. 10/07/2016 Sagar Kishor Savale 286 In-process Checks Parameter Frequency Wt. of 20 tabs Every hour by production and every two hours by QA Hardness, thickness, length, width Every hour by production, every two hours by QA Wt. variation Every half hour by production and every hour by QA DT Every half hour by production, every hour by QA

287. 10/07/2016 Sagar Kishor Savale 287 Relative density changes in manufacture of tablets

288. 10/07/2016 Sagar Kishor Savale 288 Equivalence of tablets made with different presses

289. 10/07/2016 Sagar Kishor Savale 289 Packaging

290. 10/07/2016 Sagar Kishor Savale 290 Pharmaceutical manufacturers have to pack their medicines before they can be sent out for distribution. The type of packaging will depend on the formulation of the medicine. 'Blister packs' are a common form of packaging used for a wide variety of products. They are safe and easy to use and they allow the consumer to see the contents without opening the pack. Packaging

291. 10/07/2016 Sagar Kishor Savale 291 Primary packaging is the material that first envelops the product and holds it. This usually is the smallest unit of distribution or use and is the package which is in direct contact with the contents. Secondary packaging is outside the primary packaging – perhaps used to group primary packages together Tertiary packaging is used for bulk handling, warehouse storage and transport shipping. The most common form is a palletized unit load that packs tightly into containers. Packaging Types

292. 10/07/2016 Sagar Kishor Savale 292