Compression and compaction 4rth prof

solid-air interface, Angle of Repose, Flow rates, Mass-volume relationship, Density, Heckel's plot, consolidation, Granulation, Friability, Compression (Dry method, Wet mothed, Slugging), Physics of tabletting, Tabletting machines and other equipments required, Problems involved in tabletting, Tablet Coating, Capsulation (Hard and Soft gel capsules)

1. Compression, consolidation and compaction

2. CO N TENTS Introduction Fundamentals of powder compression Powder flow properties Mass volume relationship References Contents

3. COMPRESSION the reduction in the bulk volume of a material as a result of the removal of the gaseous phase (air) by applied pressure CONSOLIDATION Involves an increase in the mechanical strength of a material resulting from particle-particle interactions. COMPACTION The compression and consolidation of a 2 phase (solid + gas) system due to an applied force.

4. DIFFERENCE BETWEEN COMPRESSION CONSOLIDATION compaction consolidation 1. It is defines as the formation of solid specimen of defined geometry by powder compression. 1 It is increase in mechanical strength of material from particle – particle interaction . 2. The compression takes place in a die by the action of two punches , the lower and upper by which compression force is applied .

5. FUNDAMENTALS OF POWDER COMPRESSION In order to study physics of tabletting process , one should have knowledge about inherent proprties of powders /granules. Attractive forces exist between particles vander Waal’s, H-bonding, Electrostatic consider a number of granules in a die to which a force is applied

6. Inherent properties of powder solids solid-air interface, Powder flow properties ( angle of repose , carr`s index, hausner`s ratio) mass volume relationship, volume density, compressibilty

7. Solid-air interface Cohesion is the attraction between like particle; Experienced by particles in bulk. Adhesion is the attraction between unlike particle; Experienced by particles at surface.

8. Powder flow properties : Powders may be free-flowing or cohesive (Sticky). Many common manufacturing problems are attributes to powder flow. Powder transfer through large equipment such as hopper. Uneven powder flow  excess entrapped air within powders  capping or lamination. Uneven powder flow  increase particle’s friction with die wall causing lubrication problems and increase dust contamination risks during powder transfer.

9. Powder storage, which for example result in caking tendencies within a vial or bag after shipping or storage time. Separation of small quantity of the powder from the bulk-specifically just before the creation of individual doses such as during tableting, encapsulation and vial filling which affect the weight uniformity of the dose (under or over dosage).

10. Powder flow problems

11. Tests to evaluate the flowability of a powder. Carr’s compressibility index. ( will be discussed in comprssibility ) Hausner ratio. The angle of repose (  ).

12. Hausner ratio Tapped density Hausner ratio = Poured or bulk density Hausner ratio was related to interparticle friction: Value less than 1.25 indicates good flow (=20% Carr).

13. Hausner ratio The p o wder with low i n terpar t icle f r ic t i o n , s u ch as coarse spheres. V alue g r e a ter t h an 1 . 5 indic a tes poor flow (= 33 % Carr’s Compressibility Index)). M o re cohesi v e, less f r e e - fl o w i n g p o w d ers s u ch as flakes. Betwe e n 1 . 2 5 and 1 . 5 add e d g l i dant improves flow.  1.5 added glidant doesn’t improve flow. n o r m ally

14. Angle of repose ( Dynamic angle) The maximum angle possible between the surface of pile of non- cohesive (free-flowing) material and the horizontal plane. Angle of repose is an indication of the flow ability of the material.

15. Angle of Repose (θ) θ = tan -1 (h/r) where h = height of pile r = radius of the base of the pile h r Angle of repose Flow property of powder <25 Excellent 25-30 Good 30-40 Passable >40 poor

16. METHODS TO MEASURE ANGLE OF REPOSE . Fixed funnel and free standing cone method. Tilting box method. c.Revolving cylinder method

17. Factors affecting the flow properties of powder Improvement of Powder Flowabilty Particle’s size & Di s t r ibu t ion Particle Shape & texture Su r f ace forces Flow Ac t i v a t o r s

18. Alteration of Particle’s size & Distribution Alteration of Particle shape & texture Alteration of Surface Forces Formulation additives (Flow activators) Factors affecting the flow properties of powder

19. Alteration of Particle’s size & Distribution There is certain particle size at which powder’s flow ability is optimum. Coarse particles are more preferred than fine ones as they are less cohesive. The size distribution can also be altered to improve flowability by removing a proportion of the fine particle fraction or by increasing the proportion of coarser particle’s such as occurs in granulation.

20. Alteration of Particle shape & texture Particle’s Shape General l y , m o r e s p herical part i cles have better fl o w properties than more irregular particles. S p h erical part i cles a re o b tain e d b y s p ray d r y i ng , or by temperature cycling crystallization.

21. Alteration of Particle shape & texture Particle’s texture Particles with very rough surfaces will be more cohesive and have a greater tendency to interlock than smooth surfaced particles.

22. Alteration of Surface Forces Reduct i on o f el e ctros t at i c cha r ges ca n i m p rove flowability. pow d er Ele c trosta t ic cha r ges ca n be reduc e d by a l t e ring process conditions to reduce frictional contacts. Moisture content of particle greatly affects powder’s flowability. A d sorbed s u rface m oisture fi l m s te n d t o in c rease bulk densi t y and reduce porosity. Drying the particles will reduce the cohesiveness and improve the flow. Hygroscopic powder’s stored and processed under low humidity conditions.

23. Formulation additives (Flow activators) Flow ac t ivators are com m o n l y r eferred a s a glidants. Flow activa t ors imp r o v e the f l owabili t y of powders by reducing adhesion and cohesion. e. g. Talc, maize starch and magnesium stearate.

24. VOLUME Open intraparticulate voids : those with in a single particle but open to the external environment. losed interparticulate voids-those within a single particle but closed to the external environment. Interparticulate voids-the air spaces between individual particles. True volume (V T ) Granule volume (V G ) Bulk volume (V B ) Relative volume (V R ) V R = V B / V T V R tends to become unity as all air is eliminated from the mass during the compression process. Mass-Volume relationships

25. D E NSIT Y : The ratio of mass to volume is known as the density of the material Types of Density: True density (ρ T = M / V T ) Granule density (ρ G = M / V G ) Bulk density (ρ B = M / V B ) Relative density (ρ R = M / V R ) M is the mass of powder

26. V Tap = Tapped volume of the same mass of powder ≈ V T Measuring Compressibility: Carr’s (Compressibility) Index = [(V B – V Tap ) / V B ] x 100 ≈ E where V B = Freely settled volume of a given mass of powder Carr’s (Compressibility) Index = [(ρ Tap – ρ B ) / ρ Tap ] x 100 ≈ E where ρ B = Freely settled bulk density of the powder ρ Tap = Tapped bulk density of the powder ≈ ρ T Compressibility: The ability of the powder bed to be compressed (under pressure) and consequently be reduced in volume.

27. Carr’s compressibility index A volume of powder is filled into a graduated glass cylinder and repeatedly tapped for a known duration. The volume of powder after tapping is measure. Tapped density- Poured or bulk density Carr’s inde x (%)= Bulk density= weight/bulk volume Tapped density=weight/true volume X 100 Tapped density

28. Carr’s compressibility index Flow description % Compressibility Excellent flow 5 – 15 Good 16 – 18 Fair 19 – 21 Poor 22 – 35 Very Poor 36 -40 Extremely poor  40 Relationship between powder flowability and % compressibility

29. Consolidation An increase in the mechanical strength of the material resulting from particle or particle interaction. ( Increasing in mechanical strength of the mass)

30. Consolidation Process Cold welding : when the surface of two particles approach each other closely enough , their free surface energies result in strong attractive force , a process known as cold welding. E.g. At separation of less than 50nm Fusion bonding : Multiple point contacts of particles upon application of load produces heat which causes fusion or melting. Upon removal of load it gets solidified & increase the mechanical strength of mass.

31. Consolidation Mechanism Mechanical theory : It occurs btw irregular shaped particles. Also increases the number of contact points btw the particles As the particle undergo deformation , the particle boundaries that the edges of the particles intermesh , forming a mechanical bond. Intermolecular force theory : Under pressure the molecules at the points of true contact between new , clean surface of the granules are close enough so that van der waals force interact to consolidate the particles. E.g , microcrystalline cellulose is believed to undergo significant hydrogen bonding during tablet compression

32. Liquid – Surface film theory : Thin liquid films form which bond the particles together at the particles surface . The energy of compression produces melting of solutions at the particles interface followed by subsequent solidification or crystallization thus in the formation of bonded surface.

33. Factors affecting consolidation The chemical nature of the material. The extent of the available surface. The pressure of the surface contaminants. The inter surface distance.

34. Role of moisture Moisture is necessary for formation of tablets. it can fill the small voids present between the particles. Moisture is also important in wet / moist granulation. A small proportion of moisture content is required in the formulation of tablet. This moisture content is important for the mechanical strength of tablet.

35. If moisture content is less there will be increase in the die wall friction. If moisture content is increased there will be decrease in compact strength . Moisture content is determined by loss on drying given by formula Percentage moisture content= (loss in wt/ initial wt) x 100

36. Eg : As a results of increasing compressional force , result in this water being squeezed out to the surface of the tablet . This expelled moisture may act as a lubricant at the die wall, but it could be cause material to stick to the punch faces .

37. Different types of states during moist granulation Pendular state (powder + binding agent) Funicular state (powder + more binding agent) Capillary state(powder + even more binding agent) Droplet state(powder + even more & more binding agent)

38. Pendular state : This state is occurs at low moisture level. In this state particles are held together by lens shaped rings of liquid . These cause adhesion because of the surface tension force of the liquid – air interface & the hydrostatic suction pressure in the liquid bridge.

39. Funicular state : This state represents an intermediate stage btw the pendular & capillary state. When the air start to displace from btw the particles , the particles arrange in funicular state. After the funicular state ,the particles arrange themselves in capillary state & there is no air btw them.

40. Capillary state : When all the air has been displaced from btw the particles the capillary state is reached . Moist granules tensile strength increases about three times btw the pendular & the capillary state . This state is most desirable state in the process of granulation.

41. Droplet state This is another state in the process but this step is undesirable . This will be important in the process of granulation by spray drying of a suspension.

42. Compression & Consolidation under high loads ( tablet punch forces) Effect of Friction Force Distribution Development of radial force Die-wall lubrication Ejection force

43. 1 . Effect of Friction : Frictional forces are inter particulate friction and die wall friction Inter particulate friction occurs due to particle- particle contact and it is more significant at low applied load .These forces are reduced using glidants. Eg : colloidal silica , talc , corn starch, Die wall friction forces occur from material pressed against die wall and moved, it is dominant at high applied load. These forces are reduced using lubricants like magnesium stearate , talc , stearic acid , waxes etc,

44. 2 . Force distribution : Most investigations are carried out on single station presses or even on isolated punches & die sets in conjugation with hydraulic press, These must be an axial balance of forces. A force is applied on cylinder on top of cylinder of powder mass

45. F A= F L +F D Where… F A …Applied force to the upper punch F L …Force transmitted to lower punch F D …Reaction at die –wall due to friction at surface

46. 3. Development of radial force : As the compressional force is increased & the repacking of tableting mass is completed ,the material may be regard as a single solid body. Then as with all the solids , compressive force applied in one direction (eg: vertical) results in a decrease in ΔH i.e. height In case of unconfined solid body , this would be accompanied by an expansion in the horizontal direction of ΔD. The ratio of these two directional changes is known as poisson ratio (λ) of the material. λ=ΔD/ΔH λ is characteristic constant for each solid

47. Consequently a radial die-wall force F R develops. Materials with larger values of λ gives rise to larger value of F R The relation ship btw F D & F R is given by the expression : F D=µw. F R µW =coefficient of radial die wall friction.

48. 4. Die-wall lubrication Most pharmaceutical tablets formulations requires the addition of a lubricants to reduces friction at the die wall, -Die-wall lubricants function by inter posing a film of low shear strength at the interface btw tableting mass & die-wall there is some chemical bonding btw boundary lubricants & the surface of die-wall as well as at edge of the tablets. -The best lubricants are those of low shear strength but have strong cohesive tendency in direction at right angle to the plane of shear

49. The shear strength of some lubricants Material Shear strength Stearic acid 1. 3 2 Calcium stearate 1. 4 7 Hard paraffin 1.86 Magnesium stearate 1.96 Potassium stearate 3.07

50. 5. Ejection force: Force necessary to eject a finished tablets. Ejection force for a finished tablets consists of 3 stages stage-1 : Peak force required to initiate ejection by breaking tablets / die wall adhesion. stage-2 : Small force , that required to push the tablets up the die wall . stage-3 : Declining force of ejection as the tablets emerges from the die.

51. Radial die wall forces and die wall friction also affects ejection of compressed tablets from die. The force necessary to eject finished tablet is known as ejection force This force can eject tablet by breaking tablet/ die wall adhesion Variation occurs in ejection force when lubrication is inadequate

52. Me a su r ements of fo r ces 1) Strain Gauge A coil of high resistant with length width ratio 2:1 & resistant 100 ohm is suitable. During compression the applied force causes a small elastic deformation of two punches. Strain gauge are connected to punch as close to the compression site . It is deformed as the punch deformed. With the deformation , the length of resistant wire decreases & its diameter is increases. The resulting decrease in resistance I measured by wheat stone bridge as a recording devise. Care must be taken to use low voltage so that heating effect do not interfere with the strain measurement.

53. Diagrametic representation of strain gauge

54. 2 ) Piezo electric load cells : Certain crystals like charge quartz may be used. When subjected to external force these develop an electrical charge proportional to the force. This transducer is connected to amplifier which convert the charge in to dc voltage. The small piezo – electrical transducer are connected to upper & lower punch holder of single station press. The disadvantage is the dissipation of charge with time , hence nit suitable for static measurement .

55. Force volume relationship In many tablets processes , when appreciable force has been applied, the relationship btw applied pressure (p) & volume parameters such as porosity E dose become linear over the range of commonly used pressure. - It can be expressed by shapiro equation Log E =Log E -K.P. Where….E =porosity when pressure is zero K=constant P= pressure - Walker expressed similarly 1/1-E=K 1 -K 2 .Log P

56. Force volume relationship. FIG. Decreasing porosity with increasing compressional force for single ended pressing initial repacking of particles Elastic deformation until elastic limit is reached . Plastic deformation or brittle fracture dominates C ompression of solid crystal lattice formation 2 2 7 7 End of compressional process is when bulk volume = tapped volume. porosity (E)= Decrease in porosity is due to two process: Filling of large spaces by Interparticulate Slippage. Filling of small voids by deformation or fragmentation at high loads. A more complex sequence of events during compression process involves four stage as shown in fig.,

57. The heckel analysis is a most popular method of deforming reduction under compression pressure . In 1961 Heckel postulated a linear relationship between the relative porosity (inverse density ) of a powder and the applied pressure. The slope of the linear regression is the Heckel constant, a material dependent parameter inversely proportional to the mean yield pressure (the minimum pressure required to cause deformation of the material undergoing compression). Large values of the Heckel constant indicate susceptibility to plastic deformation at low pressures, when the tablet strength depends on the particle size of the original powder . The intercept of the line indicates the degree of densification by particle rearrangement .  Compression Study - Heckel equation

58. 2 2 8 8 It is analogous to first order reaction , where the pores in the mass are the reactant , that is : log 1/E = K y P + K r E = porosity P = Applied pressure K y = material dependent constant K y inversely proportional to it’s yield strength (S) ( K y = 1/3S ) K r = initial repacking stage & hence E For cylindrical tablet, P = 4F/ л. D 2 here, P = applied pressure D = tablet diameter F = applied compressional force

59. E = 100×[1 – 4w/ ρ t × л ×D 2 ×H] 2 2 9 9 here, w = weight of tabletting mass. ρ t = true density. H = thickness of tablet. Heckel plot ( summary ): Heckel plot is density v/s applied pressure Follows first order kinetics . As porosity increases compression force also increases Thus the Heckel’s plot allows for the interpretation of the mechanism of bonding . Materials that are comparatively soft & that readily undergo plastic deformation retain different degree of porosity , depending upon the initial packing in the die. This in turn is influenced by the size distribution , shape etc of the original particles . Ex: sodium chloride ( shown by type a in graph) Harder material with higher yield pressure values usually undergo compression by fragmentation first , to provide a denser packing. Ex: Lactose, sucrose ( shown in type b in graph).

60. Type-a ( NaCl ) plots exhibits higher slop (Ky) then type-b. because type-a materials have lower yield stress. Type-b (Lactose) plots exhibits lower slop because brittle , hard materials are more difficult to compress .

61. APPLICATION OF HECKEL PLOT: Used to check lubricant efficacy . For interpretation of consolidation mechanisms .

62. Compression study - Kawakita Equation P a /C = 1/ab + P a /a Where C= degree of volume reduction a,b= constants characteristic to powder being compressed P= pressure it is a plot of p/c v/s p

63. Kawakita Equation modification . C = V i – V p / V t = abP a / 1+ bP a 3 3 C = degree of volume reduction, V i = initial apparent volume, V p =powder volume under applied pressure P a, V t = true volume, a & b = constants.  LIMITATION: Compaction process can be described upto certain pressure, above which the equation is no longer linear.

64. This equation describes the relationship between the degree of volume reduction of the powder column and the applied pressure The basis for the kawakita equation for powder compression is that the particles are subjected to a compressive load in a confined space are viewed as a system in equilibrium at all stages of compression, so that the product of the pressure term and volume term is a constant.

65. Cooper and Eaton Equation. 3 3 1 1  V i – V p / V i – V t = C 2 exp (-K 2 /P a ) + C 3 exp (-K 3 /P a ) C 2, C 3, K 2, K 3 = constants.  LIMITATION : Applies only to single component analysis.

66. G R A NU L ATION

67. C O N T E N T S INTRODUCTION METHODS OF GRANULATION ADVANCED GRANULATION TECHNIQUES CONCLUSION REFERENCES

68. Introduction Granulation: size elargement process in which primary powder particles are made to adhere to form larger , multi particle entities called granules. It is the process of collecting particles together by creating bonds between them .`bonds are formed by slugging or by using binding agents.

69. Need of granulation: To avoid powder segregation. To enhance the flow of powder. To produce uniform mixtures. To produce dust free formulations. To eliminate poor content uniformity. To improve compaction characteristics of mix.

70. To avoid powder segregation . -Segregation may result in weight variation .

71. To enhance the flow of powders. (Higher flowability gives better filling of the dies or containers) To produce uniform mixtures. (Mixtures of various particles tend to segregate in transport or handling because of differences in particle size, shape and density)

72. Dust free formulations. (Decrease dust generation and reduce employee exposure to drug product) To eliminate poor content uniformity.

73. Methods of granulation DIRECT COMPRESSION COMPRESSION GRANULATION WET GRANULATION

74. When To Choose DRY method? Drug dose is too high. Do not compress well after wet granulation. Heat sensitive drugs. Moisture sensitive drugs. e.g. Aspirin , Vitamins

75. Steps in Dry Granulation Compaction of powder Milling Screening

76. This method is carried out By two ways SLUGGING ROLLER C OM P A CTION Large tablet produced in heavy duty tablet press. Powder is squeezed between two rollers to produce sheet of material e.g. Chilsonator

77. Equipments Has two parts, Machine for compressing dry powder to form compacts. Mill for breaking these intermediates to granule. e.g . CHILSONATER HAMMER MILL

78. A d v an t ages Less equipments & space Eliminate need of binder solution Disadvantages No uniform color d i str i bution Process create more dust

79. COMPRESSION granulation It mainly involves three steps - Milling of drug and excipients Mixing of drug and excipients Tablet compression

80. CA P P ING E QUI P M E NTS ARE EXPENSIVE LAMINATION 1/27/2013

81. wet granulation In this, powdered medicament and other excipients are moistened with granulating agent .

82. Steps in wet granulation 1 Mixing of the drug(s) and excipients 2 Mixing of binder solution with powder mix. to form wet mass 3 Coarse screening of wet mass using a suitable sieve . (6-12 # screens) 4 Drying of moist granules. 5 Screening of dry granules through a suitable sieve (14-20 # screen). C on t d…

83. G r anulating liquid - Volatile - N o n - t o xic e.g. Water , Ethanol , Isopropanol Binding agent- Natural Polymers: Starch, P r e g elat i ni z ed Starch synthetic binders : PVP, MC, HPMC, M alt r od e xtrins

84. Limitation of wet gran u lation TIME EQUIPMENTS LOSS OF MATERIAL S P A CE ENERGY L AB O R

85. Methods Single pot granulation High shear mixture granulation Fluid bed granulation Extrusion- Spheronization

86. Single pot granulation The granulation is done in a normal high shear processor and dried in same equipment . e.g. Single Pot Processor / One-Pot Processor

87. Single pot granulator

88. High shear mixture granulation Dry Powder mixing (Approx 2-5 mins ) Liquid binder addition (Approx 1-2 mins) Wet massing Wet sieving of granules Drying Dry sieving of granules

89. Rapid mixer granulator

90. A D V A N T A GES DISADVANTAGES 94 Short processing time. Lesser amount of liquid binders required compared with FBG. Highly cohesive material can be granulated. Increase in temperature may cause chemical degradation of thermolabile material. Over wetting of granules can lead to large size lumps formation.

91. Fluid bed granulation Fluidization is the operation by which fine solids are transformed into a fluid like state through contact with a gas. Granulating and drying can be completed in one step inside the machine.

92. -Homogeneous granules . -- -Gentle product handling. - - Uniform spraying of all particles in the fluid bed . C o n t d…

93. Advantages It reduces dust formation during processing It reduces product loss It improves worker safety . Disadvantages The Fluid Bed cleaning is labor-intensive and time consuming. Difficulty of assuring reproducibility.

94. Extrusion-Spheronization Dry mixing of materials to achieve homogeneous dispersion. Wet granulation of the resulted mixture to form wet mass. Extrusion of wet mass to form rod shaped particles. Rounding off (in spheronizer) Drying

95. Extrusion-Spheronization Different steps involved in the Extrusion- Spheronization process

96. Advanced Granulation Techniques Steam Granulation Melt Granulation Moisture Activated Dry Granulation (MADG) Moist Granulation Technique (MGT) Thermal Adhesion Granulation Process (TAGP) Foam Granulation Pneumatic Dry Granulation (PDG)

97. Freeze granulation Technology Steam Granulation Melt Extrusion Technology Liquisolid Technique TOPO Technology Continuous Flow Technology

98. This process is a modification of conventional wet granulation. Here steam is used as a binder instead of water. Steam Granulation

99. Advantages Uniformly distribution the powder particles. Higher dissolution rate of granules because of larger surface area generated. Time efficient. Maintain sterility.

100. Disadvantages Requires special equipment for steam generation and transportation. Requires high energy inputs. Thermolabile materials are poor candidates. More safety measure required.

101. Here granulation is achieved by the addition of meltable binder. Binder is in solid state at room temperature but melts in the temperature range of 50 – 80˚C. Melted binder then acts like a binding liquid. There is no need of drying phase since dried granules are obtained by cooling it to room temperature. Melt Granulation

102. e.g. Polyethylene Glycol (PEG) 2000, 4000, 6000, 8000 (40-60 C) water soluble binders - water insoluble binders - e.g.. Stearic acid (46-59 C) , Cetyl or stearyl alcohol (56-60 C)

103. - Time and cost effective - Controlling and modifying the release of drugs - Water sensitive drugs are good candidates Advantages -Heat sensitive materials are poor candidates - L ower-melting-point binder may melt/ soften during handling and storage -Higher-melting-point binders require high melting temp. and can contribute instability problems for heat-labile materials. Disa d v anta g es

104. -Drug is blended with diluents and powder -A small amount of water (1-4%) Is sprayed -Agglomerate formation (size 150–500μm) MOISTURE ACTIVATED DRY GRANULATION In MADG, moisture is used to activate granule formation, without the need to apply heat to dry the granules. STAGES AGGLOMERATION MOISTURE DISTRIBUTION/ ABSORPTION - Moisture absorbents like microcrystalline cellulose or silicon dioxide, are added while mixing. -Moisture redistribution within the mixture. Entire mixture becomes relatively dry.

105. Advantages: Applicable to more than 90% of the granulation need for pharmaceutical, food and nutritional industry. Time efficient. Suitable for continuous processing Less energy involved during processing. Disadvantages: 1. Moisture sensitive and high moisture absorbing API are poor candidates .

106. A small amount granulating fluid is added to activate dry binder and to facilitate agglomeration. Moisture absorbing material like Microcrystalline Cellulose (MCC) is added to absorb any excess moisture. Drying step is not necessary. Applicable for developing a controlled release formulation. Moist Granulation Technique (MGT) :

107. Thermal Adhesion Granulation Process (TAGP) - It is applicable for preparing direct tableting formulations. -Mixture of API and excipients are heated to a temp . 30-130ºC . in closed system until granulation. It provides granules with- Good flow properties. Binding capacity to form tablets of low friability. Adequate hardness.

108. FOAM GRA N U L A TION

109. Freeze granulation Technology Developed and adopted by , Swedish Ceramic Institute (SCI). -By spraying a powder suspension into liquid nitrogen, the drops (granules) are instantaneously frozen. In a subsequent freeze- drying the granules are dried by sublimation of the ice without any segregation effects. -Finally it produces spherical, free flowing granules.

110. TOPO Technology HERMES PHARMA has developed unique technology for carrying out single pot granulation. Requires very small quantity of liquid to start the chain reaction Pure water or water-ethanol mixtures are used. Technology produces granules for tablets which contain at least one solid crystalline, organic acid and one alkaline or alkaline earth metal carbonate that reacts with the organic acid in aqueous solution to form carbon dioxide. As a result, there are no solvent residues in the finished products, granules have excellent hardness and stability.

111. The technology does not need any liquid to start the chain reaction. Granulation is carried out in an inclined drum into which powder is fed at one end and granulate is removed at the other. The process produces granule with surface protected by inactive component that do not harm to sensitive API. CF technology can produce up to 12 tons of granules every day Continuous Flow Technology

112. Key Benefits- Sensitive APIs are protected . Granules and effervescents become less sensitive to humidity and high temperature. Granules form extremely stable products. No solvent residues in the final products.

113. Sr. No. Parameters Method 1 Particle Morphology Optical microscopy 2 Particle Size Distribution Sieve analysis, laser light scattering 3 Nature Powder X-Ray Diffraction 4 Surface Area Gas adsorption 5 Granule Porosity Mercury intrusion methods 6 Granule Strength Development of a Formulation 7 Granule Flowability and Density Hopper Method, Density Apparatus G RANULATION C HARACTERIZATION :

114. Physics of tablet compression: In order to study physics of tabletting process , one should have knowledge about inherent proprties of powders /granules. COMPRESSION CYCLE / PROCESS OF COMPRESSION In pharmaceutical tableting , an appropriate volume of granules in die cavity is compressed between an upper & lower punch to consolidate the material into a single solid matrix , which is finally ejected from die cavity as a tablet .

115. EV E NTS IN PROCESS OF COMPRESSION transitional repacking or particle rearrangement Deformation at point of contact Fragmentation Bonding Decompression Ejection

116. TRANSITIONAL REPACKING OR PARTICLE REARRANGEMENT Particle size distribution determines initial repacking.. During initial stage of compression , particle subjected to low pressure , during this particle moves with respect to each other & smaller particle enters in voids between larger particle.. As result volume decreases & density increases spherical particle undergoes lesser rearrangement than irregular particle…

117. DEFORMATION AT POINT OF CONTACT When a force is applied on a material deformation occur . If the deformation disappear completely (return to original shape) upon release of stress , it is said to be ‘ elastic deformation’ A d efor m ation that not recover complete l y aft er removal of stress known as ‘plastic deformation’. The force required initial plastic deformation is known as ‘yield stress’ When granule particle so closely no further filling voids occurs ,hence further increase of compression force cause deformation at point of contact …

118. FRAGMENTATION  Compression forces increases particle starts fragmentation because of high load , particle breaks into smaller fragment leading to formation of new bonding area.  Fragmentation undergoes densification & infiltration of small fragments into voids .

119. BONDING cold welding :- When particle approach each other unsatisfied forces present on their surface leads formation of strong attractive forces called ‘cold welding’.. Fusion bonding:- Particle irregular in shape heat transmission leads increase mechanical strength . Factor affecting bonding:- Chemical nature of material Available surface Presence of surface contaminant

120. DECOMPRESSION The success or failure of intact tablet depends on stress induced by ‘ elastic rebounds ’ & the association deformation produced during decompression & ejection . Capping is due to unaxial relaxation in die cavity .. Ejection As the lower punch rises & pushed tablet upward , there is continues residual die wall pressure & energy may be expanded due to die wall friction.

121. Tablet introduction and manufacturing process

122. INTRODUCTION Tablets are compressed solid unit dosage form containing medicament or medicaments usually circular in shape and may be flat or biconvex. Tablet is defined as a compressed solid dosage form containing medicaments with or without excipients. Pharmaceutical tablets are solid, flat or biconvex dishes, unit dosage form, prepared by compressing a drugs or a mixture of drugs, with or without diluents. It is the most popular dosage form and 70% of the total medicines are dispensed in the form of Tablet.

123. Advantages of tablets : Easy to administered. Easy to dispense. More stable. Accuracy in dose. Bitter and nauseous substance can be easily dispensed. Light and compact. Economical. Sustained release product is possible by enteric coating. Disadvantages of tablets: Problem with compression to crystalline drug. Hygroscopic drugs are not suitable for compressed tablets. Drugs with low or poor water solubility, slow dissolution, may be difficult to formulate. Cost of production may be increase because of coating and encapsulation to remove bitter and unpleasant taste. Swallowing is difficult especially for children and ill (unconscious) patients.

124. 1. Compressed tablet, e.g. Paracetamol tablet 2. Multiple compressed tablets, 3. Delayed release tablet, e.g. Enteric coated Bisacodyl tablet 4. Sugar coated tablet, e.g. Multivitamin tablet (A) Tablets ingested orally 1. Buccal tablet, e.g. Vitamin-c tablet 2. Sublingual tablet, e.g. Vicks Menthol tablet 3. Troches or lozenges 4. Dental cone (B) Tablets used in oral cavity 1. Implantation tablet, e.g. Testosterone tablet 2. Vaginal tablet, e.g. Clotrimazole tablet (c) Tablets administered by other route 1. Effervescent tablet, e.g. Disprin tablet (Aspirin) 2. Dispensing tablet, e.g. Enzyme tablet (Digiplex) 3. Hypodermic tablet 4. Tablet triturates e.g. Enzyme tablet (Digiplex) (D) Tablets used to prepare solution: TYPES OF TABLET

125. TABLETS INGESTED ORALLY Compressed tablet: These are uncoated tablets made by compression of granules. These provides rapid disintegration and drug release. e.g. Paracetamol tablet. Multiple compressed tablet: These tablets are prepared to separate physically or chemically incompatible ingredients or to produce repeat action or prolonged action products. The ingredients of formulation are compressed into a core tablet and the incompatible substance with other excipients are compressed over the previously compressed core tablet. Sustained action tablet: These tablets when taken orally release the medicament in a sufficient quantity as and when required to maintain maximum effective concentration of drug in the blood. Enteric coated tablet: These tablets are coated with the material which does not disintegrate in stomach but passes through as it is i.e. enteric polymer e.g.: Hydroxypropyl methyl cellulose phthalate etc. These tablets dissolve in intestine and are site specific. Sugar coated tablet: The compressed tablets with sugar coating are called sugar coated tablets. It is done to mask the bitter and unpleasant taste and odour of the medicament. It enhances the appearance and protects the drug from atmospheric effects. e.g. Multivitamin tablet Film coated tablet: These are the compressed tablets having a film coating of film coating polymer like hydroxy propyl cellulose, ethyl cellulose , HPMC. It also protects the formulation from atmospheric effects. These are tasteless, have increase in tablet weight and have less elegance. e.g. Metronidazole tablet Chewable tablet: These tablets are chewed in mouth and are broken into small pieces. Disintegration time is reduced and rate of absorption increases. Easily administered for infants and elderly persons. e.g. Antacid tablet

126. ORAL CAVITY TABLETS Buccal Tablets: These tablets are to be placed in buccal pouch or between the gum & lip or cheek. Tablet dissolve & disintegrated slowly & absorb directly. Sublingual Tablet: These tablets are to be placed under the longue. They dissolve & disintegrated quickly & absorbed directly without passing into G.I.T. Buccal and sublingual tablet should be formulated with bland excipients, which do not stimulate salivation. Lozenge tablet & troches: These tablets are designed to exert a local effect on mouth or throat. These tablets are usually used in treatment of sore throat or control coughing. The tablets are usually used to such drug as anaesthetic, antiseptic and antibacterial agent, demulcent, astringent and antitussive agent. Lozenges were earlier called pastilles. Dental cones: These are relatively minor compressed tablet meant for placing them in the empty socket after tooth extraction. Usually, these tablets contain an antibacterial, compound which is released slowly. Prevent the growth of bacteria. These tablets may contain an astringent or coagulant to reduce bleeding. The base for these types is sodium bicarbonate, sodium chloride or it may be amines acid. These cones generally get dissolved in 20 to 40 min time.

127. TABLETS ADMINISTERED BY OTHER ROUTE Implantation tablet: These tablets are placed below the skin or inserted subcutaneously by means of a minor surgical operation and are slowly absorbed. These must be sterile and are made by heavy compression and fusion. e.g. Testosterone tablet. Vaginal tablet: These tablets are meant to dissolve slowly in vaginal cavity. These are ovoid or pear shaped and are used to release steroids, antibacterial and antiseptics etc to avoid infections. e.g. Clotrimazole tablet.

128. TABLETS USED TO PREPARE SOLUTIONS Effervescent tablet: These tablets when added in water produce effervescence. So they dissolved rapidly in water due to the chemical reaction which takes place between alkali bicarbonate and citric acid or tartaric acid. These tablets are to be protected from atmospheric moisture during storage (in well closed container). e.g. Disprin tablet (Aspirin) Dispensing tablet: These are intended to be added to a given volume of water to produce a solution of a given concentration. The medicaments given are silver proteinate and quaternary ammonium compounds. These are highly toxic if taken orally and great care must be taken in packaging and labelling. e.g. Enzyme tablet (Digiplex) Hypodermic tablet: These are compressed tablets which are composed of one or more drugs. These tablets are dissolved in sterile water and administered parenterally. Tablet triturates: These are small cylindrical, moulded or compressed tablets which contains a potent medicament with a diluent. On small scale hand operated whereas for bulk production automated machines are used. e.g. Enzyme tablet (Digiplex)

129. EXCIPIENTS IN TABLET FORMULATION Diluents: The diluent is needed to increase the bulk when quantity of medicament is very small in each tablet. e.g. Lactose, sucrose, sodium chloride, dextrose and starch etc. Disintegrating agents : To break the tablet in smaller particles when swallowed. These acts by three ways: swelling, by producing effervescence and by melting at body temperature. The disintegrating agent is divided into two parts. One part is mixed with other excipients before granules formation and the other is mixed with the dry granules before compression. e.g. Potato, maize, wheat starch etc. Granulating agents : These provides moisture to convert the fine powder into damp mass which after passing through sieve forms granules. e.g Starch paste, acacia, tragacanth. gelatin solution, iso propyl alcohol etc. Glidants: To improve the flow properties of granules. e.g magnesium stearate &Talc

130. Lubricants : To reduce the interparticular friction during compression and between tablet and die wall during ejection of tablet. e.g. Talc & magnesium stearate. Binding agents : these provides strength to the granules to keep the tablet intact and selection of which depends on the type of tablet.e.g. gum tragacanth, methyl cellulose etc. Adsorbing agents : these are used to adsorb volatile oil, liquid extracts and tincture etc. Prevent sticking e.g. Mg stearate, steraric acid etc. Colors, flavors and sweetening agents : 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.

131. Tablets manufacturing Tablets are commonly manufactured by wet granulation, dry granulation or direct compression. These methods may be considered to consist of a series of steps (unit processes) – weighing, milling, mixing, granulation, drying, compaction, (frequently) coating and packaging. Regardless of the method used the unit processes – weighing, milling and mixing, are the same; subsequent steps differ.

132. Primary goals of tablet manufacturing process T o fo r m u l a t e tablets that are stro n g and hard to withsta n d m e chanical sh o ck encountered d u ri n g m an u fact u ri n g, packing, shipping, dispensing and use. To formulate tablets that are uniform in weight and in drug content. To formulate tablets that are bioavailable according to indication requirements. To formulate tablets that are chemically and physically stable over a long period of time. To formulate tablets that have elegant product identity which is free from any tablet defects.

133. Personnel requirements during manufacture of pharmaceutical tablets Production pharmacists/ supervisors Manufacturing chemist Analytical chemist Quality assurance manager Machine operators Mechanics

134. Tablet Manufacturing Equipment/ Machines Common equipment used in pharmaceutical tablet manufacturing include: 1. Size reduction equipment e.g., Hammer mill , roller mill , fluidized energy mill , cutter mill and ball mill 2. Weighing balance/ balances e.g., bulk weighing balance (weighs in kilogram), electronic weighing balance (weighs in grams and milligrams).

135. 3. Mixing equipment e . g . , p n eu m atic tumbling m i x ers d i f f u sion/ m i x ers ( e. g . , V - b l ende r , dou b le con e b l ende r , cubic mixer, drum blender),

136. Granulators e.g. , Rotating shape granulators , dry granulator , high shear granulator etc Drying equipment e.g. spray dryer , rotary dryer , fluidized bed dryer etc Tableting machine e.g. single punch tablet press and multi station /rotary tablet press

137. 7. Quality control equipment e.g., disintegration equipment , USP Dissolution Tester, Tablet Hardness Tester, Tablet Thickness Tester, Tablet Friability Testers etc. Coating and polishing machines for coated tablets e.g., standard coating pan, perforated pan, fluidized bed/ Air suspension coating system etc. Packaging machines e.g., blister p a ckaging m a ch i n e s, s t rip p a cki n g m ac h i ne, al u m i n i u m f o il p a c k aging machine, etc.

138. Layout of Tablets manufacturing section

139. Procedure for Manufacturing Tablets Dispensing: Each ingredient in the tablet formula is weighed and accurately dispensed as per dose. This is one of the critical steps in any type of formulation process and should be done under technical supervision. Sizing: Formulation ingredients must be in finely divided form, otherwise, size reduction should be carried out for better flow property and easy mixing.

140. P o w der s u i table blending: Powders b l ender to obta i n are m i x ed u s i n g a a u n if o rm a n d homogeneous powder mix. The drug substance and excipients are mixed in geometric dilution. Granulation: Here small powder particles are gathered together into layers, and permanent aggregates to render them into free-flowing states. Drying and dry screening: Screened wet granules need to be dried for a particular time period in tray dryer or fluid bed dryer at controlled temperature not exceeding 550 degree C . Dried granules are screened through the appropriate mesh screen

141. Tablet compression: This step involves the compression of granules into a flat or convex, round, oblong, or unique shaped, scored or unscored tablets; engraved with an identifying symbol and/ or code number using tablet press . Coating: Tablets and granules are coated if there is need to mask the unpleasant taste/odour of some drug substance or to increase the aesthetic appeal of uncoated tablets as well as to modify the release or control the release of drug substance from tablets. This is achieved by enclosing or covering the core tablet or granules with coating solutions.

142. Methods used in tablet Formulation Tablets are commonly manufactured by Wet granulation Dry granulation or Direct compression

143. WET GRANULATION Wet granulation is a widely used method for the production of compressed tablet. It is essentially a process of size enlargement involving several steps and the use of an adhesive substance known as binder. Th e g r a n ule s p r oduce d u s ing this m e thod of me e ti n g all g r anul a t i o n ha s a g r e a t er p r obabil i ty of the p h y s i c al r equ i r eme n ts f or tablet formation.

144. FLOW CHAT OF WET GRANULATION

145. M e thod s : Weighing, milling and mixing of the APIs with powdered excipients (excluding the lubricant) Preparation of binder solution Mixing of binder solution with powders to form a damp mass Screening the dampened powder into pellets or granules (wet screening) using 6- to 12-mesh screen Drying of moist granules

146. Sizing the granulation by dry screening using 14- to 20-mesh screen M i x ing of the drie d g r anules w ith lubri c a n t and disintegrates Compression of granules into tablets

147. 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 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.

148. DRY GRANULATION The formation of granules by compacting powder mixtures into large pieces or compacts which are subsequently broken down or sized into gr a nules ( often referred to as dry g r anulat i on, double compression o r pre- compression) is a possible granulation method which, however, is not widely used in the manufacture of tablets.

149. Flow chat of dry granulation

150. Dry granulation method W eighing a n d Milli n g of f orm u l a t i on ingredients (drug substance and excipients) Mixing of milled powders. Compression of mixed powders into slugs. Milling and sieving of slugs. Mixing with disintegrate and lubricant. Compression into tablet.

151. Advantages These methods are not generally associated with alterations in drug morphology during processing. No heat or solvents are required. Disadvantages 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.

152. DIRECT COMPRESSION direct compression involves direct compression of powdered materials into tablets without modifying the physical nature of the materials itself. Dir e ct compression a v oids with many o f t he wet and dry probl e ms ass o ciated granulations.

153. Its successful application in tablet formulation rests on two fundamental issues: The availability of suitable excipients The availability of suitable machinery.

154. Flow chat of direct compression

155. Dry granulation method . Milling of therapeutic agent and excipients Mixing o f milled powd e rs, dis i ntegrates and lubricants Compression into tablet

156. TABLET COATING: Reasons for coating: To mask unpleasant taste and odour. To improve the appearance of tablets. To prevent the medicament from atmospheric effects. To control the site of action of drugs. To produce the sustained release product. Methods of tablet coating : Sugar coating: Film coating Enteric coating.

157. SUGAR COATING: Steps of sugar coating of tablet: 1. 2. 3. 4. 5. 6. Sieving :- The tablets to be coated are shaken in a suitable sieve to remove the fine powder or broken pieces of tablets. Sealing :- Sealing is done to ensure that a thin layer of water proof material, such as, shellac or cellulose acid phthalate is deposited on the surface of the tablets. The shellac or cellulose acid phthalate is dissolved in alcohol or acetone & its several coats are given in coating pan. A coating pan is made up of copper or stainless steel. The pan is rotated with the help of an electric motor. Sub coating :- In sub coating several coats of sugar & other material such as Gelatin, Acacia etc. are given to round of tablet and to help in building up to tablet size. Several coats of concentrated syrup containing acacia or gelatin are given. After each addition of the syrup, dusting powder is sprinkled. The dusting powder is a mixture of starch, talc & powdered acacia. Syrup coating :- This is done to give sugar coats, opacity & colour to tablets. Several coats of the syrup are applied. Colouring materials & opacity agent are also added to the syrup The process of coating is repeated until uniform coloured tablets are obtained. Finishing :- Three to four coats of sugar are applied in rapid succession without dusting powder and cold air is circulated to dry each coat. Thus forms a hard smooth coat. Polishing :- Beeswax is dissolved in organic solvent and few coats of it are given. The finished tablets are transferred to a polishing pan is rotated at a suitable speed so the wax coated tablets are rubbed on the canvas cloth. This gives a proper shining to the tablets. Sugar coating is an art.

158. FILM COATING: In this tablets are coated by a single or mixture of film forming polymers, such as Hydroxypropyl methyl cellulose, Hydroxy ethyl methyl cellulose, methyl cellulose, carbowax, PEG 400 etc. the polymer is dissolved in some volatile organic solvent and is sprayed over the tablets in a rotating pan. It is also used to make tablets waterproof before sugar coating. Film coating may be enteric or non enteric. Advantages: It is a less time consuming technique. Not much labour is required. It has no adverse affect on disintegration of tablets. Product cost is less. It protects the drug from the atmospheric changes such as light, air and moisture. Coating is resistant to cracking and chipping. It does not increase the weight of the tablet. No waterproofing is required before actual film coating.

159. ENTERIC COATING : Enteric Coated tablet: These tablets are coated with the material which does not disintegrate in stomach but passes through as it is i.e. enteric polymer e.g.: Hydroxypropyl methyl cellulose phthalate etc. These tablets dissolve in intestine. These are site specific. Enteric coating is given to the tablets when: Medicaments produce severe irritation in stomach. Action required in intestine. Medicament may decompose or destroyed by stomach pH. Drug absorption is better in intestine. Delayed action is needed.

160. MICROENCAPSULATION: Microencapsulation: Micro-encapsulation is a process in which tiny particles or droplets are surrounded by a coating to give small capsules of many useful properties. In a relatively simple form, a microcapsule is a small sphere with a uniform wall around it. The material inside the microcapsule is referred to as the core, internal phase, or fill, whereas the wall is sometimes called a shell, coating, or membrane. Microencapsulation techniques: The methods are based on: Chemical Processess Mechanical Processess The following techniques are commonly used: Pan coating Fluidised bed coating Coacervation Electrostatic deposition Polymerisation Multi-orifice centrifugal process

161. Most microcapsules have diameters between a few micrometers and a few millimeters. Applications: To mask the bitter taste of drugs like Paracetamol, Nitrofurantoin etc. To reduce gastric and other gastro intestinal (G.I) tract irritations, For eg., sustained release. A liquid can be converted to a solid for easy handling and storage, Hygroscopic properties of core materials may be reduced by microencapsulation. Protection against external environment. Microencapsulation has been employed to provide protection to the core materials Separation of incompatible substance has been achieved by encapsulation .

162. DEFECTS IN TABLETS 1. C apping: In this there is partial or complete removal of top or bottom portion of tablet. R e a s o ns : Excessive fine. Defective punch die. High speed of machine. Granules too dried. Defect can be removed: Setting the die and punch properly. Reduce % of fine. Punches should be polished. Maintain the desire moisture in granules. Maintain the speed at optimum & regulate the pressure of punches.

163. 2. Picking and sticking: The material is removed or picked up by upper punch from the upper surface of the tablet. In the sticking he material stick to the wall of the die cavity. Reasons: Use of worn out die and punch. Use of small quantity of lubricants. Presence of excess moisture in the granules. Scratches on the surface of the face of the punches. Defect in formulation. Defect can be removed: Using new set of die and adding proper quantity of lubricants in granules. Dry granules.

164. 3. Mottling: An unequal distribution of colour on the surface of a coloured tablet. Reasons: Migration of dye in the granules during drying. Use of different coloration of medicaments and excipients. Defect can be avoided: Drying the granules at low temperature. Using the dye which can mask the colour of all medicaments. 4. Weight variation: Weight variation occur during the compression of granules in a tablet machine and the tablet do not have the uniform weight. Reasons for this defect: Granules are not in uniform size. Presence of excess amount of powder in the granules. No proper mixing of lubricants and no uniform flow of granules. During compression change in capacity of die. Variation in the speed of the tablet machine.

165. 5. Hardness variation: The tablet do not have a uniform hardness. It depends on the weight of the material and space between the upper and lower punch during the stage of compression. If volume of the material varies and distance varies between punches, the hardness also varies. 6. Double impression: This effect occur when the lower punch has a monogram or some other engraving on it. During compression, tablet receive an imprint of the punch. Due to some defect in he machine lower punch move slightly upward before ejection of tablet and give second impression. This can be controlled by managing the movement of punch.

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

167. Official tests 1. Size, shape & appearance: General Appearance: The general appearance of a tablet, its identity and general elegance is essential for consumer acceptance, for control of lot- to-lot uniformity and tablet-to-tablet uniformity. The control of general appearance involves the measurement of size, shape, color, presence or absence of odor, taste etc. Size & Shape: It can be dimensionally described & controlled. The thickness of a tablet is only variables. Tablet thickness can be measured by micrometer or by other device. Tablet thickness should be controlled within a ± 5% variation of standard value. Unique identification marking: These marking utilize some form of embossing, engraving or printing. These markings include company name or symbol, product code, product name etc. Organoleptic properties: Color distribution must be uniform with no mottling. For visual color comparison compare the color of sample against standard color.

168. 2. Content of active ingredient Procedure: Perform the assay of 20 tablets as per monograph The result should lie within the range for the content of active ingredient stated in the monograph. If small no. of tablets (min 5) are used then the limits specified in the monograph may be relaxed to the extent indicated in the table. Weight of medicament in each tablet Subtract from the lower limit for sample of Add to the upper limit for sample of 15 10 05 15 10 05 0.12 g or less 0.2 0.7 1.6 0.3 0.8 1.8 >0.12 g &< 0.3 g 0.2 0.5 1.2 0.3 0.6 1.5 0.3 g or more 0.1 0.2 0.8 0.2 0.4 1.0

169. 3. Uniformity of weight: Weigh 20 tablets selected at random and determine their average weight. Not more than 2 of the individual weights may deviate from the average weight by more than the percentage deviation given in the table and none should deviate by more than twice that percentage . Sr. No. Average Wt. of a tablet deviation Percentage (%) 1 80 mg or less 10 2 More than 80 mg and less than 250 mg 7.5 3 250 mg or More 5

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

171. 5. Disintegration test: Disintegration of a tablet means to break a tablet into smaller particles after swallowing. The time required to disintegrate the tablet is called disintegration time. The apparatus consists of a rigid basket-rack assembly supporting 6 cylindrical glass tubes held vertically by two superimposed transparent plastic plates with six holes having the same diameter as the tubes. Woven wire gauze made from stainless steel is attached to the underside of the lower plate. The assembly should be raised and lowered between 28 and 32 times per minute in the liquid at 370 C. The tablets are kept immersed in the liquid within the tubes by means of cylindrical guided discs. The assembly is suspended in the liquid medium in a 1000 ml beaker. The apparatus is operated generally for 15 minutes and observed for disintegration of tablets. The tablets pass the test if all the tablets disintegrate. In case one or two tablets fail to disintegrate, repeat the test on 12 additional tablets. The tablets pass the test if not less than 16 of the total 18 tablets tested have disintegrated.

172. For Uncoated tablets: Start the disintegration test on 6 tablets, if one or two tablets from the 6 tablets fail to disintegrate completely within 30min, repeat the same test on another 12 tablet. Not less than 16 tablets should disintegrate completely within the time and if more than two tablets (from the 18) fail to disintegrate, the batch must be rejected. For Coated tablets: To remove or dissolve the coat, immerse the tablet in distilled water for 5 min. Put the tablet in the apparatus in water or 0.1 N HCl for 30min at 37 o C (according to the U.S.P). If not disintegrated, put in intestinal fluid. If one or two tablets fail to disintegrate, repeat on 12 tablets. So 16 tablets from the 18 must completely disintegrate within the time. If two or more tablets do not disintegrate within the time the batch is rejected. For Enteric coated tablets: Put the tablet in distilled water for five minutes to dissolve the coat. Put in simulated gastric fluid for two hours (emptying time) Put in phosphate buffer (PH 6.8) for one hour. If one or two tablets fail to disintegrate repeat on 12 tablets. So 16 tablets should disintegrate. If more than two tablets fail to disintegrate, reject the batch.

173. 6. Dissolution test: It is the solubilization of the drug or active moiety in to the dissolution media. It is done for measuring the amount of time required for a given percentage of the drug substance in a tablet to go into solution under specified condition. Apparatus: A cylindrical vessel (made up of glass or other transparent material) having 1000 ml capacity, fitted with a lid having four holes, one for shaft of stirrer, second for placing the thermometer and remaining two for sample removal. An electric motor A cylindrical stainless steel basket made of wire with aperture size of 425 µm attached to the disc on the driving shaft. Suitable device for withdrawal of sample.

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

175. Unofficial tests 1. Hardness test: It is defined as the force required to break a tablet in a diametric compression test. Tablet requires a certain amount of strength or hardness and resistance to friability to withstand mechanical shocks of handling in manufacture, packaging and shipping Types of hardness testers used are: 1. Monsanto hardness tester. 2. Strong cob tester. 3. Pfizer tester. Conventional tablets hardness: 2.5- 5 kg/sq cm Dispersible/ chewable tablets hardness: 2.25- 2.5 kg/sq cm Extended release tablets hardness: 5- 7.5 kg/sq cm

176. 2. Friability test : It is performed to evaluate ability of the tablet to with stand wear and tear in packing, handling, and transporting. The apparatus used to perform this test is known as "Friabilator". The apparatus consists of a plastic chamber, which is divided into two parts and it revolves at a speed of 25 rpm. Twenty tablets are weighed and placed in a plastic chamber. The chamber is rotated for 4 minutes or 100 revolutions. During each revolution the tablet falls from a distance of 6 inch. The tablets are removed from the chamber after 100 revolutions and weighed. Loss in weight indicates the friability. The tablets are considered to be of good quality if the loss in weight is less than 0.8%.

177. Quality control of tablets Official tests C o nte n t o f a c t i ve in g re d i e n t/ absol u t e d r ug content test/ assay of active ingredient. Weight uniformity test/ weight variation test Content uniformity test Disintegration time test Dissolution test

178. UNIFORMITY OF CONTENT As per IP : 10mg / less than 10% w/w of active ingredient As per BP/USP : 25mg /less than 25%w/w DISINTEGRATION TEST As per IP : 28-32 cycle per min As per BP/USP : 29-32 cycle per min

179. JSS College of Pharmacy, Mysuru Disintegration testing condition and interpretation (IP) S r . No Type of tablets Medium Temperatu re Limit 1 Uncoated Water/buffer 37 °± 2 °C 15 min or as per individual monograph 2 Film coated Water 37 °±2 °C 30 min or as per individual monograph 3 Sugar coated Water/0.1 N HCl 37 °±2 °C 60 min or as per individual monograph 4 D i s per s ibl e Tablets Water 25 °±1 °C 03 min or as per individual monograph 5 E f ferve s cen t Tablets Water 25 °±5 °C 05 min or as per individual monograph 6 E nteri c - c oa t e d Tablets 0.1 M HCl mixed phosphate buffer pH 6.8 37 °±2 °C 02 hour in HCl: no disintegration 60 min in buffer : disintegrate 7 Soluble Tablets Water 20 °±5 °C 03 minutes

180. JSS College of Pharmacy, Mysuru D i s i n t e g r a t io n t e st in g c o ndi t io n (U SP ) S r . No Type of tablets Medium Temperatu re Limit 1 Uncoated Water/as specified in monograph 37 °± 2 °C As per individual monograph 2 Coated Water/as specified in monograph 37 °±2 °C As per individual monograph 4 Enteri c - c oa t e d Tablets Simulated gastric fluid TS Simulated intestinal fluid TS 37 °±2 °C 01 hour in Simulated gastric fluid As per individual monograph: Simulated intestinal fluid TS 5 Buccal Tablets Water/as specified in monograph 37 °± 2 °C 4 hour 6 S ublingua l tablets Water/as specified in monograph 37 °± 2 °C As per individual monograph

181. non-official tests hardness test Friability test

182. Packaging and storing of tablets Before tablets are sent out for distribution, they are usual l y pac k aged using p a ckagi n g mater i al s . T he type of appr o pri a t e packag i ng material used i s a mat t er of cho i ce an d is dependent on several factors including: The degree of protection required Compat i bili t y of t h e pa c kaging material with the formulation.

183. TABLET COMPRESSION MACHINES There are following 2 types, SINGLE PUNCH/SINGLE STATION/ECCENTRIC PRESSES MULTI-STATION/ROTARY PRESSES SINGLE PUNCH/SINGLE STATION/ECCENTRIC PRESSES Single punch tablet press also known as eccentric press or single station press is the simplest machine for tablet manufacturing. This machine uses single set of station tooling (a die and a pair of upper and lower punches). The compaction force on the fill material is exerted by only the upper punch while the lower punch is static such action equivalent to hammering motion and as a result, the single punch press is referred to as stamping process. The single punch tablet press usually produces about 60-85 tablets/min .

184. WORKING MECHANISM OF SINGLE PUNCH MACHINE The working cycle is as follows FILLING WEIGHT ASDJUSTMENT COMPRESSION EJECTION FILLING: Upper 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 fill the die. WEIGHT ASDJUSTMENT Bottom punch move up to adjust the powder weight, it raises and expel the extra powder. COMPRESSION: Upper punch is driven into the die by upper cam. Bottom punch is raised by lower cam. Both punch heads pass between the heavy rollers to compress the tablet. EJECTION: Upper punch is withdrawn by the upper cam. Lower punch is pushed up and expel the tablets. Tablet is removed from the die surface by the surface plate.

185. TYPES OF SINGLE PUNCH MACHINE The different series of the single punch tableting machine includes, Automatic Single Punch Tableting Machine C&C600B Series Single Punch Tablet Press TDP - Benchtop Model Single Punch Tablet Press TDP-1 Benchtop Model Single Punch Tablet Press TDP-5 Benchtop Model Single Punch Tablet Press TDP-30 Benchtop Model Single Punch Tablet Press

186. TYPES OF SINGLE PUNCH MACHINE Automatic Single Punch Tableting Machine This machine is designed for pressing tablets from a variety of materials for Research & Development and for small-scale production of Neutraceuticals,herbals, and other products. It is designed for pressing round tablets from various granular materials. This is a bench-top unit, semi-portable, that is motor-driven but can also be hand-driven for adjustment and testing purposes. One punch & die set is included. Fill depth, tablet thickness, and punch pressure are all adjustable. This is by far our most popular unit This machine compresses powdered granular materials into tablet form. It is adjustable, operator friendly, easy to maintain, compact and light weight.

187. TYPES OF SINGLE PUNCH MACHINE C&C600B Series Single Punch Tablet Press C&C600B Series Single Punch Tablet Press is an advanced machine with new structure. It is a continuous, automatic tablet machine used in many departments such as pharmacy, laboratory which needs to make powder, and granular raw material into tablets.

188. TYPES OF SINGLE PUNCH MACHINE TDP - Benchtop Model Single Punch Tablet Press Th i s is de s igned for pres s ing t a blets from a variety of mat e ri a ls for sma ll -s c ale production of neutraceuticals, herbals, and other products. Features are same as that of automatic single punch tableting machine.

189. TYPES OF SINGLE PUNCH MACHINE TDP-1 Benchtop Model Single Punch Tablet Press This is a bench-top press unit, semi-portable. One punch and die set is included. Fill depth, tablet thickness, and punch pressure are all adjustable. This is a new unit, a little heavier-duty than the TDP Benchtop Press.

190. TYPES OF SINGLE PUNCH MACHINE TDP-5 Benchtop Model Single Punch Tablet Press This is a heavy-duty benchtop unit. It produces tablets up to 20 mm in diameter.

191. TYPES OF SINGLE PUNCH MACHINE TDP-30 Benchtop Model Single Punch Tablet Press This is an extra heavy-duty benchtop unit. It produces tablets up to 24mm in diameter. Featuring precision filling, low-noise, low-consumption of material, and smooth operation. The minimum consumption of lab material is just 200g. It is reliable and efficient for research and development labs and small scale production.

192. PARTS OF A SINGLE PUNCH TABLET PRESS Hopper: It is used to hold the materials (drug or the drug with excepients/ granules) to be compressed and supply the material to the die and removes the tablet after its compression Dies: Dies defines the shape and the size of the tablet by allowing the lower and upper punch to come close together to compress the material. Lower and upper punches: These are used for compressing of the materials (drug or the drug with excepients/ granules) within the dies. Cam track: This is the component used for guiding the movement of the punches. Capacity regulator: To adjust the position of the lower punch to accommodate the required quantity of materials by the die. Ejection regulator: To adjust the position of the lower punch, so that its highest position is at par with the surface of the die. Driving wheel: It helps in the movement of the lower punch, the upper punch and hopper shoe and also check their movement.

193. PARTS OF A SINGLE PUNCH TABLET PRESS

194. ADVANTAGES OF SINGLE PUNCH TABLET PRESS The single punch structure is rational and small. Easy to operate and it operates at a high utilization ratio. It can manufacture odd shaped products with a diameter of up to 20mm. It is ideal for development of tablets and small batch production. Single punch tablet press utilizes a high amount of pressure to reduce weight variations between tablets while maintaining a low noise level at the same time.

195. TYPES OF COMPRESSION MACHINES MULTI-STATION/ROTARY PRESSES Multi-station press is a mechanical device that unlike the single punch tablet press has several tooling station which rotates to compress granules/powder mixture into tablets of uniform size, shape (depending on the punch design) and uniform weight. It was developed to increase the output of tablets. In rotary press, the compaction force on the fill material is exerted by both the upper and lower punches leaving the powder granules to be compressed in the middle.This is known as accordion type of compression. The capacity of a rotary tablet press is determined by the rotation speed of the turret and the number of stations on the press.

196. PARTS OF A ROTARY PRESS HOPPER FEEDER SYSTEM PUNCHES DIE SYSTEM TURRET CAM TRACKS TABLET PRESS FILLING STATION & WEIGHT CONTROL COMPRESSION ROLLERS EJECTION CAM TAKE OFF BLADE AND DISCHARGE CHUTE TOUCH SCREEN CONTROL PANEL SEALING SYSTEM ELECTRIC MOTORS,GEARS AND BELTS LUBRICATION SYSTEM HYDRAULIC PUMP UNIT

197. PARTS OF A ROTARY PRESS TABLET PRESS HOPPER The tablet compression process starts from here. Hopper is basically a material feeding section. It is the point where we put all powder/grains intended to compress into tablets. Tablet press hoppers come in a wide range of shapes and designs. Whatever the shape, it should be such that the material can flow seamlessly into the tablet compression chamber. Since it is in direct contact with the material, it is made of stainless steel. Depending on the design of a tablet press machine, powder can be filled manually or using other automated systems. Hoppers may feature optimal flow angles to facilitate flow, especially where it is nearly impossible to adjust formulation. Some hoppers may have feature vibratory rods.This is done carefully to enhance product flow and to prevent possible product separation.

198. PARTS OF A ROTARY PRESS TABLET PRESS FEEDER SYSTEM Feeders feed powder/grains to the dies. Tablet press machine feeder system is made up two critical components, FEEDER HOUSING FEED PEDDLES FEEDER HOUSING Material from the hopper will enter the dye system through the housing. The feeding process should be consistent and accurate to produce high quality tablets. The feeder housing is made of stainless steel 316L since it is in contact with the product. The product must not stick on the feeder housing as it will cause inconsistencies during the feeding process. FEED PEDDLES Number of high speed rotary tablet press machines have a feed peddles. The feed peddles ensures consistent and accurate material feeding into the die systems. Without a feed peddle, especially if the machine is operating at a high speed, there could be chances of some dies being filled half way. This may result in tablets with varying thickness or the degree of compaction.

199. PARTS OF A ROTARY PRESS TABLET PRESS PUNCHES To produce the desired tablets, punches move within the die, thereby compressing powder into the desired tablets. In any tablet press machine, it has Upper punch system, the tablet press upper punches are on the upper section of the rotary system. They move vertically, in and out of the die bore. The lower punches are on the lower section of the rotary system of the tablet press machine. During the tablet compression process, the lower punches remain within the die bore throughout the entire cycle. TABLET PRESS DIE SYSTEM To produce the desired tablets, punches move within the die, thereby compressing powder into the desired tablets. The movement of tablet press machine punches, takes place within the die bore or cavity. Therefore, the punch and die must be machined together to ensure compatibility. It is in the die cavity where the powder is compressed into desired tablets of definite thickness and size. It is the die cavity that determines both the thickness and size of a tablet.

200. PARTS OF A ROTARY PRESS TABLET PRESS TURRET A rotating turret is an essential part of the rotary tablet press machine in the pharmaceutical industry. The rotating turret have holes that host the die system of a tablet making machine and punch guides to hold punches It is precisely machined to ensure both die pockets and punch guides are fully aligned for optimal tablet making process. Turrets are the heart of tablet press tooling. It is the tablet press machine turret that determines the number of stations. This helps to determine the production capacity of the machine for every complete rotation of the turret .

201. PARTS OF A ROTARY PRESS TABLET PRESS CAM TRACKS Cam tracks are critical tablet compression machine parts that play an integral role in ensuring seamless tableting process. The main work of the cam tracks is to guide the upper and lower punches in different stages in the tablet compression process. That is, as the turret rotates, it is the cam trucks that move the punches in an up and down motion. This helps to control filling, compression and ejection of already processed tablets. For example, as the upper cam withdraws top punches from the die, powder flows in filling the cavity .On the other hand, the lower cam track pushes the bottom punches upwards within the die cavity. This makes the die to be overfilled by material, allowing for accurate adjustment of the die content. To achieve a maximum compression force, the upper cam track drives the top punch and the lower cam adjusts the bottom punch. With the tablet compressed to the desired specifications, the upper cam withdraws top punches. On the other hand, the lower punches move upwards to expel the compressed tablets with the help of lower cam.

202. PARTS OF A ROTARY PRESS TABLET PRESS FILLING STATION & WEIGHT CONTROL With the help of different movements of the cam systems, material will flow into the die cavity depending on the position of the punches. A critical procedure in tablet compression process is the Weight control by controlling the depth of dye filling. With the help of lower cam track, the bottom punch moves upwards to a predetermined height. This ensures the die cavity is filled to a required depth according to required weight of tablet before any compression process begins. At this time as the bottom punch moves up, the excess powder may overflow. Therefore, to avoid wastages, the excess powder automatically moves to the next die cavity, which is just about to be filled.

203. PARTS OF A ROTARY PRESS COMPRESSION ROLLERS Tablet compression machines have a series of rollers that exert a sufficient amount of force to compress the powder. Most machines have two sets of rollers. PRE-COMPRESSION ROLLERS These are the very first rollers in rotary tablet press. Basically, these rollers apply a small amount of force on the upper and lower punches. This gives the initial compression force. The aim of this process is to remove entrapped air that could be in the die or powder particles. MAIN COMPRESSION ROLLERS Main compression rollers exert a predetermined amount of force (final compression force) for the formation of tablets. The compression force at this stage is higher than the pre-compression force. It is important that the rollers remain stable with no vibration during the entire process. This is to ensure consistency of the tablets’ thickness and size.

204. PARTS OF A ROTARY PRESS TABLET PRESS EJECTION CAM Ejection cam is located just after the main compression rollers. After compression, the tablet is always fixed within the die systems (space between lower and upper punches). The ejection cams steadily and slowly push the bottom punch upwards. At the same time, the top cams move up and so are the top punches .As a result, the fully compressed tablets leave the die cavity i.e. the compressed tablet remains just at the top of the die . TAKE –OFF BLADE AND DISCHARGE CHUTE The take –off blades are fitted just above the feeder housing. Their main role is to deflect the fully compressed tablets into the discharge chute and then are collected in containers.

205. PARTS OF A ROTARY PRESS

206. PARTS OF A ROTARY PRESS TOUCH SCREEN CONTROL PANEL HMI system control every aspect of the tablet making process. HMI can either be attached to the main machine or exist separately . SEALING SYSTEM The sealing system provides advanced dust handling capability. This isolation reduces need to clean the machine regularly and possible cross contamination. ELECTRIC MOTORS, GEARS AND BELTS The compression rollers, punches, dies, turret, etc. are all moving parts. This means that the machine uses a prime mover. We can use a servo motor or an induction motor. For example, a servo motor is a perfect choice for the filing system. This is because it is easy to control servo-motors to meet the highest degree of precisions such as 0.01mm. However, for the pre-compression and compression stages, synchronous motors offer a better speed and control. Servo motor for tableting machine Furthermore, to transmit this motion to other sections, we may use a combination of both gears and belts. Even the motor can accurately start this machine, whether under maximum load or with no load. In short, to achieve a desired motion, we need to incorporate mechanical, hydraulic and electrical systems .

207. PARTS OF A ROTARY PRESS LUBRICATIONS SYSTEMS Moving parts form integral sections of tablet compression machine parts, therefore, to avoid wear and tear due to friction, we need to lubricate moving parts. A number of tablet press machines feature a central lubrication system. The machines automatically lubricate moving components.· HYDRAULIC PUMP UNIT An efficient hydraulic pump unit will help maintain consistent pre-pressure and main pressure. This guarantees smooth and accurate tableting process. Internal section of a tablet press machine part again, to avoid possible damage that may occur on the tablet press tooling system, these machines are equipped with an overloading protective unit. This automatically stops the machine in case of overload. Other parts of the machine include, Rubber wheels (depending on the size of a machine), switches, LED light indicators, lockable polycarbonate cabinet and cooling system.

208. ADVANTAGES OF ROTARY PRESS High productivity can be gained with a minimal amount of labor while saving money. Rotary press has an output of between 9000 – 234000 tab/hour or more thus saves time and meets up with the high demand of tablet dosage form. The powder filled cavity can be automatically managed by a moving feeder. Rotary press decreases waste of valuable formulation in non-specific tablets. The machine allows independent control of both weight and hardness.

209. PRINCIPLE OF TABLET COMPRESSION MACHINE PRINCIPLE In the tablet compression machine main principle is compressing the grains/powder in upper and lower punch in a die hole. The hydraulic pressure plays a key role. This pressure is transmitted unreduced through the static fluid. Any externally applied pressure is transmitted via static fluid to all the direction in same proportion. It also makes it possible to multiply the force as needed. If we increase the hydraulic pressure more compressing force on tablet then it becomes more hard.

210. STAGES OF TABLET COMPRESSION PROCESS FILLING METERING/WEIGHT ASDJUSTMENT COMPRESSION EJECTION FILLING The filling stage of tablet compression process involves transfer of granules to the compressing machine punch-die cavity. The punch die cavity is composed of upper punch, die and lower punch. The position of lower punch within the die determines the volume of the punch-die cavity. This volume must be appropriately sized for the weight of granulation to be compressed into tablets. The granulation is overfilled on the die table (turret) to ensure complete filling of the punch-die cavity volume.

211. STAGES OF TABLET COMPRESSION PROCESS METERING/WEIGHT ASDJUSTMENT The metering stage of the tablet compressing process involves removal of excess granulation from the compressing machine. This stage enables the exact weight (volume) of granulation to be compressed into tablets. The exact weight of granulation is controlled by the height of the lower punch in the die. The height of the lower punch is controlled by the metering cam (also called the dosage cam). The lower punch is raised to the appropriate level in the die to provide the exact weight of granulation in the punch-die cavity. The excess granulation is scraped from the surface of the die table. COMPRESSION The compression stage of the tablet forms the tablet. This stage involves bringing together the upper and lower punches under pressure within the die to form the tablet. As the punches enter the compression stage, the upper and lower punches move between two large wheels called pressure rolls. These pressure rolls push the punches together to form the tablet. The distance between the upper and lower punches determines the thickness and the hardness of the tablet. When the punches are close together, a thin and hard tablet is created. When the punches are farther apart, the tablet made is softer and thicker. The proper balance of thickness and hardness determines the optimum roll distance for any specific product. These adjustments are made while keeping the tablet weight constant.

212. STAGES OF TABLET COMPRESSION PROCESS EJECTION The ejection stage of the tablet compressing process involves removal of the tablet from the lower punch-die station. In this stage, the upper punch retracts from the die cavity and rises above the turret table. Then the lower punch rises in the die, which in turn pushes the tablet upward to the top surface of the die table and out of the die cavity. A scraper (also called takeoff scraper or tablet rake-off) then pushes the tablet off the die table away from the compressing machine into the collection container through discharging chute.

213. STAGES OF TABLET COMPRESSION PROCESS

214. STAGES OF TABLET COMPRESSION PROCESS

215. CLASSIFICATION OF MULTI- STATION PRESS TOOLING CLASSIFICATION OF MULTI-STATION PRESS The punches and dies is called tablet tooling that determines the shape, size and the identification markings of the tablets. The tooling must meet the specific requirements to satisfy the needs of dosage uniformity, production efficiency and esthetic appearance. Internationally recognized standards for tablet compression tooling are as follow, TSM standard EU standard TSM STANDARD TSM is acronym for the “TABLET SPECIFICATION MANUAL”, widely recognized and exclusive in the United States. TSM tooling specifications are the sole reference on U.S. manufacturing standards for tablets and tablet tooling. Established by the American Pharmacists Association (APhA). TSM tooling specifications are the only published standards for the tablet compression industry. EU STANDARD EU, is short for “EUROSTANDARD” considered as the European standard and also globally applicable. EU, more widely used than the TSM. EU, or Euronorm standard tool configurations are not published or governed by any organization or association. The EU standard is the most common tooling configuration used outside the U.S .

216. D I FF E R E NC E S B E TW EE N T S M & E U T OO L I N G CONFIGURATIONS The TSM punch head configurations have an angled top profile versus the domed head profile of EU The TSM punch inside head angle for “B” punches is 37° compared to the EU, which is 30° Overall head thickness is greater in both “B” and “D” configurations for TSM tooling specifications in comparison to the EU spec The overall punch length of the TSM tool is 0.010 inches shorter than the EU

217. CLASSIFICATION OF MULTI -STATION PRESS CLASSIFICATION OF MULTI-STATION PRESS . Based on the standard of TSM and EU, tablet tooling is mainly classified “ B” TYPE TOOLING “D” TYPE TOOLING “B” TYPE TOOLING The B tooling punches and dies can be further classified as BB. D tooling can also be used on B tooling machine that is call as DB The “B” type configuration has a normal, punch barrel diameter of 0.750in. (19mm). The “B” type can be used with two types of die or can be said to have two different die sizes: The “B” dies with a diameter of 1.1875in. (30.16mm), suitable for all tablet sizes up to the maximum for the “B” punches. The smaller “BB” dies (small “B” die) that has a diameter of 0.945in. (24mm). This die type is suitable for tablets up to 9mm diameter or 11mm maximum. Machines that are designed to “B” type tooling exert a maximum compression force of 6.5 tones.

218. CLASSIFICATION OF MULTI -STATION PRESS “D” type This type has larger nominal barrel diameter of 1in. (25.4mm) and a die diameter of 1.500in. (38.10mm) and thus is suitable for tablets with maximum diameter or maximum length of 25.4mm. Tablet press is designed to be used with either “B” or “D” tooling but not both. The compression force obtainable in a machine depends on the type of tooling used. Machines that use the “D” type configuration exert 10 tones compression force.

219. TOOLING TERMINOLOGIES COMPRESSION MACHINE PUNCH HEAD The end of the punch that guides it through the cam track of tablet machine during Rotation. HEAD FLAT (DWELL FLAT) The flat area of the head that receives the compression force from Rollers (in upper punches) and determines the weight and ejection height (in lower punches). OUTSIDE HEAD ANGLE The area gets in touch with the roller prior to head flat , while Compression. INSIDE HEAD ANGLE This is the area, which pulls down the lower punches after ejection and lifts the upper punches after compression. NECK The relived area between the head and barrel, which provides clearance for the cams.

220. TOOLING TERMINOLOGIES BARREL The area between neck and stem of punch. This area guides the punch (while going up and down) with reference to turret guides. BARREL CHAMFER Chamfers at the ends of the punch barrel, eliminate outside corners. BARREL TO NECK RADIUS The area at junction of barrel and neck which provide smooth transition from barrel to neck. BARRELTO STEM RADIUS The are at junction of barrel and stem which provide curved transition from tip length to barrel. BARREL TO NECK CHAMFER The beveled area located between barrel and barrel to neck radius. The chamfer reduce wear to punch guide.

221. TOOLING TERMINOLOGIES BARREL TO STEM CHAMFER The beveled area located between barrel and barrel to stem radius. The chamfer allows for the proper insertion of upper or lower punch into oil seal. STEM The area of the punch opposite the head, beginning at the tip and extending to the point where the full diameter of the barrel begins. If the chamfer is present the barrel usually reaches its full diameter just above the chamfer. TIP This determines size, shape & profile TIP FACE : This area of punch is where the tablet is formed. Good surface finish is required here to get quality tablets. CUP DEPTH The depth of the cup from the highest point of the tip edge to the lowest point of the cavity

222. TOOLING TERMINOLOGIES BAKELITE TIP RELIEF An undercut groove between the lower punch tip straight and the relief; it assures a sharp corner to assist in scraping product adhering to the die wall; normally a purchased option for lower punches. TIP RELIEF The portion of the punch stem which is a undercut or made smaller than the punch tip straight. Most common for lower punches to aid in reducing friction from the punch tip and die wall as the punch travels through the compression cycle. the area where the punch tip and relief meet must be sharp to scrape product from the die wall as the lower punch travels down for the fill cycle TIP LENGTH The straight portion of the punch stem TIP STRAIGHT The section of the tip that extends from the tip relief to the end of the punch tip; it maintains the punch tip size tolerance. WORKING LENGTH This distance between bottom of the cup and the head flat is called as working length which determines weight and thickness of the tablet.

223. TOOLING TERMINOLOGIES OVERALL LENGTH Distance between top of the cup and the head flat. KEY A projection normally of mild steel which protrudes above the surface of the punch barrel. It maintains alignment of the upper punch for re-entry into the die, mandatory on upper punches with multiple tips and all tablet shapes other than round. Commonly used with embossed round tablet shapes when rotation of the punch causes a condition known as double impression KEY ANGLE The relationship of the punch key to the tablet shape. The keys position is influenced by the tablet shape, take-off angle, and turret rotation. KEY POSITION The radial and height position of a key on the punch barrel; not found in all presses .

224. TOOLING TERMINOLOGIES DOMED HEADS Increases the dwell time and hence help to achieve the better tablet hardness. DWELL TIME The time punches spends below the pressure roller while rotating in the machine. LAND The area between the edge of the punch cup and the outside diameter of the punch tip; this adds strength to the tip to reduce punch tip fracturing MAJOR AXIS The largest dimension of a shaped tablet MINOR AXIS The smallest dimension of a shaped tablet Clearance : Die bore dia – punch tip dia = Clearance.

225. TOOLING TERMINOLOGIES DIE TERMINOLOGY DIE.O.D. The outside diameter of the die, which is compatible with the die pockets in the press. DIE HEIGHT The overall height of the die. DIE BORE The cavity where the tablet is made. The Cavity’s shape and size determine the same form of tablet. CHAMFE R Entry angle of the die bore. TAPER DIES Dies with tapered bore on one or both sides is used. They are used for easy removal of entrapped air and easy ejection of tablets (mainly for double layered tablets). DIE GROOVE The groove around the periphery of the die, which allows the die to be fixed in the press. LINED (INSERT) DIES Dies fitted with a linear insert made from a much harder, more wear resistant material such as tungsten carbide and ceramic.

226. TOOL I N G T E R M I N OL OGI E S

227. SHAPES OF PUNCHES/TABLET IN REGULAR USE Round GEOMETRIC CONVEX CONVEX & BEVEL OVAL MODIFIED OVAL CAPSULE MODIFIED CAPSULE COMPOUND CUP FLAT FACED FLAT FACED BEVEL EDGED FLAT FACED RADIUS EDGED DEEP CONCAVE (ROUND/CAPSULE) EXTRA DEEP MODIFIED BALL SHALLOW CONCAVE (ROUND/CAPSULE) STANDARD CONCAVE (ROUND/CAPSULE)

228. SHAPES OF PUNCHES/TABLET IN REGULAR USE

229. SHAPES OF PUNCHES/TABLET IN REGULAR USE

230. SHAPES OF PUNCHES/TABLET FLAT FACE (FF ) Flat Face design is very simple. It cause a problem called edge attrition. The problem is created as the flat face tool entered into the compression cycle. The FF design naturally push or force the powder to the outside perimeter of the punch tip and towards the die wall, which in turn extrude through the punch and die clearance

231. SHAPES OF PUNCHES/TABLET FLAT FACE BEVEL EDGE The FFBE was designed as an alternative to the Flat Face design. FFBE solve the problem of edge attrition. The FFBE deflect or guide the powder back into the tablet, hence reducing soft edges. Although the FFBE design proved to be beneficial for reducing soft edges, it presented a new problem, which was punch tip failure. On an FF punch tip, there was virtually no cup or cup depth of the punch tip, it was simply flat, so there was not a cup limiting compression force, pressure limits were determined by the punch tip size to reduce tip bending and distortion.

232. SHAPES OF PUNCHES/TABLET

233. SHAPES OF PUNCHES/TABLET FLAT FACE RADIUS EDGE OR FFRE FFRE is an alternative to the FFBE tablet design. The FFRE is much more robust and has several advantages over the FFBE. Better uniform tablet hardness as the powder has a natural flow across the radius, which can reduce hot spots and or discoloration to the perimeter of the top of the tablet Consumer acceptance as the FFRE tablet has a softer look and is more appealing to the consumer and generally has a better mouth feel.

234. ADVANCE TOOLING DESIGNS MULTIPLE TIP TABLET PRESS TOOLING These tools are common in high capacity tablet press machines. These can produce more than one tablet in every punching station. A multi-tip tool consists of three parts, CAP THAT SERVES AS THE HOLDER FOR THE PUNCH TIPS. PUNCH BODY . INDIVIDUAL PUNCH TIPS. The replacement punches incorporate several punch tips and the replacement die has correspondingly multiple holes enabling two or more tablets to be produced from a single compression stroke of the tablet machine. Depending on the type of material and tablet press, up to 8 punch tips can replace a single conventional punch tip. Such modification therefore enables 8 tablets to be produced for every compression stroke of the tabletting machine

235. ADVANCE TOOLING DESIGNS MULTIPLE TIP TABLET PRESS TOOLING BENEFITS Increase in productivity, number of tablets per turret rotation is multiplied by the number of tips. No large capital outlay on new tablet presses mean that higher tooling costs are easily outweighed by increased output. Reduction in press run-time per output of tablets means that less maintenance is required per batch of tablets produced. Reduction in press setup-time per output of tablets. Less tablet presses required to satisfy output therefore requiring less floor space leading to more product produced per square meter. All of the above lead to reduction in overall plant running costs.

236. ADVANCE TOOLING DESIGNS The following need to be considered when contemplating the installation of multi-Tip punch tooling: The upper section of the turret must have keyways. This ensures the correct fixing of the upper punch. Modification to the feeder paddles may be required due to increased fill requirements Tablet press monitoring systems can be adjusted to monitor the multitablet outputs as standard. Granulation flow must be working effectively due to the increased fill requirement The tablet press should be in good working order and critical dimensions of the turret (punch guides and die pockets) should all be within accepted tolerance.

237. ADVANCE TOOLING DESIGNS ROTATING HEAD PUNCHES /ROTAHEADS The rotating head has two-parts , THE HEAD OF THE PUNCH KEYED PUNCH BODY The head of the punch rotates independently to the keyed punch body. This creates increased contact surface area between the cam and punch head. Back angle aging is therefore drastically reduced, allowing for less head wear and longer punch service life. Dwell time is also increased.

238. ADVANCE TOOLING DESIGNS QUICK RELEASE TOOLING For use with R&D tablet presses, Quick-Release Tooling allows to quickly change punch head configurations, to determine the ideal dwell time for a tablet formulation. Quick Release Tooling Station Comes With, ONE PUNCH BARREL. THREE INTERCHANGEABLE HEAD CONFIGURATIONS (DOMED, EXTENDED FLAT DOMED, AND FULL RADIUS) ONE CUSTOMIZED PUNCH TIP. It save both time and money. Determine the ideal production dwell time before scale-up without changing turret speed by easily and quickly changing punch head configurations. Eliminate the time and labor required to replace multiple sets of tooling during the R&D process and the cost of purchasing multiple sets of tooling Perform a detailed analysis of a formulation’s compressibility as well as greater troubleshooting capacity in the early stages of tablet development.

239. ADVANCE TOOLING DESIGNS QUICK RELEASE TOOLING

240. ADVANCE TOOLING DESIGNS CERAMIC BARREL OPTION: Requires no lubrication Less wear, less friction, and less heat buildup Absorbs less heat from surrounding metals Will not expand due to heat Reduces potential for tooling binding

241. ADVANCE TOOLING DESIGNS LINED DIES Lined dies, commonly called insert dies, are used specifically to compress abrasive and corrosive formulation. BENEFITS OF LINED DIES Increased tool life. Less head wearing. Reduced friction. Elimination of corrosion. Extended tablet quality. CARBIDE LINED DIES Recommended with abrasive granulations. Work well for neutraceutical applications. Provide a high level of wear resistance during the compression of abrasive products. Increase die life by more than 10 times due to their wear liner.

242. ADVANCE TOOLING DESIGNS CERAMIC LINED DIES Recommended for corrosive products Reduce the coefficient of friction throughout tablet compression cycles Available for round and shaped tablets Include a wear liner that prevents them from wearing Increase die life by 5-10 time

243. ADVANCE TOOLING DESIGNS DIAMOND COATING The idea here is to introduce properties of diamond to a punch and die system. Such tools are suitable for effervescent tablets. Diamond coated tools are generally abrasive resistant and durable. They don’t stick and their hardness is nearly 6 times more than the ordinary tablet presses. GALVANIC CHROME TREATMENT This tablet press tooling is suitable for most standard tablet press applications. In most cases, the coating is about 5 microns. The coating is one of the most popular types of treatment in most pharmaceutical industries. This protects the tooling system of a tablet compression machine from wear and ensures better stability. CHROME NITRIDE COATING The final surface of the tablet press tooling is better than the galvanic treatment. It has a high quality to price ratio with enhanced wear protection. ALUMINUM TITANIUM NITRIDE OR TITANIUM NITRIDE COATING This treatment is known for its smooth finish and higher surface hardness. Therefore, it is a perfect choice for most pharmaceutical tablet compression applications.

244. ADVANCE TOOLING DESIGNS INTERCHANGEABLE TURRET It allows tool free operation and dramatically reduced product change over. Faster product to product change over. Easier production planning and preparation as machine turrets can be made ready in advance. The ability to clean to a higher standard and offline. Configure the machine to maximize output through optimum tooling to product size selection. The precision drive coupling gives the strength of a fixed turret machine, so make tablets up to 100KN. Improved engineering access over fixed turret machines. Keep the initial investment down by buying the different turret sizes at a later date

245. ADVANCE TOOLING DESIGNS

246. ADVANCE TOOLING DESIGNS SEGMENTED DIE TABLE Die table segments are engineered to eliminate the need for individual dies and die lock screws. The design increase production by up to 25% and make process simpler and smoother. With Die table segments gain more die stations per turret/press. Enhance productivity. Decrease set-up time by as much as 88%. Without the need for dies and die lock screws, efficiency will skyrocket, providing a more productive process overall. In addition to providing optimum tablet production it reduce downtime for refitting, resetting, and cleaning. Segments can be changed by loosening just two fastening bolts and only between 3 to 5 segments are needed for each turret, depending on the type of tablet press.

247. ADVANCE TOOLING DESIGNS SEGMENTED DIE TABLE

248. ADVANCE TOOLING DESIGNS BENEFITS OF SEGMENTED DIE TABLE Reduced product loss. Easier compliance with hygiene requirements. Up to 40% more output. Great production reliability through easy refitting. Service life increased by up to threefold through carbide brushes.

249. Reference Adolfsson, Å., Caramella, C., Nyström, C., 1998. The effect of milling and addition of dry binder on the interparticulate bonding mechanisms in sodium chloride tablets. Int.J. Pharm. 160, 187-195 . Adolfsson, Å., Gustafsson, C., Nyström, C., 1999. Use of tablet tensile strength adjusted for surface area and mean interparticulate distance to evaluate dominating bonding mechanisms. Drug Dev. Ind. Pharm. 25, 753-764 . Adolfsson, Å., Nyström, C., 1996. Tablet strength, porosity, elasticity and solid state structure of tablets compressed at high loads. Int. J. Pharm. 132, 95-106. Stahl H, A review article on latest process advancements and innovations in Granulation technology. Yadav V. B., Yadav A. V., Liquisolid granulation technique for tablet manufacturing : an overview in Journal of Pharmacy Research. Malcolm Summers, Michael Aulton , a review on Granulation. Niro pharma system on current issues and troubleshooting fluid bed granulation,may1998. Harald Stahl,Senior pharmaceutical technologist, GEA Pharma Systems, Germany Detlev Haack . Hermes Arzneimittel GmbH – Division Hermes Pharma , Grosshesselohe (Germany ).

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