Tablets

Advantage and disadvantage, types of tablet, Excipients, granulation techniques, and IPQC parameters for tablets and coating and compression tooling

1. TABLETS 1 Prepared By: Roshni Mehta PhD Research Scholar Guided By: Dr. Yamini Shah Associate Professor Department of Pharmaceutics, L. M. College of Pharmacy, Ahmedabad

2. Advantages Disadvantages Production aspect Large scale production at lowest cost Easiest and cheapest to package and ship High stability User aspect (doctor, pharmacist, patient) Easy to handling Lightest and most compact Greatest dose precision & least content variability Some drugs resist compression into dense compacts Drugs with poor wetting is difficult or impossible to formulate and manufacture as a tablet that provide adequate or full drug bioavailability Bitter taste drugs, an objectionable odor, or sensitive to moisture may require encapsulation or entrapment prior to compression or the tablets may require coating 2

3. Types of T ablets C ompressed T ablets S ugar coated T ablets F ilm coated T ablets E nteric coated T ablets E ffervescent T ablets C hewable T ablets D ispersible T ablets M ultilayer T ablets S ublingual T ablets B uccal T ablets I mplant T ablets 3

4. Excipients Excipients are substances, other than the active drug substance, or finished dosage form. The use of appropriate excipients is important in the development of the optimum tablets. Excipients determine the speed of disintegration, rate of dissolution , release of drug, protection against moisture, stability during storage, and compatibility. Excipients should have enhance stability, bioavailability or patient acceptability and no support of microbiological growth in the product . 4

5. Excipient Functions Component Function Examples Diluents Increase size and weight of final dosage form lactose, dextrin, MCC, pre-gelatinized starch, sucrose, and calcium phosphate. Binders Promote the adhesion of particles of the formulation. Such adhesion enables preparation of granules and maintains the integrity of the final tablet. CMC, MC, EC, MCC, Acacia, Agar, Na Alginate, Guar Gum, Karaya gum, Tragacanth gum, PVA,PVP, Gelatin, Dextrin, Glucose Disintegrants The breakup of the tablets to smaller particles is important for dissolution of the drug & subsequent bioavailability Sodium starch glycolate , MCC, Na CMC, Cross Carmellose , Magnesium Aluminium Silicate Flow Aids Reduce interaction between particles Talc Lubricants capable of reducing or preventing friction, heat, and wear when introduced as a film between solid surfaces. It works by coating on the surface of particles, and thus preventing adhesion of the tablet material to the dies and punches. talc, magnesium stearate , calcium stearate , stearic acid, hydrogenated vegetable oils and (PEG) Surfactants Promotes wetting Sodium lauryl sulfate, Polysorbate 5

6. Processing Routes Fill die Coating, Packaging etc.. Compress Tablet Direct Compression Drug Diluent Glidant Disintegrant Lubricant Mixing Mixing Dry Granulation Disintegrant Glidant Lubricant Drug Diluent Lubricant Mixing Compression Comminution Screening Mixing Mixing Wetting Granulation Drying Screening Mixing Drug Diluent Binder Solvent Disintegrant Glidant Lubricant Wet Granulation Other Routes Fluidized bed granulation Extrusion / rotary granulation Tablet Compression 6

7. Unit Dose Operations Determined by what manufacturing steps are needed to combine the active ingredient with other needed ingredients to make a quality finished product. Type of unit operation Dispensing Milling/Screening Blending Granulation Drying Compression Coating Packaging 7

8. Dispensing During this step, the weight of each ingredient i n the mixture is determined according to dose. Issues: Dust control (laminar air flow booths, glove boxes) Weighing accuracy Multiple lots of active ingredient with different assays, moisture and residual solvent content Cross contamination 8

9. Milling/Screening (Particle size reduction) Advantages It increases surface area, which may enhance an actives dissolution rate Improved the tablet-to-tablet content uniformity by virtue of the increased number of particles per unit weight. Improved flow properties of raw materials. Improved color and/or active ingredient dispersion in tablet excipients. Disadvantages Excessive heat generation can lead to degradation, change in polymorphic form Increase in surface energy can lead to agglomeration May result in excessive production of fines or overly broad particle size distribution 9

10. Forces In Milling Shear (cutting forces) Compression (crushing forces) Impact (high velocity collision) Rumpf (1965), Chem Ing Tech, 37(3), 187-202 Griffith theory T = Tensile stress Y = Young’s modulus ε = Surface energy c = fault length 10

11. Milling Equipment – Screen Mills Critical parameters for a conical screen mill Screen Hole Size/Shape has largest impact on particle size reduction, milling time and energy requirements Milling work index significantly lower for smaller screen hole sizes Impeller type has largest effect on overall milling performance Impeller clearance not significant at small clearances Milling work index lower at higher mill speeds Deflection of material away from screens Speed Evaluate impact on aspirin granulation Particle size reduction Milling time and energy requirements Byers, Peck (1990), Drug Dev Ind Pharm , 16(11), 1761-1779 Milling Work Index = Size reduction / Milling work Milling Time Index = Size reduction / Milling time 11

12. Milling Equipment – Impact Mills Significant wear on surfaces Hammer mills Medium to coarse size reduction Peripheral speed 20-50 m/sec Pin mills Peripheral speed up to 200 m/sec Capable of fine grinding Can be used to mill sticky materials 12

13. Milling Equipment – Jet Mill Superfine to colloid size reduction Can be used for heat sensitive products Different configurations Pancake (spiral) jet mill: Fines exit from center Loop/oval jet mill: Fines exit from top Opposing jet mills: Particles impact each other in opposing jets Fluidized bed jet mill: Particles are jetted towards center (low wear on equipment) Fixed/moving target jet mills: Particles impact on surface of target (wear can be significant) 13

14. Milling Equipment – Stirred Media Mill Critical parameters Agitator speed Feed rate Size of beads Bead charge Density of beads Design of blades Mill chamber Residence time 14

15. Mill Selection Wibowo and Ng (1999), AIChE Journal 45 (8) 1629-1648 15

16. Energy Based Analysis – Ball Mill Macroscale energy-size relationships (Chen et al., 2004) Calculate specific energy for a given size reduction Functional form derived from theoretical considerations Rittinger’s model Energy required for particle size reduction is proportional to the area of new surface created Kick’s model Energy required to break a particle is proportional to the ratio of the particle volume before reduction to the volume after reduction Chen et al. (2004), J Pharm Sci , 93(4), 113-132 16

17. Energy Based Analysis – Ball Mill Kick’s Law High loading Low frequency Rolling attrition Rittinger’s Law Low loading High frequency Impact fragmentation Attrition Fragmentation Size Reduction of α –Lactose Monohydrate in a Ball Mill Chen et al. (2004), J Pharm Sci, 93(4), 113-132 17

18. Milling/Screening Principle: Mixing or blending is more uniform if ingredients are of similar size What are the problems What are the equipment Why do it Possible change in polymorphic form An increase in surface area may promote the adsorption of air - may inhibit wetting of the drug – could be the limiting factor in dissolution rate Fluid energy mill Comil Ball mill Hammer mill Cutting mill etc. Increased surface area - may enhance rate of dissolution Improved content uniformity due to increased number of particles per unit weight Enhanced flow properties of raw materials Uniformly sized wet granules promotes uniform drying

19. Blending The powder/granules blending are involved at stage of pre granulation and/or post granulation stage of tablet manufacturing. Each process of mixing has optimum mixing time and so prolonged mixing may result in an undesired product. So, the optimum mixing time and mixing speed are to be evaluated. Blending step prior to compression is normally achieved in a simple tumble blender. The various blenders used include blender, Oblicone blender, Container blender, Tumbling blender , Agitated powder blender, etc. 19

20. Blending – Diffusion Mixing Critical parameters Blender load Blender speed Blending time V-Blender Cross Flow Blender Bin Blender Double Cone Blender 20

21. Blending – Convective Mixing Ribbon Blenders Orbiting Screw Blenders Planetary Blenders Horizontal Double Arm Blenders Forberg Blenders Vertical High Intensity Mixers Horizontal High Intensity Mixers Diffusion Mixers with Intensifier/Agitator 21

22. Blending Blending is the most difficult operation in the manufacturing process since perfect homogeneity is practically impossible due to differences in size, shape and density of particles What are the problems What are the equipment Why do it Segregation Possible over mixing of lubricant Blend uniformity/ Content uniformity Diffusion Mixers (V,double cone, bin,drum blenders) Convection Mixers (ribbon, planetary blenders) Pneumatic Mixers To achieve optimum mixing of different ingredients in powder/granules at pre granulation and/or post granulation stages of tablet manufacturing

23. 23 Why we prepare granules when we have powders….? To avoid powder segregation: Segregation may result in weight variation. To enhance the flow of powder: 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 To produce dust free formulations: Decrease dust generation and reduce employee exposure to drug product To eliminate poor content uniformity. To improve compaction characteristics of mix .

24. Mechanism Forces Additional information Immobile liquid films Adhesional and cohesional forces Between primary particles Mobile liquid films Interfacial forces, capillary pressure Strong bonds, prerequisite for solid bridges Solid bridges Hardening of binders, partial melting or recrystallisation of materials Main mechanism in wet granulation Attractive forces Van der Waals forces, electrostatic forces Does not necessarily need any liquid Mechanical interlocking Often fibrous or flat particles 24 Mechanism of Granulation Methods Of Granulation Direct Compression Granulation Wet Granulation

25. 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 Steps in Dry Granulation Compaction of powder Milling Screening 25

26. Dry Granulation can be done By two ways Slugging: Large tablet produced in heavy duty tablet press Roller compaction: Powder is squeezed between two rollers to produce sheet of material Equipments: Has two parts, Machine for compressing dry powder to form compacts. Mill for breaking these intermediates to granule. e.g. Chilsonater , Hammer Mill Advantages Less equipments & space Eliminate need of binder solution Disadvantages No uniform color distribution, Process create more dust . 26

27. 27 Steps In Wet Granulation Wet Granulation In this, powdered medicament and other excipients are moistened with granulating agent.

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30. Methods Single pot granulation High shear mixture granulation Fluid bed granulation Extrusion- Spheronization 30 Single pot granulation: The granulation is done in a normal high shear processor and dried in same equipment.

31.   31 High Shear Mixture Granulation Advantages Short Processing Time. Lesser Amount Of Liquid Binders Required Compared With Fbg . Highly Cohesive Material Can Be Granulated. Disadvantages Increase In Temperature May Cause Chemical Degradation Of Thermolabile Material. Over Wetting Of Granules Can Lead To Large Size Lumps Formation.

32. 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. Homogeneous granules. Gentle product handling Uniform spraying of all particles in the fluid bed 32 Fluid Bed Granulation Advantages It reduces dust formation during processing It reduces product loss Disadvantages The cleaning is labor-intensive and time consuming. Difficulty of assuring reproducibility.

33. Different steps involved in the Extrusion- Spheronization process 33 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

34. 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 ) Freeze granulation Technology Steam Granulation Melt Extrusion Technology Liquisolid Technique TOPO Technology Continuous Flow Technology 34

35. Steam Granulation This process is a modification of conventional wet granulation. Here steam is used as a binder instead of water. Advantages Uniformly distribution the powder particles. Higher dissolution rate of granules because of larger surface area generated . Time efficient . Maintain sterility . Disadvantages Requires special equipment for steam generation and transportation. Requires high energy inputs. Thermolabile materials are poor candidates. More safety measure required. 35

36. Melt Granulation 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 . There is no need of drying phase since dried granules are obtained by cooling it to room temperature . water soluble binders- e.g. Polyethylene Glycol (PEG) 2000, 4000, 6000, 8000 (40-60 C) water insoluble binders- e.g.. Stearic acid (46-59 C), Cetyl or stearyl alcohol(56-60 C) Advantages Time and cost effective Controlling and modifying the release of drugs. Water sensitive drugs are good candidates Disadvantages Heat sensitive materials are poor candidates. Lower-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. 36

37. Moisture Activated Dry Granulation In MADG, moisture is used to activate granule formation, without the need to apply heat to dry the granules. Drug is blended with diluents and powder A small amount of water (1-4%) Is sprayed Agglomerate formation (size 150–500μm) Agglomeration Moisture Distribution/ Absorption Moisture absorbents like MCC or silicon dioxide, are added while mixing. Moisture redistribution within the mixture. Entire mixture becomes relatively dry. 37 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: Moisture sensitive and high moisture absorbing API are poor candidates.

38. Moist Granulation Technique (MGT) 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 . 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. 38

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40. 40 Freeze granulation Technology 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.

41. 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 . Continuous Flow Technology 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. 41

42. 42 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 Granulation Characterization :

43. Granulation Principle: A size enlargement process that converts small particles into physically stronger & larger agglomerates What are the problems What are the equipment Why do it Loss of material during various stages of processing Multiple processing steps - validation and control difficult Incompatibility between formulation components is aggravated Dry Granulator (roller compactor, tabletting machine) Wet High-Shear Granulator (horizontal, vertical) Wet Low-Shear Granulator (planetary, kneading, screw) Fluid Bed Granulator, Spray Dry Granulator, RMG Provides homogeneity of drug distribution in blend Improves flow, compressibility and hardness of tablets

44. Drying Tray dryer Fluid bed dryer 44

45. Drying Drying is a most important step in the formulation and development of pharmaceutical product. It is important to keep the residual moisture low enough to prevent product deterioration and ensure free flowing properties. The commonly used dryer includes Fluidized bed dryer, Vacuum tray dryer, Microwave dryer, Spray dryer, Freeze dryer, Turbo - tray dryer, Pan dryer, etc. •Drying Process A process of evaporating the liquid contained within aggregates produced by a wet granulation process to a predetermined moisture content  • Accomplished via 1. Tray dryer (direct contact with heating medium) 2. Fluidized bed dryer (indirect contact of the product with the heating medium 45

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

47. Fluid Bed Drying Air Flow Inlet Filter Condensor Steam Damper Damper Outlet Filter Air Flow Product Temperature Inlet Temperature Outlet Temperature From Granulator To Mill Drying Zone Filter Bag Air Flow Retaining Screein 47 Single machines utilized for both the wet granulation and drying process in one unit operation. It is a multiple step process performed in the same vessel to mix, granulate and dry the powders. Combines wetting the powders to for granules &then, drying them in the same piece of equipment.

48. Strength of the Tablets The tablet should be sufficiently strong to withstand the mechanical shocks during the subsequent handling and transport. The mechanical strength of tablet is described by the following parameters . Crushing Strength Friability Hardness Bonding Strength Fracture resistance. 48

49. Crushing Strength crushing strength, Sc, which may be defined as "that compressional force (Fc) which, when applied diametrically to a tablet, just fractures it.” It may then be described by the equation= Where S T is the tensile strength, Fc is the compressional force and D & H are the diameter and thickness of the tablet, respectively . Friability The crushing strength test may not be the best measure of potential tablet behaviour during handling and packaging. The resistance to surface abrasion may be a more relevant parameter. These test measure the weight loss on subjecting the tablets to a standardized agitation procedure. The friability, f, is given by: 49

50. Factors Affecting Strength of the Tablets Particle size Smaller particles have larger surface area & when these are exposed to atmosphere may be prone to oxidation and moisture absorption takes place which affects the strength of tablet. Extensive fragmentation during compaction of a brittle material may result in a large number of interparticulate contact points, which in turn provide a large number of possible bonding zones. The tablets made of these materials can have a high mechanical strength. Compaction pressure The compaction pressure and speed affects the strength of the resulting tablet. A fragmenting material has been shown to be less affected by variations in compression speed. The behaviour of granules during compaction, the extent to which they bond together & the strength of the inter granule bonds relative to the strength of the granules determine tablet hardness. 50

51. Particle shape & surface roughness The mechanical strength of tablets of materials with a high fragmentation tendency are less affected by particle shape and surface texture. Particle shape affects the inter particulate friction & flow properties of the powder. Spherical particles are considered to be ideal. General particle shapes and their effect on powder flow are as follows: Spherical particles - Good Oblong shaped particles - Poor Cubical shaped particles - Poor Irregular shaped particles - Medium 51

52. Binders   A binder is a material that is added to a formulation in order to improve the mechanical strength of a tablet. In direct compression, it is generally considered that a binder should have a high compactibility to ensure the mechanical strength of the tablet mixture. Addition of a binder which increases elasticity can decrease tablet strength because of the breakage of bonds as the compaction pressure is released . Lubricants   Lubricants are used to improve granule flow, minimize die wall friction & prevent adhesion of the granules to the punch faces. Lubricant decreases the strength of the tablets. When lubricants are added as dry powder to granules, they adhere & form a coat or a film around the host particles during the mixing process. The Lubricant film interferes with the bonding properties of host particle by acting as a physical barrier. When the tablet is blended lightly, the lubricant is present as a free fraction. Prolonged mixing time will produce a surface film of lubricants over the drug particles due to which inter particulate bonding is reduced. 52

53. Entrapped air When the air does not freely escape from the granules in the die cavity, the force created by the expansion of the entrapped air may be sufficient to disrupt the bonds. The presence of entrapped air will produce a tablet which can be broken easily & it lowers the tablet strength. Moisture content A small proportion of moisture content is desirable for the formation of a coherent tablet. At low moisture content there will be increase in die wall friction due to increased stress, hence the tablet hardness will be poor. At high moisture level the die wall friction is reduced owing to lubricating effect of moisture. At further increase in moisture content there will be decrease in compact strength due to reduction in inter particulate bond. Optimum moisture content is in the range of 0.5 – 4%. Porosity When particles of large size are subjected to light compression the tablet will be highly porous–low tablet strength. Reduction in porosity is due to granule fragmentation giving smaller particles which may be more closely packed & plastic deformation which allows the granules to flow into the void spaces. 53

54. Tablet Compaction Powders intended for compression into tablets must possess two essential properties: Powder fluidity The material can be transported through the hopper into the die to produce tablets of a consistent weight Powder flow can be improved mechanically by incorporate the glidant . Powder compressibility The property of forming a stable, intact compact mass when pressure is applied 54

55. Direct compression The term “direct compression” is defined as the process by which tablets are compressed directly from powder mixture of API and suitable excipients. It involves only two unite operations powder mixing and tableting. Advantages of Direct Compaction: Reduced production time &cost. P roduct stability can be improved. Faster drug dissolution due to fast disintegration into primary particles. less number of equipment are required, less process validation Elimination of heat and moisture, thus increasing not only the stability but also the suitability of the process for thermo-labile and moisture sensitive API’s. 55

56. Disadvantages of Direct Compaction Large particles must be used → (acceptable flowability and bulk density) Needs directly compressible filler that is usually expensive, e.g. microcrystalline cellulose ( Avicel ), spray dried lactose High dose drugs having high bulk volume, poor flowability and poor compressibility are not suitable for direct compression. For example , Aluminium Hydroxide, Magnesium Hydroxide Non-uniform distribution of colour , especially in tablets of deep colours Tablet Compression Machine Design: 1. Hopper for holding and feeding granules or powder to be compressed. 2. Dies that define the size and shape of the tablet. 3. Punches for compressing the granules within the dies. 4. Cam tracks for guiding the movement of the punches. 5. A feeding mechanism for moving granules from the hopper into the dies. 56

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58. Single punch tablet press is also called as a eccentric press or single station press It is most simplest machine for tablet manufacturing Single station tablet press employs a single tooling station that is a die and a pair of upper and lower punches This tablet press is available as both manually operated and power driven In this single punch tablet press, the compaction force on the fill material is exerted by only the upper punch while the lower punch is immovable such as action equivalent to hammering motion 58 Single Punch Tablet Machine

59. Single Punch press (Eccentric Press ): B ench-top models that make one tablet at a time (single-station presses) Disadvantages: Production of small batches of tablets (200 tablets per minute). Core components: Die Lower punch Upper punch 59

60. Rotary Press machine Rotary Press( Multi station Press ): It is also called multi station tablet press. Multi station presses are termed rotary because the head of the machine that holds the upper punches, dies and lower punches in place rotates. It was developed to increase the output of tablets ( 10 000 tablets per minute ), used for Large scale production. It consists of a number of dies and sets of punches (from 3 up to 60). The dies are mounted in a circle in the die table and both the die table & the punches rotate t ogether during operation of the machine. 60

61. The core components and compression cycle of rotary presses A: upper punch B: die cavity C: die D: lower punch The compression is applied by both the upper punch and the lower punch. The compression cycle of a rotary tablet press 61

62. Compression Cycle Of Rotary Presses 62

63. Compression Cycle Of Rotary Presses Stage 1: Top punch is withdrawn from the die by the upper cam, Bottom punch is low in the die so powder falls in through the hole and fills the die. Stage 2: Bottom punch moves up to adjust the powder weight-it raises and expels some powder Stage 3: Top punch is driven into the die by upper cam; Bottom punch is raised by lower cam. Both punch heads pass between heavy rollers to compress the powder. Stage 4: Top punch is withdraw by the upper cam. Lower punch is pushed up and expels the tablet. Tablet is removed from the die surface by surface plate Stage 5: Return to stage 1 63

64. Working Principle of Compression Machine: 1. Filling and Dosing of the Dies The material to be pressed reaches the rotary or gravity feeder from the material supply. The fill cam below the feeder pulls the lower punches down by a fixed amount and the dies are filled with material. The quantity of the material filled in is larger than the actual amount required i.e. excess dosing is done. Thereafter, the dosing unit lifts the lower punches until only the desired quantity of material remains in the dies. The excess material is transported back into the feeder. 2. Compression of the Tablets After that, the upper cam course lowers the upper punch until the upper punches are inserted into the dies. The lower punches are guide to the pre-compression cam. When the punches pass the pre-compression cam, they are inserted a little more into the dies and the material is pre-compressed and the slugs are formed. Thereafter, in the main compression roller, the tablets reach their final height and hardness. 64

65. 3. Ejection and Exit of the Tablets After the compression, the upper cam course pulls the upper punches into their top position and simultaneously the ejection device lifts the lower punches until the tablets are ejected from the dies. The tablet stripping device strips the tablets off the lower punches and passes them on to the discharge chute. The stages in the compression cycle are shown in figure 65

66. Auxiliary Equipments 1.Granulation Feeding Device: Speed of die table is such that the time of die under feed frame is too short to allow adequate or consistent gravity filling of die with granules, resulting in weight variation and content uniformity. These also seen with poorly flowing granules. To avoid these problems, mechanized feeder can employ to force granules into die cavity. 2. Tablet weight monitoring devices:- High rate of tablet output with modern press requires continuous tablet weight monitoring with electronic monitoring devices 3. Tablet Deduster : - Tblets coming out of a tablet machine bear excess powder on its surface and are run through the tablet deduster to remove that excess powder. 4. Fette machine Fette machine is device that chills the compression components to allow the compression of low melting point substance such as waxes and thereby making it possible to compress product with low meting points. 66

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

68. Tablet Coating Tablet properties Tablets that are to be coated must possess the proper physical characteristics. In the coating process, the tablets roll in a coating pan or cascade in the air stream as the coating solution is applied. The tablets must not chip or break.. Also the tablets are exposed to elevated temperature and humidity during the coating. The tablet surface which are brittle gets soften in the presence of heat or effected by coating solutions tends to become rough in the early phase of the coating process are unacceptable for coating, especially for film coating which deposits thin layer of coating, while sugar coating can fill the surface imperfection but upto some extent because of their high solid contents. The tablets must be robust enough to withstand these conditions. The following must be considered while designing tablets which are to be coated. a. Tablet Hardness: tablet breakage is typically seen when the hardness is inadequate a rule of thumb is the tablets to be coated should have hardness not less than 8 kp (11.2 scu , 80 N) 68

69. b. Tablet Friability: This test accurately reflects the stresses that the tablets will when tumbling in a coating pan. The maximum recommended friability for tablets to be coated is 0.5% however for best results the aim should be 0.1%. If the friability is above this limit the tablets may cap, laminate or abrades during coating process. c. Tablet core shape: The flat faced tablets have overall best surface hardness buit tend to be brittle at the edges, these tablets are not good for coating because of twinning problem. The deep concave type good mixing and no twinning problem but they offer the lowest level of surface hardness, so these are also not suitable because of high attrition at crown . The best compromise between surface hardness, mixing and twinning is offered by the normal or shallow concave shapes and these are recommended for coating. Generally the flat faced, shallow concave or capsule shaped tablets show greatest erosion at the edges while deep concave show erosion at the crown 69

70. d. Tablet porosity: Increased tablet porosity can be beneficial in increasing the force of adhesion between the tablet surface and the applied coat. It should be kept in mind increase porosity comes at the sacrifice of tablet hardness e. Tablet core ingredients: The ingredients both active and inactive can have significant effect on the interaction between the substrate and coating. The most important is the degree of adhesion. The active ingredient is often present in significant amount in the tablet formulation, this will overwhelm the influence on adhesion by other ingredients. If the active content is low and it has negative impact on film adhesion Lubricants are added to tablet formulations to minimize both die wall friction and punch adhesion, lubricants results in decrease of tablet hardness and coating adhesion Superdisintegrants are valuable materials in tablet formulation due to their ability to reduce disintegration time and increase dissolution rate. However if used indiscriminately, they can exert negative effects on other aspects of tablet quality. High levels of superdisintegrant may result in orange peel effect though the hardness and friability will be well in the limit. 70

71. Coating Process: Tablet coating is the application of coating composition to a moving bed of the tablets with concurrent use of heated air to facilitate evaporation of the solvent. Equipment: The process and equipment must provide; Distribution of the liquid coating formulation over the whole of the available tablet surface (ladling, Spraying). Continuous mixing of the tablet load in order to achieve an evenly coated product (rotation). Continuous drying to solidify the film quickly (hot air). Removal of solvent vapour (plus dust generated, plus used drying air and atomizing air). 71

72. Equipment: 1 . Standard (conventional) coating pan The standard pan is 8 – 60 inches in diameter and is rotated on its horizontal axis by a motor. Heated air is directed into the pan and onto the tablet bed surface through a duct and exhausted out by means of another duct positioned over the tablet be in front of the pan. Coating solution is applied either through ladling or spraying. 2. Immersion sword pan In this system the drying air is introduced through a perforated metal sword device that is immersed in the tablet bed. The drying air flows upward from the sword through the tablet bed thus providing efficient drying of the wetted tablets.

73. 3. Immersion Tube pan In this system a tube is immersed in the tablet bed. The tube delivers the heated air, a spray nozzle is built in the tip of the tube to deliver the coating composition. The coating solution and dry air introduced at the same time. 4. Perforated pan system This system make use of perforated or partially perforated drum (pan) that rotates on its horizontal axis in an enclosed housing. This type of coating system are more efficient in drying as compared to the conventional system. With such system mark decrease in coating time can be achieved. The current systems available include; Manesty Accela Cota Freund Hi- Caoter Driacoater Glatt Coater

74. 5. Fluidized bed (air suspension) coater This system uses columnar chamber through which high volume heated air is supplied from the bottom to fluidize the tablet bed, providing the medium for drying and the energy for mixing. These are most efficient drying and mixing equipment. These are not commonly used for tablets on large scale high attrition the tablets chip, breaks, abrades out. This system is commonly applied for particulate coating ( microencapsultion and pellet coating). The coating solution is either applied from the bottom ( Wurster ) or from the top of the chamber on to the tablet bed. 74

75. Spraying Application Systems (spray gun): Two systems are used to apply atomized spray of coating composition onto the tablets. High pressure air less system In this system the liquid is pumped at high pressure (250-3000 psig) through a small orifice (0.009-0.20 inch) in the fluid nozzle. The degree of atomization and the spray rate are controlled by the fluid pressure, orifice size, and viscosity of the liquid. The disadvantage of the system is that, Because of the small orifice the suspension may block it therefore the coating suspension may be finely milled or filtered. The airless system doesn't provide independent control of suspension application rate, degree of atomization and spray fan width. 75

76. 76 Low pressure air atomized system In this system liquid is pumped through larger orifice (0.020 – 0.06 inch) at relatively low pressure (5-50 psig). Low pressure of about 10-100 psig at the atomizer tip contact the liquid and disperse it in finely divided spray. In this system atomization can be controlled independently of the operating pressure, also fan width can be controlled. Coating Parameters During coating the tablets move through an application zone in which a portion of the tablets receive some coating. Most of the time tablets are in drying mode moving away from the application zone and recycled repeatedly through the application zone. In the coating operation (continuous) an equilibrium is maintained between coating composition application rate and the rate of evaporation of the solvent. Deviation from this equilibrium results in serious coating problems. These two parameters can be adjusted by; Spray Gun position: 6-18 inches from the bed, 45 angle to the tablet bed. Not overlapping fan width nor to far. Effect of pan load: under loading the pan will result in situation where the tablet does not cover fully the exhaust plenum, and the majority of the drying air stream will bypass the tablet bed and drying efficiency will be low.

77. Air volume and temperature: Drying is controlled by the quantity and temperature of the drying hot air, and the quantity of exhaust air. It is important to balance the inlet and exhaust air flow rates such that there is slight negative pressure in the chamber. Also the temperature difference between the inlet and exhaust must be with in 20-30oC. It is important to monitor the following three temperatures. Inlet Air temperature Tablet Bed temperature (most critical) Exhaust air temperature Coating composition: coating composition contains the ingredients that are to be applied on the surface of tablet and the solvents , which act as carrier for the ingredients. These solvents are not required in the final product and must be removed. A balance must be established between the coating composition flow rate and the three drying variables (drying air temperature/quantity and exhaust air quantity). 77

78. Types Of Coating Sugar coating Film Coating Conventional film coating 2. Enteric film coating 1. Sugar coating This involves several steps, the duration of which ranges from few hours to few days. The quality of coating depends upon the skill of the operator specially in ladling type of solution application. The sugar coating results in elegant highly glossed finished tablets. Following steps are involved in sugar coating. Sealing Subcoating Syruping (smoothing) Finishing Polishing 78

79. Seal coating (sealing) To prevent moisture penetration into the tablet core a seal coat is applied. This is specially required in pan-ladling process, to avoid over wetting of the tablet bed. Without seal coat the tablets will absorb sufficient moisture to be softened or disintegrate , effecting the physical appearance. Shellac is the most commonly applied sealant agent, but it offers the problem of increase the disintegration and dissolution time on aging because of polymerization of shellac. Zein is also used as sealant, it has no problem as associated with the shellac. The process description is Pan Speed: 10 rpm Supply air temperature: 30oC application of 800 ml of sealant solution is applied and the tablets are allowed to dry for 15-20 minutes between the application. If the tablets become tacky at any time apply sufficient talc to avoid sticking . 79

80. Sub Coating This is applied to round the edges and build up the tablet size. Sugar coating results in the increase of tablet weight by 50-100%. Usually gelatin/acacia solution is used along subcoating powder. The process description is Pan speed: 10 rpm Turn heart and inlet air off. Use exhaust air only apply 3-9 coats. Use 1-2 liters for first coat and then reduced the quantity accordingly to obtain the required weight and round edges. Allow the tablets to dry at least for 20 minutes after each application. Dust with subcoating powder at the end. After the last coat, jog the pan for at least 2-4 hours to ensure complete dryness. 80

81. 3. Syrup (smoothing/color) coating The purpose of this step is to cover and fill the imperfection in the tablet surface caused by subcoating , this is the most technical step as it requires the most skill. This step usually involves three basic phases. a. Grossing syrup (a syrup with subcoating powder dispersed in it): Process outline is Remove excess dust from the pan. Turn on the exhaust air. Adjust the temperature to achieve the exhaust air temperature of 45-48oC. Pan Speed: 15 rpm Apply 5-15 coats of grossing syrup. b. Heavy syrup: This solution contain color, maintaining the above parameters apply several coats. c. Regular syrup: The process steps are Turn off the heat, reduce the inlet and outlet air. apply few coats of regular colored syrup to achieve final smoothness, size and color development. 81

82. 4. Finishing With the heat and inlet air supply off , reduced exhaust air and pan speed of 12 rpm apply 3-4 coats of regular colored syrup rapidly. Shut off the exhaust air and apply last coat of regular syrup without colorant. This will give depth to the color and will enhance the elegance of the coat. Stop the pan while the tablets are damp and swiftly shift to jog the pan for 15-30 minutes, leave the tablets overnight to dry completely. Polishing: This is the final step, the tablets can be polished in standard coating pan or canvas line polishing pan. The steps involved are Pan speed: 12 rpm Inlet air, outlet air turned off Apply 3-4 coats warm polishing solution (waxes), approximately 300 ml per application. Apply the subsequent coat when the solvent is evaporated out. Sometimes powder wax are also applied. 82

83. Film Coating To reduce sugar coating process time and to reduce the requirement for operator skill, film coating was developed. Film coating is a technique in which a thin layer/coat of a polymer is deposited over the tablets/particulate. Depending on the coating polymer the types of coating are Normal film coating Enteric film coating Aqueous moisture barrier coating (AMB) On the basis of solvent use the types are Organic Coating Aqueous Coating 83 Materials used in film coating A typical film coating formulation is made up of Polymer (film former) Plasticizer Colouring / opacifying agent Solvent Others (surfactants, flavors, sweetening agent, active ingredients and preservatives.)

84. An Ideal Coating Material Should Have The Following Properties; Solubility in solvent of choice for coating preparation Solubility required for the intended use Capacity to produce an elegant looking product Stability in the presence of heat, light, moisture, air and substrate being coated Odorless, colorless and tasteless compatibility with other ingredients Non toxic or no pharmacologic activity Ease of application Resistant to cracking No bridging or filling formation Ease of printing on high speed machines 84

85. Polymers/Film formers The function of the polymer is to provide main structure and basic physical and chemical properties to the coating. Polymer viscosity is very important specially in aqueous coating we need to minimize the water concentration, it is to shorten the process time and to minimize product exposure to the moisture (moisture sensitive product). But the coating composition with viscosity above 500 cps are difficult to atomize and will not produce smooth product. Therefore polymers with low viscosity are preferred. 1. Hydroxypropyl methylcellulose (HPMC) Commercially it is available in different viscosity grades This polymer is widely used in air suspension and pan spray coating. The properties are Soluble in GI fluid, organic and aqueous solvent system Stability in presence of light, heat, air and reasonable amount of moisture Incorporation of colour and other additives with out difficulty. If it is used alone then it may results in bridging and filling, so it may be used in combination or proper plasticizer may be used. 85

86. 2. Methyl hydroxyethylcellulose This polymer has also different viscosity grades, it has similar properties as that of HPMC but it is soluble in few organic solvents, which has restricted its use . Ethylcellulose Depending on the ethoxy substitution different viscosity grades are available commercially. This material is water and GI fluid insoluble, therefore can not be used alone for coating. It is used in combination with water soluble polymer e.g. HPMC. These combination are a used for sustained release coating. The properties include Soluble in wide variety of organic solvents Non toxic Tasteless, odorless and colorless stable at environmental conditions Unplasticized ethyl cellulose coats are brittle. 86

87. 4. Hydroxypropylcellulose It is soluble in water below 40 o C, GI fluid and organic solvents It is very tacky and yield very flexible film, it can not be used alone It is good for sub coat but not for color or gloss coat Povidone (PVP) It is available in four viscosity grades i.e. K-15, K-30, K-60 and K-90, the average molecular weights are 10,000, 40,000, 160,000 and 360,000 respectively. It is soluble in water, GI fluid and variety of organic solvents. Povidone films are clear, hard and glossy Povidone is soluble in both acidic and intestinal media, it can be cross linked with other materials to produce enteric coating material. Povidone is used in coating composition to increase the dispersion of color. 87

88. 6. Sodium Carboxymethylcellulose It is available in low, medium ,high and extra high viscosity grades It can easily be dispersed in water to form colloidal solution, but is insoluble in most organic solvents. the film formed is brittle but adheres well to tablets . Acrylate polymers Acrylate polymers are marketed under the trademark of Eudragrit . Eudragrit E( dimethylaminoethyl methacrylate and other neutral methacrylic acid esters) is the only polymer of this group which is freely soluble in gastric fluid (acidic media). 88

89. Enteric Polymers Enteric coating polymers are those substances which resists the gastric pH (acidic) and get dissolves in intestinal fluid (alkaline). The reasons for enteric coating are To protect acid labile drugs from gastric fluid e.g. enzymes and certain antibiotics To prevent gastric distress or nausea e.g. sodium salicylate To deliver drug to intestine for local action To deliver drugs that are optimally absorbed in the small intestine To provide a delayed release component for repeat action tablets. 89

90. An ideal enteric coating polymer should have the following properties Resistance to gastric fluids (acidic pH) Ready susceptibility to or permeability to intestinal fluid (alkaline pH) Compatibility with other ingredients Non toxic or no pharmacologic activity and Ease of application Formation of continuous film stability alone and in coating solution. The film should not change with aging Ease of printing on high speed machines Cellulose Acetate Phthalate (CAP) . CAP is widely used but it has major disadvantage that it dissolves above pH 6, thus delaying the drug release as the ideal material may dissolve around pH 5. It is also hygroscopic and relatively permeable to gastric fluid. The film formed is brittle thus required plasticizer. It is available under the trademark of Aquateric from FMC. 90

91. Acrylate polymers. Two commercially available acrylates are Ex. Eudragrit L (soluble at pH 6), Eudragrit S (soluble at pH 7) 3. HPMC Phthalate Three grades are available Ex. HPMCP 55 (HP 50), HPMCP 50 (HP 55) and HPMCP 55S (HP 55S) These polymers dissolves at lower pH (at 5-5.5) than CAP and acrylates . Thus resulting in higher bioavailability of some specific drugs. Polyvinyl Acetate Phthalate (PVAP) It is similar to HP 55 in stability and pH dependant solubility. 91

92. Plasticizer The function of plasticizer is to modify the basic mechanical properties of the polymer. Plasticizers have high affinity for the polymer they are also called nonvolatile solvents. There are two techniques to modify the plasticity of the film former; Internal plasticizing External plasticizing In the former technique chemical modification is brought in the polymer which alters the physical properties of the polymer i.e. elastic modulus. In later technique other substances are used as plasticizer in the formulation. When the plasticizer is used in correct concentration it imparts flexibility by relieving the molecular rigidity. Commonly 10% of polymer concentration is used. Examples include Castor Oil Propylene glycol & Glycerin tween & span 92

93. Coloring and opacifying agent The function of these ingredients is to enhance the product quality. They provide Product identification Protect the core from light and moisture They increase the solid concentration with any impact on viscosity thus reducing the drying time. They are either soluble or form fine suspension in the solvent system. For uniform distribution the particle size must be < 10 microns. The most common colorants used are FD&C or D&C certified, these are either dyes or lakes of dyes. Examples include iron oxide, anthrocyanins , caramel, carotenoids, chlorophyll, indigo, flavones, turmeric acid and carminic acid. Opacifiers are used to give more pastel color and increase film coverage. These can provide white coat or mask the color of the tablet core. These are mostly inorganic material. The substances employed are: Titanium dioxide (Most Common), Talc, Aluminum silicate, Magnesium carbonate, Calcium sulfate, Aluminum hydroxide 93

94. Solvents The function of the solvent is to dissolve or disperse the polymers and other additives and transfer them to the surface of substrate (core) the ideal characteristics are It should either dissolve or disperse the polymer system and other ingredients . Small concentration of polymer (2-10%) should not high viscous solution It should be colorless, tasteless, odorless, inexpensive, inert and noninflammable . Should have rapid drying rate Should not have environmental impact . The most widely solvents used either alone are in combination are water, ethanol, methanol, isopropyl alcohol, chloroform , acetone , methyl ethyl ketone and methylene chloride. 94

95. Coating/Polishing Principle: Application of coating solution to a moving bed of tablets with concurrent use of heated air to facilitate evaporation of solvent What are the problems What are the equipment Why do it Blistering, chipping, cratering, picking, pitting Color variation Roughness Pan (standard/perforated) Coating Machines Fluidized Bed Coating Machines Spray Coating Machines Vacuum, Dip & Electrostatic Coating Machines Enhance appearance and colour Mask taste and odour (film/sugar) Improve patient compliance Improve stability Impart enteric, delayed, controlled release properties

96. Twinning Two tablets stick together. Most common in capsule shaped tablets . Cause Coating suspension can not be evaporated. Remedy Reducing spray rate Increasing pan speed 96

97. Cracking Small , fine cracks observed on the upper and lower central surface of tablets, or very rarely on the sidewall are referred to as ‘Cracks ’. Cause Use of higher molecular weight polymers or polymeric blends Higher internal stresses in the film ( more than tensile strength of the film ) Remedy Use low molecular weight polymer Adjust the plasticizer & pigment types and concentration to minimize internal stresses 97

98. Sticking & picking It is defect where isolated areas of film are pulled away from the surface when the tablet sticks together and then part. Picking does not occur alone it must have another tablet to be stuck with which called sticking . Cause : Inefficient drying. Higher rate of application of coating solution Over wetting Excessive film thickness Remedy : Reduce liquid application rate. Increase in drying air temperature and air volume. Sticking Picking 98

99. Blistering It is local detachment of film from the substrate forming a blister Cause : Over heating during spraying coating solution Remedy : use mild drying condition . Chipping It is the defect where film become chipped and dented , usually at the edges of tablet . Cause : Excessive attrition during coating process Remedy : Increase hardness of the film . 99

100. Orange peel effects It refers to a coating texture that resembles the surface of an orange . Cause : Rapid Drying High solution viscosity Remedy : Use mild drying conditions Use additional solvents to decrease viscosity of solution. Roughness : The surface becomes rough and no glossy Remedy: Reduce the degree of atomization 100

101. Bridging Coating fills in the letter or logo on the tablet . Cause : Improper formulation Poor logo design Improper application of coating solution Improper atomization pressure High percentage of solid in coating solution High coating viscosity Remedy : Increase plasticizer contents or change plasticizer concentration Reduce viscosity of coating solution 101

102. Filling The monogram or bisect is filled and become narrow . Cause : Applying too much solution Higher solution applying rate Remedy - Control fluid application rate Blooming (Hazing/dull film) Coating becomes dull immediately or after a prolonged storage . Normally it occurs together with surface roughness. Cause - using low molecular weight plastisizer . Remedy - increase MW & concentration of plastisizer . 102

103. Erosion Cause : Over-wetted tablet surface Inadequate drying Lack of tablet surface strength Remedy – Control drying rate & temparature Pitting It is defect whereby pits occur in the surface of tablet core Cause Incontinuous spreading of film temperature of the tablet core is greater than the melting point of the materials used in tablet formulation Remedy - control drying temperature 103

104. Color variation Two types of color variation – Individual Tablet Color variation, Whole Batch Color Variation Cause : improper mixing, uneven spray pattern, insufficient coating migration of soluble dyes , plasticizer and other additives during drying. Remedy : Use of lake dyes eliminates dye migration. A reformulation with different plasticizer and additives is the best way to solve film instability. 104

105. Cratering It is the defect of film coating whereby volcanic-like craters appears exposing the tablet surface . Cause Penetration of the coating solution into the surface of the tablet Remedy Decrease in spray application rate Use of optimum and efficient drying Blushing (whitish specks) The defect best described as whitish specks or haziness of the film . It is characterized by precipitation of polymer exacerbated by the use of high coating temperature at or above the thermal gelation temperature of the polymers. 105

106. Agglomeration Agglomeration caused by coating suspension cannot be evaporated as soon as it reach the tablet which may be caused from too much inlet coating suspension or too less inlet heat and the unevaporated suspension glue the tablets together. The amount of excess unevaporated suspension is much more than twinning . Sometimes it can cause by the leaking of coating suspension into the chamber, or too close spraying distance or too low atomizing pressure . 106

107. Capping & Laminating Capping occurs when the upper segment of the tablet separates from the main portion of the tablet & comes off as a cap. Can appear immediately after compression, or hours, even days after preparation. It is usually due to air entrapped in the granulation which is compressed in the die during the compression & then expands when the pressure is released. Cause: large amount of fines in the granulation &/or the lack of sufficient clearance between the punch and the die wall. And Too dry granules Lamination is due to the same causes as capping except that the tablet splits at the sides into two or more parts. If tablets laminate only at certain stations, the tooling is usually the cause. Solutions for capping & laminating: Increasing the binder. Adding dry binder such as gum acacia polyvinylpyrrolidone (PVP).. Decreasing the upper punch diameter. Certain degree of moisture in the granules 107

108. Mottling It is an unequal distribution of color on the surface of the tablet. Cause : A drug that differs in color from its excipients or whose degradation products are highly colored. Migration of a dye during drying of a granulation (change the solvent system, reduce the drying temperature, or grind to a smaller particle size). 108

109. Packaging Pharmaceutical manufacturers have to pack their medicines before they can be sent out for distribution. 'Blister packs' are a common form of packaging used for a wide variety of products. They are safe and easy to use and they allow the consumer to see the contents without opening the pack. Packaging Types Primary packaging is the material that first envelops the product and holds it. This usually is the smallest unit of distribution or use and is the package which is in direct contact with the contents. Secondary packaging is outside the primary packaging – perhaps used to group primary packages together Tertiary packaging is used for bulk handling, warehouse storage and transport shipping. The most common form is a palletized unit load that packs tightly into containers. 109

110. IPQC TESTS FOR TABLETS 110

111. What Do You Mean By “IPQC”…? IPQC is concerned with providing accurate , specific , & definite descriptions of the procedures to be employed, from, the receipt of raw materials to the release of the finished dosage forms. “ INSPECTION ” “ TESTING ” 111

112. In process Quality Control   In process Quality Control, IPQC tests are mostly performed within the production area. They should not carry any risk for the quality of product. In process testing enables easier identification of problems. It some time identifies a defective product batch that can be corrected by rework, whereas once that batch has been completed, this may not be possible. Failure to meet In process control specification indicates either that procedure were not followed or some factor(S) out of control. 112

113. Various Instrument Used In IPQC Department:  Disintegration apparatus Dissolution apparatus Analytical balance Muffle furnace Friability testing apparatus Bulk density apparatus Tablet hardness tester Infra red moisture content measuring apparatus U.V Spectroscopy Abbe Refractometer T.L.C. kit Karl fisher Titrimeter 113

114. Evaluation of Tablet Official and unofficial tests for evaluation of tablets Official Tests: Weight variation Disintegration Dissolution Drug content Non-Official Tests: Hardness Friability 114

115. 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. 115

116. 5. Hardness (crushing strength ): Tablet requires a certain amount of strength or hardness and resistance to friability to withstand mechanical shocks of handling in manufacture, packaging and shipping. Hardness generally measures the tablet crushing strength. Why do we measure hardness ? To determine the need for pressure adjustments on the tableting machine. Hardness can affect the disintegration. So if the tablet is too hard, it may not disintegrate in the required period of time. And if the tablet is too soft, it will not withstand the handling during subsequent processing such as coating or packaging. In general, if the tablet hardness is too high, we first check its disintegration before rejecting the batch. If the disintegration is within limit, we accept the batch. If Hardness is high + disintegration is within a time accept the batch . 116

117. Different Hardness Tester Erweka Pfizer Schleuniger Monsanto Strong- cobb 117 Factors Affecting the Hardness: Compression of the tablet and compressive force. Amount of binder. (More binder à more hardness) Method of granulation in preparing the tablet (wet method gives more hardness than direct method, Slugging method gives the best hardness). Limits: 5 kilograms minimum and 8 kilograms maximum. Make hardness test on 5 tablets and then take the average hardness.

118. 6.Friability : Friability of a tablet can determine in laboratory by Roche friabilator. Friability is a property that is related to the hardness of the tablet. It is used to evaluate the ability of the tablet to withstand abrasion in packaging, handling, and shipping. Procedure: Weigh 20 tablets together = W1 Put these tablets in the friabilator and adjust the instrument at 100 rpm (i.e. = 25 rpm for 4 min) Weigh the 20 tablets (only the intact ones) = W2 Friability (% loss) = W1 - W2/100 The tablets are reweighed. It must be less than or equal to1 % but if more we do not reject the tablets as this test is non-official.. 118

119. 7. Thickness test Thickness is an unofficial test . Thickness of the tablet is inversely proportional to hardness i.e. increase in hardness decrease the thickness & vice versa. Thickness of tablet is measured by Vernier caliper/screw gauge. It is determined for 10tablets. Vernier caliper 119

120. 8.Weight variation test (uniformity of weight) Weigh 20 tablet selected at random, Determine the average weight. X= (X1+X2 +X3+…+ Xz )/20 Limit: Upper limit = average weight + (average weight * % error) Lower limit = average weight - (average weight * % error) The individual weights are compared with the upper and lower limits. Not more than two of the tablets differ from the average weight by more than the % error listed, and no tablet differs by more than double that percentage. 120 No Average wt. of tablet(mg) Max. % difference allowed 1 130 or Less 10% 2 130-324 7.5% 3 More than 324 5% USP XX-NF STANDARDS IP STANDARDS No Average wt. of tablet(mg) Max. % difference allowed 1 84 or Less 10% 2 84- 250 7.5% 3 More than 250 5%

121. 9. Content Uniformity Test : It is an official test. Randomly select 30 tablets. 10 of these assayed individually. The Tablet pass the test if 9 of the 10 tablets must contain not less than 85% and not more than 115% of the labeled drug content and the 10 th tablet may not contain less than 75% and more than125 % of the labeled content. If these conditions are not met, remaining 20 tablet assayed individually and none may fall out side of the 85 to 115 % range . 10. Disintegration test (U.S.P.) : Disintegration test is an official test . It is the time required for the tablet to break into particles, the disintegration test is a measure only of the time required under a given set of conditions for a group of tablets to disintegrate into particles It is performed to identify the disintegration of tablet in particular time period. Disintegration test is not performed for controlled & sustained release tablets . 121

122. The U.S.P. device to test disintegration uses 6 glass tubes that are 3” long; open at the top and 10 mesh screen at the bottom end. To test for disintegration time, one tablet is placed in each tube and the basket rack is positioned in a 1-L beaker of water, simulated gastric fluid or simulated intestinal fluid at 37 ± 2 C such that the tablet remain 2.5 cm below the surface of liquid on their upward movement and not closer than 2.5 cm from the bottom of the beaker in their downward movement. Move the basket containing the tablets up and down through a distance of 5-6 cm at a frequency of 28 to 32 cycles per minute. Floating of the tablets can be prevented by placing perforated plastic discs on each tablet. According to the test the tablet must disintegrate and all particles must pass through the 10 mesh screen in the time specified. If any residue remains, it must have a soft mass. Liquids used in disintegration Water, Simulated gastric fluid (pH = 1.2 HCl ), or Simulated intestinal fluid (pH = 7.5, KH2PO4 (phosphate buffer) + pancreatic enzyme + NaOH ) 122

123. Sr no. Type of tablets Medium Temperature limit 1 Compressed uncoated 37 ± 2 C 15 minutes or as per individual monograph 2 Sugar coated If 1 or 2 tablets fail Water 0.1 N HCL 37 ± 2 C 60 minutes or as per individual monograph 3 Film coated water 37 ± 2 C 30 minutes or as per individual monograph 4 Enteric coated 0.1 N HCL & Phosphate buffer pH 6.8 37 ± 2 C 1 hr or as per individual monograph 5 Dispersible/ Effervescent water 37 ± 2 C LST < 3 minutes or as per individual monograph 6 Buccal 37 ± 2 C 4 hr or as per individual monograph Disintegration Testing Conditions And Interpretation 123 Disintegration test apparatus

124. U.S.P. method for uncoated tablets: Start the disintegration test on 6 tablets. If one or two tablets from the 6 tablets fail disintegrate completely within 30min repeat the same test on another 12 tablet. (i.e. the whole test will consume 18 tablets). Not less then 16 tablets disintegrate completely within the time. If more then 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 5min. Put the tablet in the apparatus in water or HCL for 30 min 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 not disintegrated the batch is rejected. 124

125. U.S.P. and B.P Method for Enteric coated tablets: Put in distilled water for five minutes to dissolve the coat. Then put in simulated gastric fluid (0.1M HCL) for one hour. Then put in simulated intestinal fluid for two hours. If one or two tablets fail to disintegrate, repeat this test on another 12 tablets. So 16 tablets from 18 should completely disintegrate. If more than two fail to disintegrate the Batch must be rejected. 11 . Dissolution Test Dissolution is an official test. Dissolution is performed to check the percentage release from the dosage forms.i.e.tablet. Tablet breaks down into small particles which offers a greater surface area to the dissolving media. Disintegration test does not give assurance that particles will release drug in solution at an appropriate rate, that’s why dissolution tests & it’s specifications developed for all tablet products . 125

126. 1. USP Dissolution apparatus I ( Basket method) A single tablet is placed in a small wire mesh basket attached to the bottom of the shaft connected to a variable speed motor. The basket is immersed in a dissolution medium (as specified in monograph) contained in a 1000 ml flask. The flask is cylindrical with a hemispherical bottom. The flask is maintained at 37 ± 0.5 C by a constant temperature bath. The motor is adjusted to turn at the specified speed and sample of the fluid are withdrawn at intervals to determine the amount of drug in solutions. 2 . USP Dissolution apparatus II ( Paddle method) It is same as apparatus-1, except the basket is replaced by a paddle. The dosage form is allowed to sink to the bottom of the flask before stirring. For dissolution test U.S.P. specifies the dissolution test medium and volume, type of apparatus to be used, rpm of the shaft, time limit of the test and assay procedure for. The test tolerance is expressed as a % of the labeled amount of drug dissolved in the time limit. 126

127. Sr.no. Quantity Stage/level Number of tablets tested Acceptance criteria 1 S1 6 Each unit is < D* + 5 percent** 2 S2 6 Average of 12 units (S1 +S2) is equal to or greater than (> )D, and no unit is less than D - 15 percent** 3 S3 12 Average of 24 units (S1+S2+S3) is equal to or greater than ( > )D, not more than 2 units are less than d-15 percent** and no unit is less than d-25 percent** Dissolution Testing And Interpretation IP Standards * D is the amount of dissolved active ingredient specified in the individual monograph, expressed as a percentage of the labelled content. ** Percentages of the labelled content. 127

128. Evaluation Of Precompressional Characteristics Of Tablets Or Rheological Characteristics Of Granules Particle Size & Shape Determination. Surface area. Density Bulk density True density Granular density Granule strength & friability. Flow properties. Angle of repose Percentage Compressibility Index Hausner’s ratio 6. Moisture content. 7. Percentage fines(% fines). 128

129. Evaluation Of Compression Characteristics Of Tablets Characterization Of Granules 1 ) Particle Size & Shape Determination Size affects the average weight of tablet, Disintegration Time, weight variation, friability, flowability & drying rate. The size & shape depends upon processing requirements & during granulation. The methods for determining size & shape are 1. Sieving 2. Sedimentation rate. 3. Microscopy (SEM) 4. By Light Scattering 129

130. 2. Surface Area If required particle size is measured & from this surface area is measured. Most method used is gas absorption & air permeability. In gas absorption , gas is absorbed as monolayer on particles this is in term of calculated & converted to surface area. In air permeability method the rate of air permeates a bed of powder ,is used to calculate surface area of powder sample . 3. Density Density may influence compressibility, tablet porosity & dissolution. Dense hard granules may require higher load to produce cohesive compact to reduce free granules seen on the surface of tablets. ↑ compressibility ↑ DT, Dissolution, if DT is slower dissolution is indirectly hampered. Dense granules have less friability but cause a problem in releasing the drug. 130

131. Three Methods to determine density Bulk Density – Bulk density is given by equation, ρ b = M / V b Where, ρ b- bulk density of granules, M is mass of granules in gm, V b – volume of granules in measuring cylinder in ml. More compressible bed of particulate - less flowable powder or granules. If less dense/compressible - more flowable powder or granules . 131

132. ii. True/tapped density – Tapped/true density is given by equation, ρ t = M / Vb Where, ρ t - bulk density of granules, M is mass of granules in gm, V t – volume of granules in measuring cylinder after tapping in ml. iii . Granular density It is determined by Pycnometer method. Two methods are used to determined granular density. In one intrusion fluid used-Mercury, and other Any solvent of low surface tension e.g. Benzene The accuracy of these method depends upon ability of intrusion fluid to penetrate the pores of granules. Liquids should not masks granules solubilies in it, & having property to penetrate the pores. 132

133. Density is then determine from volume of intrusion fluid displaced in pycnometer by giving mass of granulation. It is calculated by using equation, Granular Density (D) = M / Vp -Vi Where, Vp -Total volume of Pycnometer , Vi- Volume of intrusion fluid (ml) containing Mass (gm) (M) of granules required to fill pycnometer . 4. Granule Strength & Friability They are important because they affect:- 1.changes in particle size distributions of granulations. 2.compressibility into cohesive tablets. Granule strength & friability are measured by:- 1.Compressive Strength/hardness. 2.Using Friability measurements/apparatus. 133

134. 5. Flow properties. It is an ability of the granule to flow from hopper to die cavity for tablet uniformity. Flow property of granule are not uniform we are not getting tablet of uniform size. Flow property of material results from many forces Frictional force Surface tension force Mechanical force caused by interlocking of irregular shape particles Electrostatic forces Cohesive/ vander Waals forces Forces also affect granule property such as particle size, particle size distribution, particle shape, surface texture, roughness & surface area. 134

135. Fig(1) Fixed height Fig(2) fixed base cone Fig (3) Tilting angle Fig (4) Rotating cylinder Methods of determination of angle of repose 135 If particle size of powder is ≤ 150 µm the magnitude of frictional & vander waals force predominate. When particle size↑ mechanical & physical properties become more important with packing properties. Flow properties of granules are determined by measuring three parameters- Angle of repose – It is measured by two methods Static angle of repose Dynamic angle of repose. Equation is , tan θ = h/r. Where, θ - angle of repose, h – height of pile, r – radius of pile.

136. In fig.(1) height is constant & powder is added through the hopper until powder reaches tip of funnel. In fig.(2) height is varied & base cone is fixed, powder is added until height reaches at max. In fig.(3) rectangle box is filled with powder & tipped until content begins to slide. In fig.(4) revolving cylinder with transparent end is made to revolve horizontally when half filled with powder. The max. angle that the plane of powder makes with horizontal surface on rotation is taken as the angle of repose.. (1),(2) & (3) gives static angle of repose. While (4) gives kinetic or dynamic angle of repose. Sr no. Angle of repose (o) Type of flow 1 < 25 Excellent 2 25-30 Good 3 30-40 passable 4 > 40 Poor 136

137. ii. Percentage compressibility Index It is directly related to the relative flow rate cohesiveness & particle size. It is simple fast & popular method of presiding powder flow characters. It can be obtained from bulk density measurements is the % Compressibility index (C). % Compressibility index = Tapped density - Bulk density / Tapped density X 100. I = (1 – V/ V o ) x 100 Where, I – % Compressibility index, V – volume occupied by powder/ granules after tapping, V o - volume of powder/granules before tapping. SR.NO. % Compressibility index Type of flow 1 5-15 Excellent 2 12-16 Very good 3 18-21 Good 4 23-25 Passable 5 33-38 Poor 6 > 40 Very poor 137

138. iii. Hausner's Ratio Hausner’s ratio was related to interparticulate friction and as such could be used to predict powder flow characteristics. It showed that powder with low particular friction such as coarse sphere had ratio of approximately 1.2, where as more as cohesiveness- less free flowing powders such as flaks have Hausner’s ratio greater than 1.6. Hausner’s ratio = Tapped density / Bulk density 6. Moisture content The amount of moisture present in the granule is called moisture content. Generally the granules contain 2% moisture. It is required for the binding of the powder or granules during compression in die cavity. Percentage of moisture is calculated by using “moisture Balance” or “IR Balance”. IR Balance consist of simple balance which is placed I to the casing in which the IR bulb is attached which produce heat inside the chamber . 138

139. Initial reading should be note down after that we are initiated the IR Bulb as IR bulb is initiated the moisture is removed from the granules via heating after that note down the reading. % moisture content = Initial wt.- Final wt./ initial weight X 100 Moisture analyzer IR moisture balance Sarotorious MA-100 139

140. 7. Percentage Fines (% Fines) % fines means the amount of powder remain in the granule. Generally the amount is 15% of fines. It is necessary for the tablet compression because if we are using 100% granules then it is difficult to maintain hardness of tablet because they having free space in the die cavity after compression the tablet is crack due to air. % fine can be calculated by using Sieve method. % fine should not be more than 15%. 140

141. IPQC/Official Standards as per B.P. /I.P./ U.S.P. for tablets British Pharmacopoeia Uncoated tablet : -Disintegration test -Uniformity of weight Effervescent tablet: -Disintegration test -Uniformity of weight Coated tablet: -Disintegration test -Uniformity of weight Gastro resistant tablet: -Disintegration test 141 Modified release tablet: -Uniformity of weight. Dispersible tablet: -Disintegration test -Uniformity of dispersion -Uniformity of weight

142. INDIAN PHARMACOPOEIA Uncoated tablet: - Uniformity of container content -Content of active ingredient -Uniformity of weight -Uniformity of content -Disintegration test Enteric coated tablet: -Disintegration test Dispersible tablet: -Uniformity of dispersion -Disintegration Soluble tablet: -Disintegration test Effervescent tablet: -Disintegration/ Dissolution / Dispersion test. 142

143. UNITED STATES PHARMACOPOEIA Physical tests applicable to tablet formulation: -Bulk density / Tapped density of powder -Powder fineness -Loss on drying -Disintegration test -Tablet friability -Dissolution test -Drug release testing -Uniformity of dosage form -Container permeation test -Labeling of inactive ingredients 143

144. Process Control By Means Of In-process Controls 144

145. Example of an IPQC structure 145

146. Examples Of In-process Controls 146

147. Example Of Approval For Tablet Production 147

148. CONTENTS OF A SAMPLING PROCEDURE 148

149. The tablet press is a high-speed mechanical device. It compresses the ingredients into the required tablet shape with extreme precision. It can make the tablet in many shapes, although they are usually round or oval. Also, it can press the name of the manufacturer or the product into the top of the tablet . Tablet punching machines work on the principle of compression. A tablet is formed by the combined pressing action of two punches and a die. Punches & Dies Tooling Station: - The upper punch, the lower punch and the die which accommodate one station in a tablet press. Tooling Set : A complete set of punches and dies to accommodate all stations in a tablet press. Instrumented tablet machines and tooling 149

150. Properties of Tool Steels 150

151. Tool Steels Steels used to manufacture tablet press tooling have been grouped into three categories: 151

152. Selection of tool steel While procuring new punch set Collect the information about the nature of product like abrasive, corrosive etc. Collect the information on tooling related problems if the particular product is manufactured at other locations within the company. Discuss product properties & tooling related issues with Tooling manufacturer. Select the correct tool steel. 152

153. Selection of correct quality of steel 153

154. Cost factor for Tool steel 154

155. Tool Steels Tool steel is the product of a highly specialized branch of the steel industry. To be acceptable to the pharmaceutical industry the steel should be free from impurities and undesirable elements. Selection of right steel is the key to the successful performance of Tablet compression tooling. 155

156. Tooling Tablet compression machines are made in keeping in view the type of dies and punches will be used on them , The dies and punches and their setup on compression machine is called tooling , it is classified as B and D mainly .The B tooling dies and punch can be further have specifications as BB and D tooling can also be dies and punches can be utilized on B tooling machine which is called as DB Mainly there are two standards, a D and B Difference between B and D tooling 156

157. Tooling Station :- The upper punch ,the lower punch and the die which accommodate one station in a tablet press. Tooling Set :- A complete set of punches and dies to accommodate all stations in a tablet press. Punches & Dies 157

158. 158

159. Standards Internationally there are two recognized standards for tablet compression tooling the TSM standard and the EU standard. TSM is acronym for the ‘TABLET SPECIFICATION MANUAL’ and is recognized in the America and is considered exclusive in the United States. The EU tooling standard is internationally recognized and is more widely used than TSM standard.EU which is the acronym for ‘EUROSTNADARD’ is considered the European standard for interchangeable B and D type compression tools 159

160. 160

161. B and D tooling Tablet compression machines are made in keeping in view the type of dies and punches will be used on them , The dies and punches and their setup on compression machine is called tooling , it is classified as B and D mainly . The B tooling dies and punch can be further have specifications as BB and D tooling can also be dies and punches can be utilsed on B tooling machine which is called as DB. Mainly there are two standards, a D and B . 161

162. Different Shapes of Dies and Punches Round shape punch die set Oval shape punch die set Capsule shape punch die set Geometric shape punch die set Irregular shape punch die set Core rod tooling punch die set 162

163. Used by pharmaceutical and veterinary industry. Can manufacture following type of tablets: Shallow Concave Ball Shape Deep Concave Flat Faced Concave with Edges Flat with Bevel Edges Normal Concave Round shape Punch Die Set 163

164. Applicable to pharmaceutical and ayurvedic industries. Can manufacture following types of tablets: Flat Faced Flat with bevel edges Concave/Deep/Deep Concave with bevel edges. Oval Shape Punch Die Set 164

165. Applicable to pharmaceutical and ayurvedic industries. Can manufacture following types of tablets: Concave with Edges Deep Concave Flat Faced Normal concave Flat with Bevel Edges. Capsule shape punch die set 165

166. Applicable to pharmaceutical, confectionery, chemical, industrial powder metallurgy industries.Can manufacture following types of tablet: Triangular Benzene Rhombus Rectangular Square Geometric Shape Punch Die Set 166

167. Are applicable to confectionery industries. Available with different size, concavity, and flat in plain or engraved break line. Irregular Shape Punch Die Set 167

168. Fig. Standard sizes of B- and D-tooling 168

169. Comparison between B-tooling and D-tooling 1) B-tools subcategories with EU19, TSM 19 And D-tools subcategories with EU1, TSM 1 2) D-tooling is thicker than B-tooling 3) European toolings (both B- and D-types) are longer compared to TSM (USA/Japan) types. 169