Tablet technology

Pharmaceutical Preparations

1. Pharmaceutical Technology Part 1 By: Dr. ABDRHMAN GAMIL Associate Professor of Pharmaceutics Al- Neelain University - Khartoum

2. Pharmaceutical Preparations DEFINITION Pharmaceutical preparations are medicinal products generally consisting of active substances that may be combined with  excipients , formulated into a dosage form suitable for the intended use, where necessary after reconstitution, presented in a suitable and appropriately labelled container.

3. Types of Pharmaceutical Preparations Pharmaceutical preparations may be licensed by the competent authority, or unlicensed and made to the specific needs of patients according to legislation. There are 2 categories of unlicensed pharmaceutical preparations: — extemporaneous preparations, i.e. pharmaceutical preparations individually prepared for a specific patient or patient group, supplied after preparation; — stock preparations, i.e. pharmaceutical preparations prepared in advance and stored until a request for a supply is received . Unlicensed Preparations should comply the pharmacopoeial requirements, risk assessment and ethics guidelines.

4. PRODUCTION Manufacture/preparation must take place within the framework of a suitable quality system and be compliant with the standards relevant to the type of product being made. Licensed products must comply with the requirements of their license. Formulation During pharmaceutical development or prior to manufacture/preparation, suitable ingredients, processes, tests and specifications are identified and justified in order to ensure the suitability of the product for the intended purpose. This includes consideration of the properties required in order to identify whether specific ingredient properties or process steps are critical to the required quality of the pharmaceutical preparation. Active substances and  excipients Active substances and  excipients  used in the formulation of pharmaceutical preparations comply with the requirements of the relevant pharmacopoeial monographs, physicochemical characteristics of active substances and functionality-related characteristics (FRCs) of excipients  (e.g. particle-size distribution, viscosity,  polymorphism ) 

5. Microbiological quality The formulation of the pharmaceutical preparation and its container must ensure that the microbiological quality is suitable for the intended use. A suitable container is selected. Consideration is given to the intended use of the preparation, the properties of the container, the required shelf-life, and product/container incompatibilities . Stability requirements of pharmaceutical preparations are dependent on their intended use and on the desired storage time . TESTS Relevant tests to apply in order to ensure the appropriate quality of a particular dosage form are described in the specific dosage form monographs.

6. Appearance: size shape and colour. Identification identification of the active substance(s); — identification of specific excipient(s), such as preservatives; — purity tests (e.g. investigation of degradation products,  residual solvents   or other related impurities, sterility. — safety tests (e.g. safety tests for biological products). Uniformity; Pharmaceutical preparations presented in single-dose units comply with the test(s) as prescribed in the relevant specific dosage form monograph. ASSAY Unless otherwise justified and authorised , contents of active substances and specific  excipients  such as preservatives are determined in pharmaceutical preparations. Limits must be defined and justified. Suitable and validated methods are used. If assay methods prescribed in the respective active substance monographs are used, it must be demonstrated that they are not affected by the presence of the  excipients and /or by the formulation . Reference standards LABELLING AND STORAGE The relevant labelling requirements given in the general dosage form monographs apply.

7. Powders and Granules A formulation in which the drug substance is mixed wi th other powdered excipients to produce a final product. The function of excipients depends upon the function of esch ingredients. Colouring , flavouring and sweetening agents may be added.

8. Types Oral use External use Inhalation. Give examples Insufflation Powder for oral suspension Powder for injection May be bulk or in divided doses….

9. Advantages & Disadvantages Stability Convenient for large dose Faster bioavialability Less convenient to carry Masking of taste Not suitable forb potent drugs Not suitable for drugs causing damage or inactivated in the stomach.

10. Tablets Introduction TABLETS

11. DEFINITION Tablets are solid preparations each containing a single dose of one or more active substances. They are obtained by compressing uniform volumes of particles or by another suitable manufacturing technique, such as extrusion, moulding or freeze-drying ( lyophilisation ). Tablets are intended for oral administration. Some are swallowed whole, some after being chewed, some are dissolved or dispersed in water before being administered and some are retained in the mouth where the active substance is liberated. The particles consist of one or more active substances with or without  excipients  such as diluents, binders, disintegrating agents, glidants , lubricants, substances capable of modifying the behaviour of the preparation in the digestive tract, colouring matter authorised by the competent authority and flavouring substances. Tablets are usually straight, circular solid cylinders, the end surfaces of which are flat or convex and the edges of which may be bevelled . They may have break-marks and may bear a symbol or other markings. Tablets may be coated.

12. Categories of tablets for oral use — uncoated tablets; — coated tablets; — gastro-resistant tablets; — modified-release tablets; — effervescent tablets; — soluble tablets; — dispersible tablets; — orodispersible tablets; — chewable tablets; — tablets for use in the mouth; — oral lyophilisates .

13. Uncoated Tablets Uncoated tablets include single-layer tablets resulting from a single compression of particles and multi-layer tablets consisting of concentric or parallel layers obtained by successive compression of particles of different composition. The  excipients  used are not specifically intended to modify the release of the active substance in the digestive fluids.

14. COATED TABLETS Coated tablets are tablets covered with one or more layers of mixtures of various substances such as natural or synthetic resins, gums, gelatin, inactive and insoluble fillers, sugars, plasticisers , polyols, waxes, colouring matter authorised by the competent authority and sometimes flavouring substances and active substances. The substances used as coatings are usually applied as a solution or suspension in conditions in which evaporation of the vehicle occurs. When the coating is a very thin polymeric coating, the tablets are known as film-coated tablets. Coated tablets have a smooth surface, which is often coloured and may be polished; a broken section, when examined under a lens, shows a core surrounded by one or more continuous layers with a different texture.

15. GASTRO-RESISTANT TABLETS Gastro-resistant tablets are delayed-release tablets that are intended to resist the gastric fluid and to release their active substance(s) in the intestinal fluid. Usually they are prepared from granules or particles already covered with a gastro-resistant coating or in certain cases by covering tablets with a gastro-resistant coating (enteric-coated tablets).

16. MODIFIED-RELEASE TABLETS Modified-release tablets are coated or uncoated tablets that contain special  excipients  or are prepared by special procedures, or both, designed to modify the rate, the place or the time at which the active substance(s) are released. Modified-release tablets include prolonged-release tablets, delayed-release tablets and pulsatile-release tablets.

17. EFFERVESCENT TABLETS Effervescent tablets are uncoated tablets generally containing acid substances and carbonates or hydrogen carbonates, which react rapidly in the presence of water to release carbon dioxide. They are intended to be dissolved or dispersed in water before administration.

18. SOLUBLE TABLETS Soluble tablets are uncoated or film-coated tablets. They are intended to be dissolved in water before administration. The solution produced may be slightly opalescent due to the added  excipients  used in the manufacture of the tablets. DISPERSIBLE TABLETS Dispersible tablets are uncoated or film-coated tablets intended to be dispersed in water before administration, giving a homogeneous dispersion.

19. Orodispersible tablets Orodispersible tablets are uncoated tablets intended to be placed in the mouth where they disperse rapidly before being swallowed. CHEWABLE TABLETS Chewable tablets are intended to be chewed before being swallowed. TABLETS FOR USE IN THE MOUTH Tablets for use in the mouth are usually uncoated tablets. They are formulated to effect a slow release and local action of the active substance(s) or the release and absorption of the active substance(s) at a defined part of the mouth. ORAL LYOPHILISATES Oral lyophilisates are solid preparations intended either to be placed in the mouth or to be dispersed (or dissolved) in water before administration.

20. Tablets administered by other routes Implantation tablets: depot tablets to be implanted subcutaneously under the skin for prolonged release of the therapeutic agent. these tablets should be sterile. Vaginal tablets: They are tablets prepared by compression intended to be inserted into the vaginal cavity by special insertion device. It contains soluble substances with adjusted pH.

21. Advantages of Tablets Accurate stable dose with high precision and uniformity. Easy to carry, handle and use. Attractive, convenient and elegant in appearance. Physically, chemically and microbiologically more stable dosage form. High speed production, bulk production could be attained and hence lowers the cost. Packaging and shipping is easy and of low cost. Unpleasant taste and odour can be masked. Wide range of tablet types offering range of release rates and duration of clinical effects. Can offer release of active substance at a particular site. Combination of more than one therapeutic agent. Tablet can be divided offering different doses for use. All classes of therapeutic agents with exception of proteins can be formulated in tablet form Easy to be identified due to differences in shapes and colours .

22. Disadvantages Increased product loss due to the long series of unit process. Absorption is dependent in physiological factors giving interpatient variations. Poor compressibility of certain therapeutic agents. Difficulty in administration to certain groups like children but swallow problems can be overcome by using effervescent tablets . Agents that are liquid in nature is difficult to be formulated as tablets. Oxygen sensitive agent may require special measures. Drugs having poor wetting properties, slow dissolution profile and high optimal gastrointestinal absorption are difficult to be formulated as tablets.

23. Characteristics required Deliver the correct amount of drug in a proper form at or over proper time. Elegant free from defects like cracks, chips, contamination, discolouration …etc. Maintain its chemical and physical integrity over time. should be capable to maintain the chemical and physical properties of the therapeutic agent. Withstand the rigorous mechanical shocks during manufacturing, shipping and storage. Release medicaments in the body in predictable and reproducible manner.

24. Formulation of tablets Active Pharmaceutical Ingredients ( API ). Excipients

25. Desired Properties of API Purity :In accordance with the respective pharmacopoeia. High stability Compatibility with excipients: e.g primary amine and lactose. Optimum bulk powder properties to have good flow, prevent segregation and to optimize the tablet size. Uniformity of particle size distribution to obtain uniformity in content, uniformity in weight, disintegration time, friability, drying rate uniformity, enhanced powder flow, good compression, regular dissolution and bioavailability. fine particles increase surface area hence increases the surface energy giving good compressibility. Spherical shape provides good flow. Irregular particle shape may lead to interlocking

26. Desired Properties of API - contd 7. Good powder flow: measured using angle of repose and can be improved by addition of glidants , addition of fines, using wet granulation and increase the density. 8. Optimum moisture content: lack of moisture in brittle tablets. increased moisture affects uniformity of content, make sticking and picking Moisture can be controlled by; Use of anhydrous salt Use of nonaquous solvent. Optimum drying time. Addition of adsorbent like Magnesium oxide. 9. Good compressibility. This is an intrinsic nature of elasticity, plasticity and brittle fracture of particles upon compression. 10. Absence of static charges and if any can be removed by granulation, addition of diluent or lubricant or coating by colloidal silica. 11. Good organoleptic properties.

27. Excipients – ( Additives ) Diluents Binders Lubricants Glidants Disintegrants Coloring Agents Flavoring Agents Sweeting Agents Toxicity. Availability. Compatibility. Stability. Bioavailability. Cost.

28. Functions of excipients. Operation run satisfactory. Ensure that tablets of specified quality are prepared. Impart weight, accuracy and volume. Improve solubility Increase stability. Enhance bioavailability. Modify drug release. Assist product identification. Increase patient acceptability. Facilitate dosage form design.

29. Diluents / Fillers Normally tablet size is more than 50 mg and diameter above 2-3 mm. Fillers increase the bulk of the powder to produce the desired size. Secondary functions are to improve the powder cohesion, to allow direct compression, to enhance powder flow and to adjust the weight as per die capacity. It constitutes 5 – 80% of the tablet weight.

30. General properties of diluents Chemically inert and of no microbiological load. No-hygroscopic. Compatible to the manufacturing process and other tablet constituents. Good and consistent biochemical properties. Fair compactibility and dilution capacity. Acceptable taste and color. Low cost.

31. Types of diluents Organic: S tarch, sugars, cellulose derivatives. Inorganic: Calcium phosphates. Co- processed diluents . combining two or more materials by appropriate process.

32. Starch It is polysaccharide composed of amylose and amylopectin. Pregelatinised grade which provide free flow of powder. Used as a diluent, binder and disintegrant…… details later.

33. Lactose – different particle size, crystal form and properties . Property Monohydrate Anhydrous Spray dried Moisture content 5% Pick up moisture at high RH Depend on the extend of drying Flow Poor Poor Free flow Compressibility Wet granulation Directly compressible Directly compressible Maillard reaction (Brownian) Take place In the presence of moisture In presence of excess moisture Cost Cheap Cheap Expensive Solubility Soluble Soluble Soluble Disintegrant Needed No need No need

34. Mannitol Generally used for chewable tablets due to inherent sweetness and negative heat of solution properties. Unlike sucrose it is free from grittiness. Most expensive sugar. It requires high lubricant content. Often combined with its isomer sorbitol.

35. Celluloses – Microcrystalline cellulose MCC Highly compressible and widely used in direct compression. Hard tablet at low compression can be obtained. Fair flow. Binding and disintegration properties. Commonly used grades are Avicel Ph101, Avicel Ph 102. PH : Pharmaceutical use NOT pH Avicel PH 101 : Nominal particle size 50 microns Avicel PH 102 : Nominal particle size 100 microns

36. Calcium Phosphates - Excellent compressibility and flow. Bulk density is higher. Hard tablets are obtained. Non – hygroscopic and inexpensive. Because of its alkalinity in moisture it is a source of instability in acidic products. Interact with some API such as Tetracycline. Dibasic calcium phosphate, dicalcium phosphate, calcium hydrogen phosph dehydrate. Tribasic calcium phosph , tricalcium phosph , tricalcium orthophosphate .

37. Binders – Adhesives Added to cause particles of drug and other excipients to cohere into a granular form of required mechanical strength. It can be termed as granulating agent. Generally binders are polymeric in nature.

38. Types of binders Sugars Natural Synthetic / semisynthetic polymers Sucrose Liquid sucrose Acacia Tragacanth Gelatin Starch paste Pregelatinized starch Alginic acid Cellulose Methyl cellulose Ethylcellulose Hydroxypropylmethylcellulose HPMC Hydroxypropylcellulose Sodium carboxymethylcellulose Polyvinylpyrrolidone PVP Polyethylene glycol PEG Polyvinyl alcohol Polymethacrylates

39. List of Direct Compression Binders MCC ( Avicel PH 101 ) Silicified microcrystalline cellulose. Partialy Pregelatinized Starch. Low density starch. DC lactose anhydrous. DC- Dibasic calcium phosphate dihydrate .

40. Characters of Commonly Used Binders Binder Concentration Characters Starch paste 5 – 25% w/w Freshly prepared paste. Pregelatinized starch 5 – 10% w/w Direct compression Starch that processed chemically and mechanically to rupture all or part o granules in the presence of water then dried. Partially & Fully PGS 5 – 75% w/w Wet granulation Obtained from potato, maize or rice starch. Used as diluent, binder, disintegrant and flow aid. Can use cold water. HPMC 2 – 5% w/w Can be used in either wet or dry granulation. PVP 0.5 – 5% w/w added to powder blend in dry state then water is added during granulation. PEG 10 – 15% w/w Used as meltable binder. Anhydrous granulating agent. I improve plasticity of other binders. Prolong disintegration time.

41. methods of adding the binder As a dry powder mixed with the other ingredients before wetting. As a solution which is used as agglomerating liquid during wet agglomeration. As dry powder which is mixed with other ingredients before compaction. ( dry binder).

42. Lubricants Lubricants are materials that acts at the interface between the surface of the tablet and the face of die preventing the adhesion of the tablet material to the surface of the die and punch reducing the friction and facilitate ejection of the tablet from the die cavity. Critical factors for optimizing lubricant function: Concentration of lubricant. Inadequate concentration result in tablet with pitted surface and inability of tablet to detach from the die. High concentration result in prolonged disintegration. Insoluble lubricant can be added at the final mixing stage before compression. Stage and way of mixing. Mixing of lubricant with the disintegrant together lead to formation of lubricant film around the disintegrant which reduces the wettability and water uptake by the disintegrant resulting in disintegration failure. Intensity and duration of mixing. Over mixing or high intensity of mixing result disintegration and dissolution failure. Lubricant Particle Size. S maller particle size enhance lubricant efficiency.

43. Commonly used lubricants Material Concentration W/W Water Solubility Magnesium stearate 0.25% - 0.5% Insoluble Stearic acid 1% - 3% Insoluble Glyceryl behenate 1% - 3% Insoluble Glyceryl palmitostearate 1% - 3% Insoluble PEG 4000 – 8000 mol.wt Soluble Polyoxyethylene stearate 1% - 2% Soluble Sodium lauryl sulphate 1% - 2% Soluble

44. Glidant s They are water insoluble materials of a very fine particle size enhancing the powder flow properties of the granules within the hopper into the tablet die by reducing the friction due to their ability of particles to be located within the spaces between the granules. As they are almost hydrophobic , increase in concentration will reduce the disintegration and dissolution time. Talc asbestos-free ( hydrated Magnesium silicate) is insoluble but not hydrophobic 5 – 30% but its use was restricted because it will result in granuloma if inhaled. Colloidal Silicon Dioxide ( Aerosil ) 0.1 -0.5% w/w was used due to its hydrophobic properties and fine particle size less than 15nm.

45. Adsorbents: If liquid or semisolid is to be incorporated in the solid powder and the powder is required to be attained solid, and adsorbent is required to is included in the formula ( e.g. magnesium oxide/ carbonate, kaolin/bentonite. Sweeting agents / Flavours : to improve the taste and odour of the chewable tablets. Mannitol, lactose, sucrose and dextrose – saccharin, cyclamate, aspartame. Colours: Can be used for the powder or for the coating material to give elegant appearance, to serve the manufacturer and patient in drug identification . e.g. iron oxide, carentoids , anthrocyanins . Surface active agents: To improve the wetting properties of hydrophobic tablets . To increase the aqueous solubility of poorly soluble drugs( sodium lauryl sulphate )

46. Disintegrants Bioavailability of a drug depends in its absorption which is affected by its dissolution and permeability across the GIT membrane. The rate of dissolution is greatly influenced by the rate of disintegration. Disintegration must occur within the specifications defined by the pharmacopoeia ( generally 15 minutes ). Disintegrant was added to the formulation to achieve this specification.

47. Mechanism of action of disintegrants Increase the porosity and wettability of the tablet matrix enabling the GIT fluids to penetrate and thereby enable tablet breakdown to occur. Concentration 5 – 20%w/w. Starch, corn and potato starches. MCC Avicel 101 & Avicel 102. 10 -20% w/w. Sodium starch glycolate 5% w/w. Swelling of disintegrant in the presence of the aqueous fluid leading to tablet disintegration due to increase in the internal pressure within the tablet matrix. Sodium starch glycolate Croscarmellose sodium 0.5-5% w/w. Crospovidone 2 – 5% w/w. Pregelatinized starch 5% w/w. Liberation of gas – Effervescent tablets.

48. Mode of addition of disintegrant Intragranular addition. Extragranular addition. 50% intragranular and 50% extragranular .

49. Factors affecting disintegration Effect of fillers: soluble fillers increase the viscosity of the penetrating fluid which tend to reduce the effect of the swollen disintegrating agent which tend to dissolve rather than disintegrate. Insoluble fillers disintegrate more rapidly. 2. Effect of lubricants: as lubricants are hydrophobic, they inhibit wetting and consequently disintegration of tablets. Sod. starch glycolate remains unaffected as disintegrant . 3. Effect of binders: Increase in the concentration of the binder increases the disintegration time. 4. Effect of Surfactants: The speed of water penetration is increased by addition of surfactants.

50. Excipient Function Diluent ( filler) Required bulk of tablet Binder Provide necessary bonding to form granules Disintegrant To bring disintegration within the specified time. Lubricant To reduce friction in the die and ejection of tablet from the die cavity. Antiadherent To prevent sticking of powder to the faces of punch and die. Glidant Promote powder flow. Wetting agent To aid disintegration Buffer To improve stability and bioavailability. Antioxidant to attain stability Chelating agent Complex with heavy metals to prevent autooxidation . Preservative To prevent growth of microorganism Color Disguise off color drugs, product identification and more elegant colour Flavour To improve odour and taste Sweetener To give pleasant taste for chewable tablets.

51. Manufacturing Process Wet granulation. Dry granulation Direct compression

52. G ranulation Advantages of use of granules: Prevention of segregation of powder components during the tableting process. Enhancement of flow properties. Enhancement of compressibility. Lower incidence of dust production.

53. Wet Granulation

54. Wet granulation stage 1, Mixing Drug and excipients excluding lubricants. Mixing time and speed should be enough to produce homogeneous mixture. Planetary bowel mixer. Rotating drum mixer. High-speed mixers. Ribbon / trough mixers.

55. Planetary bowel mixer. The mixing shaft rotate around the bowel and around itself. Planetary like movement. Material used is stainless steel

56. Rotating drum mixer. ( double cone) The mixing shaft rotate and hence the drum is rotated. Material used is stainless steel

57. Ribbon / trough mixer Mixing blades. Material used is stainless steel

58. Rapid mixer granulator Rapid mixer granulator is a mixing unit with a bottom entry agitator and side mounted chopper for granulation. Can be used for dry blending, wet mixing and granulation. The principle is agitation of the content at moderate speed and then running the cutting blade at high speed. Dry mixing 3-5 min, wet mass 5-10 min then 5-10 min to produce 0.5 – 1.5 mm granules.

59. Wet granulation stage 2, Wet granules formation Fluid simultaneously incorporated in the powder mix. Granulation fluids are water, isopropanol, ethanol or mixture. The binder is either incorporated in the solid state within the powder mix or dissolved in the granulation fluid. Wet Granulation Techniques A- Oscillating granulator B- Fluidized bed granulation C- Extrusion spheronization D- Rapid mixture granulator RMG E. Spray drying granulation.

60. Oscillating granulator Low sheer is used, The binder in the granulating fluid is added whilst maintaining mixing. The wetted powder mass is then passed into an oscillating granulator which forces the powder mass through a metal screen under the action of an oscillatory stress.

61. Fluidized bed granulator The powder is suspended by vertical flow of air from the bottom of the granulator. The granulation fluid is sprayed on the powder from the top of the granulator. Tangential air flow provides circular powder suspension. Air applied with controlled temperature.

62. Extruder Premixed powder to which the granulation fluid being added is placed into the barrel of the extruder via hopper. In the barrel the wet mass moves horizontally via single or twin screws from the hopper end by a turning motion. Passed through a perforated plate into lengths. The extruded strands should break to produce granules of uniform particle size.

63. Rapid mixer granulator Rapid mixer granulator is a mixing unit with a bottom entry agitator and side mounted chopper for granulation. Can be used for dry blending, wet mixing and granulation. The principle is agitation of the content at moderate speed and then running the cutting blade at high speed. Dry mixing 3-5 min, wet mass 5-10 min then 5-10 min to produce 0.5 – 1.5 mm granules.

64. Drying of the granules Tray dryer: Traditional oven . Wet granules are placed horizontally in a shallow plates. Air entered the drier warmed by heaters. Vacuum can be applied. Condensed water is collected and disposed. FBD: often used in the industry and having the advantages of: Excellent heat transfer and rapid in action. Accurate control of the drying conditions. And of limitation: Attrition of granules. Powder waste. Development of static electricity . Freeze drying, microwave dryer, spray dryer.

65. Milling of the granules ( Resizing) To produce the required particle size and distribution to improve the flow of powder into the die and its filling. The granule size decreases as the tablet size decreases. Size reduction methods includes: Oscillating granulator using defined mesh . Quadro Comil conical chamber containing defined mesh . Granules pass through the screen in a centrifugal manner by the action of rotating impeller.

66. Incorporating the lubricant Mixing the lubricant with the dried granules usually takes place in the same mixing equipment used in the first stage. Noted that the time of mixing and the shear rate are crucial.

67. Granules formation Particle –particle interactions facilitated by the formation of liquid bridges . Pendular state. Funicular state Capillary state Over-wetted state

68. Granule formation

69. Granules formation - contd Particle – Particle interactions facilitated by the formation of solid bridge. They are formed from the polymeric binder following drying. These bridges contribute to the mechanical properties of the resulting granules. Crystallization of the binder followed by crystallization of the water soluble drug may affect directly the quality of produced tablets.( sugars)

70. Advantages of wet granulation Reduce segregation during process and storage leading to intra and inter-batches variations. Useful for tablets contain low concentration of therapeutic agent. Employs conventional excipients. Most plants had been built around wet granulation. Tablets produced have good mechanical strength and hence can withstand coating and packing procedures.

71. Disadvantages of wet granulation Several process steps. Presence of solvent lead to: In materials having susceptibility to Hydrolysis. Soluble drugs may crystallize during drying. Heat to remove the solvent make the process expensive. Thermally labile therapeutic agents may undergo degradation. Issues regarding the use of alcohol if used.

72. DRY GRANULATION For thermolabile material For materials that can be affected by solvent Ingredient having enough cohesive properties.

73. Methods for dry granulation Slugging Roller compaction.

74. Dry Granulation - Slugging Slugging is the process of compressing dry powder by tablet press having large die cavity, flat-faced punches and high compression pressure. Slugs are then undergo size reduction by screening and milling.

75. Dry Granulation – Roller Compaction Slugging is the process of compressing dry powder by tablet press having large die cavity, flat-faced punches and high compression pressure. Slugs are then undergo size reduction by screening and milling.

76. Chilsonator Dry granulation – Compactor – Chilsonator The powder was compressed between the two rolls which are connected to a pressure regulator. Slugs pass down to granulator then the particles screened. Fine powders are hen recycled. High pressure was used.

77. Excipients used in dry granulation Excipient Material Diluents Anhydrous lactose or lactose monohydrate Starch Dibasic calcium phosphate MCC Disintegrants Starch MCC Sodium starch glycolate . Croscarmellose Crospovidone Lubricants Stearates Glycerylbehenate , glyceryl palmitostearate PEG Sodium lauryl sulphate Glidants Talc Colloidal silicon dioxide Miscellaneous Colours, sweeting agents, flavours … etc.

78. Mechanism of granules formation in dry granulation Electrostatic forces. Initial cohesive interaction between particles. Van der Waals interactions Van der Waals forces increases as the distance between the particles decreases. Melting of components within the powder mix Due to partial melting of excipients upon cooling solidification occur resulting in increased interactions between adjacent particles.

79. Advantage of dry granulation No need for special excipients No heat , no solvent No change in the morphology of ingredients.

80. Disadvantage of dry granulation Soft tablet incapable for further processing like coating. Dust generation and powder loss. Segregation of components may occur post mixing. Special equipment required. Problems with powder flow.

81. Direct compression Mixing and subsequent compression. Interactions of particles are similar to dry granulation. To obtain same and uniform particle size of ingredients, this may require milling. Qudro Comil High energy mill Fitzmill Mixing in the same mixers as wet granulation.

82. Colloidal mill Fitzmill

83. Excipients – Direct Compression Specific grades are required ( spray dried) to achieve certain particle size distribution and flow properties. Diluent Spray dried lactose Encompress calcium phosphate. Spray dried mannitol sorbitol - MCC Avicel PH- 102 Compression aid Avicel PH- 102 Disintegrant PGS Sodium starch glycolate ( Primogel ) Croscarmellose sodium Crospovidone - polyplasdone Lubricants - Stearates Glidants Talc Colloidal silicon dioxide

84. Advantages of DC Fewer processing steps and cost effective. No use of water or solvent, no heat so produce more stable product and lessens the cost. Lubricant is incorporated in the same vessel.

85. Disadvantage of DC Specialist more expensive excipients. Similar particle size and density for the excipients and the therapeutic agent are required to minimize segregation. Powder flow within the tableting machine. Tablets produced are soft making it difficult for further processing. If the API is more than 10%, it will affect compressibility. Colourants could not be used. Dust and waste.

86. Compression Process

87. Compression Tools Die

88. Stages of compression Stage1 : Filling the die with the granules / powder: The powder or granules are fed from the hopper of machine into the die filling the space between the lower and upper punches. The space is determined by the position of the lower punch which can be altered to increase or decrease the tablet size.

89. Stages of compression Stage2 : compression ofthe granules / powder bed: Retraction of the shoe. Upper punch descend and compress the powder.

90. Stages of compression Stage 3 : Tablet ejection: Upper punch is elevated to its original position. The lower punch moves upwards until it flush with the die plate. The shoe moved across the die plate pushing the tablet from the lower press. The lower punch returns to its original position to start new cycle.

91. Types of Tablet Presss Single-Punch tableting Machines This tablet press composed of only one set of punches and die. Used in pilot-scale manufacturing and in R&D or in dry granulation (slugging) Speed is up to 200 tablets per minute.

92. Adjusting the single punch machine

93. Rotary Tablet Press Single rotary tablet machine High speed double rotary rotary tablet machine

94. Rotary Tablet Press For large scale , produce up to 10,000 tablet per minute. Have up to 60 sets of punches and dies. Dies table rotate in a circular motion. Lower and upper Punches being held by the turrets are lowered and elevated by an upper and lower rollers. The powder l granules are fed from the hopper on the upper surface of the die table. Then transported by a feed frame into the die, where they are subsequently compressed by the simultaneous movement of the upper and lower punches. The tablets are removed from the rotating die table into a chute from which they are collected.

95. Rotary Tablet machine

96. Rotary tablet press

97. Concept of tablet compression

98. Compression Cycle Powder or granules fed to the hopper, emptied into the feed frame by gravity. The interconnected compartments of the feed frame spread the powder over the area and fill the dies. The pull down cam guide the lower punches downwards allowing dies overfill. Punches pass over a weight-control cam, which reduces the fill into the dies to the desired amount. A wipe off blade at the end of the feed frame removes the excess. The lower punches move over the lower compression roll while the upper punches ride beneath the upper compression roll and enter into the dies while the lower punches are raised to squeeze the powder within the die.( moment of compression) The upper punches are withdrawn following the upper cam, the lower punches ride up the lower cam bringing the tablets up the surface of the dies. The tablet strike the sweep off blade in front of the feed frame and slide it down the chute into the container.

99. Relationship between Stress and Strain Elastic region: If the powder properties is elastic , will result in delamination and tablet failure. Stress required for the manufacturing of tablet should be greater than that required for elastic deformation. Plastic region: Due to the movement of the molecules in t he direction of stress, irreversible deformation occurs. Components undergo plastic deformation, yield a successful compression. Fragmentation : Applying the ultimate tensile strength, particles will fracture. Further stress will result in more particle fractures so, increasing the surface area allowing more sites for particle-particle interaction.

100. Behavior of the powder bed during compression Stage 1: Rearrangement of the powder bed upon application of stress, minimize the free space between the particles. Stage 2 : Deformation of the powder under applied stress.(plastic deformation and fragmentation Stage 3 : Bonding of the compressed powder by inter-particle bonding resulting in intact tablet. Bonding by adsorption ( van der Waals forces) and by diffusion ( increased molecular mobility) .

101. Compression & time 1- Dwell time : time at maximum 2- consolidation time: Time to maximum force. 3- Ejection time: time during which ejection occur. 4- residence time: time during which the formed compact is within the die, 5 - contact time: time for compression and decompression excluding ejection time

102. Auxiliary equipment Mechanical feeder To force granules into the die cavity. To minimize weight variation and obtain uniformity in content. Tablet weight monitoring device Monitoring force at each compression station by electronic strain gauge technology. Tablet deduster : To remove the excess powder on the surface of tablets.

103. Problems in tablet manufacturing

104. Capping The upper or the lower segment of the table separates horizontally, either partially or completely. Causes may be either due to the formulation or due to machine. Reason : Air entrapped in compact during compression and subsequent expansion on ejection from the die or handling.

105. Capping due to formulation causes & its remedies Causes Remedies Large amount of fines in the granulation. Remove fines through 100 -200 mesh screen. Too dry or very low moisture leading to loss of binding action Moist the granules or add hygroscopic e.g sorbitol, PEG 4000. Not thoroughly dried granules. Dry the granules properly Insufficient or improper binder Increase or change binder. Insufficient or improper lubricant Increase or change lubricant Granular mass too cold to compress Compress at room temperature.

106. Capping due to machine causes & its remedies Causes Remedies Poorly finished dies. Polish dies properly Deep concave punches or beveled edge faces of punches Use flat punches Lower punch remain below the level of the die plate during ejection Make proper setting Incorrect adjustment of sweep-off blade Adjustment of ejection blade. High turret speed Increase dwell time

107. Lamination Tablet may undergo separation into two or more horizontal layers. Causes may be either due to the formulation or due to machine. Reason : Air entrapped in compact during compression and subsequent release on ejection. The condition exaggerated by higher speed of turret.

108. Lamination due to formulation causes & its remedies Causes Remedies Oily or waxy materials granules Modify mixing process Add adsorbent or absorbent Too much of hydrophobic lubricant e.g Magnesium stearate - Decrease the amount or change the lubricant. Lamination due to machine causes and its remedies Rapid relaxation of the peripheral regions of the tablet, on ejection from a die - Use tapered die , upper part of the die bore has an outward taper of 3 -5˚ Rapid decompression - Use precompression step . - Reduce turret speed and reduce the final compression pressure.

109. Cracking Small cracks on the centre of the upper or lower surfaces. Causes may be either due to the formulation or due to machine. Reason : Rapid expansion of tablet especially when deep concave punches are used.

110. Cracking due to formulation causes & its remedies Causes Remedies Large size of granules Reduce granules size Add fines Too dry granules Moisten the granules properly Add proper amount of binder Tablets expand Improve granulation Add dry binder Too cold granulation Compress at room temperature. Cracking due to machine causes and its remedies Tablet expand on ejection due to air entrapped - Use tapered die , upper part of the die bore has an outward taper of 3 -5˚ Deep cavities cause cracking while removing tablets - Use less concave punches. - Use gentle take-off ejection device..

111. Picking Tablet material adhere to the punch. Causes may be either due to the formulation or due to machine. Reason : Air entrapped in compact during compression and subsequent release on ejection. The condition exaggerated by higher speed of turret.

112. Capping due to formulation causes & its remedies Causes Remedies Moist granules Determine optimum time for drying Insufficient or improper lubricant Increase lubrication Use colloidal silica as polishing Low melting point of substance Use high melting point materials Too warm granules Cool the system Excess binder Reduce or change the binder

113. Picking due to machine causes & its remedies Causes Remedies Rough or scratched surface of punch Polish punch face properly Imposing or engraving letters Design letters as large as possible Too deep dividing line or bevels Reduce depth and sharpness Insufficient pressure Optimize the pressure

114. Sticking / Filming Tablet material adhere to the die faces. Filming is a slow form of sticking due to excess moisture. Causes may be either due to the formulation or due to machine. Reason : Improperly dried or improperly lubricated granules

115. Sticking due to formulation causes & its remedies Causes Remedies Moist granules, hygroscopic material Determine optimum time for drying, control humidity Insufficient or improper lubricant Increase lubrication Use colloidal silica as polishing Too much binder Decrease or change the binder Oily or waxy material Modify mixing process, add adsorbent Too soft or weak granules Optimize binding , change granulation technique.

116. Sticking due to machine causes & its remedies Causes Remedies Rough or scratched surface of die Polish die face properly Die design Use tapering dies Too fast speed Reduce speed Insufficient pressure Optimize the pressure

117. Chipping The tablet adhere or tear in the die. A film is formed un the die and ejection is hindered. Tablet edges are cracked. Causes may be either due to the formulation or due to machine. Reason : Excessive moisture, lack of lubricant, worn dies

118. Chipping due to formulation causes & its remedies Causes Remedies Too moist granules expanded around the lower punch Optimum drying Insufficient or improper binder Increase of change lubricant Too large granules Reduce the size or add fines or add more lubricant Too hard granules for the lubricant to be effective Reduce granular size or modify the granulation method Too abrasive granules and cutting into the die Reduce granular size Granular mass too warm stick to the die during compression Reduce temperature

119. Chipping due to machine causes & its remedies Causes Remedies Poorly finished dies. Polish dies properly Rough dies due to abrasion or corrosion Change dies Undersized dies Use proper die size Too much pressure Reduce pressure or modify granulation

120. Pitting Pit marks on the surface of the tablet Corrected by polishing the punch surface and increasing the lubricant, its time and rate of mixing. Reason : Rough surface of the punch or insufficient lubricant

121. Binding Sticking of the tablet to the die and do not eject properly. Causes and remidies are the same as chipping. Reason : Excessive moisture, insufficient lubrication or use of worn die

122. Mottling Uneven distribution of colour with black or light spots in the surface. May be due to the formulation or the tableting machine. Reason : Spotted colouration on the surface of the tablet.

123. Mottling causes & its remedies Causes Remedies A coloured drug used with white excipients. Use appropriate colouring agent A dye migrate to the surface of the granules during drying Change the solvent & binder Reduce the drying temp Use smaller particle size Improperly mixed dye - Reduce size and mix properly Improper mixing of coloured binder Incorporate dry color during blending then add dry binder, mix then add the granulating fluid. Waxes and oils of machine parts lubrication - Check the seals Dust - Clean and clear the environment

124. Double impression It takes place in only those punches having engraving. At the moment of compression, the tablet receives the imprint, the upper or lower punch rotate freely and travelling a distance which may result another contact with the tablet resulting in double impression. Revise setting of machine and tie the punch by tooling key. Use punches with male and female anti-turning lock to prevent rotation. Reason : Free rotation of either the lower or upper punches during ejection of tablet.

125. Weight variation. Mechanical strength. Hardness . Friability Disintegration failure. Dissolution failure. Uniformity in content Down stream processing Particle size reduction. Mixing Granulation Drying Force feed frame.

126. Tablet Coating PURPOSES OF TABLET COATING To prevent degradation in the stomach – ( enteric coating ) To prevent drug induced irritation at the stomach-( NSAI) To provide controlled release of the drug throughout the GIT. To target drug release at specific site in the GIT. ( colon) To mask the taste of the drug. To improve the appearance of tablet. To protect the tablet – shelf-life & stability TYPES OF TABLET COATING PROCESS Sugar Coating Film Coating. Press Coating TYPES OF COATING EQUIPMENTS Standard coating pan Perforated coating pan Fluidized bed ( air suspension) coaters.

127. Sugar coating Coloured or uncoloured of sucrose - based layer around the tablet. Improve the appearance and mask the taste. Insulate the tablet. Permit imprint. Dramatically decreased practice due to advantages of film coating. Conventional Pan

128. Process of sugar coating Stages of process: Sealing of tablet cores. Sub-coating Smoothing Colouring Polishing Printing General description of the process: Tablets are placed in the coating pan and agitated. The coating solution is sprayed on the surface of the tablets. Warm air is passed over the tablets to facilitate removal of the solvent. When solvent has evaporated, the tablets will be coated with the solid components of the coating solution.

129. 1-Sealing of tablet cores. An insoluble impermeable polymer solution is applied to seal the tablet against entry of water. Shellac Cellulose acetate phthalate Polyvinylacetate phthalate Hydroxypropylmethyl cellulose

130. 2-Subcoating Sub-coating solution Gelatin 6% W/W 3.3 % W/W Acacia 8 7.7 Sucrose 45 55.3 Distilled water To 100 To 100 Sub-coating suspension Sucrose 40% W/W Calcium carbonate 20 Talc 12 Gum acacia 2 Titanium dioxide 1 Distilled water 25 Applying the gum based solution followed by sucrose based powder then drying. Application of a suspension of powder in gum-sucrose solution Powders as Calcium carbonate or Talc .

131. 3- Smoothing Rough surface can be smoothened by application of few coating layers of simple syrup. The simple syrup may contain starch, acacia, gelatin and opacifier .

132. 4- Colouring Application of several layers of colour solution in 60 – 70% sucrose syrup. Colours should be approved by the regulatory authority. Predispersed lake ( pigment) is superior because: The colour is water insoluble. It is opaque. Maintenance of batch to batch colour. Reduction in the overall process time. Reduction in the thickness of the colour coating layer.

133. 5- Polishing Commonly used method is an application of organic solvent to get suspension or solution of waxes. Carnauba wax Beeswax An emulsion may be used and stabilized by acceptable surfactant. Other methods involves the use wax-lines pan and use finely powdered wax application. Mineral oil application.

134. 6- Printing Why sugar coated tablets requires printing for and not other method for identification? Edible pharmaceutical ink formulation: Shellac Alcohol Pigment Lecithen Antifoam Organic solvent

135. Film Coating A deposition of a thin film layer of polymer or mixture of polymers around the conventional tablets core. Polymers that are used in film coating which dissolve in the stomach to enable disintegration and dissolution : Hydroxypropylmethyl cellulose.HPMC Hydroxypropyl cellulose HPC Eudragit E 100 Target drug release film coated tablets are coated by insoluble Ethylcellulose . Eudragit RS & RL

136. Comparison between Sugar & Film coating Features Sugar coating Film coating Appearance Rounded with degree of polish Retains contour of the original tablet – not shiny Weight increase 30 – 50 % 2 – 3 % Logo or break-lines Not possible Possible Other dosage form Of no industrial importance possible - multiparticulates Stages of process Multistage process Single Batch coating time 8 hours 2 hours Functional coating Generally not practical Controlled release

137. Advantages of Film coating Elegance and glossy appearance. Maintain the logo and break line. Improve mechanical strength an integrity and improve resistance for handling and shipping. Flexibility in types of formulation. Minimal weight increase. Less time consuming. Minimize dust. Automated equipment are used. Single process and not requires excessive training.

138. Formulation of the coating fluid Polymer ( may be enteric or nonenteric ) Plasticizer Colourant Opaquant – extender Solvent

139. Polymers for Enteric-coating Cellulose acetate phthalate / cellulose acetate butyrate Hydroxypropylmethyl cellulose succinate. Methacrylic acid co-polymers [ Eudragit ®] Eudragit L-100 dissolve at pH > 5.5 Eudragit S-100 use for target organ drug release ( colon) dissolve at pH > 7.

140. Polymers for Film-coating Hydroxypropylmethyl cellulose. Hydroxy propyl cellulose. Edragit E100 Ethylcellulose : insoluble at all pH, drug released by diffusion and subsequent partitioning into the gastrointestinal fluid. Needs placiticiser . Eudragit RS and RL: insoluble used for delayed action. Dissolve in the stomach , freely soluble in the gastric fluid

141. Plasiticizer To increase the flexibility of the film. 1- 50% by weight of the coating solution. Polyols: glycerol, propylene glycol, polyethylenglycol . Organic esters : water insoluble e.g Diethylphthalate , dibutylphthalate , Acetyl triethyl citrate, Acetyl tributyl citrate, tributyl citrate. Water miscible as triethyl citrate and glyceryl triacetate. - Oils : they are water insoluble e.g castor oil, Acetylated monoglyceride , Fractionated coconut oil.

142. Colourants Powdered colourant should be micronized < 10 microns. Inorganic: iron oxide. Natural, anthocyanins , carotenoids. Magenta red dye, mica

143. Opaquant -extender They are very fine powder of inorganic material used to provide more pastel colours and increase film coverage. Titanium dioxide Silicate ( talc and aluminum silicates) Magnesium Carbonate. Magnesium Oxide. Aluminum hydroxides.

144. Solvents They are used to dissolve or disperse the polymers and the other additives and convey them to tablet surface. Solvent requirements: Easily dissolve or disperse the polymer system. Easily disperse the other additives. Should not be extremely viscous when mixed with the polymer. Colourelss , odourless , tasteless, inexpensive, noniflammable , nontoxic, inert. Rapid drying rate No environmental pollution. Water, ethanol, methanol, isopropanol, chloroform, acetone, methylene chloride………..

145. 3. Press Coating Compaction of the coating material around the tablet core. Other limited coating processes: Compressed coating. Electrostatic coating. Dip coating. Vacuum film coating.

146. Tablet Coating Equipment – Standard Coating Pan 60 – 80 inches circular metal pan mounted angularly on a stand. It rotates horizontally around its axis by a motor. Heated air is directed to the face of the tablet bed and exhausted by means of a duct located at the front of the pan.. Coating solution applied by spraying onto the rotating tablet bed.

147. Tablet Coating Equipment – Pellegrini Coating Pan Has a baffled pan and diffuser that distribute the drying air uniformly over the tablet bed surface. Use an atomized spray system.

148. Suitable for pellets, granules. Recommended for enteric coating and sustained release. Not suitable for tablets

149. Factors Controlling the efficiency of the coating Process Temperature and solvent vapor pressure directly influence the evaporation rate and the process timing. Fluidized air volume within the chamber affect the velocity of the coating fluid droplets and their pattern. If the relative humidity within the chamber is high, evaporative cooling may occur resulting in lowering the temperature below the dew point resulting in condensation of water on the tablet surface. Excessive spray rate results in poor adhesion of the coat to the tablet surface. Avoid droplet aggregation. Increased viscosity affects the atomization process. 1- Evaporation rate of the solvent 2- Fluidized air volume. 3- Specific humidity 4- Spray rate and duration

150. Coating Process Parameters Air capacity value represents the quantity of solvent that can be removed by the quantity and temperature of air flowing and the quantity of water that the inlet air contains. Thickness and viscosity of the fluid influence the rate of drying Increase on the surface area of tablets increases as the tablet size decreases. Resulting in more cycles required to complete the process. Equipment coating efficiency = net increase in the coated tablet weight × 100 weight of nonvolatile coating fluid applied Ideally 90% - 95%. - For sugar coating it is 60%. 1- Air capacity 2- Coating composition. 3- Surface area 4- Equipment efficiency

151. Problems and remedies in tablet coating

152. Defect : Blistering Description : detachment of the film from the substrate forming a blister Reasons : entrapment of gases underneath the film due to overheating. Causes Remedies Effect of temperature on he strength, elasticity and adhesion of the film Use mild drying conditions Defect : Chipping Description : film becomes chipped and dented usually at the edges. Reasons : decreased fluidizing air or high speed of rotation. Causes Remedies High degree of attrition Increase hardness, use high molecular weight polymer.

153. Defect : Cratering Description : volcanic like craters on the tablet surface Reasons : the coating solution penetrate the surface causing local disintegration . Causes Remedies high rate of coating fluid application Inefficient drying Increase viscosity to decrease the rate. Optimize the drying conditions. Defect : Picking Description : isolated areas of the film being pulled away from the surface when tablets sticks together. Reasons : O ver wetting the tablets then they stick together Causes Remedies - Inefficient drying Increase the inlet air temperature - High rate of fluid application - Decrease the application rate by increasing viscosity

154. Defect : Pitting - roughness Description : pits occur in the film without its disruption Reasons : temperature used is more than the melting point of tablet material. Causes Remedies High temperature f the inlet air Modify the temperature of the inlet air, not grater than the melting point Defect : Blooming Description : .dull tablets Reasons : collection of low molecular weight of ingredients on the surface. Causes Remedies High concentration or low molecular weight of plasticizer. Decrease concn of plasticizer or use that of high molecular weight

155. Defect : Blushing Description : whitish or haziness speck in the film Reasons : due to precipitation of the polymer due to high drying temperature Causes Remedies High drying temperature Use of sorbitol which causes fall in the thermal gelation of HPMC/cellulose ethers Decrease the drying temperature Avoid use of sorbitol with cellulose esters Defect : Colour Variations Description : .inconsistent colour of tablets Reasons : alternation of the frequency and duration of appearance of the tablets to the spray zone or irregularity in the spray zone . Causes Remedies Improper mixing, uneven spray, insufficient coating, migration of the dye into the tablet core Appropriate mixing, mild drying conditions, mask the effect of migration

156. Defect : Filling tablet markings Description : filling the marks render them indistinct. Reasons : inability of foam spray to break, droplet on the surface of marking. Causes Remedies low drying temperature and low rotation speed. Excessive volume of coating fluid. Bubbles or foams during spray Deep marking. increase the drying temperature and rotation speed Adjust the spray nozzle. Defect : Orange peel /roughness Description : .rough surface and nonglossy like that of an orange surface. Reasons : drying takes place before reaching the tablet surface. Causes Remedies Rapid drying Highly viscous fluid - Decrease temp and increase spray rate - Decrease viscosity of coating fluid.

157. Defect : Crack formation / splitting Description : cracks across the tablet crown or splitting at the edges Reasons : internal strength exceeds the tensile strength of the film Causes Remedies Inadequate plasticizer. The polymer has low resistance to tensile. Increase or change plasticizer Use appropriate polymer Defect : Tablet abrasion Description : damage of the tablet surface Reasons : sheering stress resulted from the collisions of tablets with each other and with the chamber walls. Causes Remedies Inappropriate tablet hardness, irregular tablet shape, heavy tablet bed, excessive speed of rotation, high rate of fluidizing air inlet. Adjust hardness and change tablet shape. Reduce the tablet load within the chamber. Decrease the rotation speed and inlet air.

158. Defect : Poor adhesion of the coating to the tablet Description : easily removable film Reasons : poor adhesion of the coating fluid to the tablet. Causes Remedies High RH within the chamber, while using organic solvent system. High coating spray rate of the fluid. Low polymer concentration. Too low temperature. Air fluidization rate and rotation speed are too low. Tablets have minimum required curvature. Adjust humidity. Appropriate rate of spray. Increase polymer concentration. Increase the temperature. Adjust the speed of rotation and the rate of air inlet. Increase curvature of tablet faces.

159. IN PROCESS QUALITY CONTROL TESTS

160. General appearance Control of tablet to tablet uniformity and batch to batch uniformity. Shape & Size: Thickness measured using the Vernier and variation should not exceed ±5%. Diameter of tablet. Unique identifying marking. Organoleptic properties: Colour may be measured using photometer or spectrophotometry. Odour may be characteristic in some cases as vitamins but usually presence of odour may be due to the film or stability problem. Pleasant taste may be desired for chewable tablet – unpleasant taste requires coating.

161. Weight variations – mass uniformity* ( Ph.Eur . method 2.9.5 ) – BP 2016 Weigh individually 20 units taken at random or, for single-dose preparations presented in individual containers, the contents of 20 units, and determine the average mass. Not more than 2 of the individual masses deviate from the average mass by more than the percentage deviation shown in the Table. and none deviates by more than twice that percentage Uncoated and film coated tablets Average Mass Percentage Deviation 80 mg or less 10 More than 80 mg and less than 250 mg 7.5 250 mg or more 5 When the average mass is equal or below 40 mg , it is not submitted to mass uniformity test but to the test for uniformity of content of single- dose preparations.

162. Resistance to Crushing – hardness testing Tablet should have certain hardness or mechanical strength to withstand the upcoming processes but should not be too hard to fail disintegration and dissolution and consequently bioavailability. OPERATING PROCEDURE Place the tablet between the jaws, taking into account, where applicable, the shape, the break-mark and the inscription; for each measurement orient the tablet in the same way with respect to the direction of application of the force. Carry out the measurement on 10 tablets, taking care that all fragments of tablets have been removed before each determination. This procedure does not apply when fully automated equipment is used . Express the results as the mean, minimum and maximum values of the forces measured, all expressed in newtons .

163. APPARATUS The apparatus consists of 2 jaws facing each other, one of which moves towards the other. The flat surfaces of the jaws are perpendicular to the direction of movement. The crushing surfaces of the jaws are flat and larger than the zone of contact with the tablet. The apparatus is calibrated using a system with a precision of 1 newton.

164. Friability Test For tablets with a unit mass equal to or less than 650 mg, take a sample of whole tablets corresponding as near as possible to 6.5 g. For tablets with a unit mass of more than 650 mg, take a sample of 10 whole tablets. The tablets are carefully dedusted prior to testing. Accurately weigh the tablet sample, and place the tablets in the drum. Rotate the drum 100 times, and remove the tablets. Remove any loose dust from the tablets as before, and accurately weigh. If obviously cracked, cleaved, or broken tablets are present in the tablet sample after tumbling, the sample fails the test. If the results are difficult to interpret or if the weight loss is greater than the targeted value, the test is repeated twice and the mean of the 3 tests determined. A maximum loss of mass (obtained from a single test or from the mean of 3 tests) not greater than 1.0 per cent is considered acceptable for most products. Dropping distance is 6 inches. Rotation speed is 25 rpm.

165. Disintegration Test Disintegration time is defined as the time required under a given set of conditions for a group of tablet to disintegrate into particles w hich will pass through 10 mesh screen. Procedure:   Place 1 dosage unit in each of the 6 tubes of the basket and, if prescribed, add a disc. Operate the apparatus using the specified medium, maintained at 37 ± 2 °C, as the immersion fluid. At the end of the specified time, lift the basket from the fluid and observe the dosage units: all of the dosage units have disintegrated completely. If 1 or 2 dosage units fail to disintegrate, repeat the test on 12 additional dosage units. The requirements of the test are met if not less than 16 of the 18 being disintegrated . Complete disintegration is defined as that state in which any residue of the unit, except fragments of insoluble coating or capsule shell, remaining on the screen of the test apparatus or adhering to the lower surface of the discs, if used, is a soft mass having no palpably firm core.

166. Disintegration Apparatus 6 glass tubes of 3 inches length, opened at the top and 10 mesh screen at the bottom in a basket rack with 1-L beaker container equipped with thermostat. The motor moves the basket assembly up and down for a distance of 58 mm at speed of 29 – 32 cycles per min. tablets should not be closer more than 25 mm from the bottom and 15 mm from suface .

167. Disintegration conditions and interpretation Type of tablet Medium Temperature Time limit Uncoated tablets Water 37 ± 2 ˚C 15 min Sugar coated Water, 0.1 N HCl if 1 or 2 failed 37 ± 2 ˚C 60 min Film coated Water 37 ± 2 ˚C 30 min Enteric coated 0.1 N HCl + Phosphate buffer pH 6.8 37 ± 2 ˚C 37 ± 2 ˚C 1 hour + 1 hour = 2 hours Dispersible / Effervescent Water 37 ± 2 ˚C 3 min Buccal Water 37 ± 2 ˚C 4 hours

168. Dissolution Dissolution is the amount of drug substance that goes into solution per unit time under standardized condition of liquid / solid interface, temperature and solvent composition. the dissolution rate is the rate of mass transfer from a solid surface into the dissolution medium or solvent under standardized conditions of liquid/solid interface, temperature and solvent composition per unit time. There is a significant correlation between dissolution and bioavailability ( INIVC).

169. Dissolution test Apparatus BP -2016, There are four types of dissolution apparatus Apparatus 1 : Basket Apparatus. Apparatus 2 : Paddle Apparatus. Apparatus 3 : Reciprocating Cylinder. Apparatus 4 : Flow-through Cell. Generally for tablets apparatus 1 and apparatus 2 are used.

170. Apparatus 1 : Basket apparatus A basket of 22 mesh screen fastened to a bottom of a stainless shaft is immersed in one litre glass cylinder of flanged top edges. The cylinder is placed in water bath maintaining temperature 37˚C ±2. Basket is placed at a distance of 25 mm from the bottom of the cylinder and the shaft is centered within 2 mm from the vertical axis of the cylinder. One tablet is placed in the basket , the apparatus turned on, then the basket rotate ( Stirring mode), samples are taken every interval from the dissolution medium for analysis to determine the amount of drug being released.

171. Apparatus 2 : Paddle apparatus A paddle of a stainless composed of a blade fixed to a shaft is immersed in one litre glass cylinder of flanged top edges. The cylinder is placed in water bath maintaining temperature 37˚C ±2. Paddle at a distance of 25 mm from the bottom of the cylinder and the shaft is centered within 2 mm from the vertical axis of the cylinder. One tablet is placed in the bottom of the cylinder and not allowed to float , the apparatus turned on, then the paddle rotate ( Stirring mode), samples are taken every interval from the dissolution medium for analysis to determine the amount of drug being released.

172. End of Tablet Technology