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  1. 1. *EVOLUTION* ‘A GLIMPSE ON PHARMACEUTICS’ GROOMING FOR GPAT & NIPER, MOHALI CONTACT:   TABLETS Are Unit dosage form, tamperproof solid dosage form. Manufacture of Granulations Direct  Compression  e.g. NaCl, KBr etc.  Compression granulation  Wet granulation  Direct compression: Some crystalline substances which can be compressed directly. A directly compressible diluents added e.g. microcrystalline cellulose. Disadvantages: Differences in particle size & bulk density between drug & diluents leads to stratification within granulation resulting in poor content of uniformity of drug in compressed tablet. In direct compression diluents may interact with the drug e.g. Milard’s reaction that is yellow discolouration between amine groups and hydrous lactose. Because of dry nature of direct compression a static charge develops which may prevent uniform distribution of drug in the granulation. The maximum percentage of non compressible content in direct compression can be upto 30%. Compression granulations: Used when drug is sensitive to heat, moisture (wet granulations) e.g. vitamins, aspirin etc. Powder blend slugs Screened or milled to produce granular form Equipments: 1. Roller Compactor 2. Chilsonator 3. Hut’s compactor 3. Wet granulations: Forms the granules by binding the powder together with an adhesive, instead of by compaction. Equipment used for wet granulation:
  2. 2. *EVOLUTION* ‘A GLIMPSE ON PHARMACEUTICS’ GROOMING FOR GPAT & NIPER, MOHALI CONTACT:   i. Sigma blade (mixture) ii. Nauta mixer iii. Fluidised bed dryer (Dryer) iv. Littleford lodige mixture (mixer/granulator) v. Diosna mixer/granulator vi. Gral mixer/granulator Why granulation 1) To improve flow by increasing particle size since larger particles flow more readily than smaller ones. 2) To prevent the segregation which is mainly due to differences in the particle size of API and excipients because granulation produces a homogenous mixture, as in granulation particles get stuck together and cannot separate. 3) Improves the compressive characteristics. 4) It reduces the dust. Wet granulation: API + Diluent/Filler Mixing Water Binding Wetting Granulation Drying Sieving Mixing Compression Lubricant Glidant Disintegrating agent
  3. 3. *EVOLUTION* ‘A GLIMPSE ON PHARMACEUTICS’ GROOMING FOR GPAT & NIPER, MOHALI CONTACT:   Direct compression: API Diluent Lubricant Glidant Disintegrating agent Weighing and Mixing Compression • No drying stage/heating, no moisture involvement. Tablet disintegrates into primary particles rather than granular aggregates, which results in increase in surface area available for dissolution resulting in faster drug release. • The one limitation of direct compression is that it depends upon the fluidity & compressibility of tablet diluents. So it cannot be used for the drug which have low potency i.e. high dose of active ingredients, in such cases the incorporation of the diluents (at least 30% of the formula) required for direct compression leads to larger tablets which are unacceptable. • Most widely used diluents in directly compressible tablet is Avicel/microcrystalline cellulose (aggregates of microcrystals isolated from α-wood cellulose by acid hydrolysis) due to its excellent flow & superior compressibility.
  4. 4. *EVOLUTION* ‘A GLIMPSE ON PHARMACEUTICS’ GROOMING FOR GPAT & NIPER, MOHALI CONTACT:   Tablet excipients A. Diluents/Fillers They are used to produce tablet of reasonable size i.e. minimum diameter of 3 mm. Potent drug < 60 mg (A) Lactose: It is disaccride & α-lactose monohydrate (Wet granulation) is most widely used, hydrous lactose can cause Maillard reaction → interaction of amine drugs with hydrous lactose in the presence of lubricant like magnesium stearate resulting in yellowish discolouration time to time. Spray dried lactose (3% moisture): It is diluents used for direct compression. But it is prone to darkening in presence of excess of moisture, amines, furaldehyde. Hydrous lactose → Wet granulations Anhydrous lactose → No Millard’s reaction/direct compression (B) Starch: It may give rise to soft tablets. Moisture content 11-14%. Sta- Rx – 1500 free flowing & directly compressible. It is diluents, binder, disintegrating agent and self lubricating, glidant (0.25%). Emdex & celutab (contains 90-92% dextrose, 3-5% maltose) are hydrolyzed starches & are free flowing and directly compressible. They are sweet in taste & can be used in replace of mannitol. (C) Dextrose: It is sometimes used to replace the spray dried lactose to reduce the tablet to darken. (D) Mannitol: Negative heat of salvation, its slow solubility & pleasant feeling in mouth, used mainly in the chewable tablets. It is non-hygroscopic so can be used in vitamin formulation which are moisture sensitive. But Mannitol have poor flow so require high amounts of lubricants. (E) Sorbitol: It is optical isomer of Mannitol but is hygroscopic above humilities 65%. (F) Sugar based diluents: Sugar tab → 90-92% sucrose + 7-10% invert sugar Dipac → 97% Sucrose + 3% dextrins Nutab → 95% sucrose + 4% invert sugar with small amount of corn starch & magnesium stearate. (G) Microcrystalline Cellulose (Avicel) Direct compressible Avicel – 101 → Powder Avicel – 102 → Granules
  5. 5. *EVOLUTION* ‘A GLIMPSE ON PHARMACEUTICS’ GROOMING FOR GPAT & NIPER, MOHALI CONTACT:   This produces cohesive compacts, disintegrating agent (H) Calcium Slats: DCP (Dibasic calcium phosphate) and calcium sulfate have low concentration of unbound moisture. The bound water of calcium sulfate is not released upto 800 C. DCP is virtually insoluble in water and hence used in conjunction with disintegrating agent. Calcium based diluents can cause interaction with tetracyclines API. A. Binders & Adhesives Sugars  e.g. Sucrose,  Glucose  Natural e.g. Starch paste,  Acacia, Tragacanth,  Gelatin, Alginates  Synthetic/Semisynthetic e.g. HPMC, PEG, Poly vinyl  pyroolium, Poly vinyl  alcohol  Acacia & Tragacanth → 10-25% Starch → 5-10% Gelatin → 5-20% Glucose → 50% Sucrose → 70% Acacia & Tragacanth: Natural origin so variable in composition easily attacked by microorganism. Starch paste: Prepared by dispersing starch into water when heated. The paste must be translucent rather than clear. On heating starch hydrolyzed to dextrin & glucose. While clear paste indicates complete conversion to glucose. Methyl cellulose, Hydroxy propyl methyl cellulose (HPMC), Hydroxy propyl cellulose (HPC) [for both alcoholic & aqueous solution], are common binder for direct compression & their aqueous solution is adhesive. Polyvinyl pyrrolidone (PVP) → It is adhesive in either aqueous or alcoholic solution. Its concentration used is 0.5- 3%. Ethyl cellulose → It is used only with solution alcoholic & it can retard the disintegration & dissolution of drugs. C. Disintegrants
  6. 6. *EVOLUTION* ‘A GLIMPSE ON PHARMACEUTICS’ GROOMING FOR GPAT & NIPER, MOHALI CONTACT:   Starch → Most commonly used (5-20%). Modified starch primogel and explotab are low substituted carboxy methyl starches (1-8%). Clays & bentonite → 10% but can give off white appearance. AC-Di- Sol → Internally cross linked sodium carboxymethyl cellulose i.e. Na CMC. Cross linked polyvinyl pyrrolidone. These two are called super disintegrants. E.g. sodium starch glycoate, cros carmellose (cross linked CMC), cros povidone, palacrillin K+ → It is a cation exchange resin. Sodium glycine carbonate: Source of CO2 for effervescent tablets. D. Lubricants, Antiadherants & Glidants Lubricants: They are intended to reduce the friction during tablet ejection between walls of the tablet and walls of the die cavity in which tablet was formed. E.g. Magnesium stearate but not glidant. Antiadherents: They are used to reduce the sticking & adhesion of any of tablet granulation/powder to the punches of die wall. Glidants: They are intended to promote flow of the tablet granules from hoper & reducing the friction between the particles. E.g. colloidal silicon dioxide [No lubricant activity, Aerosil, cab-O-Sil, Soluble]. Calcium & Magnesium Stearates → 0.25 – 1%. Talc (5%) Both glidant + lubricant activity (Contains Iron, so carefully used if any formula contains drug which breakdown is catalysed by Fe2+ ) PEG Colloidal silicas → 0.25 – 5% Starch Liquid Paraffin → 5% Lubricants based upon fatty acids are insoluble in water & hence can retard the disintegration & dissolution time. Water soluble lubricants: PEG 6000, [Macrogol 6000 or carbowax], Magnesium Lauryl Sulfate, Fumaric acid. Microcrystalline cellulose/Avicel: Low coefficient of friction, when compressed mcc particles deform physically and surfaces form H-bonding. MCC is hygroscopic & water causing the weaking of interparticulate hydrogen bonds.
  7. 7. *EVOLUTION* ‘A GLIMPSE ON PHARMACEUTICS’ GROOMING FOR GPAT & NIPER, MOHALI CONTACT:   Mechanism of disintegrants: Those that enhance the action of capillary forces in producing rapid intake of aqueous liquids. So disintegrant have porous structure & show low interfacial tension towards aqueous fluids. Rapid penetration by water in the tablet matrix resulting in breakup of tablet. E.g. Starch, MCC, Cationic resins, sodium starch glycolate Those which swells on contact with water. E.g. Acacia, Tragacanth. One problem can be they produce sticky/gelatinous mass that resists break up of tablet, so optimize concentration within granulation. Gas Production: They are sensitive to small changes in humidity levels. They are disintegrants mainly in the effervescent tablets. The most common are mixture of citric acid & tartaric acid plus carbonates/bicarbonates, Sodium glycine carbonate. Glidants: They get absorbed or interposing their particles between those of other components which results in reduction of adhesive tendencies or lower the interparticular friction system. So they are also called as flow promoters. E.g. colloidal SiO2, Starch, talc. Calcium stearates (Lubricant) can cause Maillard reaction with amine drugs like aminophylline with lactose. A common mistake during the tablet granulation is adding both disintegrant & lubricant in one mixing step. This results in disintegrant to be coated with lubricant & often results in both decrease in disintegrants porosity & decrease in the efficiency of disintegrants. E. Colors, Flavors & Sweeteners Lakes: They are dyes that has been absorbed on hydrous (Al(OH)3) oxide and usually employed as dry powders for coloring. They contain 10-30% of pure dye & maximum upto 50%. During the wet granulation, care must be taken to prevent colour migration during drying (mottling) [mainly with soluble dyes]. Colorant should not be more than 2%. Flavor oil maximum upto 0.5-0.75%. Mannitol is 72% solvent as sucrose. Saccharin 500 times sweeter than sucrose but it is carcinogenic in nature. Aspartame (dipeptide aspartic acid + Phenylalanine) replace saccharin but this aspartame lack stability in the presence of moisture and it is hygroscopic. Wetting agents: They are used to increase water uptake and enhancing disintegration and assisting dissolutions. E.g. sodium Lauryl sulphate (LSL) or Docussate sodium known to enhance the dissolution as it is anionic surfactant which causes destruction of membrane of intestines. These wetting agents are added when drug is hydrophobic.
  8. 8. *EVOLUTION* ‘A GLIMPSE ON PHARMACEUTICS’ GROOMING FOR GPAT & NIPER, MOHALI CONTACT:   Tablet coating 1) Used to mask taste, odor, and color to provide physical and chemical protection. 2) To control the release of drug from tablet. 3) To protect the drug from gastric environment of stomach with acid resistant enteric coating. 4) To incorporate another drug/formula adjuvant in coating to avoid chemical incompatibility and sequential drug release. A. Sugar Coating Skilled person requirement & tablet are deep convex surfaces with thin round edges. Sugar coating increase the 50-52% thickness of tablets. Steps involved are: (i) Sealing: Water proof coating because without it tablets would absorb excess moisture leading to tablet softening/disintegration. Shellac: It is mostly sealant but undergo aging due to polymerization resulting in lengthening or increase in tablet disintegration and dissolution time. Zein: Alcohol soluble protein derivative from corn is also effective sealant. (ii) Sub coating: To round the edges & build up the tablet size. Sugar coating increase the tablet weight by 52%. Sub coating steps consists of alternatively applying a sticky binder (acacia/gelatin) solution to tablets followed by a dusting of sub coating (Talc, CaCO3) powders & then drying. The process is repeated until desired thickness is achieved (3-4 sub coats). (iii) Syrup coating/colour coating: It is to cover & fill the imperfections in tablet surface caused by sub coating step and impart desired colour to the tablet. This step requires most skill person. The first syrup coats usually contain some suspended powders called as grossing syrups. No colour should be added until tablets become smooth. (iv) Polishing: It is done by powdered wax i.e. beeswax or carnauba wax or warm solution of these waxes in naphtha or suitable volatile solvents. B. Film coating (Weight gain is only 2-6%) Film formers: The solubility is the one of the important parameter e.g. free water solubility, slow water solubility (for controlled release), pH dependent solubility (Enteric coating) A. Non-enteric film formers: (Mostly cellulose derivatives) a. HPMC (Hydroxy propyl methyl cellulose): Mostly used Alkali treated cellulose + CH3Cl → Introduce methoxy groups To introduce propylene glycol ether
  9. 9. *EVOLUTION* ‘A GLIMPSE ON PHARMACEUTICS’ GROOMING FOR GPAT & NIPER, MOHALI CONTACT:   Different grades are available depending upon the viscosity, generally low grades are preferred. When used alone, the polymers have tendency to bridge or fill the debased tablet surfaces. Ethyl cellulose: It is totally water insoluble & GIT fluids polymer & pH independent so should not be used alone. It is mostly used for delayed/sustained release tablets in combination with water soluble additives. Povidone: It is 1-vinyl 2-pyrrolidinone. It also acts as binder & hence improves the dispersion of colorants in coating solution for uniformity. 4 viscosity grades given by K values i.e. K-15 [10000], K30 [40000] (tablet binder & tablet coating), K45 & K 60. Hydroxy propyl cellulose (HPC): It is soluble in H2O below 400 C & insoluble above 450 C. It produces the film extremely tacky. Sodium carboxymethyl cellulose: Water soluble polymer easily dispersed in water to form colloidal solution but it is insoluble in most of organic solvents. PEG: PEG – 200-600 molecular weight. Liquid at room temperature & used as plasticizer for coating solution filtrate. PEG 900-8000 are white waxy solids at room temperature. These polymers used in combination with other polymers to modify the film properties. Combination PEG waxes + Cellulose acetate phthalate (CAP) provides films are soluble in gastric fluids. So used for non enteric coating process. Acrylate polymers or carbopol: e.g. Eudragit E is a cationin polymer. Dimethyl aminoethyl methacrylate + methacrylic acid ester. Eudragit E → is only Eudragit material that is freely soluble in gastric fluid up to pH 5. Eudragit RL & RS → pH independent polymers so for delayed release. Eudragit L & S → Enteric coating & soluble above pH 6 & 7 respectively. Eudragit E → non enteric coating Mostly these polymers are available in Isopropanol solvents. B. Enteric Coating Polymers Mostly esters of phthalates, So protect acid-labile drugs from gastric fluid e.g. enzymes and antibiotics, to prevent the gastric distress e.g. sodium salicylate, to deliver the drugs intended for local action in intestine. E.g. Shellac, phalates & Eudragit L & S. The pH of stomach contents varies from pH 1.5-4.
  10. 10. *EVOLUTION* ‘A GLIMPSE ON PHARMACEUTICS’ GROOMING FOR GPAT & NIPER, MOHALI CONTACT:   The pH of the material approaching pylorus (last part of stomach) is nearly 5. So an ideal eneteric polymer should dissolve or become permeable near and above pH 5. The above pH these polymers with CAP, HPMCP, Polyvinyl, acetate phthalate [which are dicarboxylic acid, pthalic acid] in partially esterified form starts to lose their film integrity due to ionization of carboxylic group on chain and subsequent hydration. Further the presence of esterases in intestinal fluid breakdown ester linkage of polymer chains. a. Cellulose acetate phthalate (CAP): Dissolves above pH 6, it is hygroscopic, films are brittle, usually formulated with hydrophobic film (to prevent hygroscopic) forming material for better enteric films. E.g. Diethyl phthalate. Aqueous enteric coating called as aquateric, used with colloidal dispersion of latex particles + CAP. b. HPMCP: Hydroxy propyl methyl cellulose phthalate. E.g. HP 50, 55. HPMC + Pthalic anhydride → HPMCP Dissolves at pH 5-5.5 (pylorus pH) Polyvinyl acetate phthalate (PVAP): Supplied as ready to use or ready to disperse enteric systems. Acrylate polymers: Eudragit L → Soluble at pH 6 Eudragit S → Soluble at pH 7 Solvents for film coating: To dissolve or disperse the polymers & other additives. Small concentrations of polymers i.e. 2-10%. Should not result in extremely viscous solution system i.e. > 300 cps, it should have rapid drying rate i.e. the ability to coat 300 kg load in 3-5 hrs. Water- Drugs can hydrolyse, increase in viscosity of coating solution or the drug must require initial seal coat with non aqueous solvent based coating. Isopropanolol, acetone, C2H5OH, CH3OH, Methyl ethyl ketone. Plasticizers: Isothermal plasticizing technique: It is the chemical modification of basic polymer that alters the physical properties of the polymer. E.g. degree of substitution, type of substitution, chain length etc. polymer properties are varied.
  11. 11. *EVOLUTION* ‘A GLIMPSE ON PHARMACEUTICS’ GROOMING FOR GPAT & NIPER, MOHALI CONTACT:   External plasticizing techniques: Here a plasticizer is added to achieve desired effects. The external plasticizer can be non-volatile liquid or another polymer which when incorporated with the primary polymeric film former, changes the flexibility, tensile strength or adhesion property of the resulting film. Plasticized range from 1-50% by weight of a film former. Commonly used plasticizer are – castor oil, PEG 200 – 400 and surfactants like Polysorbates (tween), sorbitan esters (Spans). For aqueous coating mostly water soluble plasticizer used are PEG & PPG (poly propylene glycol) Castor oil & spans are used for organic solvents based coating solutions. Colorants: To achieve proper distribution of suspended colorants in coating solution requirement uses of fine powdered colorants < 10 µ. Lakes are dyes absorbed on Al(OH)3 or Talc become choice for sugar and film coating systems. Natural coloring materials: Anthocyanins, caramel, carotenoids, carminic acid, Indigo, Flavones etc. Opaquant: Provide white coating or more pastel colors. E.g. Titanium dioxide (TiO2), Talc, Al(OH)3 Film Defects 1. Sticking and Picking: Due to over wetting or excessive film tackiness causes tablets to stick each other or with coating pan. 2. Orange Peel Effect: Due to inadequate spreading of coating solution before drying causes a bumpy or orange peel effect indicates that spreading is impeded by too rapid drying or high viscosity coating solution. 3. Bridging & filling: During drying the film may shrink& pull away from sharp corners or bisect resulting in bridging. It can be overcome by increasing plasticizer content. 4. Filling: It is caused by applying too much solution resulting in a thick film that fills & narrow the monogram or bisect. 5. Blistering: When coated tablets require further drying in ovens, too rapid evaporation of solvent from the care which affect the strength, elasticity and adhesion properties of film results in blistering. So milder drying conditions are used. 6. Hazing/Dull film/Bloom: Loss of glass mainly due to high processing temperature or high humid condition. Dulling is particularly with cellulosic polymers. 7. Mottling: It is migration of dyes (soluble), plasticizer & other additives during drying. Use lake dyes. 8. Cracking: It occurs when internal stress in the film exceeds the tensile strength of the film. Tensile strength of the film can be increased by using high molecular weight polymers or polymer blends.
  12. 12. *EVOLUTION* ‘A GLIMPSE ON PHARMACEUTICS’ GROOMING FOR GPAT & NIPER, MOHALI CONTACT:   Coating Equipment   Standard Coating  Pan  Immersion sword  Pellegrini  Perforated Coating Pan Accela – cota  Hi‐Coater  Crlatt Coater  Fluidized bed colour (Air  Suspension) 
  13. 13. *EVOLUTION* ‘A GLIMPSE ON PHARMACEUTICS’ GROOMING FOR GPAT & NIPER, MOHALI CONTACT:   Tablet defects a. Capping: Means partial or complete separations of the top or bottom crowns of tablet from body. b. Lamination: Separation of tablet into two or more distinct layer which is also due to entrapment of air. 1. Mainly due to air entrapment which is itself actually due to high compression force. When force compression crosses the zero voidage. So beyond zero voidage particles behave elastic in nature when they compressed and after removal of compression force due to elastic in nature particles try to regain original shape which results in air entrapment. 2. Both capping & lamination are due to deep concave punches so can be avoided by flat punches which eliminate additional shear stress. 3. A certain % of moisture is often essential for good compaction & granulations that too dry tends to cap or laminate. So an additional hygroscopic substance like sorbitol, PEG 400, methyl cellulose help to maintain a proper moisture level. 4. Capping & Lamination may be due to direct compression because some powder or fines may not be compressible or may have poor compression properties. So higher concentration of times should not be used. 5. Capping may also be when dies develop wear ring in the area of compression. Dies of tungsten carbide inserts so used to prevent it. c. Picking and sticking: Picking is particular concern when punches tips have engraving or embossing. So small areas like those found in letters B,A & O are difficult to manufacture cleanly. d. Sticking: It mainly refers to tablet material adhere to die wall. When sticking occurs, additional force is required to overcome the friction between tablet & die wall during ejection. Serious sticking at ejection can cause chipping at tablet edges & produce rough edge. i. Also sticking problem does not allow lower punches free movement & therefore unusual stress on the cam tracks & punches heads resulting in their damage. Plotting of punch faces with chromium is method to produce smooth, non adherent force to prevent picking. ii. Some low melting point substances either active or additives like stearic acid and PEG may soften from heat of compression resulting to cause sticking. So low melting point lubricant replaced with high melting point lubricant. iii. Excessive moisture may be responsible for sticking. e. Mottling: unequal distribution of colour on tablet, with light or dark areas . (i) It can be due to when drug color differs from color of tablet excipients or drug whose degradation products are colored.
  14. 14. *EVOLUTION* ‘A GLIMPSE ON PHARMACEUTICS’ GROOMING FOR GPAT & NIPER, MOHALI CONTACT:   (ii) A dye can cause mottling by migration to the surface of granulation during drying. So to overcome this change the solvent system reduces drying temperature; grind to smaller particles. (iii) Certain colored adhesive gel solution may not be distributed well because they must be hot when added to much cooler powder mixtures. The adhesive then precipitates from solution & carries most of the colour with it. (iv) Therefore , generally incorporate fine powder adhesives such as acacia and tragacanth into the product before adding granulating fluid. f. Weight variation: Poor flow (Add glidant like Talc, Colloidal silica). Depending upon the shape of hopper causes of poor flow either arching and rat-holing. When poor flow occurs, it is controlled by vibrator attached to the hopper sides. But sometimes these vibrations induce segregation and stratification. The larger particles tend to drift upward while smaller particles sift downward, which leads to weight variation with poor content of uniformity because the drug is not distributed between larger and smaller particles. Punches variation: i.e. when lower punches are unequal lengths because die fill is volumetric. Hausner′ s ratio Tapped density Bulk density or pored density < 1.25 Good flow 1.25-1.5 Moderate >1.5 Poor % Compressibility/Carr’s Index % 5-15% Excellent 12-16% Good 18-22% Fair 24-35% Poor > 40% Extremely poor 25 Excellent
  15. 15. *EVOLUTION* ‘A GLIMPSE ON PHARMACEUTICS’ GROOMING FOR GPAT & NIPER, MOHALI CONTACT:   Good Passable 40 Very poor Flow Official tests Unofficial tests Weight variation or uniformity of weight Disintegration time Dissolution testing Content uniformity Size & shape Tablet thickness Color uniformity Unique identification markings Hardness Friability Porosity (Film coating test) Physical stability Tablet Diluents Diluent Comment Calcium Carbonate Insoluble in water Glucose Hydroscopic, reducing sugar Calcium Hydrogen Phosphate Insoluble in water good flow properties α-lactose Inexpensive, inert and most common diluents Mannitol Popular for chewable tablets, freely soluble in water, cool taste Sodium chloride Freely soluble, used in solution tablet taste problem Sucrose Hygroscopic, sweet taste used in lozenges in conjuction with lactose Microcrystalline cellulose Excellent compression propertical, highly stables also disintegration therapy. Directly compressible tablet diluent Microcrystalline cellulose Microfine cellulose Modified starch Dextrates Sucrose-dextrin coprecipitate Calcium hydrogen phosphate Anhydrous lactose Spray dried lactose Binders and Granulating fluid
  16. 16. *EVOLUTION* ‘A GLIMPSE ON PHARMACEUTICS’ GROOMING FOR GPAT & NIPER, MOHALI CONTACT:   Substance Concentration Acacia mucilage Up to 20% Glucose Up to 50% Gelatin 5-20% Providone (PVP) 2-10% Starch mucilage 5-10% Sucrose Up to 70% Tragacanth mucilage Up to 20% Tablet Disintegrants Alginic acid, sodium alginate 2-10% Aluminium magnesium silicate carbon dioxide Up to 10% Sodium carbonyl methyl cellulose or carmellose, sodium Cationic exchange resins Up to 10% Microcrystalline cellulose (CMC) Starch Up to 10% Modified starch 2-10% Sodium starch glycollate, cross carmellose sodium 1-10% Crospovidone 2% Tablet Glidants Glidant Concentration (%) Colloidal silica 0.1-0.5 Talc 1-2% Tablet Lubricants Substance Concentration in tablet (%w/w) Comments Fumaric acid 5 Water soluble Hydrogenated vegetable oil 0.5-2.0 Lubritab Liquid paraffin Upto 5 Dispersion problems Magnesium lauryl sulphate 1-2 Water soluble Macrogol 4000 and 6000 2-5 Water soluble Sodium benzoate 5 Water Soluble, taste problems Sodium lauryl sulphate 0.5-5.0 Wetting agent, often used in conjuction with stearates Sodium Stearyl fumarate 1-2 Soluble in hot water Stearates calcium magnesium stearic acid 0.25-1.0 Very effective lubricants, prolong distintegration time blet crushing strength.
  17. 17. *EVOLUTION* ‘A GLIMPSE ON PHARMACEUTICS’ GROOMING FOR GPAT & NIPER, MOHALI CONTACT:   Film formers 1. Hydroxypropyl methylcellulose 2. Methyl hydroxyethyl cellulose 3. Ethylcellulose 4. Hydroxypropylcellulose 5. Povidone 6. Sodium Carboxymethylcellulose 7. Polyethylene glycols 8. Acrylate polymers Classification of Powders Coarse Powder Powder passing through Mesh aperture of 1700 micrometer (Sieve number 10) and not more than 40% by weight pass through a sieve with normal aperture of 355 micrometer (Sieve number 44) Moderately Coarse All the particles pass through sieve with nominal mesh aperture of 710 micrometer (22) and not more than 40% by weight pass through the sieve with nominal mesh aperture of 250 micrometer (60) Moderately fine powder All particles pass through a sieve with nominal mesh aperture of 355 micrometer (44) and not more than 40% by weight pass through size with nominal mesh aperture of 180 micrometer (85). Fine powder All particles passes through a sieve with nominal mesh aperture of 180 micrometer (85) and not more than 40% by weight pass through a sieve with nominal mesh aperture of 125 micrometer (120) Very fine powder All the particles passes through a sieve with nominal mesh aperture of 125 micrometer (120) and not more than 40% by weight passes through the sieve with nominal mesh aperture of 45 micrometer (325). Microfine powder A powder of which is not less than 90% by weight of particles passes through a sieve with nominal mesh diameter of 45 micrometer (325). Superfine powder A powder with not less than 90% by number are less than 10 micrometer in size. Difference between lakes & Dyes Characteristics Lakes Dyes Solubility Insoluble in most solvents Soluble in water, propylene glycol and glycerin Method of coloring By dispersion By solution Pure dye content 10-40% Primary colors – 90-93%
  18. 18. *EVOLUTION* ‘A GLIMPSE ON PHARMACEUTICS’ GROOMING FOR GPAT & NIPER, MOHALI CONTACT:   Rate of Use 0.1 – 3% 0.01-0.03% Particle Size < 0.5 micrometer 12-200 mesh Stability Light Heat Better Better Good Good Cooling Strength Not proportional to dye content Directly proportional to pure dye content Shades Varies with pure dye content Constant
  19. 19. *EVOLUTION* ‘A GLIMPSE ON PHARMACEUTICS’ GROOMING FOR GPAT & NIPER, MOHALI CONTACT:   Quality control of Tablets A. Uniformity of weight: This test is not applicable to coated tablets other than film-coated tablets and to tablets that are required to comply with the test for uniformity of content for all active ingredients. Weigh 20 tablets selected at random and calculate the average weight. Not more than two of the individual weights deviate from the average weight by more than the percentage shown in table and none deviates by more than twice that percentage B. Uniformity of content: This test is applicable to tablets that contain less than 10 mg or less than 10% w/w of active ingredient. For tablets containing more than one active ingredient carry out the test for each active ingredient that corresponds to the aforementioned conditions. The test for Uniformity of content is not applicable to tablets containing multivitamins and trace elements. Determine the content of active ingredient(s) in each of 10 tablets taken at random using the method given in the monograph or by any other suitable analytical method. The tablets comply with the test if not more than one (9 tablets out of 10) of the individual values thus obtained is outside the limits 85 to 115% of the average value and none is outside the limits 75 to 125% of the average value. If two or three of the individual values are outside the limits 85 to 115% of the average value and none is outside the limits 75 to 125%, repeat the determination using another 20 tablets. The tablets comply with the test if in the total sample of 30 tablets not more than three of the individual values are outside the limits 85 to 115% and none is outside the limits 75 to 125% of the average value. C. Disintegration: This test is not applicable to modified-release tablets and tablets for use in the mouth. The water medium at 37± 20 C. Basket move up and down through a distance of 5-6 cm at a frequency of 28-32 cycles/ min 1. Uncoated tablets disintegrate within 15 minutes
  20. 20. *EVOLUTION* ‘A GLIMPSE ON PHARMACEUTICS’ GROOMING FOR GPAT & NIPER, MOHALI CONTACT:   2. Coated tablets Operate the disintegration apparatus for 30 minutes for film-coated tablets and for 60 minutes for other coated tablets unless otherwise directed in the individual monograph. For coated tablets other than film-coated tablets, if any of the tablets have not disintegrated, repeat the test on a further 6 tablets, replacing the water in the vessel with 0.1M hydrochloric acid. The tablets comply with the test if all 6 tablets have disintegrated in the acid medium. 3. Enteric coated tablets If the tablet has a soluble external coating, immerse the basket in water at room temperature for 5 minutes. Suspend the assembly in the beaker containing 0.1M hydrochloric acid and operate without the discs for 120 minutes, unless otherwise stated in the individual monograph. Remove the assembly from the liquid. No tablet shows signs of cracks that would allow the escape of the contents of disintegration, apart from fragments of coating. Replace the liquid in the beaker with mixed phosphate buffer pH 6.8, add a disc to each tube and operate the apparatus for a further 60 minutes. Remove the assembly from the liquid. The tablets pass the test if all six have disintegrated. 4. Dispersible and Soluble Tablets: Disintegrate within 3 minutes when examined by the disintegration test for tablets and capsules, using water at 24o to 26o , unless otherwise stated in the individual monograph. 5. Effervescent Tablets: Place one tablet in a 250-ml beaker containing water at 20o to 30o ; numerous gas bubbles are evolved. When the evolution of gas around the tablet or its fragments has ceased the tablet shall have disintegrated, being either dissolved or dispersed in the water so that no agglomerates of particles remain. Repeat the operation on a further 5 tablets. The tablets comply with the test if each of the 6 tablets disintegrates in the manner prescribed within 5 minutes, unless otherwise stated in the individual monograph. D. Uniformity of color and gloss on tablet surface is measured by micro reflectance photometer. E. Crown thickness is measured by micrometer or sliding caliper. F. Hardness tester: 2 kg ----------------- Soft 4kg --------------------Good 6kg---------------------Hard
  21. 21. *EVOLUTION* ‘A GLIMPSE ON PHARMACEUTICS’ GROOMING FOR GPAT & NIPER, MOHALI CONTACT:     Monsanto Hardness‐Tester   (Compressible spring held b/w two plungers)  Strong –Cobb   Hardness tester  (uses Hydraulic pressure )          Pfizer – Hardness tester                                                          Erweka Hardness tester    Schleuniger Hardness Tester  (Most widely used ) 
  22. 22. *EVOLUTION* ‘A GLIMPSE ON PHARMACEUTICS’ GROOMING FOR GPAT & NIPER, MOHALI CONTACT:   G. Roche Friability tester: the plastic chamber revolves at 25 rpm. Normally preweighed tablet sample is placed in friabilator which is then operated for 100 revolutions. The tablets that less than 0.5-1% of their weight is generally acceptable. H. Tablet thickness should be controlled within ± 5 % variation of standard value. It is important for tablet packaging. DISINTEGRATION TEST FOR TABLETS AND CAPSULES This test determines whether tablets or capsules disintegrate within a prescribed time when placed in a liquid medium under the prescribed experimental conditions. For the purpose of this test, disintegration does not imply complete solution of the tablet or capsule or even its active constituent. Disintegration is defined as that state in which no residue of the tablet or capsule remains on the screen of the apparatus or, if a residue remains, it consists of fragments of insoluble coating of the tablets or of capsule shells or is a soft mass with no palpable core. If discs have been used with capsules, any residue remaining on the lower surfaces of the discs consists only of fragments of shells. Apparatus
  23. 23. *EVOLUTION* ‘A GLIMPSE ON PHARMACEUTICS’ GROOMING FOR GPAT & NIPER, MOHALI CONTACT:   a. A rigid basket-rack assembly supporting six cylindrical glass tubes, 77.5 ± 2.5 mm long, 21.5 mm in internal diameter and with a wall thickness of about 2 mm. b. The tubes are held vertically by two superimposed transparent plastic plates, 90 mm in diameter and 6 mm thick perforated by six holes having the same diameter as the tubes. The holes are equidistant from the centre of the plate and are equally spaced from one another. Attached to the underside of the lower plate is a piece of woven gauze made from stainless steel wire 635 mm in diameter and having nominal mesh apertures of 2.00 mm. The upper plate is covered with a stainless steel disc perforated by six holes, each about 22 mm in diameter, which fits over the tubes and holds them between the plastic plates. The holes coincide with those of the upper plastic plate and the upper open ends of the glass tubes. c. The plates are held rigidly in position and 77.5 mm apart by vertical metal rods at the periphery and a metal rod is also fixed to the centre of the upper plate to enable the assembly to be attached to a mechanical device capable of raising and lowering it smoothly at a constant frequency of between 28 and 32 cycles per minute through a distance of 50 to 60 mm. The design of the basket-rack assembly may be somewhat different provided specifications for the glass tubes and the screen mesh size are unchanged. d. A cylindrical disc for each tube, each 20.7 ± 0.15 mm thick in diameter and 9.5 ± 0.15 mm thick, made of transparent plastic with a relative density of 1.18 to 1.20, and pierced with five holes, each 2 mm in diameter, one in the centre and the other four spaced equally on a circle of radius 6 mm from the centre of the disc. Four equally-spaced grooves are cut in the lateral surface of the disc in such a way that at the upper surface of the disc they are 9.5 mm wide and 2.55 mm deep and at the lower surface 1.6 mm square. e. The assembly is suspended in the liquid medium in a suitable vessel, preferably a 1000-ml beaker. The volume of liquid is such that the wire mesh at its highest point is at least 25 mm below the surface of the liquid, and at its lower point is at least 25 mm above the bottom of the beaker. f. A thermostatic arrangement for heating the liquid and maintaining the temperature at 37° ± 2°C. Method Unless otherwise stated in the individual monograph, introduce one tablet or capsule into each tube or total six tablets and, if directed in the appropriate general monograph, add a disc to each tube. Suspend the assembly in the beaker containing the specified liquid and operate the apparatus for the specified time. Remove the assembly from the liquid. The tablets or capsules pass the test if all of them have disintegrated. If 1 or 2 tablets or capsules fail to disintegrate, repeat the test on 12 additional tablets or capsules; not less than 16 of the total of 18 tablets or capsules tested disintegrate. If the tablets or capsules adhere to the disc and the preparation being examined fails to comply, repeat the test omitting the disc. The preparation complies with the test if all the tablets or capsules in the repeat test disintegrate.
  24. 24. *EVOLUTION* ‘A GLIMPSE ON PHARMACEUTICS’ GROOMING FOR GPAT & NIPER, MOHALI CONTACT:   DISSOLUTION TEST FOR TABLETS AND CAPSULES Use Apparatus 1 unless otherwise directed. All parts of the apparatus that may come into contact with the preparation being examined or with the dissolution medium are chemically inert and do not adsorb, react or interfere
  25. 25. *EVOLUTION* ‘A GLIMPSE ON PHARMACEUTICS’ GROOMING FOR GPAT & NIPER, MOHALI CONTACT:   with the preparation being examined. All metal parts of the apparatus that may come into contact with the preparation or the dissolution medium must be made from stainless steel, type 316 or equivalent or coated with a suitable material to ensure that such parts do not react or interfere with the preparation being examined or the dissolution medium. No part of the assembly, including the environment in which the assembly is placed, contributes significant motion, agitation or vibration beyond that due to the smoothly rotating element. An apparatus that permits observation of the preparation being examined and the stirrer during the test is preferable. Apparatus 1 Basket type (for tablet or capsule) An assembly consisting of the following: a. A cylindrical vessel, A, made of borosilicate glass or any other suitable transparent material, with a hemispherical bottom and with a nominal capacity of 1000 ml (see Fig.7.3-1). The vessel has a flanged upper rim and is fitted with a lid that has a number of openings, one of which is central. b. A motor with a speed regulator capable of maintaining the speed of rotation of the paddle within 4% of that specified in the individual monograph. The motor is fitted with a stirring element which consists of a drive shaft and blade forming a paddle, B (see Fig. 7.3-2). The blade passes through the diameter of the shaft so that the bottom of the blade is flush with the bottom of the shaft. The shaft is positioned so that its axis is within 2 mm of the axis of the vessels and the lower edge of the blade is 23 to 27 mm from the inside bottom of the vessel. The apparatus operates in such a way that the paddle rotates smoothly and without significant wobble. c. Water -bath set to maintain the dissolution medium at 36.5° to 37.5°. The bath liquid is kept in constant and smooth motion during the test. The vessel is securely clamped in the water-bath in such a way that the displacement vibration from other equipment, including the water circulation device, is minimized. Apparatus 2 Paddle type The assembly is the same as in Apparatus 1 except that in the stirring element the paddle is replaced by a basket, D (see Fig 7.3-3 and 7.3-4). The metallic shaft rotates smoothly and without significant wobble. The basket consists of two components. The top part, with a vent, is attached to the shaft C. it is fitted with three spring clips, or other suitable means, that allow removal of the lower part for introduction of the preparation being examined and that firmly hold the lower part of the basket concentric with the axis of the vessel during rotation. The lower detachable part of the basket is made of welded-steam cloth, with a wire thickness of 0.254 mm diameter and with 0.381mm square openings, formed into a cylinder with narrow rim of sheet metal around the top and the bottom. The basket may be plated with a 2.5m m layer of gold for use with acidic media. The distance between the inside bottom of the vessel and the basket is maintained at 23 to 27mm during the test.
  26. 26. *EVOLUTION* ‘A GLIMPSE ON PHARMACEUTICS’ GROOMING FOR GPAT & NIPER, MOHALI CONTACT:   Dissolution medium: Use the dissolution medium specified in the individual monograph. If the medium is a buffered solution, adjust the solution so that its pH is within 0.05 units of the pH specified in the monograph. The dissolution medium should be deaerated prior to testing. Time: Where a single time specification is given in the monograph, the test may be concluded in a shorter period if the requirement for the minimum amount dissolved is met. If two or more times are specified, specimen are to be withdrawn only at the stated times, within a tolerance of ± 2%. Method: Introduce the stated volume of the dissolution medium, free from dissolved air, into the vessel of the apparatus. Warm the dissolution medium to between 36.5° and 37.5°. Unless otherwise stated use one tablet or capsule. When Apparatus 1 is used, allow the tablet or capsule to sink to the bottom of the vessel prior to the rotation of the paddle. A suitable device such as a wire of glass helix may be used to keep horizontal at the bottom of the vessel tablets or capsules that would otherwise float. Care should be taken to ensure that air bubbles are excluded from the surface of the tablet or capsule. When Apparatus 2 is used, place the tablet or capsule in a dry basket at the beginning of each test. Lower the basket into position before rotation. Operate the apparatus immediately at the speed of rotation specified in the individual monograph. Within the time interval specified, or at each of the times stated, withdraw a specimen from a zone midway between the surface of the dissolution medium and the top of the rotating blade or basket, not less than 10mm from the wall of the vessel. Except in the case of single sampling, add a volume of dissolution medium equal to the volume of the samples withdrawn. Perform the analysis as directed in the individual monograph. Repeat the whole operation five times. Where two or more tablets or capsules are directed to be placed together in the apparatus, carry out six replicate tests. For each of the tablet or capsule tested, calculate the amount of dissolved active ingredient in solution as a percentage of the stated amount where two or more tablets or capsules are placed together, determine for each test the amount of active ingredient in solution per tablet or capsules and calculate as a percentage of the stated amount. If the results do not conform to the requirements at stage S1 given in the accompanying acceptance tablet, continue testing with additional tablets or capsules through stages S2 and S3 unless the result conform at stage S2. Where capsule shells interfere with the analysis, remove the contents of not less than 6 capsules as completely as possible, and dissolve the empty capsule shells in the specified volume of the dissolution medium. Perform the analysis as directed in the individual monograph. Make any necessary correction.