2Tablets are solid dosage forms consisting of active ingredient(s) and suitable pharmaceutical excipients. They may vary in size, shape, weight, hardness, thickness, disintegration and dissolution characteristics, and in other aspects. They may be classyfied, according to the method of manufacture, as compressed tablets or molded tablets.
3Advantages Production aspect Large scale production at lowest cost Easiest and cheapest to package and shipHigh stabilityUser aspect (doctor, pharmacist, patient)Easy to handlingLightest and most compactGreatest dose precision & least content variability
4Disadvantages Some drugs resist compression into dense compacts Drugs with poor wetting, slow dissolution, intermediate to large dosages may be difficult or impossible to formulate and manufacture as a tablet that provide adequate or full drug bioavailabilityBitter taste drugs, drugs with an objectionable odor, or sensitive to oxygen or moisture may require encapsulation or entrapment prior to compression or the tablets may require coating
7EXCIPIENTS FOR COMPRESSED TABLETS Compressed tablets usually contain a number of pharmaceutical adjuncts, known as excipients, in addition to the medicinal substance. The use of appropriate excipients is important in the development of the optimum tablets. Excipients determine the bulk of the final product in dosage forms such as tablet, capsule, etc., the speed of disintegration, rate of dissolution,release of drug, protection against moisture, stability during storage, and compatibility . Excipients should have no bioactivity, no reaction with the drug substance, no effect on the functions of other excipients, and no support of microbiological growth in the product .
8A. DILUENTSDiluents increase the volume to a formulation to prepare tablets of the desired size. Widely used fillers are lactose, dextrin, microcrystalline cellu-lose starch, pregelatinized starch, powdered sucrose, and calcium phosphate.
9The diluent is selected based on various factors, such as the experience of the manufacturer in the preparation of other tablets, its cost, and compatibility with other formulation ingredients. For example, in the preparation of tablets or capsules of tetracycline antibiotics, a calcium salt should not be used as a diluent since calcium interferes with absorption of the antibiotics from the GI tract.
10B.BINDERSBinders promote the adhesion of particles of the formulation. Such adhesion enables preparation of granules and maintains the integrity of the final tablet. As listed in the Table, Commonly used binding agents include: starch, gelatin and sugars (sucrose, glucose, dextrose, and lactose).
12C. LUBRICANTSLubricant is a substance capable of reducing or preventing friction, heat, and wear when introduced as a film between solid surfaces. It works by coating on the surface of particles, and thus preventing adhesion of the tablet material to the dies and punches. Glycerylmonostearate(USP/NFCH2(OH)CH(OH)CH2O2CC17H35) is one example of a lubricant. Lubricants play more than one role in the preparation of tablets as described below.
131. Lubricants improve the flow of granules in the hopper to the die cavity. 2. Lubricants prevent sticking of tablet formulation to the punches and dies during formulation.3. Lubricants reduce the friction between the tablet and the die wall during the tablet’s ejection from the tablet machine.4. Lubricants give a sheen to the finished tablets.
14Commonly used lubricants include: talc, magnesium stearat, calcium stearate ,stearic acid, hydrogenated vegetable oils and (PEG).
15D. DISINTEGRATORSThe breakup of the tablets to smaller particles is important for dissolution of the drug and subsequent bioavailability. Disintegrators promote such breakup. To rupture or breakup of tablets, disintegrating agents must swell or expand on exposure to aqueous solution. Thus, the most effective disintegrating agents in most tablet systems are those with the highest wa-ter uptake property. In general, the more hydrophilic, the better disinte-grating agents are therefore highly hydrophilic. A list of typical disinte-grants is tabulated in Table
17E. WETTING AGENTSWater molecules attract each other equally in all directions. Water molecules on the surface, however, can only be pulled into the bulk water by water molecules underneath, since there are no water molecules to pull in the opposite direction. The surface tension of water is strong enough to support the weight of tiny insects such as water striders. The surface ten-sion in action can be visualized by placing a small drop of alcohol on a thin layer of water. Alcohol with lower surface tension mixes with water causing reduction in the surface tension in the local region. Owing to the higher surface tension of water in the neighbor, water is pulled from the alcohol dropped region into the neighbor, and this leads to the formation of a dry spot in the middle of the water layer.
18Compressed tablet manufacture The classification of manufacturing methodswet granulation: suitable for drugs that are stable to moisture and heatdry granulation: suitable for drugs that are sensitive to moisture and heatpowder compression : suitable for drugs that are sensitive to moisture and heat, fill material possessing, good flowability and compressibilitygranulationdirectcompressioncrystal compression：suitable for drugs with proper crystal form and good flowability
19wet granulation adhesive drug smash sieving mix prilling excipients lubricantpressdryprocessinggranulemix
23wet granulation technology (一)wet granulation methods and equipment:1.Extrusion grain methods and equipment: first prescription drug powder and the auxiliary materials mixed evenly to join adhesive soft material system, then with soft material compulsory extrusion way through has a certain size screen hole and granulating method.
25Compressed tablet manufacture —— wet granulation The steps of wet granulationweighing and blending the ingredients(disintegrant)preparing a damp massscreening the damp mass into pellets or granulesdrying the granulationsizing the granulation by dry screeningadding lubricant and disintegrant, and blendingtableting by compression(liquid binder)Internal(内加法)External(外加法)
26The classification of tablet presses a. single-punch pressesb. multi-station rotary presses
27The main components of single-punch tablet presses Core components:dielower punch upper punch
28The basic mechanical process of tableting with single-punch presses a) filling materialb) scraping away the excessive granulationc) forming a tablet by compressiond) pushing up the tablet to stage surfacee) shoving the tablet aside
29A picture of multi-station rotary press hopperfeed-framehead: upper turret, lower turret, die tableupper turretdie tablelower turret
31The core components and compression cycle of rotary presses A: upper punchB: die cavityC: dieD: lower punchThe compression is applied by both the upper punch and the lower punch.The compression cycle of a rotary tablet press
33Compressed tablet manufacture —— Direct compression tableting Suitable for1) granular chemicals possessing free flowing and cohesive propertiese.g. potassium chloride2) chemicals added with special pharmaceutical excipients which impart the necessary qualities for the production of tablets by direct compression
34The direct compression tableting excipients include: a) fillers, as spray-dried lactose, microcrystals of alphamonohydrate lactose, sucroseinvert ,sugar – corn starch mixtures, microcrystalline cellulose, crystalline malt and dicalcium phosphate;d) disintegrants, as direct-compression starch, sodium carboxymethyl starch, cross-linked carboxymethylcellulose fiber, and cross-linked polyvinylpyrrolidone;c) lubricants, as magnesium stearate and talc;d) glidants, fumed silicon dioxide
37table 1 the influence of different adhesive to Tablet hardness formula1234adhesive10%Starch10%PVP（water）10%CMC-Na10%PVP (Ethanol)Hardness（Kg）0.680.830.75particles deformed
38table 2 the influence of different fillers to Tablet hardness formula5678fillersstarchPregelatinized starchlactose10%PVP ( Ethanol)Hardness（Kg）0.680.773.143.55
39level 80 120 160 10 15 20 table 3 factor level Factor A [The amount of Microcrstalline cellulose(g)]80120160A [Concentration of PVP solution（%，g/ml)]101520
40table 4 Result of Orthogonal test A×B ResultTotalTest NO. A BⅠ Ⅱ123456789K1K2K312317.824.224.412323.021.821.612321.422.512322.222.00.6R×
41table5 Analysis of variance table variance sourceSSVMSFPtotal variance5.658A4.69822.34933.5620.0001B0.1910.0961.3660.3034A×B0.13940.0350.9930.4077error0.63090.070
42table６ 微晶纤维素用量影响苦豆子片硬度的ｑ检验（ｎ＝６） Comparison group两均数之差standardvalue of q errorNumber of groupα =0.05α= 0.01PA1andA3-1.10.107434.346.33<0.01A1andA2-1.0-9.31023.465.24A2andA3-0.1>0.05ｑ界值
43Tablet coating The reasons for tablet coating 1) to protect the medicinal agent against destructive exposure to air and/or humidity;2) to mask the taste of the drug;3) to provide special characteristics of drug release;4) to provide aesthetics or distinction to the product;5) to prevent inadvertent contact by nonpatients with the drug substance
44The general methods involved in coating tablets are as follows 1) sugarcoating tablets2) film-coating tablets3) enteric coating4) pan coating5) fluid-bed or air suspension coating6) compression coating
45The sugarcoating of tablets may be divided into the following steps: 1) waterproofing and sealing (if needed)2) subcoating3) smoothing and final rounding4) finishing and coloring (if desired)5) polishing
501) waterproofing and sealing (if needed) aim: to prevent the components from being adversely affected by moisture; one or more coats; shellac , zein , or a polymer as cellulose acetate phthalate2) Subcoating aim: to bond the sugar coating to the tablet and provide roundinga) 3 to 5 subcoats of a sugar-based syrup are applied. The sucrose and water syrup also contains gelatin, acacia, or PVP.
51b) When the tablets are partially dry they are sprinkled with a dusting powder, usually a mixture of powdered sugar and starch but sometimes talc, acacia, or precipitated chalk as well.c) Then drying the tablets. Repetition (15 to 18 times) the subcoating process until the tablets are of the desired shape and size.
523) smoothing and final rounding aim: to complete the rounding and smooth the coatings5 to 10 additional coatings of a thick syrup; This syrup is sucrose-based with or without additional components as starch and calcium carbonate.4) finishing and coloringaim: to attain final smoothness and the appropriate colorseveral coats of a thin syrup containing the desired colorant
535) imprintingaim: to impart identification codes and other distinctive symbols to the productThe imprint may be debossed, embossed, engraved, or printed on the surface with ink.6) polishingaim: to render the tablets the desired sheen/gloss/lustera) pans lined with canvas cloth impregnated with carnauba waxand/or beeswaxb) Pieces of wax may be placed in a polishing panc) light-spraying of the tablets with wax dissolved in a nonaqueous solvent
54Tablet coating —— film-coating tablets 1) The disadvantages of sugarcoating processa) time-consumingb) requiring the expertise of highly skilled techniciansc) doubling the size and weight of the original uncoated tabletsd) may vary in size from batch to batch and within a batche) large tablets are not as easily swallowed as are small tablets.
552) The advantages of film-coating process a) coated tablets having essentially the same weight, shape, and size as the originally compressed tabletb) The coating is thin enough to reveal any identifying monograms.c) far more resistant to destruction by abrasion than are sugar-coated tabletsd) the coating may be colored to make the tablets attractive and distinctive.
563) The components of nonaqueous film-coating solutions: a) film former: e.g. CAPb) alloying substance: to provide water solubility or permeability to the film e.g. PEGc) plasticizer: to render flexibility and elasticity to the coating e.g. castor oild) surfactant: to enhance spreadability of the film e.g. polyoxyethylene sorbitan derivativese) opaquants and colorants: e.g. titanium dioxide, FD&C or D&C dyesf) sweeteners, flavors, and aromas: saccharin, vanilling) glossant: beeswaxh) volatile solvent: alcohol-acetone mixture
574) The components of a typical aqueous film-coating solutions: a) film-forming polymer (7-18%): e.g. cellulose ether polymers as HPMC, HPC and MCb) plasticizer ( %): e.g. glycerin, propylene glycol, PEG, diethyl phthalate, and dibutyl subacetatec) colorant and opacifier (2.5-8%): FD&C or D&C lakes and iron oxide pigmentsd) water
585) Some problems with aqueous film-coating a) picking and peeling the appearance of small amounts or large amounts of film fragments flaking from the tablet surfaceb) orange peel effect roughness of the tablet surface due to failure of spray droplets to coalescec) mottling an uneven distribution of color on the tablet surfaced) bridgingfilling-in of the score-line or indented logo on the tablet by the filme) tablet erosiondisfiguration of the core tablet
595) Some problems with aqueous film-coating a) picking and peeling the appearance of small amounts or large amounts of film fragments flaking from the tablet surfaceb) orange peel effect roughness of the tablet surface due to failure of spray droplets to coalescec) mottling an uneven distribution of color on the tablet surfaced) bridgingfilling-in of the score-line or indented logo on the tablet by the filme) tablet erosiondisfiguration of the core tablet
60The reasons for capping, splitting or laminating of tablets 1) air entrapment2) not immaculately cleaned or not perfectly smoothed punches3) too great a proportion of fine powder4) Tablets have aged or have been stored improperly
61quality standards and compendial requirements The apparent physical features of compressed tablets:1) shape: round, oblong, unique ) thickness: thick or thin3) diameter: large or small ) flat or convex5) unscored or scored in halves, thirds and quadrants6) engraved or imprinted with an identifying symbol and/or code number7) coated or uncoated 8)colored or uncolored 9) number of layer.The die and punches determine the physical features of compressed tablets.
62quality standards and compendial requirements Other physical specifications and quality standards:tablet weight weight variationcontent uniformity tablet thicknesstablet hardness tablet disintegrationdrug dissolutionin-process controlsverification after the production
63Weight variation limit quality standards and compendial requirements —— tablet weight and Chp weight variationChp weight variation: sample amount 20 tabletsTablets should comply with the following requirements stated in the table below.Average weightWeight variation limitLess than 0.3 g± 7.5%0.3 g or more± 5%
65quality standards and compendial requirements —— tablet weight and Chp weight variation The procedure of weight variation determination in Chp:Weigh accurately 20 tablets and calculate the average weight, then weigh individually each of the 20 tablets. Compare the weight of each tablet with the labelled tablet (if no labelled weight is stated, compare the weight of each tablet with the average weight calculated). No more than 2 of the individual weights exceed the weight variation limit stated in the table above and none doubles the limit.
66quality standards and compendial requirements —— tablet hardness and friability 1)The greater the pressure applied, the harder the tablets.2) The hardness required by different tabletsa) lozenges and buccal tablets: hard (dissolve slowly)b) the tablets for immediate drug release: soft3) measurementa) special dedicated hardness testersb) multifunctional equipment
67quality standards and compendial requirements —— content uniformity applys to potent drug of low dose.USP method, 10 tablets are individually assayed for their content.The amount of active ingredient in each tablet lies within the range of 85% to 115% of the label claim and the RSD is less than 6.0%.
68quality standards and compendial requirements —— tablet hardness and friability (continued) 1) It is used to determine a tablet’s durability2) Method: allowing the tablets to roll and fall within the rotating apparatus (friabilator); determine the loss in weight;3) requirement: weight loss ≤1%
74quality standards and compendial requirements —— tablet dissolution 1) The importance of in vitro dissolution testa) to guide the formulation and product development process toward product optimizationb) to monitor the performance of manufacturing processc) to assure bioequivalence from batch to batchd) as a requirement for regulatory approval for product marketing for products registered with the FDA and regulatory agencies of other countries.
752) The goal of in vitro dissolution is to provide a reasonable prediction of the product’s in vivo bioavailability.Basis: The combinations of a drug’s solubility and its intestinal permeability are supposed as a basis for predicting the likelihood of achieving a successful in vivo – in vitro correlation (IVIVC).
76Considered are drugs determined to have: a) high solubility and high permeability (IVIVC may be expected.)b) low solubility and high permeability (IVIVC may be expected.)c) high solubility and low permeabilityd) low solubility and low permeability
773) The formulation and manufacturing factors affecting the dissolution of a tablet a) the particle size of the drug substanceb) the solubility and hygroscopicity of the formulationc) the type and concentration of the disintegrant, binder, and lubricant usedd) the manufacturing method, particularly, the compactness of the granulation and the compression forcee) the in-process variables
784) Test methoda) A volume of the dissolution medium is placed in the vessel and allowed to come to 37℃±0.5℃.b) The stirrer is rotate at the specified speed.c) At stated intervals, samples of the medium are withdrawn for chemical analysis5) Requirement for rate of dissolutionThe specific required rates of dissolution are different for tablets containing different medicinal agents.e.g. not less than 85% of the labeled amount is dissolved in 30 minutes
796) Inconsistencies in dissolution occur not between dosage units from the same production batch, but rather between batches or between products from different manufacturers.Pooled dissolution testing has emerged. This process recognizes the concept of batch characteristics and allows pooled specimens to be tested.