Tablets - PDF | Quizgecko

TABLETS Prof Thiru Govender Discipline of Pharmaceutical Sciences Advantages of Tablets 1. Enables accurate dosage of active → simple to administer by patient. 2. Easy for bulk transport/ for patient to carry. 3. More stable than liquid preparations. 4. Drug release can be modified → to suit specific purposes. 5. Mass production can be simple/ quick → has low production costs. Types of Tablets Tablets to be swallowed whole Effervescent tablets Chewable tablets Sublingual tablets Sustained/ Controlled release Coated tablets (prevent decomposition/ mask taste) Multilayer tablets Properties of Tablets Desirable attributes: 1. Must be strong/resistant to abrasion → to withstand handling during manufacture, packaging, shipping and use. 2. Drug must be bioavailable. 3. Tablet must have uniform weight and drug content. 4. Must have elegant appearance (colour, shape markings). 5. Tablets must retain all functional attributes e.g. stability. Unit Processes Properties of tablets are affected by formulation and method of manufacture. Main unit processes involved in tablet manufacture include: Solid-Solid mixing Solid-Liquid mixing Milling (Size reduction) Drying Compaction Strict temperature/humidity control is required. Work area/procedures are designed to prevent cross contamination. 3 Methods of Tablet Manufacture Wet Granulation Dry Granulation Direct Compression Steps in the Different Methods of Tablet Manufacture Direct Wet Granulation Dry Granulation Compression 1. Milling of drugs & 1. Milling of drugs 1. Milling of drugs & excipients excipients & excipients 2. Mixing of 2. Mixing of milled powders 2. Mixing of milled powders ingredients 3. Compression into large, 3. Tablet 3. Preparation of binder solution hard tablets, to make slugs compression 4. Mixing of binder solution with 4. Screening of slugs powder to form wet mass 5. Coarse screening of wet mass 5. Mixing with lubricant & using 6 to 12 mesh screen disintegrating agent 6. Drying of moist granules 6. Tablet compression 7. Screening of dry granules through 14 to 20 mesh screen 8. Mixing of screened granules with lubricant and disintegrant 9. Tablet compression Wet Granulation Direct compression is much simpler and less expensive, therefore its important to understand advantages of wet granulation. Purpose: ↑ particle size of powder and obtain uniform particles → this improves flow through hopper into the dies. Advantages 1. Addition of binder improves cohesiveness and compressibility → therefore can form agglomerates (granules). Excipients are therefore modified and compressibility is improved. 2. Lower compression pressure needed → leads to improved tooling life and machine wear. 3. High dosage drugs with poor flow/ poor compressibility need wet granulation for suitable flow/ cohesion. 4. The addition of drugs (low dosage)/ colour additives to binder solution during manufacture→ provides good distribution and uniform content. 5. Prevents segregations of components during processing/ transferring/ handling. 6. Proper choice of solvent and binder→ can ↑ dissolution rate of hydrophobic drug. Limitations COST!!! → expensive because of labor, time, equipment, energy and space requirements. Not suitable for thermolabile/ hydrolysable drugs. Direct Compression Does not require equipment and handling expenses required in wetting/ drying procedures. Avoids hydrolysis of H2O-sensitive drugs Most drugs – require compression vehicle to aid compression. Compression vehicle divided into 3 groups based on disintegration/ flow properties a) Disintegration agents with poor flow e.g. microcrystalline cellulose, microfine cellulose and directly compressible starch. b) Free flowing materials which do not disintegrate, e.g. dibasic calcium phosphate c) Free flowing powders which disintegrate e.g. dextrose, sucrose, mannitol. Method: Drug + Compression vehicle = blended → and compressed directly. Direct compression agents must be free flowing, inert, tasteless, colourless and promote rapid disintegration Dry Granulation / Slugging It is a dry method for moisture/ heat sensitive drugs. Blend of powders → forced into die of tablet press → forms a compacted mass = “slugs” OR Powder blend is squeezed into a solid cake between rollers = roller compaction. Slugs/ roller compacts → milled/ screened to produce granular form → this flows more uniformly. Advantage: over direct compression → no segregation of drug/ excipient can occur. Useful for hydrolysable and thermolabile drugs Disadvantage: lengthy process, high cost of equipment. Methods of Manufacture Tablets are made by compressing drugs and excipients on tablet press. Tablet press: Hopper for holding and feeding granulation Feeding mechanism to feed the granulation to the die cavity. Die + upper punch + lower punch to compress tablets and eject for packaging. First Stage: Lower punch is lowered to preset point to form a cavity in the die to provide a volume with correct fill weight of the tablet. Shoe moves over to fill granules. Shoe is pulled out of way → upper punch descends into die to compress powder/granules. Lower punch is raised flush within surface of the dies table → feed shoe ejects tablet as it moves over → fill cycle is repeated. Schematic of a single-punch tablet press The sequence of events involved in the formation of tablets Tablet Excipients Tablet = Active drug + Excipients Excipients = Diluents, Moistening agents, Binding agents, Glidants, Disintegrants, Colour and flavor additives. Diluents (“Bulk Agents”) Used to ↑ bulk of tablet → improves compression. Are inert and can also improve binding/flow properties. Not required if drug dose is high. Tablet weight should not be less than 70mg. Widely used diluent = lactose → has pleasant taste, dissolves in H2O rapidly, absorbs little moisture, neutral in rxn. Deforms easily under pressure. Disadvantage : Expensive + Poor flow properties Dicalcium phosphate is also used commonly → it is insoluble, makes good hard, white granules. Absorbs less moisture than lactose and therefore used for hygroscopic drugs. Other diluents Dextrose → hygroscopic Mannitol → freely soluble, used for chewable tablets Microcrystalline Cellulose → Excellent compression → has some disintegrating properties. Sucrose → Sweet taste, hygroscopic. Moistening Agents Required for wet granulation e.g. water. When H2O cannot be used, alcohol is used. Absolute alcohol is expensive → therefore industrial methylated spirits used. All traces of alcohol has to be removed during drying. Glidants Improves flow properties of the granulations. Act by ↓ interparticulate friction. Common glidant = silica → added at 0.1% w/w to powder/ granules Lubricants Required to prevent adherence of granules to punch faces and dies. Ensures smooth ejection of tablet from the die. Enhances flow properties of granules. Talc and Mg stearate are commonly used. Incorporated by blending with dry granules prior to compression up to 1% w/w. ↑ [lubricant] → Increases disintegration time → which ↓ dissolution because it is hydrophobic. Also causes ↓ bonding forces between granules. Mixed for 2-5min only→ because overmixing ↑ disintegration time and causes loss of bonding in tablet matrix. Examples of Glidants / Lubricants Name L or G [ ] in tablet (% w/w) Stearates e.g L 0.25 – 1 Magnesium Talc L and G 1-2 PEG L 2-5 Starch G 2 - 10 Silica G 0.1 - 0.5 Disintegrants Purpose: is to break up tablet and after administration → to ↑ surface area of tablet fragments and ↑ rapid release of drug. Acts by swelling in the presence of water to burst open the tablet. Common disintegrant: Starch → acts by swelling. Another mechanism: Those that do not swell, act by capillary action i.e. liquid drawn through capillary pathways within the tablet → therefore this causes interparticulate bonds to rupture. Incorporated in many ways: Added to other ingredients → and mix is granulated. 2/3 can be added before wet granulation → and remainder added in dry form to dried granules. Can be added in dry form all at once to dried granules. Not popular because e.g. starch between granules may decrease bonding – which will produce soft tablets. Examples of Disintegrants Substance [ ] in tablet (% w/w) Alginic acid 2 - 10 MCC Up to 10 Na starch glycollate 1 - 10 Starch 2 - 10 Crosslinked PVP Binding Agents (Adhesive) Act as adhesives to bind powders together → therefore provides bonding to form granules. Also helps to bind granules together during compression. Too little binding agent → leads to soft granules Too much binding agent → leads to hard, large granules Can be added to formulation via 2 ways (depends on granulation method): As a powder in the formulation (dry granulation/slugging) As a solution to mixed powders (wet granulation) Criteria for selection Must be compatible with other tablet components. Must impart sufficient cohesion for normal processing, but must allow tablet to disintegrate and drug to dissolve to be bioavailable to patient. Common binding agents: Starch → common, good (2% used in formulation). Incorporated in mucilage in H2O. Gelatin → Forms gel in cold water, therefore warm solution used, is a strong adhesive Polyvinyl pyrollidone (PVP) → soluble in H2O and alcohol → releases drug faster. Examples of Adhesives & Concentration in Granulating Fluid [ ] in Granulating Substance Fluid (% w/w) Gelatin 5 - 20 Glucose 50 PVP 2 - 10 Starch mucilage 5 - 10 Sucrose Up to 70 Colour Additives Has aesthetic value. Distinguishes one product from another during manufacture. Identifies medication to patient. Pastel shades - more common - less likely to show mottling than darker colours. Colours must be certified by Food and Drug Administration on (FDA). Colourant is added to binder liquid during wet granulation→ allows uniform dispersion and colour distribution to produce homogenous granulation and tablets. Flavours Used to mask bitter, sour, salty and other unpleasant taste of drugs in liquid or solid dosage forms e.g. chewable tablets. Salt → may be used to overcome excessive sweetness. Chocolate - good masking agent for bitter tastes such as quinine. Raspberry - good for salty tastes such as ammonium chloride. Other fruit flavours, cherry, orange, mint. Evaluation of Tablets All evaluated for chemical, physical and biological properties. Describes total quality of tablet formulation according to method of manufacture in its package/ container under specific storage conditions. Tablet Thickness Hardness Disintegration Dissolution Colour Unique Identification Markings Weight Friability Content Uniformity/ Assay Tablet Thickness Should be controlled within 5% or less of standard value. Any variation should not be apparent to the unaided eye to maintain product acceptance by patient. If thickness/ volume differs → it leads to packaging problems. Tablet thickness generally controlled by tablet weight. Measured by micrometer. Hardness Tablet requires certain amount of strength, or hardness to withstand mechanical shocks of handling in manufacture, packaging and shipping. Must also be able to withstand reasonable abuse when in the hands of the consumer. Tablet hardness is NB for tablet disintegration and also dissolution. Important to monitor hardness for drug products that have real/potential bioavailability problems or sensitive to dissolution release profiles as a function of compression force. Tablet hardness defined as force required to break a tablet in a diametrical compression test: tablet placed between 2 anvils, po applied to the anvils and crushing strength that causes tablet to break is recorded e.g. Monsanto, Erweka. Factors that might alter tablet hardness = machine speed, changes in particle size, distribution of granules. Appropriate balance between minimum accepted tablet hardness to have adequate friability and maximum acceptance hardness to have adequate dissolution is required. A hardness of approx. 5kg → is minimal for uncoated tablets, Chewable tablets may be softer. Weight Tablet dimensions / density of mix determines weight. Weight of tablet will determine amount of weight variation allowed by USP e.g. < 80mg 10 % difference 80 - 250 7.5 % > 250mg 5% Weight of tablet directly relates to potency. Content Uniformity / Assay Composite sample of tablets taken, ground up, mixed and analysed to produce an average potency value (Assay). Must be e.g. 95-105% of stated value. Weight is not used as a potency except for tablets where drug is 90 - 95 % of formulation. To ensure uniform potency → Content Uniformity Test is applied. 30 tablets selected randomly → 10 tablets are assayed individually. Preparation complies with test if each individual content is 85 - 115% of the average content. Impurities/Degradation products are also quantified. Friability Is another measure of strength. Related to tablets ability to withstand shock, abrasion without crumbling during manufacturing, shipment, packaging and patient use. Tablets which powder, chip and fragment when handled leads to lack of elegance, poor consumer acceptance, and causes tablet weight variation and content uniformity problem. Laboratory friability testing machine: Roche Friabilator Subjects a number of tablets (20) to abrasion and shock by using a plastic chamber revolving at 25 rpm, dropping tabs a distance of 6 inch. within each revolution. Pre-weighed tablet sample are placed in a friabilator → this is operated for 100 revolutions → tablets rare then dusted and reweighed. Acceptance: Loss in weight = 0.5 – 1 % If capping is observed - tablets are unacceptable irrespective of weight loss. Factors affecting friability = moisture content of granules, conditions of particles. Disintegration For drug to be available → it has to be in solution. First step → breakdown of tablets into smaller particles/ granules= DISINTEGRATION Test: Uses 6 glass tubes, 3 inch. long, open at top, held against a 10-mesh screen at bottom end of the basket rack assembly. One tablet placed in each tube, rack is placed in 1-litre beaker of water (gi fluid etc) at 37 ± 2°C→ tablets remain 2.5cm below surface of liquid on their upward movement. Std motor driven device used to move the basket assembly with the tablets up and down through a distance of 5-6 cm at a frequency of 28-32 cycles per minute. Disks may be placed on top of tablets to prevent floating. To comply with USP, tablets must disintegrate and all particles pass through 10 mesh screen in specified time. Factors affecting disintegration: compression po, amount of binder, lubricant and disintegrant and also test parameters. Dissolution Orally administered drugs must be in solution before absorption takes place. Rate of drug absorption determined by drug dissolution from the tablet. Design of the tablet and dissolution profile may determine total amount of drug absorbed / rate of absorption. NB to determine whether tablet releases drug contents when placed in GIT. In vitro dissolution testing of tablet done to achieve above. Objectives: Release of drug is close as 100% as possible. Rate of release is uniform batch to batch. Rate of release does not change with time. * See previous (physical pharmacy) notes for Dissolution Testing instruments and factors influencing release rate Colour Colour used for rapid ID and consumer acceptance. NB for colour to be uniform from tablet to tablet, lot to lot. Evaluation is normally subjective (Spectrophotometric techniques may be used). Unique Identification Markings Unique markings also used for rapid ID. May be embossing, engraving and printing. Increased No. of items compressed on tablet → can cause ↑ problems of sticking/ picking. Problems in Tablet Manufacture Binding Sticking Capping and Lamination Chipping and Cracking Binding Due to insufficient lubricant. Refers to resistance of tablet to ejection because of adherence to die wall. With sufficient lubrication: tablets are smooth, have glossy edges/ sides. With insufficient lubrication: tablets have rough sides/ edges and scratches caused by abrasion on ejection. Other causes of binding Rapid and excessive expansion of tablets. Granulation too cold or too warm. Worn dies and high moisture content. Remedies: 1. ↑ lubrication 2. Use more efficient lubrication 3. Improve method of lubricant addition 4. Modify moisture / size of granulation 5. Taper dies Sticking Also known as filming / picking. Due to incompletely dried / improperly lubricated granulations. Some of the granulation sticks to punch faces. Tablets may chip or break if picking occurs on the lower punch or may pull apart from the upper punch. May also be due to loss of polish of the punch faces → leads to dull, roughened punch faces. Remedies: 1. ↓ moisture content of granulation 2. Change or ↓ the lubricant 3. ↑ proportion of binder in the granulation 4. Clean punch faces with 5% light mineral oil in isopropanol Capping and Lamination Capping → top/ upper segment of tablet is cracked around the edge or separated as a cap. Due to air entrapped in the die which is compressed as the punches move together to apply po, then expands when po is released. Common with granulations having large % of fines. Excess moisture of granules/ too little or too much of lubrication will also cause capping. Laminating → caused by some factors as above but ↑ses at high speed. Tablet split/ crack on sides by air expansion when po is released. May also be due to poorly cohesive granules Remedies: 1. Remove some/ all of fines 2. ↑ or change lubricant 3. Dry or moisten granulation 4. ↑ binder concentration Chipping and Cracking Chipping → pieces broken / chipped out of the tablet. May occur on faces but usually on edges. May be due to sticking / damaged punches. Cracking → tablets that are cracked anywhere, but often in the centre of the top. Remedies: 1. Replace or reface nicked / chipped punches 2. Improve granulation by ↑ binder/wetting of granulation 3. Polish punch tips 4. Remove some/ all fines 5. ↓ granule size Lozenges Are compressed tablets → at least 18mm in diameter. Has no disintegrant → is sucked to dissolve in mouth. Flavours added for palatability 2 types of lozenges: 1. Produces a local effect in mouth or throat e.g. contain antiseptic / antibiotic. Must be palatable / slowly soluble. Contains some sucrose, lactose and gelatin solution for smooth taste. Compressed between flat-faced punches→ allows greater po to be applied. 2. Produces a systemic effect e.g. lozenge containing vitamin supplements. Are sucked → provides palatable way of administering vitamins. Sublingual & Buccal Tablets Tablet placed under the tongue (sublingual) or in side of the cheek (buccal) → produces immediate systemic effect → drug directly absorbed through mucosa. Examples are isoprenaline sulphate (bronchodialator) and glyceryl trinitrate tablets (vasodialator). Tablets → small and flat → no disintegrant → compressed lightly to produce fairly soft tablet. Sucrose used for sweetness. SUBLINGUAL BUCCAL Implants Are small pellets of drug only without excipients 2-3mm in diameter – prepared in aseptic manner to be sterile. Inserted into body tissues by surgical procedures → then slowly absorbed over period of months. Used for hormones e.g. testosterone, stilboestrol Produced manually → die filled by hand since drug does not normally flow. Particle size normally large for slow rate of absorption PELLET Effervescent Tablet Tablet broken up by internal liberation of CO2. Increases palatability. When alkali metal carbonates or bicarbonates combined with tartaric / citric acid → CO2 is liberated when tablet placed in H2O. H2O soluble lubricant added to prevent insoluble “scum” on water surface. Sweetness achieved with saccharin. Chewable Tablets Attractive alternative for pxts with difficulty in swallowing/ children who have not yet learnt to wash tablets down with water. Can be taken at any time place when water is not available. Mannitol use as chewable base diluent → has pleasant, cooling sensation in mouth → alsomasks taste of unpleasant excipients/ drugs. Prepared by wet granulation. Granules must not be too hard → must have high amounts of flavouring agent (for palatability). Disintegrant not required (because tablet is broken by teeth). Multilayer Tablets Consists of several different granulations → compressed, on top of each other → forms single tablet composed of > 2 layers. Each layer fed from separate feed frame with individual weight control. Mainly used for incompatible substances – virtually no reaction takes place. Dust extraction important during compression to avoid cross contamination. Sustained Release Tablets Designed to release drug slowly after ingestion. Advantages: ↓ frequency of administration, therefore improved patient compliance (ie: 1-2 tabs to be taken daily) Activity can be extended throughout the night - no need to be awakened In hospital → has time saving benefit for nurses Has reduced peak-through fluctuations → therefore ↓ side effects. Disadvantages: Cost → tablets – more per unit dose than conventional dosage form. Accidental poisoning → special treatment problems. Large dose used → therefore ↑ physical size → therefore swallowing problems. Failure of drug release mechanism → causes dose dumping. Example Consider the following formulation for 1 tablet in mg: Drug X 500 Lactose 160 Polyvinyl pyrollidone in ethanol 28 Magnesium stearate 0.5 What method of manufacture is used? What is wrong with the formulation.? What are functions of above excipients.? What is weight of 1 tablet.? What is weight of 100 000 tablets.?

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