Tablet Manufacturing PDF

Tablet Manufacturing Greg Purcell [email protected] 1 Learning outcomes Discuss the advantages and disadvantages of compacted tablets as a pharmaceutical dosage form Identify key quality attributes of a...

Tablet Manufacturing Greg Purcell [email protected] 1 Learning outcomes Discuss the advantages and disadvantages of compacted tablets as a pharmaceutical dosage form Identify key quality attributes of a tablet Explain the uses of various excipients used in the formulation of tablets Classify tablets according to their type Explain the compression and compaction mechanisms used to produce tablets 2 1  Tablets Patent for a hand-operated compression machine granted in 1843 Consisted of a hole (or die) bored through a piece of metal Powder was compressed between two cylindrical punches First used to produce compacts of potassium bicarbonate 3 Tablets Solid preparations each containing a single dose of one or more active substances Obtained by compressing uniform volumes of particles Or by another suitable manufacturing technique  extrusion, moulding or freeze-drying (lyophilisation) 4 2  Advantages Production aspect Large-scale production at low cost Easy and cheap to package and ship High stability (mechanical, chemical and microbiological) compared to liquids User aspect (doctor, pharmacist, patient) Easy to handle/convenient to use/self-administered Light and compact Great dose precision & minimal content variability Can contain more than one therapeutic agent Can mask taste of bitter tasting medicine 5 Disadvantages Inability to use when unconscious and during vomiting Possibility of tablets cementing during long-term storage Series of unit operations needed during the manufacturing process Slower action of API from tablets Tablets include many auxiliary substances  may be harmful Poor bioavailability of poorly water-soluble or poorly absorbed drugs Local irritation can be caused by API  harm to GIT mucosa 6 3  Desired Attributes Should include the correct dose of the API Appearance should be elegant Weight, size and appearance should be consistent Release of the API should be controlled and reproducible Should be biocompatible (not harm patients) Have sufficient mechanical strength to withstand fracture and erosion during handling Must be chemically, physically and microbiologically stable throughout the shelf- life Must be acceptable to the patient Packed in a safe manner 7 Types of Tablets Tablets for oral administration Tablets for vaginal administration Tablets for implantation (pellets) 8 4  Tablets for Oral Administration Immediate release tablets Chewable tablets Effervescent tablets Coated tablets Sugar coated tablets Film coated tablets Enteric coated tablets Buccal and sublingual tablets Troches (lozenges) Controlled release tablets Slow release tablets (SR) Modified release tablets (MR) 9 Immediate Release Tablets Disintegrating tablets Can be single layer or multilayer Most common form of tablets Disintegration  drug dissolution  absorption Disintegration affected by: Disintegrant used in formulation Other excipients  diluent/filler/lubricant Production conditions 10 5  Immediate Release Tablets Dissolution affected by: Solubility of API Addition of substances forming salts with API during dissolution Surface area of API Absorption affected by: Lipophilicity of drug  esterification Substances that alter GIT cell membrane permeability Absorption enhancers 11 Chewable Tablets Mechanically disintegrate in mouth Quick and complete disintegration Dissolution occurs in GIT Ideal in paediatrics and geriatrics Do not contain disintegrants Do contain flavours and colourants 12 6  Compressed Lozenges Drug is dissolved in saliva Diluent/excipients contribute to pleasant taste Flavours and colourants used Sorbitol and glucose Should be water soluble 13 Effervescent Tablets Rely on the reaction of carbonate/bicarbonate and weak acid in water Carbon dioxide is liberated  facilitates disintegration and dissolution High bicarbonate content increases pH of the stomach Leads to quicker emptying Faster absorption Contain flavours and colourants Must be protected from moisture in storage 14 7  Buccal and Sublingual Tablets Small, flat, oval tablets  tend to be porous to improve dissolution Buccal  in the side of the cheek Sublingual  under the tongue Dissolution and absorption take place in the mouth Skip hepatic first-pass metabolism  increased bioavailability Some newer approaches use tablets that melt at body temperatures Matrix of the tablet solidified while the drug is in solution  after melting, the drug is automatically in solution and available for absorption Must be retained at the site of application and should not stimulate saliva production 15 Coated Tablets Compressed tablets with a coating Coating: Sugar coating Film coating Enteric coating 16 8  Sugar Coated Tablets Compressed tablets covered by sugar coating Coating is useful for: Masking tastes Masking odours Providing colour to overall tablet Protecting API/excipients from oxidation 17 Film Coated Tablets Compressed tablets covered with a thin layer or film Film consists of a water-soluble material A number of polymeric substances with film-forming properties may be used  cellulose ethers, vinyl polymers, glycols Film coating  same general uses as sugar coating But requires much less time than sugar coating 18 9  Enteric Coated Tablets Compressed tablets coated with substances that resist disintegration in gastric fluid  disintegrate in the intestine Used for: Tablets containing API which are inactivated or destroyed in the stomach Tablets containing API which irritate the mucosa Delayed release of API Various compounds can be used  fatty acids, waxes, shellac, alginates, etc 19 Controlled Release Tablets Designed to release an initial therapeutically effective amount of a drug followed by maintaining this effective level over an extended period of time Advantages: Maintenance of therapeutic effect for a longer time Reduced frequency of administration Enhanced patience compliance 20 10  Tablets Tablets contain: Active Pharmaceutical Ingredient Excipients Diluents/fillers Binders Solution Dry Disintegrants Lubricants Glidants Antiadherents Miscellaneous adjuncts 21 Excipients In addition to active ingredients, tablets contain inert materials  excipients Excipients are classified according to their role in the finished tablet Two groups: Those which help to impart satisfactory processing and compression characteristics to the formulation Diluents, binders, glidants and lubricants Those that help to give additional desirable physical characteristics to the finished tablet Disintegrants, colours, flavours, sweetening agents, polymers, waxes or other solubility-retarding materials 22 11  Diluents Tablets should weigh ± 50 mg  suitable for handling If the API is low dose  require substance to increase bulk volume & tablet size Diluents Not necessary if dose of drug is high Ideal properties of diluents: Chemically inert Non-hygroscopic Biocompatible Suitable properties  biopharmaceutically and technically Acceptable taste Cheap 23 Diluents Widely used diluents/fillers: Lactose Kaolin Microcrystalline cellulose and derivatives Pregelatinized starch Powdered sucrose Calcium phosphate Diluents in direct compression formulas  require prior processing to improve flowability and compressibility 24 12  Diluents Lactose Potential intolerance; available in crystalline and amorphous forms Kaolin Cellulose derivatives Biocompatible; inert; also useful as dry binders and disintegrants Microcrystalline cellulose and derivatives Degrees of crystallinity depending on source  can affect properties Calcium phosphate Insoluble in water; non-hygroscopic; hydrophilic; slightly alkaline 25 Binders Promote adhesion of particles of the formulation Maintains the integrity of the final tablet Enables preparation of granules Granules tend to entrap less air than powders when compressed Can be dry powder before wet granulation or can be solution Commonly used binding agents include: Water Ethanol Polymers polyvinylpyrrolidone, hydroxy propyl methyl cellulose Starch, sugars, gelatin  solution binders 26 13  Disintegrants Disintegration  breakup of tablets to smaller particles Disintegrants  promote breakup Two steps of disintegration: Tablet wetted  liquid penetrates into pores Tablet breaks into smaller fragments Primary aggregates Primary drug particles (fast dissolution) Disintegrants can either: Facilitate water uptake Rupture the tablet 27 28 14  Disintegrants Facilitate water uptake: Surface active agents Capillary forces Rupturing: Disintegrant swells  compromises tablet structure Non-swelling  repulsion of particles in contact with water; recovery of deformed particles In general, the more hydrophilic, the better Sodium starch glycolate Croscarmellose sodium Crospovidone Pregelatinised starch 29 Lubricants Reduce friction, heat, and wear when introduced as a film between solid surfaces Coat surface of particles  prevent adhesion of tablet to dies and punches Multiple uses: Equalize pressure distribution in compressed tablets Increase density of particles prior to compression Commonly used lubricants include: Talc Magnesium stearate Calcium stearate Stearic acid Hydrogenated vegetable oils PEG 30 15  Glidants Enhance flow properties of powders within the hopper into tablet die and press Minimise separation of granules caused by vibration Particle size must be small  fill the smaller spaces in granules Must be arranged at surface of particles/granules Are usually hydrophobic Therefore concentration used is critical Commonly used glidants include: Talc  1-2% Colloidal silicon dioxide  0.1-0.5% 31 Antiadherents Useful in formulas which have a tendency to pick easily Prevent adhesion of tablet powder to dies and presses May be particularly necessary with engraved punches Commonly used antiadherents: Magnesium stearate Talc Starch Colloidal silica 32 16  Adsorbents Used when including liquid or semi-solid components in formulation Commonly used adsorbents: Kaolin 1-2% Bentonite 1-2% Magnesium oxide 0.5-1% Magnesium carbonate 0.5-1% 33 Sweetening Agents When API is unpalatable, sweetening agents may be required Especially when formulated in chewable tablets Added at the lubrication step  some may hydrolise or volatilize Commonly used sweetening agents: Mannitol Sucrose Lactose Dextrose Saccharin Potential carcinogenicity of artificial sweeteners (cyclamates and saccharin)  reduced use in modern products 34 17  Flavours/Colours/Fragrances Flavours: Added as needed in conjunction with sweeteners for particular cases Add after heating processes  generally thermolabile Fragrances: Added as needed in conjunction with flavours Colourants: Improve the appearance of tablets Assist in the identification of specific tablets When API is coloured  tablet may be speckled due to API colour Add water-soluble colour and incorporate into formulation  monotone colour 35 Surface Active Agents Useful to improve the wettability of API or other excipients Increases rate of dissolution of drugs Variety of surface active agents available Sodium lauryl sulphate Spans Tweens Function of surfactant in a preparation depends on concentration 36 18 37 38 19 39 Tablet Manufacturing The classification of manufacturing methods Wet granulation: suitable for drugs that are stable to moisture and heat Granulation Dry granulation: suitable for drugs that are sensitive to moisture and heat Powder compression: Suitable for: Direct  Drugs that are sensitive to moisture and heat Compression  Fill material possessing good flowability and compressibility 40 20  Tablet Manufacturing 41 Tablet Manufacturing In the tablet-pressing process: All ingredients must be fairly dry Powdered or granular Somewhat uniform in particle size Freely flowing Flow: powders must be somewhat fluid Good flow granulated sugar Bad flow  powdered sugar Uniformity: Mixed particle sizes can segregate during manufacturing Tablets with poor drug or API content uniformity Content uniformity  same API dose is delivered with each tablet 42 21  Tablet Manufacturing Direct compression  Tablets made by blending the dry powdered ingredients together, and then compressing into tablets Powders blend together with other ingredients and stay mixed Combination of ingredients will flow, compress and eject from the tablet press Show good hardness, friability, and dissolution If powders do not compress, don’t flow well, are too fluffy or separate after blending  require binder Dry granulation  Dry binder used Wet granulation  Binder is put into water or solvent and sprayed 43 Powder Flow and Blending Powder flow in manufacturing depends on multiple variables: Particle size, shape and distribution, particle surface texture, cohesivity, surface coating, particle interaction, static electricity, recovery from compaction and wear/attrition while in the holding container Most powders cannot flow at speeds required for high-speed tabletting Require the aid of granulation and flow agents All powders have the capacity to form bridges/arches, create rat holes and stick to contact surfaces A “good” final blend is often viewed as such because it has good content uniformity and potency, not by its ability to flow However, good flow is imperative to attaining a good tablet 44 22  Uniform Blending Materials go from an unmixed state to a state of relative homogenous consistency Homogenous blends achieved through combination of time and mechanical energy With enough time  components pass from unblended state to a relatively homogenous blend More time  back to an unblended state Blend studies determine the optimum endpoint All blends have a unique pathway to their optimum state of uniformity Note that under blending and over blending have similar symptoms 45 Mixing Most pharmaceutical powders are neutral mixtures Energy is required to form the mixture but it stays mixed Degree of mixing depends on dose Hard to achieve a perfect mix But a perfect mix is important where API dose is small and the risk of underdosing is higher 46 23  Mixing Perfect Random Probability of selecting a particular type of particle is the same at all positions 47 Powder Segregation Also known as ‘de-mixing’ 48 24  Minimising Segregation Narrow particle size range Milling to a defined size Controlled crystallization Excipient selection with similar densities Granulation Reduce powder vibration or movement Reduce residence time in hoppers Use multi-process equipment Create an ordered mix 49 50 25 51 Granulation 52 26  Why Granulate? To improve powder flow  low weight variation To improve compressibility To reduce fines  fine particles escape during compression- capping To control the tendency of powders to segregate To control bulk density  uniform die filling To capture and fuse small quantities of active material To achieve homogenous tablet colour 53 Why Granulate? The final goal is to make a quality tablet that has: Good weight, thickness and hardness control Good ejection No capping, lamination and sticking Good friability, disintegration and dissolution 54 27  Granulation All powders have varying characteristics May require small amount of binder May require large amounts of binder Many powders require some level of intense mixing while adding a liquid binder Comparable to kneading dough when making bread Once the powder and binding solution are kneaded they are then milled for drying Bonds holding particles together can withstand the milling process Uniform size granule formed Result is a compressible powder called a granulation Steps: pre-blending  binder addition  milling  drying  final blending 55 Granulation Granulation  formation of small agglomerates  “granules” Each granule will contain a proper mix of the ingredients of the formula Final density of granules  amount of liquid binding solution and mechanical energy created by the type of machine used Machines used to blend powders and add liquid  “granulators” After wet granulation  excess moisture must be removed Some granulators allow for drying of excess moisture Many granulators do not  wet granulation must be moved to the dryer If powders are sensitive to liquids, heat, or both  dry granulation 56 28  Granule Formation Three mechanisms of granule formation: Nucleation Transition Ball growth Nucleation  formation starts with loose agglomerates or single particles Wetted by binding solution  form small granules by pendular bridging More binding solution and tumbling action consolidates and strengthens granules Transition stage  granules continue to grow by single particle addition and multiple granule formation At the end of the transition stage  large number of small granules With a fairly wide size distribution 57 Dry Granulation Dry granulation can be done in two ways: Large tablet (slug) is produced in a heavy-duty tabletting press Or the powder is squeezed between two rollers to produce a sheet of materials (roller compactor/chilsonator) Tablet press  powders may not possess enough natural flow to feed the product uniformly into the die cavity Resulting in varying degrees of densification Roller compactor (granulator-compactor)  uses a feed system that consistently delivers powder uniformly between two pressure rollers Powders are compacted into a ribbon or small pellets between these rollers and milled through a low-shear mill 58 29  Dry Granulation Slugging Old process that is being phased out Pre-compaction of ‘slugs’ or tablets using a conventional tablet machine Results in ‘work hardening’ giving granules poor compressibility properties 59 Dry Granulation Roller Compaction Economical Can be applied to a wide range of materials Low equipment investment costs Granules have uniform mechanical strength Work hardening is not as much of a problem 60 30  Wet Granulation Mixing of dry primary powder mix with a liquid granulating fluid Known as wet massing Liquid contains binding agent Liquid can be aqueous or non-aqueous 61 62 31 63 Wet Granulation Process Steps Pre-mix Powders to be granulated are added and mixed prior to introduction of binder Wet massing Binder is added to the mixture and the components are massed to a predetermined end-point Drying Wet mass is dried to a predetermined end-point Commonly measured with loss on drying test Milling Finished granulation milled to reduce the size of any caked material into a standardized particle size distribution Distribution is measured using a series of screens from largest screen to a dust-pan Final blend  lubricant is added to granulation  producing the final blend 64 32  Wet Granulators Shear Granulators Not frequently used due to: - Multiple equipment needed - Loss on transfer - Extremely slow and unpredictable process 65 High Speed Mixer/Granulators 66 33  Fluidized-Bed Granulators 67 Testing of Granules Four standardized tests for milled or finished granules: 1. LOD  water content 2. Bulk Density  mg/ml 3. Particle Size Distribution 4. Angle of Repose  flow gradient LOD and Particle Size Distribution are commonly performed on the production floor In some cases, only the LOD is performed and the other three tests are performed in the QC lab 68 34  Milling Milling equipment  used to improve flow, reduce segregation, enhance drying, and limit wide particle size distribution Milling machinery is categorized according to mechanical energy Low, Medium or High energy Mills impart shear force on powders Different mills are used within different operations throughout the complete manufacturing process: At weigh-up for de-lumping Before blending for proper particle size distribution After wet granulating to enhance drying After dry granulating to prepare powders for final blending and tablet compression 69 Final Blend The final blend represents the result of the dispensing, granulating and lubrication effort Blends are tested to: Optimize blend time Demonstrate lack of segregation after blending is completed Confirm that specified blend conditions produce acceptable uniformity during validation An individual powder or finished blend may flow very well under one set of circumstances and not flow well under another 70 35  Tablet Compression Essential to understand machine operation Must be able to identify the difference between a machine issue and a granulation issue Important for fixing issues in formulation Final granulation to be compressed have three critical characteristics Flow, Compress and Eject Understanding the basics of compression is the key to understanding all tablet presses. The tablet press is the report card on all previous unit operations The tablet press is only half responsible for the final tablet quality The formula and powder preparation operation is the other half A good press cannot improve a bad formula. 71 Tablet Compression Tablet weight control Consistent flow of a granulation allows for tablet weight control Consistent tablet weight  repeatable tablet hardness Tablet hardness is a function of tablet thickness and tablet weight Given volume of granulation compressed to specific thickness  results in a given hardness Excipients play a large role in disintegration and dissolution rate of tablets BUT  so does tablet hardness The three most important variables of making a good tablet are; weight control, weight control and weight control. 72 36  Disintegration, Dissolution, Absorption Tablet is taken  Disintegrates or falls apart Forms small aggregates  drug dissolves in GI contents  available for local effect or to be absorbed for systemic effect Tablet must remain intact through: Compression, coating, packaging, storage, distribution, dispensing, administration Must have an acceptable degree of hardness and friability Disintegration mechanism is built into the formulation Must oppose function of compression binder Must also oppose effect of water  humidity can cause softening Many opposing, non-linear complex relationships required in the art/skill of drug dosage design 73 74 37  Types of Tablet Press Tablet presses differ in rate of production: 1. Single-punch press Composed of one die and one pair of punches Produce up to 200 tab/ min Used for small-scale production 2. Rotary tablet press Contains ≥ 60 dies Produces 10,000 tablets/min Used for large-scale production 3. Hydraulic press: For research work 75 76 38 77 Tablet Machines Machines built to compress tablets consist of: Hopper  holds granulations for compressing Feed frame  distributes materials into the dies Dies  control the size and the shape of the tablet Punches  compress the granulations within the dies Cam tracks  guiding the movement of the punches 78 39 79 80 40  Rotary Tablet Press 81 82 41  Compression The compression cycle on a rotary tablet press: Die fill  the die is filled past its maximum Weight adjustment  the volume of the fill is adjusted Compression  the punch is pressed down to compress the tablet and remove air Ejection  the tablet is pushed from the die When setting up the tablet press parameters can be adjusted Tablet weight, thickness Must balance above with machine speed for proper hardness 83 Compression Die filling: Powders (or granules) of formulation flow from a hopper into the die The die is closed at its lower end by the lower punch Tablet formation: The upper punch descends and enters the die The powder/granules is compressed until a tablet is formed The lower punch may be stationary or moving upward in the die After maximum applied force is reached, the upper punch leaves the die Tablet ejection: The lower punch rises up  tip reaches the die top The tablet is subsequently removed by a pushing device 84 42  Compressed Tablets Tablet diameters and shapes  determined by die and punches used Thickness of tablets  determined by amount of fill in die and pressure applied during compression The tablet is formed by the pressure exerted on the granulation by the punches within the die cavity Round tablets are more generally used However shapes such as oval, square, and triangular may be used Curvature of punch face determines the curvature of the tablets 85 Tooling Tablet shape Circular, oblong and oval Side view – flat or convex Break marks and symbols Debossed  indented into the tablet Embossed  raised on the tablet surface Tools control the size, shape and appearance Fabricated from steel Various grades – cost, formulation compressed Surface may be coated with chrome Modify hardness and corrosiveness 86 43  Tablet Characterization/Quality Standards Appearances: Dissolution Tablet thickness Disintegration Tablet shape and size Friability of uncoated tablets Microbiological quality Resistance to crushing of Quantity of active tablets: substances (assay) Hardness or breaking strength Identification of active Uniformity of dosage units substances Uniformity of mass (weight variation) Uniformity of content 87 Common Tablet Defects Impossible to completely avoid defects Must occasionally show up when making multiple large batches Some products start with problems and end with them Variations in weight will create defects Consistent tablet weight is essential to making a good tablet. Without good and consistent weight control, solving other defects will be difficult (if not impossible) because of how a tablet press operates 88 44  Common Tablet Defects Common tablet defects are: Weight variation Friability variation Picking and Sticking Capping and Laminating Chipping Double pressing 89 Weight Variability Factors in controlling variability of weight: Product uniformity in particle size Uniformity in particle density Proper tablet press set-up Flow rates into the die cavity 90 45  Friability Friability testing Weigh tablets first Tumble tablets at set RPM See how well they withstand the tumbling action Weigh tablets after  determine Replicates typical handling situations If tablets are too friable  tablets chip/break apart 91 Picking and Sticking Picking and Sticking  granules stick to punch faces during compression Punch face design and debossing can be modified to eliminate the problem Sometimes granules are not dried properly Become case hardened during the drying process  dry outside, wet inside During compression these granules break open  wet product sticks to the punch faces If this occurs, the drying process must be improved Can overcome sticking by increasing hardness Making the tablet thinner Increase dwell time  make wet granules adhere to other granules rather than punch face Lubricant should protect granule from sticking  if not the case, blend could be incomplete If all else fails polish the punch surface 92 46  Picking and Sticking 93 Capping Capping  separation of top of tablet from main portion Can be related to air entrapment  air usually removed between granules during compression If air is not removed  top of tablet is likely to separate The tooling (punches & dies)  designed to allow air to escape during compression Air escapes along the upper punch tip and die wall  capping occurs on the top “cap” of the tablet Compression can push very fine dry granules out with air  closer to the top of the die Dry, light particles unlikely to lock together  capping 94 47  Capping 95 Laminating Lamination  tablet splits apart anywhere except at the upper cap Lamination can be caused by: Over-compressing Too much compression  granules flatten  no longer lock together Groups of fine and light particles in formulation do not lock together Can reduce lamination by: Reduce thickness Increase dwell time Slow machinery down OR add pre-compression Pre-compression  initial compression step before the main compaction step Pre-compression is a means of compacting the powder but at a lighter pressure than the main compression step 96 48  Laminating 97 Chipping Tablets may be susceptible to chipping after compression Can be related to punch tip edge damage “Take off blade” for tablet ejection  blade too high, tablet could catch beneath Overly friable tablets  chip moving off press  down chute  through metal detector  into de-duster  into collection bin  packaging Movement of tablets through production and transferring of finished tablets can often be linked to poor handling 98 49  Double Impressions As the name implies Happen when punches are allowed to twist or jump Round punch tips want to twist naturally due to the rotation of the press Usually occur on the bottom of the tablet from the lower punches Can mean that lower punch retainers are loose punches are “jumping” during compression Can adjust by: Making certain lower punch retainers are clean and not worn Replaced retainers as often as needed Tightness of retainers will vary depending on if machine is cold or warm  adjust tightness In newer machines  punch seals are used  susceptible to wear 99 Tablet Coating Why coat tablets? To protect the API against destructive exposure to air and/or humidity To mask the taste of the drug To provide special characteristics of drug release To provide aesthetics or distinction to the product To prevent inadvertent contact by non-patients with the drug substance 100 50  Tablet Coating Most pharmaceutical tablets are coated with a thin film coating This coating is sprayed as a solution Water-based solution sprayed in a very fine mist  dries almost immediately as it reaches the tablets As water dries it leaves the solids as a thin film on each tablet Coating system continuously supplies hot air and pulls air through small holes in the coating drum Tablets must be tough enough to tumble while the solution is added  ensures solution is distributed evenly Spraying, distribution and drying all take place at the same time 101 Tablet Coating 102 51  Coating Process Tablets are loaded into the coating pan  bed of tablets Require enough tablets to attain good mixing But not so many that the tablets spill when the door is opened The tablet bed is tumbled slowly  warm air is introduced  dust collector pulls dust off tablets and into a collection bin When the tablet bed reaches the proper temperature the spraying can begin Tablet defects can occur if the temperature, spray rate and air volume are allowed to fluctuate 103 Tablet Coater 104 52