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Tablets [email protected] - Introduction - Excipients - Tablet Manufacturing Process - Solid Dosage Processing - Unit Operations - Processing Problems [email protected] Contents This is the question that your experiment answers 2 Introduction Tablets 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. Introduction Advantages Disadvantages Production aspect Large scale production at lowest cost Easiest and cheapest to package and ship High stability User aspect (doctor, pharmacist, patient) Easy to handling Lightest and most compact Greatest dose precision & least content variability 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 bioavailability Bitter 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 Introduction The manufacture of oral solid dosage forms such as tablets is a complex multi-stage process under which the starting materials change their physical characteristics a number of times before the final dosage form is produced. Traditionally, tablets have been made by granulation, a process that imparts two primary requisites to formulate: compactibility and fluidity. Both wet granulation and dry granulation (slugging and roll compaction) are used. Regardless of weather tablets are made by direct compression or granulation, the first step, milling and mixing, is the same; subsequent step differ. Numerous unit processes are involved in making tablets, including particle size reduction and sizing, blending, granulation, drying, compaction, and (frequently) coating. Types of Tablets Compressed Tablets Sugar coated Tablets Film coated Tablets Enteric coated Tablets Effervescent Tablets Chewable Tablets Dispersible Tablets Sustained release Tablets Multilayer Tablets Sublingual Tablets Troches Buccal Tablets Implant Tablets Hypodermic Tablets Solution Tablets Vaginal Tablets Excipients To aid in the processing of the drug delivery system during its manufacture; To protect, support, or enhance stability, bioavailability or patient acceptability; To assist in product identification; To enhance any other attribute of the overall safety, effectiveness, or delivery of the drug during storage or use. Excipients are substances, other than the active drug substance, or finished dosage form, that have been appropriately evaluated for safety and are included in drug delivery systems: Excipient functions Component Function Examples Fillers Increase size and weight of final dosage form Microcrystalline cellulose, sucrose Binders Promote particle aggregation Pregelatinized starch, hydroxypropyl methylcellulose Disintegrants Promote break down of aggregates Sodium starch glycolate Flow Aids Reduce interaction between particles Talc Lubricants Reduce interactions between particles and surfaces of processing equipment Magnesium stearate Surfactants Promotes wetting Sodium lauryl sulfate, Polysorbate Modified Release Agents Influences the release of active Hydroxypropyl methylcellulose, Surelease, Hlinak (2005) EXCIPIENTS FOR COMPRESSED TABLETS Compressed Tablets or Standard compressed Tablets are uncoated tablets made by compression and intended to provide rapid disintegration and drug release. 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 . EXCIPIENTS FOR COMPRESSED TABLETS Conventional oral tablets for ingestion usually contain the same classes of components in addition to the active ingredient, which are one or more agents functioning as Diluents Binders Lubricants Disintegrators Wetting agents A. DILUENTS Diluents increase the volume to a formulation to prepare tablets of the desired size. Widely used fillers are lactose, dextrin, microcrystalline cellulose starch, pre-gelatinized starch, powdered sucrose, and calcium phosphate. The 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. B. BINDERS Binders promote the adhesion of particles of the formulation. Such adhesion enables preparation of granules and maintains the integrity of the final tablet. Carboxymethylcellulose, sodium Karaya gum Cellulose,microcrystalline(Avicel®) Starch, pregelatinized Ethylcellulose Tragacanth gum Hydroxypropyl methylcellulose Poly(acrylic acid) Methylcellulose Polypvinylpyrrolidone Acacia gum Gelatin Agar Dextrin Algin acid Glucose Guar gum Molasses C. LUBRICANTS Lubricant 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. Commonly used lubricants include: talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils and (PEG). 1. 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. Lubricants play more than one role in the preparation of tablets D. DISINTEGRATORS The breakup of the tablets to smaller particles is important for dissolution of the drug & 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 water uptake property. In general, the more hydrophilic, the better disintegrating agents are therefore highly hydrophilic. E. WETTING AGENTS Water 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 tension 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. Stages of pharmaceutical manufacturing API Excipients Primary Packaging Secondary Packaging API Finished Product Starting Materials (Chemicals) Drug product manufacture Dosage Form Wet granulation milling blending Fluid Bed Dryer lubrication tableting coating imprinting Process combines the drug and excipients into the dosage form Excipients API crystallization filtration oven drying Dry granulation / milling Direct compression Flow Chart API Filler Mixing of granulation blend Granulation Binder(s) Preparation of binder solution Drying Milling LOD Disintegrant screening screening Initial Blending lubricant screening Final Blending Compression Solvent Film coating agent Preparation Film Coating of Tablets Packaging and Labelling Weight Hardness Friability Manufacturing Methods DIRECT COMPRESSION DRY GRANULATION WET GRANULATION Milling/Screening Milling/Screening Milling/Screening Blending Pre-blending Pre-blending Compression Slugging/roller compaction Addition of binder Dry screening Screening of wet mass Blending of lubricant Drying of the wet granules Compression Screening of dry granules Blending of lubricant (and disintegrant) Compression Solid dosage processing Dosage forms Quality factors Excipients Particle properties Processing routes Unit operations Size reduction (milling) Blending Dry granulation (roll compaction) Wet granulation Drying Tablet compaction Coating Quality factors for solid dosage forms Functional quality factors Disintegrates to desired size quickly The constituent particle size of the dosage form should dissolve and be absorbed in the GI tract at a pre-determined rate Physical quality factors Must not break up on processing, packaging, transportation, dispensing or handling Surface of tablet or capsule must be free of defects Must be stable under anticipated environmental conditions Have the same weight and composition for each tablet or capsule Sensorial quality factors Easy and pleasant to swallow Fung and Ng (2003), AIChE Journal, 49(5), 1193-1215 Models at different scales Scale Subject Problems Enterprise Business process Sourcing, contract manufacturing, capacity planning Plant Process synthesis, simulation, development Generation of process alternatives, process optimization Equipment Equipment selection, performance, sizing, costing Mixing, classification, granulation, milling Continuum Flow and handling of powders Granular flow Particle Particle attributes: composition, size distribution, density, strength, shape Interparticle forces, breakage Molecule Enantiomers and polymorphs, material properties Polymorph prediction, prediction of physical and chemical properties Ng (2002), Powder Technology, 126, 205-210 Product and process functions Product function Product property: Content uniformity, dissolution, flowability, dust formation Particle Properties: Particle size, particle shape, surface characteristics Process function Process parameters: Type of unit operation, operational parameters Product property = F(particle properties, formulation) Particle properties = F(process parameters, raw material/intermediate properties) Particle properties Potential Impact Processing Behavior Product Quality Factors Property Flow Blending Wetting Drying Mechanical Dissolution Stability Particle Size X X X X X X X Surface Area X X X X X X X Particle Shape X Surface Energy X X X Bulk Density X X X Pore Size X X X Internal Friction X X Wall Friction X X Hygroscopicity X X X Hlinak et al, Journal of Pharmaceutical Innovation, 1 (2006) Product property = F(particle properties, formulation) Mean particle size and flowability Bodhmage, A. (2006). Correlation between physical properties and flowability indicators for fine powders. MS Thesis, Department of Chemical Engineering, University of Saskatchewan. Size distributions for various powders Bodhmage, A. (2006). Correlation between physical properties and flowability indicators for fine powders. MS Thesis, Department of Chemical Engineering, University of Saskatchewan. Powder flow and tablet weight variations Hancock, Bruno (2007). Dosage Form Specific Tests. Short course on Material Properties, Purdue University. Processing routes Fill die Coating, Packaging etc.. Compress Tablet Direct Compression Drug Diluent Glidant Disintegrant Lubricant Mixing Mixing Dry Granulation Disintegrant Glidant Lubricant Drug Diluent Lubricant Mixing Compression Comminution Screening Mixing Mixing Wetting Granulation Drying Screening Mixing Drug Diluent Binder Solvent Disintegrant Glidant Lubricant Wet Granulation Other Routes Fluidized bed granulation Extrusion / rotary granulation Tablet Compression Unit operations Unit Operation Every separate manufacturing step. Unit Dose Operations Determined by what manufacturing steps are needed to combine the active ingredient with other needed ingredients to make a quality finished product. Type of unit operation Dispensing Milling/Screening Blending Granulation Drying Compression Coating Packaging Dispensing This is the question that your experiment answers 31 Dispensing One of the most critical steps in pharmaceutical manufacturing manual weighing on a weight scale with material lifting assistance like vacuum transfer and bag lifters automated weighing Issues: dust control (laminar air flow booths, glove boxes) weighing accuracy multiple lots of active ingredient with different assays, moisture and residual solvent content cross contamination Dispensing is the first step in any pharmaceutical manufacturing process. Dispensing is one of the most critical steps in pharmaceutical manufacturing; during this step, the weight of each ingredient in the mixture is determined according to dose. Issues like: weighing accuracy, dust control (laminar air flow booths, glove boxes), during manual handling, lot control of each ingredient, material movement into and out of dispensary should be considered during dispensing. 33 Dispensing Raw Material Dispensing Record RM Code Ingredient Qty Kg AR No Gross Wt. Tare Wt. Net Wt. Weighed by Checked by Date API √ √ √ √ √ √ Exp 1 √ √ √ √ √ √ Exp 2 √ √ √ √ √ √ Exp 3 √ √ √ √ √ √ Exp 4 √ √ √ √ √ √ Exp 5 √ √ √ √ √ √ Considerations Theoretical quantity of API [100% assay (anhydrous) and nil water] = 30 Kg Sr. No. AR No. Total available quantity (as is basis) (Kg) (A) Actual Assay (%) (B) Water content (% w/w) (C) Equivalent quantity on 100% assay and nil water basis (Kg) (D) Equivalent quantity on as is basis (Kg) (E) 1 AP-18 23.50 99.4 0.34 23.28 23.50 2 AP-22 60.00 99.1 0.50 6.72 6.815 ∑E 30.00 ∑E 30.315 Milling/Screening This is the question that your experiment answers 36 The sizing (size reduction, milling, crushing, grinding, pulverization) is an impotent step (unit operation) involved in the tablet manufacturing. In manufacturing of compressed tablet, the mixing or blending of several solid ingredients of pharmaceuticals is easier and more uniform if the ingredients are approximately of same size. Advantages associated with size reduction in tablet manufacture are as follows: i) It increases surface area, which may enhance an actives dissolution rate and hence bioavailability. ii) Improved the tablet-to-tablet content uniformity by virtue of the increased number of particles per unit weight. iii) Improved flow properties of raw materials. iv) Improved colour and/or active ingredient dispersion in tablet excipients. 37 Particle size reduction Particle size reduction Excessive heat generation can lead to degradation, change in polymorphic form Increase in surface energy can lead to agglomeration May result in excessive production of fines or overly broad particle size distribution Disadvantages Forces in milling Shear (cutting forces) Compression (crushing forces) Impact (high velocity collision) Griffith theory T = Tensile stress Y = Young’s modulus ε = Surface energy c = fault length Rumpf (1965), Chem Ing Tech, 37(3), 187-202 Milling equipment – screen mills Critical parameters for a conical screen mill Screen Hole Size/Shape Impeller Type Impeller Clearance Speed Evaluate impact on aspirin granulation Particle size reduction Milling time and energy requirements Overall milling performance Milling Work Index = Size reduction / Milling work Milling Time Index = Size reduction / Milling time Byers, Peck (1990), Drug Dev Ind Pharm, 16(11), 1761-1779 Milling equipment – screen mills Screen hole size has largest impact on particle size reduction, milling time and energy requirements Milling work index significantly lower for smaller screen hole sizes Impeller type has largest effect on overall milling performance Impeller clearance not significant at small clearances Milling work index lower at higher mill speeds Deflection of material away from screens Byers, Peck (1990), Drug Dev Ind Pharm, 16(11), 1761-1779 Milling work index= Particle size reduction / Milling work Milling equipment – impact mills Significant wear on surfaces Hammer mills Medium to coarse size reduction Peripheral speed 20-50 m/sec Pin mills Peripheral speed up to 200 m/sec Capable of fine grinding Can be used to mill sticky materials Milling equipment – jet mill Superfine to colloid size reduction Can be used for heat sensitive products Different configurations Pancake (spiral) jet mill Fines exit from center Loop/oval jet mill Fines exit from top Opposing jet mills Particles impact each other in opposing jets Fluidized bed jet mill Particles are jetted towards center (low wear on equipment) Fixed/moving target jet mills Particles impact on surface of target (wear can be significant) Milling equipment – stirred media mill Critical parameters Agitator speed Feed rate Size of beads Bead charge Density of beads Design of blades Mill chamber Residence time Mill selection Wibowo and Ng (1999), AIChE Journal 45 (8) 1629-1648 Energy based analysis – ball mill Macroscale energy-size relationships (Chen et al., 2004) Calculate specific energy for a given size reduction Functional form derived from theoretical considerations Rittinger’s model Energy required for particle size reduction is proportional to the area of new surface created Kick’s model Energy required to break a particle is proportional to the ratio of the particle volume before reduction to the volume after reduction Chen et al. (2004), J Pharm Sci, 93(4), 113-132 Energy based analysis – ball mill Kick’s Law High loading Low frequency Rolling attrition Rittinger’s Law Low loading High frequency Impact fragmentation Attrition Fragmentation Size Reduction of α–Lactose Monohydrate in a Ball Mill Chen et al. (2004), J Pharm Sci, 93(4), 113-132 Milling/Screening Principle: Mixing or blending is more uniform if ingredients are of similar size What are the problems What are the equipment Why do it Possible change in polymorphic form An increase in surface area may promote the adsorption of air - may inhibit wetting of the drug – could be the limiting factor in dissolution rate Fluid energy mill Comil Ball mill Hammer mill Cutting mill etc. Increased surface area - may enhance rate of dissolution Improved content uniformity due to increased number of particles per unit weight Enhanced flow properties of raw materials Uniformly sized wet granules promotes uniform drying World Health Organization 2 September, 2014 48 Manufacturing Instructions screening Step Instructions Time start Time end Performed by Verified by Date 1.1 API …… Kg Exp 1 …… Kg Pass through # 40 screen of Vibratory sifter and collect material in tared double PE lined container √ √ √ √ √ 1.2 Exp 2 …… Kg Exp 3 …… Kg Pass through # 20 screen of Vibratory sifter and collect material in tared double PE lined container √ √ √ √ √ Blending This is the question that your experiment answers 50 The powder/granules blending are involved at stage of pre granulation and/or post granulation stage of tablet manufacturing. Each process of mixing has optimum mixing time and so prolonged mixing may result in an undesired product. So, the optimum mixing time and mixing speed are to be evaluated. Blending step prior to compression is normally achieved in a simple tumble blender. The various blenders used include blender, Oblicone blender, Container blender, Tumbling blender, Agitated powder blender, etc. 51 Powder Blending Blending – diffusion mixing Critical parameters Blender load Blender speed Blending time V-Blender Cross Flow Blender Bin Blender Double Cone Blender Blending – convective mixing Ribbon Blenders Orbiting Screw Blenders Planetary Blenders Horizontal Double Arm Blenders Forberg Blenders Vertical High Intensity Mixers Horizontal High Intensity Mixers Diffusion Mixers with Intensifier/Agitator Blending Blending is the most difficult operation in the manufacturing process since perfect homogeneity is practically impossible due to differences in size, shape and density of particles What are the problems What are the equipment Why do it Segregation Possible over mixing of lubricant Blend uniformity/ Content uniformity Diffusion Mixers (V,double cone, bin,drum blenders) Convection Mixers (ribbon, planetary blenders) Pneumatic Mixers To achieve optimum mixing of different ingredients in powder/granules at pre granulation and/or post granulation stages of tablet manufacturing Mixer and blender 9/2/2014 55 Granulation This is the question that your experiment answers 56 The dry granulation process is used to form granules without using a liquid solution because the product to be granulated may be sensitive to moisture and heat. Forming granules without moisture requires compacting and densifying the powders. In this process the primary powder particles are aggregated under high pressure. Dry granulation can be conducted under two processes; either a 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, commonly referred to as a chilsonator). Dry Granulation Advantage: Avoid exposure of the powder to moisture and heat. Used for powders of very low bulk density to ↑ their bulk density. Disadvantage: Tablet disintegration and dissolution may be retarded due to double lubrication and compaction Dry Granulation • The blend of finely divided powders is forced into the dies of a large capacity tablet press. • Then, compacted by means of flat faced punches (Compacted masses are called slugs and the process is slugging) or roll compactor to produce sticks or sheets. • Slugs or sheets are then milled/screened to produce granules (flow more than the original powder mixture). Steps of Dry Granulation Slugging technique If a tablet press is used for the compaction process, the term slugging is used. But since particles with a small particle size do not flow well into the die of a tablet press, the results are weight differences from one tablet (slug) to another. This in turn causes large fluctuations in the forces applied onto the individual slugs, with translates in variations of the slug’s mechanical strength. Therefore, the properties of these granulates obtained by milling the slugs cannot be controlled well either. This is one of the main reasons why slugging is hardly used any more as a dry granulation method. Methods of Dry Granulation B. Roller compaction technique A Roller compactor generally consist of three major units: A feeding system, which conveys the powder to the compaction area between the rolls A compaction unit, where powder is compacted between two counter rotating rolls to a ribbon by applying a force A size reduction unit, for milling the ribbons to the desired particle size. Methods of Dry Granulation Roll compaction Critical parameters Roll speed and pressure Horizontal and vertical feed speed, deaeration Roll diameter and surface Advantages Improve powder flow Reduce segregation potential No moisture addition, drying Johanson’s theory Slip Region Nip Region Johanson’s theory Slip region Nip region Yu et al. (2013), Chem Eng Sci, 86, 9-18 Compressibility Eff. angle of friction Wall angle of friction Eff. angle of friction and peak pressure (Johanson’s theory) Eff. Angle of Friction Eff. angle of friction and nip angle (Johanson’s theory) Eff. Angle of Friction Nip Angle Effect of lubrication on friction properties Yu et al. (2013), Chem Eng Sci, 86, 9-18 Effect of lubrication on peak roll pressure Yu et al. (2013), Chem Eng Sci, 86, 9-18 Effect of lubrication on nip angle Yu et al. (2013), Chem Eng Sci, 86, 9-18 Effect of entrained air on feeding and discharging Johanson (1989), Powder Bulk Eng, Februay, 43-46 Characterization of flowability Hausner ratio = tapped density / bulk density Excellent 1.05–1.10 Good 1.11–1.15 Fair 1.15–1.20 Passable 1.21–1.25 Poor 1.26–1.31 Very Poor 1.32–1.37 Extremely Poor 1.38–1.45 Roll compaction and flow properties Soares et al. (2005), Dry granulation and compression of spray dried plant extracts, AAPS PharmSciTech Before Compaction (poor) After Compaction (excellent) In the pharmaceutical industry, granulation refers to the act or process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. It is the process of collecting particles together by creating bonds between them. Bonds are formed by compression or by using a binding agent. Granulation is extensively used in for the manufacturing of tablets, pellets (or spheroids). The granulation process combines one or more powders and forms a granule that will allow tableting or spheronization process to be within required limits. Wet Granulation Granulation is carried out for various reasons, one of those is to prevent the segregation of the constituents of powder mix. Segregation is due to differences in the size or density of the component of the mix. Normally, the smaller and/or denser particles tend to concentrate at the base of the container with the larger and/or less dense ones on the top An ideal granulation will contain all the constituents of the mix in the correct proportion in each granule and segregation of granules will not occur. Some powders are difficult to compact even if a readily compactable adhesive is included in the mix, but granules of the same powders are often more easily compacted. Wet Granulation A process of size enlarging a mix of active ingredient and excipient powder particles into stable aggregates exhibiting desired properties of: • Compressibility • Cohesiveness • Flowability • Bulk density Granules may be a final product or an intermediate product that needs further processing Wet Granulation It involves massing of a mix of dry primary powder particles using a granulating fluid. The fluid contain a solvent that must be volatile and non-toxic e.g water, or organic solvent. The granulating solvent may contain a binding agent to ensure particle adhesion after drying. Povidone, which is a polyvinyl pyrrolidone (PVP), is one of the most commonly used pharmaceutical binders. PVP is dissolved in water or solvent and added to the process. Wet Granulation Typical liquids include: 1. Water : may adversely affect drug stability, causing hydrolysis ,it needs a longer drying time. This increases the length of the process. The advantage :non-flammable and economic. 2. Ethanol, Isopropanol or combination (organic solvents) used with water sensitive drugs, alternative to dry granulation or when rapid drying time is required. Wet Granulation Steps of Granule formation Agitation of a powder in the presence of a liquid. It forms the granules by binding the powders together with an adhesive. Once the granulating liquid has been added, mixing continues until uniform dispersion is attained (15 min. to an hour). High shear wet granulation Advantages Improve flow Improve uniformity Increase bulk density Enhance resistance to segregation Critical parameters Amount of binder Rate of addition Time of granulation Speed Mixer Blade Bowl Chopper Blade Discharge Wet granulation – monitoring liquid addition Jorgensen et al. (2004), J Pharm Sci, 93(9), 2232-2243 0.24 ml/g Impeller Torque for α–Lactose Monohydrate/MCC granulation (C) 0.47 ml/g agglomeration (B) 0.36 ml/g nucleation (D) 0.53 ml/g agglomerate growth Wet granulation – monitoring liquid addition Jorgensen et al. (2004), J Pharm Sci, 93(9), 2232-2243 0.24 ml/g (1 min) SEM of α–Lactose Monohydrate/MCC granules (C) 0.47 ml/g (2 min) agglomeration (B) 0.36 ml/g (1.5 min) nucleation (D) 0.53 ml/g (2.25 min) agglomerate growth bar = 500 μm Granulation Principle: A size enlargement process that converts small particles into physically stronger & larger agglomerates What are the problems What are the equipment Why do it Loss of material during various stages of processing Multiple processing steps - validation and control difficult Incompatibility between formulation components is aggravated Dry Granulator (roller compactor, tabletting machine) Wet High-Shear Granulator (horizontal, vertical) Wet Low-Shear Granulator (planetary, kneading, screw) Fluid Bed Granulator, Spray Dry Granulator, RMG Provides homogeneity of drug distribution in blend Improves flow, compressibility and hardness of tablets Manufacturing Instructions blending & granulation Mixing SOP No.: Granulation SOP No.: Step Instructions Time start Time end Performed by Verified by Date 2.1 Load material from 1.1 & 1.2 in RMG Exp 4 ……….Kg and mix for 5 minutes with following settings: Impeller speed-fast; Chopper speed-fast √ √ √ √ √ 2.2 Spray purified water into contents of RMG Impeller speed – fast; Chopper speed - fast Peristaltic pump atomization press: 0.5-2.5 b Spray until all purified water is sprayed Ammeter reading 18-22 amps √ √ √ √ √ Manufacturing Instructions wet milling Wet Milling SOP No.: Step Instructions Time start Time end Performed by Verified by Date 3.1 Pass wet mass through 1mm screen of Multi Mill Speed – fast; Knives - forward collect in FBD √ √ √ √ √ Recent Advances in Granulation Techniques Steam Granulation: Modification of wet granulation; steam is used as a binder instead of water; granules are more spherical and exhibit higher rate of dissolution Melt Granulation / Thermoplastic Granulation: Granulation is achieved by the addition of meltable binder i.e. binder is in solid state at room temperature but melts in the temperature range of 50 – 80˚C [e.g. PEG (water soluble), stearic acid, cetyl or stearyl alcohol (water insoluble)] - drying phase unnecessary since dried granules are obtained by cooling them to room temperature Moisture Activated Dry Granulation (MADG): Involves distribution of moisture to induce agglomeration – drying time is reduced Recent Advances in Granulation Techniques Moist Granulation Technique (MGT): A small amount of granulating fluid is added to activate dry binder and to facilitate agglomeration. Then a moisture absorbing material like Microcrystalline Cellulose (MCC) is added to absorb any excess moisture making drying step unnecessary. Mainly employed for controlled release formulations Thermal Adhesion Granulation Process (TAGP): Granules are prepared by moisturizing excipient mixtures with very little solvent in a closed system (tumble mixing) with low heating – mainly employed for preparing direct compression formulations Foam Granulation: Binders are added as aqueous foam Drying Tray dryer Fluid bed dryer This is the question that your experiment answers 87 Drying is a most important step in the formulation and development of pharmaceutical product. It is important to keep the residual moisture low enough to prevent product deterioration and ensure free flowing properties. The commonly used dryer includes Fluidized bed dryer, Vacuum tray dryer, Microwave dryer, Spray dryer, Freeze dryer, Turbo - tray dryer, Pan dryer, etc. Drying • A process of evaporating the liquid contained within aggregates produced by a wet granulation process to a predetermined moisture content • Accomplished via 1. Tray dryer (direct contact with heating medium) 2. Fluidized bed dryer (indirect contact of the product with the heating medium Drying Process Drying Purpose: To reduce the moisture level of wet granules What are the problems What are the equipment Why do it Over drying (bone dry) Excess fines Possible fire hazard Direct Heating Static Solids Bed Dryers Direct Heating Moving Solids Bed Dryers Fluid Bed Dryer Indirect Conduction Dryers To keep the residual moisture low enough (preferably as a range) to prevent product deterioration Ensure free flowing properties Manufacturing Instructions drying Drying SOP No.: LOD: 1.0-2.5% (moisture balance at 105ºC) Date Verified by Performed by Time end Time start Instructions Step √ √ √ √ √ √ √ √ √ √ FBD in let temp 60ºC Damper 80% open for 15 min Damper 50% open after 15 minutes ; LOD ……..% 3.2 Fluid bed drying Air Flow Inlet Filter Condensor Steam Damper Damper Outlet Filter Air Flow Product Temperature Inlet Temperature Outlet Temperature From Granulator To Mill Drying Zone Filter Bag Air Flow Retaining Screein Single machines utilized for both the wet granulation and drying process in one unit operation. Use Fluid Bed Dryer (FBD) It is a multiple step process performed in the same vessel to mix, granulate and dry the powders. Combines wetting the powders to for granules &then, drying them in the same piece of equipment. Fluid bed drying A. Reduced product handling B. Closed process suitable to: Gentle product handling. Intensive mixing of the solid material. Uniform spraying of all particles in the fluid bed. Uniform, reproducible product quality. Potent compounds Minimizing product/operator exposure Minimizing cross contamination and product loss Reduced cleaning and overall process time Reduced equipment and floor space requirements Advantages of Fluid bed drying Tablet Compaction This is the question that your experiment answers 95 Powders intended for compression into tablets must possess two essential properties: Powder fluidity The material can be transported through the hopper into the die to produce tablets of a consistent weight Powder flow can be improved mechanically by incorporate the glidant. Powder compressibility The property of forming a stable, intact compact mass when pressure is applied. Tablet Compaction The term “direct compression” is defined as the process by which tablets are compressed directly from powder mixture of API and suitable excipients. It involves only two unite operations powder mixing and tableting. Advantages of Direct Compaction: Reduced production time &cost. Product stability can be improved. Faster drug dissolution due to fast disintegration into primary particles. less number of equipment are required, less process validation Elimination of heat and moisture, thus increasing not only the stability but also the suitability of the process for thermo-labile and moisture sensitive API’s. The chances of batch-to-batch variation are negligible, because the unit operations required for manufacturing processes is fewer. Direct compression Disadvantages of Direct Compaction Large particles must be used → (acceptable flowability and bulk density) Many active ingredients are not compressible either in crystalline or amorphous forms. Needs directly compressible filler that is usually expensive, e.g. microcrystalline cellulose (Avicel), spray dried lactose Problems in the uniform distribution of low dose drugs. High dose drugs having high bulk volume, poor flowability and poor compressibility are not suitable for direct compression. For example, Aluminium Hydroxide, Magnesium Hydroxide Non-uniform distribution of colour, especially in tablets of deep colours Direct compression Design: 1. Hopper for holding and feeding granules or powder to be compressed. 2. Dies that define the size and shape of the tablet. 3. Punches for compressing the granules within the dies. 4. Cam tracks for guiding the movement of the punches. 5. A feeding mechanism for moving granules from the hopper into the dies. Tablet Compression Machine Die filling Gravitational flow of the powder from hopper via the die table into the die. (The die is closed at its lower end by the lower punch). Tablet formation The upper punch descends, enters the die, the powder is compressed until a tablet is formed. after maximum applied force is reached, the upper punch leaves the powder i.e. compression phase. Tablet ejection The lower punch rises until its tip reaches the level of the top of the die. The tablet is subsequently removed from the die and die table by a pushing device. Stages of Tablet Formation (Compaction Cycle) Powders fed into a die Powder compressed between punches Tableting Process Tablet Presses Single Punch Rotary Press High Speed Rotary Press Multi-layer Rotary Press Single Punch press Core components: Die Lower punch Upper punch Single Punch press (Eccentric Press): Bench-top models that make one tablet at a time (single-station presses) Disadvantages: Production of small batches of tablets (200 tablets per minute). Rotary Press Rotary Press( Multi station Press): It was developed to increase the output of tablets (10 000 tablets per minute), used for Large scale production. It consists of a number of dies and sets of punches (from 3 up to 60). The dies are mounted in a circle in the die table and both the die table & the punches rotate together during operation of the machine. Rotary Press machine The core components and compression cycle of rotary presses A: upper punch B: die cavity C: die D: lower punch The compression is applied by both the upper punch and the lower punch. The compression cycle of a rotary tablet press Compression cycle of rotary presses Stage 1: Top punch is withdrawn from the die by the upper cam, Bottom punch is low in the die so powder falls in through the hole and fills the die. Stage 2: Bottom punch moves up to adjust the powder weight-it raises and expels some powder Stage 3: Top punch is driven into the die by upper cam; Bottom punch is raised by lower cam. Both punch heads pass between heavy rollers to compress the powder. Stage 4: Top punch is withdraw by the upper cam. Lower punch is pushed up and expels the tablet. Tablet is removed from the die surface by surface plate Stage 5: Return to stage 1 Compression cycle of rotary presses Tablet tooling; punches and dies Caplet Shape Dies Oval Shapes Dies Round Shapes Dies Star Shapes Dies Tablet tooling; punches and dies Compression Principle: Powder/granules are pressed inside a die and compressed by two punches into required size, shape and embossing What are the problems What are the equipment Why do it Poor flow in hopper Inadequate lubrication Capping, chipping, cracking, lamination, sticking, picking, binding, mottling Double compression Multiple Stations (Rotary) and High Speed Tablet Presses To compress powder into tablets Manufacturing Instructions compression Balance no.: Vernier Caliper no.: Hardness tester no.: Friability tester no.: Disintegration tester no.: Tooling No. of units Checked by Verified by Upper punch: …mm x …mm oval shaped concave embossed……. 55 Lower punch: …mm x …mm oval shaped concave embossed……. 55 Dies: …mm x ….mm oval shaped 1 Manufacturing Instructions compression Parameter Limit Results Machine speed 20 rpm (15-25 rpm) Wt. of 20 tabs 12.00g +2 (11.76-12.24g) Theoretical weight/tab 600mg Hardness 25Kg (20-30 Kg) Thickness (av. of 10 tabs) 4.10mm +0.15mm (3.95 – 4.25mm) Length 10mm + 0.1 mm (9.9 – 10.1 mm) Width 5 mm + 0.1mm (4.9 – 5.1 mm) Disintegration time NMT 15 mins Wt. variation + 3% of Av. Wt. Friability (10 tabs) NMT 1.0% w/w In-process Checks Parameter Frequency Wt. of 20 tabs Every hour by production and every two hours by QA Hardness, thickness, length, width Every hour by production, every two hours by QA Wt. variation Every half hour by production and every hour by QA DT Every half hour by production, every hour by QA Relative density changes in manufacture of tablets Hancock et al. (2004), Pharm Tech, April 2003, 64-80 Equivalence of tablets made with different presses Hancock et al. (2004), Pharm Tech, April 2003, 64-80 Coating This is the question that your experiment answers 116 Coating Once a good tablet is made, we often need to add a coating. The coating can serve many purposes; it makes the tablet stronger and tougher, improves taste, adds color, and makes the tablet easy to handle and package. Tablet coating The reasons for tablet coating to protect the medicinal agent 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 The general methods involved in coating tablets are as follows 1) Sugarcoating tablets 2) Film-coating tablets 3) Enteric coating 4) Pan coating 5) Fluid-bed or air suspension coating 6) Compression coating Tablet coating The sugarcoating of tablets may be divided into the following steps: 1) Waterproofing and sealing (if needed) 2) Subcoating 3) Smoothing and final rounding 4) Finishing and coloring (if desired) 5) Polishing Tablet coating 1) 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 phthalate 2) Subcoating Aim: to bond the sugar coating to the tablet and provide rounding 3 to 5 subcoats of a sugar-based syrup are applied. The sucrose and water syrup also contains gelatin, acacia, or PVP. 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. Then drying the tablets. Repetition (15 to 18 times) the subcoating process until the tablets are of the desired shape and size. Tablet coating 3) Smoothing and final rounding (Aim: to complete the rounding and smooth the coatings) 5 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 coloring (Aim: to attain final smoothness and the appropriate color) Several coats of a thin syrup containing the desired colorant 5) Imprinting (Aim: to impart identification codes and other distinctive symbols to the product.) The imprint may be debossed, embossed, engraved, or printed on the surface with ink. 6) Polishing (Aim: to render the tablets the desired sheen/gloss/luster) a) pans lined with canvas cloth impregnated with carnauba waxand/or beeswax b) Pieces of wax may be placed in a polishing pan c) light-spraying of the tablets. with wax dissolved in a nonaqueous solvent Tablet coating Film-coating machine Pan coating Benefits Mask taste Chemical barrier Controlled release Appearance Critical Parameters Air flow Spray Drum dynamics Rotational speed Fill fraction Air+Moisture Dry Air Rotation Baffle Spray Nozzle Air Flow Inlet Filter Steam Inlet Temperature Inlet Air Outlet Air Outlet Filter Outlet Temperature Coating/Polishing Principle: Application of coating solution to a moving bed of tablets with concurrent use of heated air to facilitate evaporation of solvent What are the problems What are the equipment Why do it Blistering, chipping, cratering, picking, pitting Color variation Roughness Pan (standard/perforated) Coating Machines Fluidized Bed Coating Machines Spray Coating Machines Vacuum, Dip & Electrostatic Coating Machines Enhance appearance and colour Mask taste and odour (film/sugar) Improve patient compliance Improve stability Impart enteric, delayed, controlled release properties Manufacturing Instructions coating Step Instructions Time start Time end Performed by Verified by Date 6.1 Introduce compressed tablets into Auto Coater and spray coating solution Inlet air temp …….ºC (30-60ºC) Pan speed……..rpm (2-8 rpm) Solution rate …..ml/min (20-60 ml/min) Distance of gun from tablet bed……cm (20-40cm) √ √ √ √ √ Packaging This is the question that your experiment answers 127 Pharmaceutical manufacturers have to pack their medicines before they can be sent out for distribution. The type of packaging will depend on the formulation of the medicine. 'Blister packs' are a common form of packaging used for a wide variety of products. They are safe and easy to use and they allow the consumer to see the contents without opening the pack. Packaging Primary packaging is the material that first envelops the product and holds it. This usually is the smallest unit of distribution or use and is the package which is in direct contact with the contents. Secondary packaging is outside the primary packaging – perhaps used to group primary packages together Tertiary packaging is used for bulk handling, warehouse storage and transport shipping. The most common form is a palletized unit load that packs tightly into containers. Packaging Types Tablet Defects & Processing Problems This is the question that your experiment answers 130 Moisture Improper drying High speed machines Tools setting problem Excess use of binders Lack of proper lubricant selection Air interaction Lack of knowledge Improper training Abnormal ratio of excipients Temperature adjustment Size, shape Sources of Tablet Defects Binding Sticking, Picking and Filming Capping Lamination Chipping Mottling Weight Variation Poor flow Hardness variation Double impression Cracking Processing Problems It is the adhesion of the granules to the die wall and this cause the resistance of the tablet to eject from the die, it is usually due to insufficient lubrication, which produce tablets with rough and vertical score marks on the edges. Can be improved by: 1. Increasing lubrication. 2. Improve lubricant distribution. 3. Increasing the moisture content of the granulation Binding Adhesion of the material to the punch faces. Sticking : (whole adhesion) is usually due to improperly dried or lubricated granulation causing the whole tablet surface to stick to the punch faces → dull, scratched, or rough tablet faces. Picking : (localized adhesion) is a form of sticking in which a small portion of granulation sticks to the punch face & a portion of the tablet surface is missed. Filming: is a slow form of sticking and is largely due to excess moisture in the granulation Sticking, Picking & Filming Capping occurs when the upper segment of the tablet separates from the main portion of the tablet & comes off as a cap. Can appear immediately after compression, or hours, even days after preparation. It is usually due to air entrapped in the granulation which is compressed in the die during the compression & then expands when the pressure is released. Capping & Laminating Reasons of capping : 1. large amount of fines in the granulation &/or the lack of sufficient clearance between the punch and the die wall. 2. In new punches and dies that are tight fitting. 3. Too dry granules Lamination is due to the same causes as capping except that the tablet splits at the sides into two or more parts. If tablets laminate only at certain stations, the tooling is usually the cause. Capping & Laminating Solutions for capping & laminating: Increasing the binder. Adding dry binder such as gum acacia polyvinylpyrrolidone (PVP). Decreasing the upper punch diameter. Certain degree of moisture in the granules It is an unequal distribution of color on the surface of the tablet. Cause : A drug that differs in color from its excipients or whose degradation products are highly colored. Migration of a dye during drying of a granulation (change the solvent system, reduce the drying temperature, or grind to a smaller particle size). 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