1 Ert 430: pharmaceutical process engineeringDr Khairul Farihan Kasim School of Bioprocess Engineering UniMAP

2 overview Pharmaceutical Solid Dose FormulationPharmaceutical processing CO2: Ability to evaluate the pharmaceutical engineering processes in pharmaceutical formulation and production.

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4 Before their use in the preparation of pharmaceutical products, solid materials first are characterized to determine their chemical and physical features, including: Morphology Purity Solubility Flowability Stability Particle size Uniformity Compatibility

5 Pharmaceutical Solid Dose FormulationTablets Powders Granules Capsules

6 overview Definition Advantages and disadvantages Method of preparationProcessing problems Manufacturing techniques Shelf life and storage Containers and packaging British Pharmacopoeia (BP)

7 POWDERS

8 Powders - DEFINITION BP – solid particles in the range of < 1.25 μm to 1.7 mm in diameter Mixtures of dry, finely divided drugs and/or chemicals that may be intended for internal (oral powder) or external (topical powder) use.

9 Powders - DEFINITION Although the use of medicated powders in therapeutics is limited, the use of powdered substances in the preparation of other dosage forms is extensive. When it used to describe a dosage form, it describes a formulation in which a drug powder has been mixed with other powdered excipients to produce the final product. Excipient(s) is /are added: Depends upon the intended use of the product Eg. Colouring, flavoring, and sweetening agents (for oral use) Example: May be blended with powdered fillers and other pharmaceutical ingredients to fabricate solid dosage forms as tablets and capsules Maybe dissolved or suspended in solvents or liquid vehicles to make various liquid dosage forms May be incorporated into semisolid bases in the preparation of medicated ointments and creams.

10 Oral powder - definitionOral powders are preparations consisting of solid, loose, dry particles of varying degrees of fineness. They contain one or more active substances, with or without excipients and, if necessary, colouring matter authorized by the competent authority and flavouring substances. They are generally administered in or with water or another suitable liquid. They may also be swallowed directly. They are presented as single-dose or multidose preparations. Multidose oral powders require the provision of a measuring device capable of delivering the quantity prescribed. Each dose of a single-dose powder is enclosed in an individual container, for example a sachet or a vial.

11 topical powder - definitionPowders for cutaneous application are preparations consisting of solid, loose, dry particles of varying degrees of fineness. They contain one or more active substances, with or without excipients and, if necessary, colouring matter authorised by the competent authority. Powders for cutaneous application are presented as single-dose powders or multidose powders. They are free from grittiness. Powders specifically intended for use on large open wounds or on severely injured skin are sterile. Multidose powders for cutaneous application may be dispensed in sifter-top containers, containers equipped with a mechanical spraying device or in pressurised containers. Powders dispensed in pressurised containers comply with the requirements of Pressurised pharmaceutical preparations.

12 Classification of powdersClassification on the basis of the use: Bulk powder for internal use Bulk powder for external use Divided or unit doses powder to internal use Insufflations for ear, nose or throat use Other preparations which may be presented as powders Antibiotic syrups to be reconstituted before use Powders for injection

13 advantages More stable than liquidShelf life of powders of antibiotic syrups is 2-3 years but once reconstituted with water, it is 1-2 weeks More convenient to swallow even in large bulk, especially if mixed with drink food. Can be taken orally by some patients who are unable to swallow other solid dosage forms such as capsules and tablets Rapid therapeutic effect due to large surface area. The smaller particle size of powders causes more rapid dissolution in body fluids, increases drug bioavailability, and decreases gastric irritation compared with tablets Fast dissolution rate for soluble medicaments Tablets and capsules must disintegrate first before the drug dissolves Drug absorption will be faster than tablets or capsule if the dissolution rate limits the rate of drug absorption

14 disadvantages Less convenient to carryAs compared to a small container of tablets or capsule Modern packaging methods for divided preparations have overcome the problem with individual doses in convenient carry package Difficult to mask unpleasant tastes Not a method of administering potent drugs with a low dose Individual doses are extracted from the bulk using a spoon and this method is subjected to variation in spoonfill and the bulk density of different batches of a powder It is not an accurate method Not suitable method for the administration of drugs which are inactivated in the stomach Not suitable for drugs unstable in atmospheric conditions

15 Particle Size of Powders The following terms are used in the description of powders: Coarse powder - Not less than 95 per cent by mass passes through a number 1400 sieve and not more than 40 per cent by mass passes through a number 355 sieve. Moderately fine powder - Not less than 95 per cent by mass passes through a number 355 sieve and not more than 40 per cent by mass passes through a number 180 sieve. Fine powder - Not less than 95 per cent by mass passes through a number 180 sieve and not more than 40 per cent by mass passes through a number 125 sieve. Very fine powder - Not less than 95 per cent by mass passes through a number 125 sieve and not more than 40 per cent by mass passes through a number 90 sieve. These term are related to the proportion of powder that is capable of passing through the opening of standard sieves of varying fineness in a specified period while being shaken, generally in a mechanical sieve shaker

16 Particle size determinationSieving Particles are passed by mechanical shaking trough a series of sieves of known and successively smaller size and the proportion of powder passing through or being withheld on each sieve is determined (range about 40 to 9500m, depending upon sieve sizes)

17 This figure represents the standard sieve numbers and the openings in each, expressed in milimeters and microns

18 Other methods Microscopic analysis (0.2 to 100 m)Sedimentation Rate (0.8 to 300 m) Light Scattering (0.2 to 500 m) Permeability methods ( 1 m) Laser diffraction analyzer (0.02 to 2000 m) Laser holography (1.4 to 100 m) Electronic particles counters Coulter counter Particle size analyzer

19 Effects of particle sizeParticle size can influence a variety of important factors, including the following: Dissolution rate of particles intended to dissolve; drug micronization can increase the rate of drug dissolution and its bioavailability Suspendability of particles intended to remain undissolved but uniformly dispersed in a liquid vehicles (e.g., fine dispersions have particles approximately 0.5 to 10 m Uniform distribution of a drug substance in a powder mixture or solid dosage form to ensure dose-to-dose content uniformity Penetrability of particles intended to be inhaled for deposition deep in the respiratory tract (e.g., 1 to 5 m) Lack of grittiness of solid particles in dermal ointments, cream, and ophthalmic preparations (e.g., fine powders may be 50 to 100 m in size)

20 Important magnitude in powder technologyFlow of powder Factors that decrease the flow of powder: Superficial adhesiveness Shape of the particles: Spherical particles flow quickly while irregular shaped particles flow slowly Surface of the particles : Wrinkled surface has low flowability while smooth surface have high flowability The presence of electrostatic charges on the surface of the particles The hygroscopicity of the powders

21 Advantages of Good Powder FlowDisadvantages of a bad powder flow: An incomplete & irregular filling of dies or bottles is achieved Advantages of Good Powder Flow Filling the dies in very short time This means complete and regular filling of dies or bottles

22 Flow enhancer or GlidantsFlow enhancers improve the flowability of the powder by reducing interparticle friction Excipients that have anti-adherent or lubricant properties may enhance powder flowability Usually glidants are hydrophobic types substance Talc Mg stearate Starch Silica gel

23 If bad flowability is due toThe humidity Hygroscopicity The use of MgO & SiO2 Lipophilic glidants decrease Disintegration of tablets Dissolution of the active material  Thus, minimum quantity of glidant should be used

24 Angle of repose Tan q = h/rThe angle of repose is a relatively simple technique for estimating the flow properties of a powder. It can easily be determined by allowing a powder to flow through a funnel and fall freely onto a surface. The height and diameter of the resulting cone are measured and the angle of repose is calculated from this equation: Tan q = h/r

25  = tan-1 (h/r) where h = height of pile r = radius of the base of the pileExcellent flowability if  < 25 Good flowability if 25 <  < 30 Passable flowability if 30 <  < 40 Very poor flowability if  > 40

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27 Mass-volume RelationshipTypes of Volume True volume (VT ) Bulk volume (VB) Relative volume (VR) VR = VB / VT VR tends to become unity as all air is eliminated from the mass during the compression process

28 Types of density Types of density

29 Tapped density = M / Tapped VThe bulk density of powder is the ratio of the mass of an untapped powder sample and its volume including the contribution of the interparticulate void volume. The bulk density is expressed in grams per millilitre (g/mL) The tapped density is obtained by mechanically tapping a graduated measuring cylinder or vessel containing the powder sample. Tapped density = M / Tapped V

30 Porosity () :

31 Preparations of PowdersReduction of particle size of all ingredients to the same range to prevent stratification. Sieving. Weighing of each ingredient. Mixing Packaging

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33 Reduction of Particle SizeAlso known as comminution of drug Objectives Facilitate crude drug extraction Increase the dissolution rates of drugs Aid in the formulation process Enhance absorption The manually operated procedures are trituration, pulverization and levigation

34 Trituration is the continuous rubbing or grinding of the powder in a mortar with a pestle. This method is used when working with hard, fracturable powders. A porcelain (rough surface) preferred than glass mortar (smooth surface) A glass mortar is preferable for chemicals that stain a porcelain. When granular or crystalline materials are to be incorporated into powdered product, these materials are comminuted individually and then blended together in the mortar.

35 Pulverization by Intervention is used with hard crystalline powders that do not crush or triturate easily, or gummy-type substances. The first step is to use an "intervening" solvent (such as alcohol or acetone) that will dissolve the compound. The dissolved powder is then mixed in a mortar or spread on an ointment slab to enhance the evaporation of the solvent. As the solvent evaporates, the powder will recrystallize out of solution as fine particles.

36 Levigation reduces the particle size by triturating it in a mortar or spatulating it on an ointment slab or pad with a small amount of a liquid in which the solid is not soluble. The solvent should be somewhat viscous such as mineral oil or glycerin. This method is also used to reduce the particle size of insoluble materials when compounding ointments and suspensions.

37 Methods of Powder MixingHand mixing 1.1 Spatulation (spatula + tile) 1.2 Trituration (mortar + pestle) 1.3 Tumbling (wide mouth closed container) Mechanical mixing

38 Small-scale Mixing Equipment1-Mortar and Pestle The pharmacist most generally employs the mortar and pestle for the small-scale mixing The mortar and pestle method is a single operation. Thus, it is particularly useful where some degree of particle size reduction as well as mixing is required as in the case of mixtures of crystalline material

39 Small-scale Mixing Equipment2- Spatulation The blending of powders with a spatula on a tile or paper used sometimes for small quantities or when the mortar and pestle technique is undesirable. It is not suitable for large quantities of powders or for powders containing one or more potent substance because homogenous blending may not occur.

40 Small-scale Mixing Equipment3- Sieving Sieving usually is employed as a pre-or post-mixing method to reduce loosely held agglomerates and to increase the overall effectiveness of blending process

41 Small-scale Mixing Equipment4- Tumbling Powder is mixed in rotating chamber Mixing is thorough but time consuming. Mostly used in industry

42 tUMBLERS

43 Planetary mixers

44 Double Cone Tumbling MixerV Type Pharmaceutical Mixer

45 Mixing of powders For Large Scale Mixing Equipment, the ideal mixer should produce a complete blend rapidly to avoid product damage it should be cleaned and discharged easily be dust-tight require low maintenance and low power consumption

46 On a large scale, various types of mills and pulverizers may be used to reduce particle size.The following figure shows one such piece of equipment, a FitzMill comminuting machine with a product containment system. Through the grinding action of rapidly moving blades in the comminuting chamber, particle are reduced in size and passed through a screen of desired dimension to the collection container. The collection and containment system: Protects the environment from chemical dust Reduces product loss Prevents product contamination

47 Blending powders When two or more powdered substances are to be combined to form a uniform mixture, it is best to reduce the particle size of each powder individually before weighing and blending Depending on the nature of the ingredients, the amount of powder, ad the equipment, powders may be blended by spatulation, trituration, sifting and tumbling

48 Factors In Blending Size Shape Density Electrostatic Forces Limits of Blend Segregation Mechanisms

49 Segregation Segregation is an undesirable separation of the different components of the blend. Segregation may occur by sifting or percolation, air entrapment(fluidization), and particle entrapment (dusting) Fine particles tend to sift or percolate through course particles and end up at the bottom of the container and actually ‘lift’ the larger particles to the surface Dusting occurs when the finer, lighter particles remain suspended in air longer and do not settle as quickly as the larger or denser particles

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52 Problems encountered in powDer formulationHygroscopic and Deliquescent Powder Efflorescent powders Eutectic Mixtures Explosive mixtures

53 1-Hygroscopic and Deliquescent PowderProblem: Absorption of moisture from air leading to partial or complete liquefaction Solution: Reduce the amount of surface area exposed to the moisture Packed in aluminium foil or in plastic film packets Addition of light magnesium oxide to reduce the tendency to damp Addition of adsorbent materials such as starch Examples: Ammonium Bromide/Chloride/Iodide, Calcium Bromide/Chloride, Ephedrine Sulfate Hyoscyamine HBr/Sulfate, Lithium Bromide, Phenobarbital Sodium, Potassium Acetate/Citrate

54 2-EFFLORESCENT POWDERS(Is the loss of water (or a solvent) of crystallization from a hydrated or solvated salt to the atmosphere on exposure to air). Problem: Crystalline substances which during storage loose their water of crystallization and change to powder (to be efflorescent). The liberated water convert the powder to a paste or to a liquid. Examples: Alum-atropine sulphate- citric acid- codeine phosphate.. Solution: Using the anhydrous form + treating it in manner similar to hygroscopic powder (include drying bulky powder)

55 3- Eutectic Mixtures A proportion of components that will give the lowest melting point Problem: mixture of substances that liquefy when mixed, rubbed or triturated together. The melting point of many eutectic mixtures are below room temperature Examples: menthol – thymol- phenol- salol- camphor… Solution: A- using inert adsorbent such as starch, talc, lactose to prevent dampness of the powder B- dispensing the components of the eutectic mixture separately

56 4-Explosive mixtures Oxidising agents give oxygen to another substance. Reducing agents remove oxygen from another substance. Problem: oxidizing agents (ex. Pot. Salt of chlorate, dichromate, permanganate and nitrate-sod. Peroxide- silver nitrate and silver oxide explore violently when triturated in a mortar with a reducing agents (ex. Sulfides- sulphur- tannic acid- charcoal). Solution: A- comminute each salt separately B-subject to a minimum pressure

57 Shelf life and storage of internal powdersShelf life of internal powders is 2-4 weeks Proprietary powders often have a longer shelf life because of protective packaging Storage for these powders should be moisture proof and airtight

58 Shelf life and storage of external powdersShelf life of external powders is 4 weeks Dry powders should remain stable for long period of time if packaged and protected from atmosphere Store in a cool and dry place

59 Containers for internal powdersExtemporaneously prepared individually wrapped of powders are often dispensed in a paperboard box It is preferable to use a screw-top glass or plastic container which provides an air tight seal and protection against moisture Bulk powders are packed in an airtight glass or plastic jar

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61 Containers for external powdersPowders for external use may be packed in glass, metal or plastic containers with a sifter type cap. Some are also available commercially in pressurized containers, containing other excipients such as propellant and lubricants

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63 GRANULES

64 GRANULES - DEFINITION Granules are preparations consisting of solid, dry aggregates of powder particles sufficiently resistant to withstand handling. They are intended for oral administration. Some are swallowed as such, some are chewed and some are dissolved or dispersed in water or another suitable liquid before being administered. Granules contain one or more active substances with or without excipients and, if necessary, colouring matter authorised by the competent authority and flavouring substances. Granules are presented as single-dose or multidose preparations. Each dose of a multidose preparation is administered by means of a device suitable for measuring the quantity prescribed. For single-dose granules, each dose is enclosed in an individual container, for example a sachet or a vial.

65 Granules - DEFINITION A dosage form consist of powder particles which have been aggregated to form a larger particle (2-4 mm diameter) This is much larger than granules prepared as an intermediate for tablet manufacture

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69 REASONS FOR GRANULATION1. To prevent segregation of the constituents of the powder mix Segregation is due to differences in the size or density of the components of the mix, the smaller and/or denser particles concentrating at the base of a container with the larger and/or less dense ones above them An ideal granulation will contain all the constituents of the mix in the correct proportion in each granule, and segregation of the ingredients will not occur

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71 It is also important to control the particle size distribution of the granules because, although the individual components may not segregate, if there is a wide size distribution the granules themselves may segregate. If this occurs in the hoppers of capsule-filling machines or tablet machines, products with large weight variations will result. This is because these machines fill by volume rather than weight, and if different regions in the hopper contain granules of different sizes (and hence bulk density), a given volume in each region will contain a different weight of granules. This will lead to an unacceptable distribution of the drug content within the batch of finished product.

72 2. To improve the flow of the mixtureMany powders, because of their small size, irregular shape or surface characteristics, are cohesive and do not flow well. Poor flow will often result in a wide weight variation within the final product owing to variable fill of tablet dies etc. Granules produced from such a cohesive system will be larger and more isodiametric, both factors contributing to improved flow properties.

73 3. To improve the compaction characteristics of the mixtureSome powders are difficult to compact even if a readily compactable adhesive is included in the mix, but granules of the same formulation are often more easily compacted and produce stronger tablets. This is associated with the distribution of the adhesive with the granule. Often solute migration occurring during the postgranulation drying stage results in a binder-rich outer layer to the granule. This in turn leads to direct binder-binder bonding, which assists the consolidation of weakly bonding materials.

74 4. Reduce the hazerd of toxic dust powderThe granulation of toxic materials will reduce the hazard associated with the generation of toxic dust that may arise when handling powders. Suitable precautions must be taken to ensure that such dust is not a hazard during the granulation process. Thus granules should be non- friable and have a suitable mechanical strength.

75 5. Reduce the hazard of hygroscopic powder adhesionMaterials which are slightly hygroscopic may adhere and form a cake if stored as a powder. Granulation may reduce this hazard, as the granules will be able to absorb some moisture and yet retain their flowability because of their size. 6. More convenient for storage Because granules are denser than the powder mix, they occupy less volume per unit weight. They are therefore more convenient for storage or shipment.

76 Categories of granulesSeveral categories of granules may be distinguished: effervescent granules coated granules gastro-resistant granules modified-release granules

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85 METHOD OF PREPARATION Granules are generally prepared by two methodsDry method Wet method

86 Dry granulation In the dry methods of granulation, the primary powder particles are Granulation: (aggregation) under high pressure without the use of a liquid using one of the following processes. Roller compactors Sluggers Milling: The intermediate products are broken using a suitable milling technique to produce granular material, which is usually sieved to separate the desired size fraction. The unused fine material may be reworked to avoid waste.

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90 Roller compactors Alexanderwerk roller compactors

91 Hut Roller compactor

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94 ADVANTAGES OF DRY GRANULATIONAvoid heat-temperature combinations that might cause degradation Thus dry method may be used for drugs which are sensitive to moisture

95 Wet granulation Wet granulation involves the massing of a mix of dry primary powder particles using a granulating fluid The fluid contains a solvent which must be volatile so that it can be removed by drying, and be non-toxic The granulation liquid may be used alone or, more usually as a solvent containing a dissolved adhesive (binding agent) which is used to ensure particle adhesion once the granule is dry In the traditional wet granulation method the wet mass is forced through a sieve to produce wet granules which are then dried. A subsequent screening stage breaks agglomerates of granules and removes the fine material, which can than be recycled.

96 Typical liquids includeWater ethanol and isopropanol, either alone or in combination.

97 The primary advantages of water are that: It is non-flammable, which means that expensive safety precautions not be taken. Water is commonly used for economical reasons. Disadvantages of water as a solvent are that: It may adversely affect drug stability, causing drug hydrolysis. It needs a longer drying time than do organic solvents, that increases the length the process and again may effect stability because of the extended exposure to heat Organic solvents are used when water-sensitive drugs are processed, as an alternative to dry granulation, or when a rapid drying time is required.

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100 Wet granulators There are many types of granulators used in the pharmaceutical industry for wet granulation. Shear granulators High speed mixers/granulators Spray driers Spheronizers/pelletizers Rotor granulators

101 SHEAR GRANULATORS Planetary mixerPowder mixing in a separate operations using suitable mixing equipment A planetary mixer is used for wet massing of the powders With some formulations, such as those containing two or three ingredients in equal quantities, it is suitable to mix power in the planetary mixer The mixed powders are fed into the bowl of the planetary mixer and granulating liquid is added as the paddle of the mixer agitates the powders. Planetary mixer

102 The moist mass has been transferred to a granulator, as oscillating granulator.The rotor bars of the granulator oscillate and force the moist mass through the sieve screen, the size of which determine granule size The mass should be sufficiently moist to form discrete granules when sieved. If excess liquid is added, string (filament) of material will be formed and if the mix is too dry the mass will be sieved as powder and granules will not be formed.

103 The granules can be collected on trays and transferred to a drying ovenTray drying has three major disadvantages: 1. The drying time is long. 2. Dissolved material can migrate to the upper surface of granules’bed, as the solvent is only removed from the upper surface of the bed on the tray. 3. Granules may aggregate owing to bridge formation at the points of contact of the granules. To deaggregate the granules and remix them, a sieving stage is necessary after drying.

104 Advantages of shear granulation processThe process is not very sensitive to changes in the characteristic of the granule ingredients (e.g surface are variations in different batches of an excipient) The end-point of the massing process can often be determined by examination. The disadvantages of Shear granulation process: Long duration The need for several pieces of equipment The high material losses because of the transfer stages

105 High speed mixer/granulatorsThe granulator has a stainless steel mixing bowl containing a three-bladed main impeller, which revolves in the horizontal plane, and a three bladed auxiliary chopper (breaker blade) which revolves either in the vertical or the horizontal plane.

106 The unmixed dry powders are placed in the bowl and mixed by the rotating impeller for a few minutes.Granulating liquid is then added via a port in the lid of the granulator while the impeller is turning. The granulating fluid is mixed into the powders by the impeller. The chopper is usually switched on when the moist mass is formed, as its function is to break up the wet mass to produce a bed of granular material. Once a granule has been produced, the granular product is discharged, passing through a wire mesh which breaks up any large aggregates, into the bowl of a fluidized-bed drier.

107 Advantages of high speed mixer granulation:Mixing and granulation are all performed within a few minutes in the same piece of equipment. Disadvantages of high speed mixer/granulation: The process need to be controlled with care as the granulation progresses so rapidly that a usable granule can be transformed very quickly into an unusable, overmassed system. Thus it is often necessary to use suitable monitoring system to indicate the end of the granulation process, i.e when a granule of the desired properties has been attained The process is also sensitive to variations in raw materials, but this may be minimized by using a suitable end-point monitor.

108 Fluidizer-bed granulator

109 Fluidizer-bed granulator (glatt)The powder particles are fluidized in a stream of air Granulation fluid is pumped from a reservoir and sprayed from a nozzle on to the bed of powders Heated and filtered air is blown through the bed of unmixed powders to fluidize the particles and mix the powders

110 The fluid causes the primary powder particles to adhere when the droplets and powders collideEscape of material from the granulation chamber is prevented by exhaust filters, which are periodically agitated to reintroduce the collected material into fluidized bed Sufficient liquid is sprayed to produce granules of the required size, at which point the spray is turned off but the fluidizing air continued The wet granules are then dried in the heated fluidizing air stream

111 Fluidized-bed granulatorsAn alternative method is to dry the granules using a fluidized-bed drier This is quicker and as it keeps the individual granules separated during drying. It reduces the problems of aggregation and intergranular solute migration, thereby reducing the need for a sieving stage after drying

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113 Advantages of fluidized-bed granulationAll the granulation processes, which require separate equipment in the conventional method, are performed in one unit, saving labor cost, transfer losses and time. The process can be automated once the conditions affecting the granulation have been optimized. Disadvantages of fluidized-bed granulation The equipment is expensive Optimization of process parameters affecting granulation needs extensive development work.

114 Spray-driers Granular product is made form a solution or a suspension rather than initially dry primary powder particles. The resultant granules are free-flowing hollow spheres and the distribution of the binder in such granules results in good compaction properties.

115 Spray drying can convert hard elastic materials into more ductile ones The primary advantages of the process are the short drying time and the minimal exposure of the product to heat owing to the short residence time in the drying chamber. This means that little deterioration of heat sensitive materials takes place.

116 Spheronizers /PelletizersFor some applications it may be desirable to have a dense, spherical pellet of the type difficult to produce with the previous equipments. Such pellets are used for controlled drug release. A commonly used process involves: Separation of wet massing. Extrusion of this wet mass into Rod-shaped granules and subsequent spheronization of these granules.

117 Advantage of granulation using Extrusion/SpheronizationExtrusion/spheronization process is used to make uniformly sized spherical particels It is used primarily to produce multiparticulates for controlled drug release applications The major advantaged over other methods of producing drug loaded spheres or pellets is the ability to incorporate high levels of active ingredients without producing excessively large particles (minimal excipients) Ideal flow behavior and disability Compact structure Low hygroscopicity High bulk density

118 The main steps of the process are:

119 Extrusion Schematic representation of production extruder

120 Spheronization The function of spheronization is to round off the rods produced by extrusion into spherical particles. This is carried out in spheronizer which consists of a bowl with fixed side walls and a rapidly rotating bottom plate or disc. The rounding of the extrudate into spheres is dependent on frictional forces generated by particle-particle and particle equipment collisions.

121 ROTOR GRANULATION In the Freund granulator, the powder mixture is added to the bowl and wetted with granulating liquid form a spray. The base plate rotates at high speed and centrifugal force keeps the moist mass at the edges of the rotor

122 The velocity difference between the rotor and the static walls, combined with the upward flow of air around the rotor plate, causes the mass to move in a toroidal motion, resulting in the formation of isolated spherical pellets. The spheres are dried by the heated inlet air from the air chamber, which acts as a positive pressure seal during granulation.

123 Process principle Powder is mixed and moistened and the powder bed set into centrifugal motion (fluid bed pelletizing in the rotor) The impact and acceleration forces that occur in this process result in the formation of agglomerates, which become rounded out into uniform and dense pellets and then dried

124 Principle of the powder layering processUsing this technique it is possible to continue the process and coat the pellets by spraying coating solution on to the rotating dried pellets. In layered pellets can be produced by using uncoated pellets as nuclei in a second granulation with a powder mix of a second ingredient or ingredients.

125 GRANULATION MECHANISMSTo form granules, sufficiently strong bonds must be formed between powder particles so that they adhere and prevent breakdown of the granule to powder during handling. There are four primary bonding mechanisms between particles: Adhesion and cohesion forces in the immobile liquid films between individual primary powder particles. Interfacial forces in mobile liquid films within the granules. The formation of solid bridges after solvent evaporation. Attractive forces between solid particles.

126 Granulation PropertiesThe process variables involved in the granulation steps (formulation ingredients and their concentrations, the type of granulating equipment and processing conditions employed) can affect the characteristics of the granulations produced. Particle Size and Shape. Surface Area. Density. Strength and Friability. Flow Properties. Compaction.

127 Particle Size and Shape.The particle size of a granulation is known to affect the average tablet weight, disintegration time, granule friability, granulation flowability and the ding rate kinetics of wet granulations.

128 Surface Area. The surface area of the drug has a significant effect upon dissolution rate. An inverse relationship normally exists between particle size and surface area; Methods for determining surface area of solid particles are gas adsorption and air permeability. In gas adsorption method, the amount of gas that is adsorbed onto the powder to form a monolayer is measured and then used to calculate the surface area of the powder sample. Air permeability, the rate at which air permeates a bed of powder, is used to calculate the surface area of the powder sample.

129 Density Granule density may influence compressibility, tablet porosity and dissolution. Dense, hard granules may require higher compressible loads to produce a cohesive compact. The higher compression load, increase the tablet disintegration and drug dissolution times. Even if the tablets disintegrate readily, the harder, denser granules may dissolve less readily.

130 Methods used to determine granule density involve the use of a pycnometer.Where, the intrusion fluid is mercury, and in the other, it is a solvent of low surface tension (e.g., benzene) in which the granules are not soluble. These pycnometer methods depends on the ability of the intrusion fluids to penetrate the pores of the granules.Density is calculated from the volume of intrusion fluid displaced in the pycnometer by a given mass of granulation

131 Strength and FriabilityA granule is an aggregation of component particles that is held together by bonds of finite strength. The strength of a wet granule is due to the surface tension of liquid and capillary forces. These forces are responsible for initial agglomeration of the wet powder. Upon drying, the granule has strong bonds resulting from fusion or recrystallization of particles and curing of the adhesive or binder.

132 Measurements of granule strength estimate the magnitude of attractive forces that hold the granule together The resultant strength of a granule depends on base material, the kind and amount of granulating agent used and the granulating equipment used Granule strength and friability are important, as they affect changes in particle size distribution of granulations and compressibility into cohesive tablets

133 Methods used for measuring granule strength are:Compression strength. Where a granule is placed between anvils, and the force required to break the granule is measured. Friability measurements. measuring the tendency of granules to break into smaller pieces when subjected to disturbing forces.

134 Flow properties Frictional forces Surface tension forcesMechanical forces caused by interlocking of particles of irregular shape Electrostatic forces Cohesive or van der waals forces They can affect granule properties such as: Particle size, particle size distribution, particle shape, surface texture or roughness, surface energy, and surface area.

135 With fine powders (<150m), the magnitude of the frictional and van der waals forces are predominate For larger particles (>150m) such as granules produced by a wet granulation, frictional forces are predominate by a wet granulation, frictional forces are predominate over van der waals forces Flow measure the effect of all the interparticulate forces acting at once Two methods are used: Angle of repose Hopper flow rate measurements

136 compaction The process of compacting powder or granule materials to form a tablet is complex, owing to the numerous internal events that act simultaneously. The basic tool that has been developed for studying the compression process is the tablet press. Tablet presses are instrumented by affixing transducers to measure the forces applied during the compression process. The signals produced by the transducer system are monitored by computer.

137 Effervescent granulesEffervescent salts are granules or coarse powder containing a medicinal agent in a dry mixture usually composed of sodium bicarbonate, citric acid, and tartaric acid. When added to water, the acids and base react to liberated carbon dioxide, resulting in effervescence. The resulting carbonated solution masks the usually saline or undesirable taste of the medicinal agent present.

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144 Powders and granules Saya akana Ggggg hhhh Hhhh

145 Powders and granules Saya akana Ggggg hhhh Hhhh

146

147

148