all about tablets (pharma)
TRANSCRIPT
- Introduction
- Excipients
- Tablet Manufacturing Process
- Solid Dosage Processing
- Unit Operations
- Processing Problems
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 ExamplesFillers 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
A. Diluents
B. Binders
C. Lubricants
D. Disintegrators
E. 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
PrimaryPackaging
SecondaryPackaging
API FinishedProduct
Starting Materials(Chemicals)
Drug product manufacture
Dosage Form
Wetgranulation
milling
blending
Fluid Bed Dryer
lubrication
tabletingcoating
imprintingProcess combines the drug and excipients into the dosage form
Excipients API
crystallization
filtration
oven drying
Dry granulation/ milling
Directcompression
Flow Chart
APIFiller Mixing of
granulation blend
GranulationBinder(s)Preparation of binder solution
Drying
Milling
LOD
Disintegrant
screening
screening Initial Blending
lubricant screening Final Blending
Compression
SolventFilm coating agent Preparation
Film Coating of Tablets
Packaging and Labelling
WeightHardnessFriability
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 ProblemsEnterprise 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 StabilityParticle 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
DrugDiluentGlidantDisintegrant
Lubricant Mixing
Mixing
Dry Granulation
Disintegrant GlidantLubricant
DrugDiluentLubricant
Mixing
Compression
Comminution
Screening
Mixing
Mixing
Wetting
Granulation
Drying
Screening
Mixing
DrugDiluent
BinderSolvent
Disintegrant GlidantLubricant
Wet Granulation
Other Routes
Fluidized bed granulationExtrusion / 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
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
• 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
YTc
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 screensByers, 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
1 1PR R
P F
m tE CW x x
lnP FK K
P
m t xE CW x
Energy based analysis – ball millKick’s LawHigh loadingLow frequencyRolling attrition
Rittinger’s LawLow loadingHigh frequencyImpact fragmentation
1F
PR
xxk t
exp( )p F Kx x k t
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 sizeWhat 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
Manufacturing Instructionsscreening
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
• 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 FlowBlender
Bin Blender
Double ConeBlender
Blending – convective mixingRibbon Blenders Orbiting Screw Blenders
Planetary Blenders
Horizontal Double Arm Blenders
Forberg Blenders
Vertical High Intensity Mixers
Horizontal High Intensity MixersDiffusion 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 particlesWhat 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 oftablet manufacturing
Mixer and blender
05/02/202355
Granulation
• 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 rollcompactor 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
A. 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
(A) 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
(A) 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 agglomeratesWhat 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
startTime 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 dryerFluid bed dryer
• 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 FilterCondensorSteamDamper
Damper Outlet Filter
Air Flow
ProductTemperature
InletTemperature
OutletTemperature
From Granulator
To Mill
Drying Zone
Filter Bag
Air Flow
RetainingScreein
• 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
Powders intended for compression into tablets must possess two essential properties:
1. Powder fluidityThe 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.
2. 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
1. Large particles must be used → (acceptable flowability and bulk density)2. Many active ingredients are not compressible either in crystalline or amorphous
forms. 3. Needs directly compressible filler that is usually expensive, e.g. microcrystalline
cellulose (Avicel), spray dried lactose 4. Problems in the uniform distribution of low dose drugs.5. High dose drugs having high bulk volume, poor flowability and poor compressibility
are not suitable for direct compression. For example, Aluminium Hydroxide, Magnesium Hydroxide
6. 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
1. 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).
2. 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.
3. 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 pressh o p p e r
f e e d
s h o e
l o w e r
p u n c h
d i e
u p p e r
p u n c h
t a b l e t w e i g h t
a d j u s t o r
t a b l e t e j e c t o r
a d j u s t o r
t a b l e t
h a r d n e s s
a d j u s t o r
S c h e m a t i c d i a g r a m o f t h e m a i n
c o m p o n e n t s o f s i n g l e - p u n c h p r e s s
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c a v i t y
Core components:1. Die
2. Lower punch
3. 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 punchB: die cavityC: dieD: 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 byUpper 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 ResultsMachine speed 20 rpm (15-25 rpm)Wt. of 20 tabs 12.00g +2 (11.76-12.24g)Theoretical weight/tab 600mgHardness 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 minsWt. variation + 3% of Av. Wt.Friability (10 tabs) NMT 1.0% w/w
In-process Checks
Parameter FrequencyWt. 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
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 AirRotation
Baffle
Spray Nozzle
Air Flow
Inlet FilterSteamInlet
Temperature
Inlet Air
Outlet Air
Outlet Filter
OutletTemperature
Coating/Polishing
• Principle: Application of coating solution to a moving bed of tablets with concurrent use of heated air to facilitate evaporation of solventWhat 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)
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Packaging
• 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
• 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 granulesLamination 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).
Mottling
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