Pharmaceutical Technology

Part 1By: Dr. ABDRHMAN GAMIL

Associate Professor of PharmaceuticsAl-Neelain University - Khartoum

Pharmaceutical Preparations

• DEFINITION

Pharmaceutical preparations are medicinal products generally consisting of active

substances that may be combined with excipients, formulated into a dosage form

suitable for the intended use, where necessary after reconstitution, presented in a

suitable and appropriately labelled container.

Types of Pharmaceutical Preparations

• Pharmaceutical preparations may be licensed by the competent authority, or unlicensed and made to the specific needs of patients according to legislation. There are 2 categories of unlicensed pharmaceutical preparations:• — extemporaneous preparations, i.e. pharmaceutical preparations individually prepared for a specific patient or patient group, supplied after preparation;• — stock preparations, i.e. pharmaceutical preparations prepared in advance and stored until a request for a supply is received.

Unlicensed Preparations should comply the pharmacopoeial requirements, risk assessment and ethics guidelines.

PRODUCTION

• Manufacture/preparation must take place within the framework of a suitable quality system and be compliant with the standards relevant to the type of product being made. Licensed products must comply with the requirements of their license.• Formulation• During pharmaceutical development or prior to manufacture/preparation, suitable

ingredients, processes, tests and specifications are identified and justified in order to ensure the suitability of the product for the intended purpose. This includes consideration of the properties required in order to identify whether specific ingredient properties or process steps are critical to the required quality of the pharmaceutical preparation.• Active substances and excipients• Active substances and excipients used in the formulation of pharmaceutical preparations

comply with the requirements of the relevant pharmacopoeial monographs,• physicochemical characteristics of active substances and functionality-related

characteristics (FRCs) ofexcipients (e.g. particle-size distribution, viscosity, polymorphism)

• Microbiological quality• The formulation of the pharmaceutical preparation and its container must ensure

that the microbiological quality is suitable for the intended use.• A suitable container is selected. Consideration is given to the intended use of the

preparation, the properties of the container, the required shelf-life, and product/container incompatibilities.• Stability requirements of pharmaceutical preparations are dependent on their

intended use and on the desired storage time.• TESTS• Relevant tests to apply in order to ensure the appropriate quality of a particular

dosage form are described in the specific dosage form monographs.

• Appearance: size shape and colour.• Identification • identification of the active substance(s);

— identification of specific excipient(s), such as preservatives;— purity tests (e.g. investigation of degradation products, residual solvents or other related impurities, sterility.— safety tests (e.g. safety tests for biological products).

• Uniformity; Pharmaceutical preparations presented in single-dose units comply with the test(s) as prescribed in the relevant specific dosage form monograph. • ASSAY• Unless otherwise justified and authorised, contents of active substances and specific excipients

such as preservatives are determined in pharmaceutical preparations. Limits must be defined and justified.• Suitable and validated methods are used. If assay methods prescribed in the respective active

substance monographs are used, it must be demonstrated that they are not affected by the presence of the excipientsand/or by the formulation.

• Reference standards• LABELLING AND STORAGE• The relevant labelling requirements given in the general dosage form monographs apply.

Tablets Introduction

Tablets

• DEFINITION• Tablets are solid preparations each containing a single dose of one or more

active substances. They are obtained by compressing uniform volumes of particles or by another suitable manufacturing technique, such as extrusion, moulding or freeze-drying (lyophilisation). Tablets are intended for oral administration. Some are swallowed whole, some after being chewed, some are dissolved or dispersed in water before being administered and some are retained in the mouth where the active substance is liberated.• The particles consist of one or more active substances with or without

excipients such as diluents, binders, disintegrating agents, glidants, lubricants, substances capable of modifying the behaviour of the preparation in the digestive tract, colouring matter authorised by the competent authority and flavouring substances.• Tablets are usually straight, circular solid cylinders, the end surfaces of which

are flat or convex and the edges of which may be bevelled. They may have break-marks and may bear a symbol or other markings. Tablets may be coated.

Categories of tablets for oral use

1. — uncoated tablets;2. — coated tablets;3. — gastro-resistant tablets;4. — modified-release tablets;5. — effervescent tablets;6. — soluble tablets;7. — dispersible tablets;8. — orodispersible tablets;9. — chewable tablets;10.— tablets for use in the mouth;11.— oral lyophilisates.

Uncoated Tablets

• Uncoated tablets include single-layer tablets resulting from a single

compression of particles and multi-layer tablets consisting of concentric

or parallel layers obtained by successive compression of particles of

different composition. The excipients used are not specifically intended

to modify the release of the active substance in the digestive fluids.

COATED TABLETS

• Coated tablets are tablets covered with one or more layers of mixtures of various substances such as natural or

synthetic resins, gums, gelatin, inactive and insoluble fillers, sugars, plasticisers, polyols, waxes, colouring matter

authorised by the competent authority and sometimes flavouring substances and active substances. The

substances used as coatings are usually applied as a solution or suspension in conditions in which evaporation of

the vehicle occurs. When the coating is a very thin polymeric coating, the tablets are known as film-coated tablets.

• Coated tablets have a smooth surface, which is often coloured and may be polished; a broken section, when

examined under a lens, shows a core surrounded by one or more continuous layers with a different texture.

GASTRO-RESISTANT TABLETS• Gastro-resistant tablets are delayed-release tablets that are intended to resist the

gastric fluid and to release their active substance(s) in the intestinal fluid. Usually

they are prepared from granules or particles already covered with a gastro-

resistant coating or in certain cases by covering tablets with a gastro-resistant

coating (enteric-coated tablets).

MODIFIED-RELEASE TABLETS

• Modified-release tablets are coated or uncoated tablets that contain special

excipients or are prepared by special procedures, or both, designed to modify the

rate, the place or the time at which the active substance(s) are released.

• Modified-release tablets include prolonged-release tablets, delayed-release

tablets and pulsatile-release tablets.

EFFERVESCENT TABLETS

• Effervescent tablets are uncoated tablets generally containing acid substances

and carbonates or hydrogen carbonates, which react rapidly in the presence of

water to release carbon dioxide. They are intended to be dissolved or dispersed in

water before administration.

• SOLUBLE TABLETS

• Soluble tablets are uncoated or film-coated tablets. They are intended to be

dissolved in water before administration. The solution produced may be slightly

opalescent due to the added excipients used in the manufacture of the tablets.• DISPERSIBLE TABLETS

• Dispersible tablets are uncoated or film-coated tablets intended to be dispersed

in water before administration, giving a homogeneous dispersion.

• Orodispersible tablets• Orodispersible tablets are uncoated tablets intended to be placed in the mouth

where they disperse rapidly before being swallowed.

• CHEWABLE TABLETS• Chewable tablets are intended to be chewed before being swallowed.

• TABLETS FOR USE IN THE MOUTH• Tablets for use in the mouth are usually uncoated tablets. They are formulated to

effect a slow release and local action of the active substance(s) or the release and absorption of the active substance(s) at a defined part of the mouth.• ORAL LYOPHILISATES• Oral lyophilisates are solid preparations intended either to be placed in the

mouth or to be dispersed (or dissolved) in water before administration.

Tablets administered by other routes

•Implantation tablets: • depot tablets to be implanted subcutaneously under the skin for

prolonged release of the therapeutic agent. these tablets should be sterile.

•Vaginal tablets: • They are tablets prepared by compression intended to be inserted

into the vaginal cavity by special insertion device. It contains soluble substances with adjusted pH.

Advantages of Tablets1. Accurate stable dose with high precision and uniformity.2. Easy to carry, handle and use.3. Attractive, convenient and elegant in appearance.4. Physically, chemically and microbiologically more stable dosage form.5. High speed production, bulk production could be attained and hence lowers the cost.6. Packaging and shipping is easy and of low cost.7. Unpleasant taste and odour can be masked.8. Wide range of tablet types offering range of release rates and duration of clinical

effects.9. Can offer release of active substance at a particular site. 10. Combination of more than one therapeutic agent.11. Tablet can be divided offering different doses for use.12. All classes of therapeutic agents with exception of proteins can be formulated in

tablet form13. Easy to be identified due to differences in shapes and colours.

Disadvantages1. Increased product loss due to the long series of unit process.2. Absorption is dependent in physiological factors giving interpatient

variations.3. Poor compressibility of certain therapeutic agents.4. Difficulty in administration to certain groups like children but swallow

problems can be overcome by using effervescent tablets .5. Agents that are liquid in nature is difficult to be formulated as tablets.6. Oxygen sensitive agent may require special measures. 7. Drugs having poor wetting properties, slow dissolution profile and high

optimal gastrointestinal absorption are difficult to be formulated as tablets.

Characteristics required

1. Deliver the correct amount of drug in a proper form at or over proper time.

2. Elegant free from defects like cracks, chips, contamination, discolouration …etc.

3. Maintain its chemical and physical integrity over time.

4. should be capable to maintain the chemical and physical properties of the therapeutic

agent.

5. Withstand the rigorous mechanical shocks during manufacturing, shipping and storage.

6. Release medicaments in the body in predictable and reproducible manner.

Formulation of tablets

1. Active Pharmaceutical Ingredients ( API ).

2. Excipients

Desired Properties of API1. Purity :In accordance with the respective pharmacopoeia.2. High stability3. Compatibility with excipients: e.g primary amine and lactose.4. Optimum bulk powder properties to have good flow, prevent segregation and to

optimize the tablet size.5. Uniformity of particle size distribution to obtain uniformity in content, uniformity in

weight, disintegration time, friability, drying rate uniformity, enhanced powder flow, good compression, regular dissolution and bioavailability. fine particles increase surface area hence increases the surface energy giving good compressibility.

6. Spherical shape provides good flow. Irregular particle shape may lead to interlocking

Desired Properties of API - contd7. Good powder flow: measured using angle of repose and can be improved by addition of glidants, addition of fines, using wet granulation and increase the density.8. Optimum moisture content: lack of moisture in brittle tablets. increased moisture affects uniformity of content, make sticking and picking• Moisture can be controlled by;

Use of anhydrous salt Use of nonaquous solvent. Optimum drying time. Addition of adsorbent like Magnesium oxide.

9. Good compressibility. This is an intrinsic nature of elasticity, plasticity and brittle fracture of particles upon compression.10. Absence of static charges and if any can be removed by granulation, addition of diluent or lubricant or coating by colloidal silica.11. Good organoleptic properties.

Excipients – (Additives) Diluents

Binders

Lubricants

Glidants

Disintegrants

Coloring Agents

Flavoring Agents

Sweeting Agents

•Toxicity. •Availability.•Compatibility.• Stability.•Bioavailability.•Cost.

Functions of excipients.

•Operation run

satisfactory.

• Ensure that tablets of

specified quality are

prepared.

• Impart weight, accuracy and volume.• Improve solubility• Increase stability.• Enhance bioavailability.•Modify drug release.• Assist product identification.• Increase patient acceptability.• Facilitate dosage form design.

Diluents / Fillers • Normally tablet size is more than 50 mg and diameter above 2-3 mm. Fillers

increase the bulk of the powder to produce the desired size.

• Secondary functions are to improve the powder cohesion, to allow direct

compression, to enhance powder flow and to adjust the weight as per die

capacity.

• It constitutes 5 – 80% of the tablet weight.

General properties of diluents• Chemically inert and of no microbiological load.• No-hygroscopic.• Compatible to the manufacturing process and other tablet

constituents.• Good and consistent biochemical properties.• Fair compactibility and dilution capacity.• Acceptable taste and color.• Low cost.

Types of diluentsI. Organic:

Starch, sugars, cellulose derivatives.II. Inorganic:

Calcium phosphates.III. Co- processed diluents.

combining two or more materials by appropriate process.

Starch • It is polysaccharide composed of amylose and amylopectin.• Pregelatinised grade which provide free flow of powder. • Used as a diluent, binder and disintegrant…… details later.

Lactose – different particle size, crystal form and properties.Property Monohydrate Anhydrous Spray dried

Moisture content 5% Pick up moisture at high RH

Depend on the extend of drying

Flow Poor Poor Free flow

Compressibility Wet granulation Directly compressible Directly compressible

Maillard reaction Take place In the presence of moisture

In presence of excess moisture

Cost Cheap Cheap Expensive

Solubility Soluble Soluble Soluble

Disintegrant Needed No need No need

Mannitol • Generally used for chewable tablets due to inherent sweetness

and negative heat of solution properties.

• Unlike sucrose it is free from grittiness.

• Most expensive sugar.

• It requires high lubricant content.

• Often combined with its isomer sorbitol.

Celluloses – Microcrystalline cellulose MCC

• Highly compressible and widely used in direct compression.

• Hard tablet at low compression can be obtained.

• Fair flow.

• Binding and disintegration properties.

• Commonly used grades are Avicel pH 101, Avicel pH 102.

PH : Pharmaceutical use NOT pHAvicel PH 101 : Nominal particle size 50 micronsAvicel PH 102 : Nominal particle size 100 microns

Calcium Phosphates - • Excellent compressibility and flow.

• Bulk density is higher.

• Hard tablets are obtained.

• Non – hygroscopic and inexpensive.

• Because of its alkalinity in moisture it is a source of instability in acidic products.

• Interact with some API such as Tetracycline.

• Dibasic calcium phosphate, dicalcium phosphate, calcium hydrogen phosph dehydrate.

• Tribasic calcium phosph, tricalcium phosph, tricalcium orthophosphate.

Binders – Adhesives

• Added to cause particles of drug and other excipients to cohere into a granular form of required mechanical strength.• It can be termed as granulating agent.• Generally binders are polymeric in nature.

Types of bindersSugars Natural Synthetic / semisynthetic

polymers

• Sucrose

• Liquid sucrose Acacia Tragacanth Gelatin Starch paste Pregelatinized starch Alginic acid Cellulose

Methylcellulose EthylcelluloseHydroxypropylmethylcellulose HPMCHydroxypropylcellulose Sodium carboxymethylcellulosePolyvinylpyrrolidone PVPPolyethylene glycol PEGPolyvinyl alcoholPolymethacrylates

•List of Direct Compression Binders

o MCC ( Avicel pH 101 )

o Silicified microcrystalline cellulose.

o Partialy Pregelatinized Starch.

o Low density starch.

o DC lactose anhydrous.

o DC- Dibasic calcium phosphate dihydrate.

Characters of Commonly Used BindersBinder Concentration Characters

Starch paste 5 – 25% w/w Freshly prepared paste.

Pregelatinized starch

5 – 10% w/w Direct compression

Starch that processed chemically and mechanically to rupture all or part o granules in the presence of water then dried.

Partially & Fully PGS

5 – 75% w/wWet granulation

Obtained from potato, maize or rice starch. Used as diluent, binder, disintegrant and flow aid. Can use cold water.

HPMC 2 – 5% w/w Can be used in either wet or dry granulation.

PVP 0.5 – 5% w/w added to powder blend in dry state then water is added during granulation.

PEG 10 – 15% w/w Used as meltable binder. Anhydrous granulating agent. I improve plasticity of other binders. Prolong disintegration time.

methods of adding the binder• As a dry powder mixed with the other ingredients before wetting.

• As a solution which is used as agglomerating liquid during wet agglomeration.

• As dry powder which is mixed with other ingredients before compaction. ( dry binder).

Lubricants Lubricants are materials that acts at the interface between the surface of the tablet and

the face of die preventing the adhesion of the tablet material to the surface of the die and punsh reducing the friction and facilitate ejection of the tablet from the die cavity.

Critical factors for optimizing lubricant function: o Concentration of lubricant. Inadequate concentration result in tablet with pitted

surface and inability of tablet to detach from the die. High concentration result in prolonged disintegration. Insoluble lubricant can be added at the final mixing stage before compression. o Stage and way of mixing. Mixing of lubricant with the disintegrant together lead to

formation of lubricant film around the disintegrant which reduces the wettability and water uptake by the disintegrant resulting in disintegration failure.o Intensity and duration of mixing. Over mixing or high intensity of mixing result

disintegration and dissolution failure.oLubricant Particle Size. Smaller particle size enhance lubricant efficiency.

Commonly used lubricants Material Concentration

W/WWater Solubility

Magnesium stearate 0.25% - 0.5% Insoluble

Stearic acid 1% - 3% Insoluble

Glyceryl behenate 1% - 3% Insoluble

Glyceryl pamitostearate 1% - 3% Insoluble

PEG 4000 – 8000 mol.wt Soluble

Polyoxyethylene stearate 1% - 2% Soluble

Sodium lauryl sulphate 1% - 2% Soluble

Glidants They are water insoluble materials of a very fine particle size enhancing the

powder flow properties of the granules within the hopper into the tablet die by reducing the friction due to their ability of particles to be located within the spaces between the granules.

As they are almost hydrophobic , increase in concentration will reduce the disintegration and dissolution time.

Talc asbestos-free ( hydrated Magnesium silicate) is insoluble but not hydrophobic 5 – 30% but its use was restricted because it will result in granuloma if inhaled.

Colloidal Silicon Dioxide (Aerosil) 0.1 -0.5% w/w was used due to its hydrophobic properties and fine particle size less than 15nm.

Disintegrants • Bioavailability of a drug depends in its

absorption which is affected by its dissolution

and permeability across the GIT membrane.

• The rate of dissolution is greatly influenced by

the rate of disintegration.

• Disintegration must occur within the

specifications defined by the pharmacopoeia

( generally 15 minutes ).

• Disintegrant was added to the formulation to

achieve this specification.

Mechanism of action of disintegrants∆ Increase the porosity and wettability of the tablet matrix enabling the GIT fluids to

penetrate and thereby enable tablet breakdown to occur. Concentration 5 – 20%w/w.- Starch, corn and potato starches.- MCC Avicel 101 & Avicel 102. 10 -20% w/w.- Sodium starch glycolate 5% w/w.

∆ Swelling of disintegrant in the presence of the aqueous fluid leading to tablet

disintegration due to increase in the internal pressure within the tablet matrix.- Sodium starch glycolate - Croscarmellose sodium 0.5-5% w/w.- Crospovidone 2 – 5% w/w.- Pregelatinized starch 5% w/w.

∆ Liberation of gas – Effervescent tablets.

Mode of addition of disintegrant

• Intragranular addition.

• Extragranular addition.

• 50% intragranular and 50% extragranular.

Factors affecting disintegration 1. Effect of fillers:

soluble fillers increase the viscosity of the penetrating fluid which tend to reduce the effect of the swollen disintegrating agent which tend to dissolve rather than disintegrate. Insoluble fillers disintegrate more rapidly.

2. Effect of lubricants: as lubricants are hydrophobic, they inhibit wetting and consequently disintegration of tablets. Sod. starch glycolate remains unaffected as disintegrant.

3. Effect of binders:Increase in the concentration of the binder increases the disintegration time.

4. Effect of Surfactants:The speed of water penetration is increased by addition of surfactants.

• Adsorbents: If liquid or semisolid is to be incorporated in the solid powder and the powder is required to be attained solid, and adsorbent is required to is included in the formula (e.g. magnesium oxide/ carbonate, kaolin/bentonite.• Sweeting agents / Flavours: to improve the taste and odour of the chewable tablets. Mannitol, lactose, sucrose and dextrose – saccharin, cyclamate, aspartame.• Colours: Can be used for the powder or for the coating material to give elegant appearance, to serve the manufacturer and patient in drug identification. e.g. iron oxide, carentoids, anthrocyanins.

Excipient Function

Diluent ( filler) Required bulk of tablet

Binder Provide necessary bonding to form granules

Disintegrant To bring disintegration within the specified time.

Lubricant To reduce friction in the die and ejection of tablet from the die cavity.

Antiadherent To prevent sticking of powder to the faces of punch and die.

Glidant Promote powder flow.

Wetting agent To aid disintegration

Buffer To improve stability and bioavailability.

Antioxidant to attain stability

Chelating agent Complex with heavy metals to prevent autooxidation.

Preservative To prevent growth of microorganism

Color Disguise off color drugs, product identification and more elegant colour

Flavour To improve odour and taste

Sweetener To give pleasant taste for chewable tablets.

Manufacturing Process

• Wet granulation.

• Dry granulation

• Direct compression

Granulation

• Advantages of use of granules:

• Prevention of segregation of powder components during the tableting

process.

• Enhancement of flow properties.

• Enhancement of compressibility.

• Lower incidence of dust production.

Wet Granulation

Wet granulation stage 1, Mixing• Drug and excipients excluding lubricants.•Mixing time and speed should be enough to produce

homogeneous mixture.

• Planetary bowel mixer.

• Rotating drum mixer.

• High-speed mixers.

• Ribbon / trough mixers.

Planetary bowel mixer.

• The mixing shaft rotate around the bowel and

around itself.

• Planetary like movement.

• Material used is stainless steel

Rotating drum mixer. ( double cone)

• The mixing shaft rotate and hence the drum is

rotated.

• Material used is stainless steel

Ribbon / trough mixer

• Mixing blades.

• Material used is stainless steel

Rapid mixer granulator • Rapid mixer granulator is a

mixing unit with a bottom entry agitator and side mounted chopper for granulation. Can be used for dry blending, wet mixing and granulation. The principle is agitation of the content at moderate speed and then running the cutting blade at high speed. • Dry mixing 3-5 min, wet mass 5-

10 min then 5-10 min to produce 0.5 – 1.5 mm granules.

Wet granulation stage 2, Wet granules formation• Fluid simultaneously incorporated in the powder mix. Granulation fluids are water,

isopropanol, ethanol or mixture.• The binder is either incorporated in the solid state within the powder mix or

dissolved in the granulation fluid.• Wet Granulation Techniques

A- Oscillating granulator

B- Fluidized bed granulation

C- Extrusion spheronization

D- Rapid mixture granulator RMG

E. Spray drying granulation.

Oscillating granulator• Low sheer is used,• The binder in the granulating

fluid is added whilst maintaining mixing.

• The wetted powder mass is then passed into an oscillating granulator which forces the powder mass through a metal screen under the action of an oscillatory stress.

Fluidized bed granulator• The powder is suspended by vertical

flow of air from the bottom of the

granulator.

• The granulation fluid is sprayed on

the powder from the top of the

granulator.

• Tangential air flow provides circular

powder suspension.

• Air applied with controlled

temperature.

Extruder • Premixed powder to which the granulation fluid

being added is placed into the barrel of the

extruder via hopper.

• In the barrel the wet mass moves horizontally

via single or twin screws from the hopper end

by a turning motion.

• Passed through a perforated plate into lengths.

• The extruded strands should break to produce

granules of uniform particle size.

Rapid mixer granulator • Rapid mixer granulator is a

mixing unit with a bottom entry agitator and side mounted chopper for granulation. Can be used for dry blending, wet mixing and granulation. The principle is agitation of the content at moderate speed and then running the cutting blade at high speed. • Dry mixing 3-5 min, wet mass 5-

10 min then 5-10 min to produce 0.5 – 1.5 mm granules.

Drying of the granules1. Tray dryer: Traditional oven . Wet granules are placed horizontally in a shallow plates. Air entered the drier

warmed by heaters. Vacuum can be applied. Condensed water is collected and disposed.

2. FBD: often used in the industry and having the advantages of:

1. Excellent heat transfer and rapid in action.

2. Accurate control of the drying conditions.

3. And of limitation:

4. Attrition of granules.

5. Powder waste.

6. Development of static electricity .

3. Freeze drying, microwave dryer, spray dryer.

Milling of the granules ( Resizing)• To produce the required particle size

and distribution to improve the flow of powder into the die and its filling. The granule size decreases as the tablet size decreases.• Size reduction methods includes:• Oscillating granulator using defined mesh.• Quadro Comil conical chamber containing defined mesh . Granules pass through the screen in a centrifugal manner by the action of rotating impeller.

Incorporating the lubricant

• Mixing the lubricant with the dried granules usually takes place in the

same mixing equipment used in the first stage.

• Noted that the time of mixing and the shear rate are crucial.

Granules formation

• Particle –particle interactions facilitated by

the formation of liquid bridges.

• Pendular state.

• Funicular state

• Capillary state

• Overwetted state

Granule formation

Granules formation - contd

• Particle – Particle interactions facilitated by the formation of solid

bridge.

• They are formed from the polymeric binder following drying.

• These bridges contribute to the mechanical properties of the resulting granules.

• Crystallization of the binder followed by crystallization of the water soluble drug

may affect directly the quality of produced tablets.( sugars)

Advantages of wet granulation• Reduce segregation during process and storage leading to intra and

interbatches variations.• Useful for tablets contain low concentration of therapeutic agent.• Employs conventional excipients.• Most plants had been built around wet granulation.• Tablets produced have good mechanical strength and hence can withstand

coating and packing procedures.

Disadvantages of wet granulation• Several process steps.

• Presence of solvent lead to:

• In materials having susceptibility to Hydrolysis.

• Soluble drugs may crystallize during drying.

• Heat to remove the solvent make the process expensive.

• Thermally labile therapeutic agents may undergo degradation.

• Issues regarding the use of alcohol if used.

DRY GRANULATION For thermolabile materialFor materials that can be affected by solventIngredient having enough cohesive properties.

Methods for dry granulation

• Slugging

• Roller compaction.

Dry Granulation - Slugging

• Slugging is the process of compressing dry powder by tablet

press having large die cavity, flat-faced punches and high

compression pressure.

• Slugs are then undergo size reduction by screening and milling.

Dry Granulation – Roller Compaction • Slugging is the process of compressing dry powder by tablet

press having large die cavity, flat-faced punches and high

compression pressure.

• Slugs are then undergo size reduction by screening and milling.

ChilsonatorDry granulation – Compactor –

Chilsonator • The powder was compressed between

the two rolls which are connected to a

pressure regulator.

• Slugs pass down to granulator then the

particles screened.

• Fine powders are hen recycled.

• High pressure was used.

Excipients used in dry granulationExcipient Material

Diluents - Anhydrous lactose or lactose monohydrate- Starch- Dibasic calcium phosphate- MCC

Disintegrants - Starch- MCC- Sodium starch glycolate.- Croscarmellose- Crospovidone

Lubricants - Stearates - Glycerylbehenate, glyceryl palmitostearate- PEG- Sodium lauryl sulphate

Glidants - Talc - Colloidal silicon dioxide

Miscellaneous Colours, sweeting agents, flavours … etc.

Mechanism of granules formation in dry granulation• Electrostatic forces.Initial cohesive interaction between particles.• Van der Waals interactionsVan der Waals forces increases as the distance between the particles decreases.• Melting of components within the powder mixDue to partial melting of excipients upon cooling solidification occur resulting in increased interactions between adjacent particles.

Advantage of dry granulation• No need for special excipients• No heat , no solvent• No change in the morphology of ingredients.

Disadvantage of dry granulation• Soft tablet incapable for further processing like coating.• Dust generation and powder loss.• Segregation of components may occur post mixing.• Special equipment required.• Problems with powder flow.

Direct compression • Mixing and subsequent compression.• Interactions of particles are similar to dry granulation.• To obtain same and uniform particle size of ingredients, this may

require milling.• Qudro Comil• High energy mill• Fitzmill

•Mixing in the same mixers as wet granulation.

Colloidal millFitzmill

Excipients – Direct Compression • Specific grades are required ( spray dried) to achieve certain particle size

distribution and flow properties.Diluent - Spray dried lactose

- Encopress calcium phosphate.- Spray dried mannitol- sorbitol- MCC Avicel PH- 102

Compression aid Avicel PH- 102Disintegrant - PGS

- Sodium starch glycolate ( Primogel)- Croscarmellose sodium- Crospovidone - polyplasdone

Lubricants - Stearates Glidants - Talc

- Colloidal silicon dioxide

Advantages of DC• Fewer processing steps and cost effective.• No use of water or solvent, no heat so produce more stable product

and lessens the cost.

• Lubricant is incorporated in the same vessel.

Disadvantage of DC 1. Specialist more expensive excipients.2. Similar particle size and density for the excipients and the

therapeutic agent are required to minimize segregation.3. Powder flow within the tableting machine.4. Tablets produced are soft making it difficult for further

processing.5. If the API is more than 10%, it will affect compressibility.6. Colourants could not be used.7. Dust and waste.

•Compression Process

Compression Tools

Die

Stages of compression • Stage1 : Filling the die with the granules / powder:• The powder or granules are fed from the hopper of machine into the die filling

the space between the lower and upper punches.• The space is determined by the position of the lower punch which can be altered

to increase or decrease the tablet size.

Stages of compression • Stage2 : compression ofthe granules / powder bed:• Retraction of the shoe.• Upper punch descend and compress the powder.

Stages of compression • Stage 3 : Tablet ejection:• Upper punch is elevated to its original position.• The lower punch moves upwards until it flush with the die plate.• The shoe moved across the die plate where it pushes the tablet from the lower

press.• The lower punch returns to its original position to start new cycle.

Types of Tablet Presss• Single-Punch tableting

Machines• This tablet press

composed of only one set of punches and die.• Used in pilot-scale

manufacturing and in R&D or in dry granulation (slugging)• Speed is up to 200 tablets

per minute.

Adjusting he single punch machine

Rotary Tablet Press

Single rotary tablet machine

High speed double rotary rotary tablet machine

Rotary Tablet Press• For large scale , produce up to 10,000 tablet per minute.

• Have up to 60 sets of punches and dies.

• Dies table rotate in a circular motion.

• Lower and upper Punches being held by the turrets are lowered and elevated by an upper and

lower rollers.

• The powder l granules are fed from the hopper on the upper surface of the die table. Then

transported by a feed frame into the die, where they are subsequently compressed by the

simultaneous movement of the upper and lower punches.

• The tablets are removed from the rotating die table into a chute from which they are collected.

Rotary Tablet machine

Rotary tablet press

Concept pf tablet compression

Compression Cycle1. Powder or granules fed to the hopper, emptied into the feed frame by gravity.2. The interconnected compartments of the feed frame spread the powder over the

area and fill the dies.3. The pull down cam guide the lower punches downwards allowing dies overfill.4. Punches pass over a weight-control cam, which reduces the fill into the dies to the

desired amount.5. A wipe off blade at the end of the feed frame removes the excess.6. The lower punches move over the lower compression roll while the upper punches

ride beneath the upper compression roll and enter into the dies while the lower punches are raised to squeeze the powder within the die.( moment of compression)

7. The upper punches are withdrawn following the upper cam, the lower punches ride up the lower cam bringing the tablets up the surface of the dies.

8. The tablet strike the sweep off blade in front of the feed frame and slide it down the chute into the container.

Relationship between Stress and Strain Elastic region:If the powder properties is elastic , will result in delamination and tablet failure. Stress required for the manufacturing of tablet should be greater than that required for elastic deformation.Plastic region:Due to the movement of the molecules in the direction of stress, irreversible deformation occurs. Components undergo plastic deformation, yield a successful compression.Fragmentation :Applying the ultimate tensile strength, particles will fracture. Further stress will result in more particle fractures so, increasing the surface area allowing more sites for particle-particle interaction.

Behavior of the powder bed during compression• Stage 1:Rearrangement of the powder bed upon application of stress, minimize the free space between the particles.• Stage 2 :Deformation of the powder under applied stress.(plastic deformation and fragmentation• Stage 3 :Bonding of the compressed powder by inter-particle bonding resulting in intact tablet. Bonding by adsorption ( van der Waals forces) and by diffusion ( increased molecular mobility) .

Behavior of the granules bed during compression• Stage 1:Rearrangement of the granule structure upon application of stress.• Stage 2 :Deformation of the granules and bond formation elastic then plastic deformation• Stage 3 :Bonding of the compressed granules by inter-granular bonding resulting in intact tablet. Bonding by adsorption ( van der Waals forces) and by diffusion ( increased molecular mobility because of the binder effect) .

Compression & time

1- Dwell time : time at maximum 2- consolidation time: Time to maximum fore.3- Ejection time: time during which ejection occur.4- residence time: time during which the formed compact is within the die,5- contact time: time for compression and decompression excluding ejection time

Auxiliary equipment•Mechanical feeder • To force granules into the die cavity.To minimize weight variation and obtain uniformity in content.• Tablet weight monitoring deviceMonitoring force at each compression station by electronic strain gauge technology. • Tablet deduster :To remove the excess powder on the surface of tablets.

Problems in tablet manufacturingCapping

Lamination

Cracking

Chipping

Picking

Sticking to die surface

Pitting

Binding

Mottling

Double impression

Capping •The upper or the lower segment of the table separates horizontally, either partially or completely.•Causes may be either due to the formulation or due to machine.

Reason:Air entrapped in compact during compression and subsequent expansion on ejection from the die or handling.

Capping due to formulation causes & its remedies Causes Remedies Large amount of fines in the granulation. Remove fines through 100 -200 mesh

screen.Too dry or very low moisture leading to loss of binding action

Moist the granules or add hygroscopic e.g sorbitol, PEG 4000.

Not thoroughly dried granules. Dry the granules properly

Insufficient or improper binder Increase or change binder.

Insufficient or improper lubricant Increase or change lubricant

Granular mass too cold to compress Compress at room temperature.

Capping due to machine causes & its remedies Causes Remedies

Poorly finished dies. Polish dies properly

Deep concave punches or beveled edge faces of punches

Use flat punches

Lower punch remain below the level of the die plate during ejection

Make proper setting

Incorrect adjustment of sweep-off blade Adjustment of ejection blade.

High turret speed Increase dwell time

Lamination •Tablet may undergo separation into two or more horizontal layers.•Causes may be either due to the formulation or due to machine.

Reason:Air entrapped in compact during compression and subsequent release on ejection. The condition exaggerated by higher speed of turret.

Lamination due to formulation causes & its remedies Causes Remedies

Oily or waxy materials granules - Modify mixing process- Add adsorbent or absorbent

Too much of hydrophobic lubricant e.g Magnesium stearate

- Decrease the amount or change the lubricant.

Lamination due to machine causes and its remedies

Rapid relaxation of the peripheral regions of the tablet, on ejection from a die

- Use tapered die , upper part of the die bore has an outward taper of 3 -5˚

Rapid decompression - Use precompression step .- Reduce turret speed and reduce the final compression pressure.

Cracking •Small cracks on the centre of the upper or lower surfaces.•Causes may be either due to the formulation or due to machine.

Reason:Rapid expansion of tablet especially when deep concave punches are used.

Cracking due to formulation causes & its remedies Causes Remedies Large size of granules - Reduce granules size

- Add fines

Too dry granules - Moisten the granules properly- Add proper amount of binder

Tablets expand - Improve granulation- Add dry binder

Too cold granulation Compress at room temperature.

Cracking due to machine causes and its remedies Tablet expand on ejection due to air entrapped - Use tapered die , upper part of the die bore

has an outward taper of 3 -5˚

Deep cavities cause cracking while removing tablets

- Use less concave punches.- Use gentle take-off ejection device..

Picking •Tablet material adhere to the punch.•Causes may be either due to the formulation or due to machine.

Reason:Air entrapped in compact during compression and subsequent release on ejection. The condition exaggerated by higher speed of turret.

Capping due to formulation causes & its remedies Causes Remedies

Moist granules Determine optimum time for drying

Insufficient or improper lubricant - Increase lubrication- Use colloidal silica as polishing

Low melting point of substance Use high melting point materials

Too warm granules Cool the system

Excess binder Reduce or change the binder

Picking due to machine causes & its remedies Causes Remedies

Rough or scratched surface of punch Polish punch face properly

Imposing or engraving letters Design letters as large as possible

Too deep dividing line or bevels Reduce depth and sharpness

Insufficient pressure Optimize the pressure

Sticking / Filming

•Tablet material adhere to the die faces. Filming is a slow form of sticking due to excess moisture.•Causes may be either due to the formulation or due to machine.

Reason:Improperly dried or improperly lubricated granules

Sticking due to formulation causes & its remedies Causes Remedies

Moist granules, hygroscopic material Determine optimum time for drying, control humidity

Insufficient or improper lubricant - Increase lubrication- Use colloidal silica as polishing

Too much binder Decrease or change the binder

Oily or waxy material Modify mixing process, add adsorbent

Too soft or weak granules Optimize binding , change granulation technique.

Sticking due to machine causes & its remedies Causes Remedies

Rough or scratched surface of die Polish die face properly

Die design Use tapering dies

Too fast speed Reduce speed

Insufficient pressure Optimize the pressure

Chipping •The tablet adhere or tear in the die. A film is formed un the die and ejection is hindered. Tablet edges are cracked. •Causes may be either due to the formulation or due to machine.

Reason:Excessive moisture, lack of lubricant, worn dies

Chipping due to formulation causes & its remedies Causes Remedies Too moist granules expanded around the lower punch

Optimum drying

Insufficient or improper binder Increase of change lubricant

Too large granules Reduce the size or add fines or add more lubricant

Too hard granules for the lubricant to be effective

Reduce granular size or modify the granulation method

Too abrasive granules and cutting into the die

Reduce granular size

Granular mass too warm stick to the die during compression

Reduce temperature

Chipping due to machine causes & its remedies Causes Remedies

Poorly finished dies. Polish dies properly

Rough dies due to abrasion or corrosion Change dies

Undersized dies Use proper die size

Too much pressure Reduce pressure or modify granulation

Pitting •Pit marks on the surface of the tablet•Corrected by polishing the punch surface and increasing the lubricant, its time and rate of mixing.

Reason:Rough surface of the punch or insufficient lubricant

Binding •Sticking of the tablet to the die and do not eject properly.•Causes and remidies are the same as chipping. Reason:

Excessive moisture, insufficient lubrication or use of worn die

Mottling •Uneven distribution of colour with black or light spots in the surface.•May be due to the formulation or the tableting machine. Reason:

Spotted colouration on the surface of the tablet.

Mottling causes & its remedies Causes Remedies

A coloured drug used with white excipients. Use appropriate colouring agent

A dye migrate to the surface of the granules during drying

- Change the solvent & binder- Reduce the drying temp- Use smaller particle size

Improperly mixed dye - Reduce size and mix properly

Improper mixing of coloured binder Incorporate dry color during blending then add dry binder, mix then add the granulating fluid.

Waxes and oils of machine parts lubrication - Check the seals

Dust - Clean and clear the environment

Double impression

• It takes place in only those puncheshaving engraving. At the moment of compression, the tablet receives the imprint,

the upper or lower punch rotate freely and travelling a distance which may result another contact with the tablet resulting in double impression.

Revise setting of machine and tie the punch by tooling key. Use punches with male and female anti-turning lock to prevent

rotation.

Reason:Free rotation of either the lower or upper punches during ejection of tablet.

• Weight variation.• Mechanical strength.

- Hardness.- Friability

• Disintegration failure.• Dissolution failure.• Uniformity in content Down stream

processing

• Particle size reduction.

• Mixing • Granulation• Drying • Force feed

frame.

Tablet Coating• PURPOSES OF TABLET COATING1. To prevent degradation in the

stomach – ( enteric coating )2. To prevent drug induced irritation at

the stomach-( NSAI)3. To provide controlled release of the

drug throughout the GIT.4. To target drug release at specific site

in the GIT. ( colon)5. To mask the taste of the drug.6. To improve the appearance of tablet.7. To protect the tablet – shelf-life &

stability

• TYPES OF TABLET COATING PROCESS1. Sugar Coating2. Film Coating.3. Press Coating• TYPES OF COATING EQUIPMENTS1. Standard coating pan2. Perforated coating pan3. Fluidized bed ( air suspension)

coaters.

Sugar coating• Coloured or uncoloured of

sucrose - based layer around the tablet.• Improve the appearance and

mask the taste.• Insulate the tablet.• Permit imprint.• Dramatically decreased

practice due to advantages of film coating.

Conventional Pan

Process of sugar coating• Stages of process:1. Sealing of tablet cores.2. Sub-coating 3. Smoothing 4. Colouring 5. Polishing 6. Printing

• General description of the process:1. Tablets are placed in the coating pan and agitated.

2. The coating solution is sprayed on the surface of

the tablets.

3. Warm air is passed over the tablets to facilitate

removal of the solvent.

4. When solvent has evaporated, the tablets will be

coated with the solid components of the coating

solution.

1-Sealing of tablet cores.

• An insoluble impermeable polymer solution is applied to seal the tablet against entry of water.

1. Shellac2. Cellulose acetate phthalate3. Polyvinylacetate phthalate4. Hydroxypropylmethyl cellulose

2-Subcoating

Sub-coating solutionGelatin 6% W/W 3.3 % W/W

Acacia 8 7.7

Sucrose 45 55.3

Distilled water

To 100 To 100

Sub-coating suspensionSucrose 40% W/WCalcium carbonate

20

Talc 12Gum acacia 2Titanium dioxide 1Distilled water 25

1. Applying the gum based solution followed by sucrose based powder then drying.

2. Application of a suspension od powder in gum-sucrose solution

3. Powders as Calcium carbonate or Talc.

3- Smoothing • Rough surface can be smoothened by application of few coating

layers of simple syrup.• The simple syrup may contain starch, acacia, gelatin and opacifier.

4- Colouring

• Application of several layers of colour solution in 60 – 70% sucrose syrup.• Colours should be approved by the regulatory authority.• Predispersed lake ( pigment) is superior because:

1. The colour is water insoluble.2. It is opaque.3. Maintenance of batch to batch colour.4. Reduction in the overall process time.5. Reduction in the thickness of the colour coating layer.

5- Polishing • Commonly used method is an application of organic solvent to

get suspension or solution of waxes.• Carnauba wax• Beeswax • An emulsion may be used and stabilized by acceptable

surfactant.• Other methods involves the use wax-lines pan and use finely

powdered wax application.• Mineral oil application.

6- Printing • Why sugar coated tablets requires printing for and not

other method for identification?• Edible pharmaceutical ink formulation:• Shellac• Alcohol • Pigment• Lecithen • Antifoam• Organic solvent

Film Coating

• A deposition of a thin film layer of polymer or mixture of polymers around the conventional tablets core.• Polymers that are used in film coating which dissolve in the stomach

to enable disintegration and dissolution :• Hydroxypropylmethyl cellulose.HPMC• Hydroxypropyl cellulose HPC• Eudragit E 100

• Target drug release film coated tablets are coated by insoluble • Ethylcellulose. • Eudragit RS & RL

Comparison between Sugar & Film coatingFeatures Sugar coating Film coating

Appearance Rounded with degree of polish

Retains contour of the original tablet – not shiny

Weight increase 30 – 50 % 2 – 3 %

Logo or break-lines Not possible Possible

Other dosage form Of no industrial importance

possible - multiparticulates

Stages of process Multistage process Single

Batch coating time 8 hours 2 hours

Functional coating Generally not practical Controlled release

Advantages of Film coating• Elegance and glossy appearance.• Maintain the logo and break line.• Improve mechanical strength an integrity and improve

resistance for handling and shipping.• Flexibility in types of formulation.• Minimal weight increase.• Less time consuming.• Minimize dust.• Automated equipment are used.• Single process and not rquires excessive training.

Formulation of the coating fluid Polymer ( may be enteric or nonenteric)

Plasticizer

Colourant

Opaquant – extender

Solvent