You are on page 1of 24

1.

Prerennial allergic rhinitis: It is a type of allergic rhinitis which occurred throughout the year when the body
overreacts to indoor allergen such as dust mites, pet dander and mold.
2. Impalpable grade : a grade that is difficult to perceive
Functions of each ingredient in Citrizine
Citrizine HCl- The active ingredient which is a second generation antihistamine
Lactose monohydrate
Lactose consists of one molecule of D-glucose and one molecule of D-galactose. It is commercially available in three
forms which are alpha monohydrate, beta anhydrous and spray dried. The main use is alpha monohydrate.
1. Filler or diluents- Added to provide improved cohesion, to allow direct compression manufacturing, to enhance flow
and to adjust the weight of the tablet as per die capacity. It fill out the size of tablet practical to produce and make it
possible to have proper volume for patient handling. They must meet certain criteria like:
Should not react with the drug substance / excipients (inert)
Should have no physiological or pharmacological activity of its own
Have constant physical and chemical properties
2. Binder
3. Disinfectant- Applied on non- living objects to destroy microorganisms. Disinfection does not necessarily kill all
microorganisms, especially nonresistant bacterial spores; it is less effective than sterilisation.
- Sweetener: Slightly sweet due to the presence of sugar moiety
There are various lactose grades commercially available that have different physical properties such as particle size
distribution and flow characteristics. This permits the selection of the most suitable material for a particular application.
For example, the particle size range selected for capsules is often dependent on the type of encapsulating machine used.
Usually, fine grades of lactose are used in the preparation of tablets by wet granulation method or when milling during
processing is carried out, since the fine size permits better mixing with other formulation ingredients
Various grades commercially available, e.g. impalpable (unperceivable to the touch) grade, capsulating grade,
inhalation grade, milled or sieved
Based on particle size or flow properties
Microcrystalline cellulose
1. Binder - Added to form granules.
The granules have lower angle of repose hence better flow properties, ensures that bonds with sufficient strength is
formed during compression, and to prevent segregation of content of powder mix
Binders may be added as:
Dry powder followed by addition of granulating liquid
Binder solution
Dry binder for direct compression
Spray onto a bed of the powder or spraying a suspension of the powder
2. Disintegrant- Added to the tablet formulation to achieve a faster rate of drug release from tablet
They swell when in contact with water and thereby rupture the tablet matrix
Others work by capillary action- create channels within the tablet matrix that allows liquid to penetrate leading to
disintegration
They lead to larger surface area of the tablet fragments- there would be more efficient wetting by liquids, leading to
faster dissolutions rates.
3. Filler/ diluents
Avicel PH-101 : (diameter of 50 m, < 5% water content, 0.29 g/ml density.)
Most popular grade, suited for all tableting processes, esp wet granulation and globular granule production.
Various grades which differ in bulk density, particle size and moisture content.
Avicel RC-591 :
Microcrystalline cellulose + carboxymethylcellulose sodium

Mixtures of both are dispersible in water and suitable as suspending vehicles in formulations. It is typically used in
pharmaceutical liquids, suspensions or emulsions. It is used to:
Maintain suspension uniformity by preventing settling
Stabilise emulsion
Impart a thixotropic viscosity profile
Increase formulation stability across a wide range of pH and extreme temperatures
Amount of carboxymethylcellulose present vary between 8.3% and 18.8% w/w depending on grade of material.
Different grades available that differ in method of manufacture :
Larger particle size grades provide better flow properties.
Low moisture grades used with moisture-sensitive materials.
Higher density grades have improved flowability.
How does Avicel RC-591 function as suspension/emulsion aids?
In the presence of water and mild sheer, the powder particles swell and are then peptized, forming a dispersion of
cellulose microcrystals. These microcrystals create a stable lattice structure for use in the formulation of suspensions and
emulsions.
Croscarmellose sodium
Disintegrant : The cross-linking reduces water solubility while still allowing the material to swell (like a sponge) and
absorb many times its weight in water. As a result, it provides superior drug dissolution and disintegration characteristics,
thus improving formulas' subsequent bioavailability by bringing the active ingredients into better contact with bodily
fluids.
In tablet formulations, Croscarmellose sodium may be used in both direct-compression and wet-granulation processes.
- When used in wet granulations the Croscarmellose sodium is best added in both the wet and dry stages of the process
(intra- and extra granularly) so that the wicking and swelling ability of the disintegrant is best utilized.
Croscarmellose at concentrations up to 5% used as disintegrant. 2% used in tablets by direct compression and 3%
w/w in tablets by wet granulation process.
Oral consumption of large amounts of croscarmellose sodium may have laxative effect, although quantities used
in solid dosage formulations are unlikely to cause such problems.
* Titanium dioxide (Opaquant extender)
Description:
- Used in tablet coating process as a white pigment
Applications:
(1) Owing to its high refractive index, titanium dioxide has light-scattering properties that used as opacifier.
For eg : titanium dioxide with average particle size of 230nm scatters visible light while titanium dioxide with average
particle size of 60nm scatters ultraviolet light and reflects visible light.
Protect light-sensitive active ingredients from photodegradation because titanium dioxide is an opaque material. (block
light)
(2) Provide more pastel colours and increase film coverage in film-coated tablets.
Aesthetics (beautiful) - Added as a pigment for colouring (colouring agent).
Usually added to aid in identification and improve patient compliance.
For tablets, they are usually added to the formulation in the form of a solution during the addition of the binder
solution.
Alternatively, the dye is absorbed onto other excipients and then added to the formulation during the dry, mixing
stage.
All artificial colourants used in the formulations must be approved/ certified
The colour to the molecules is due to the chromophores which are certain structural elements in the molecules: Azo
and Nitroso

Magnesium stearate
1. Lubricant-To prevent sticking of formed tablets to the die and on punches, therefore facilitate ejection of tablets
from the die
Stearates also improve granule flow properties by reducing interparticle friction- resulting in tablets with
lower tensile strength
Normally used in a concentration below 1%
They also form a thin coat:
Fluid lubrication: Layer of liquid is locates on the surface of tablet and die wall
Boundary lubrication: Sliding surfaces are separated by a thin layer of lubricant
Applications:
(1) Added to a powder blend to prevent the compacted powder mass from sticking to the equipment during the tabletting
or encapsulation process.
(2) Aids the ejection of the tablet from the dies.
(3)Help improve powder flow.
(4) Magnesium stearate may affect the release time of the active ingredients in tablets, etc., but not that it reduces the
over-all bioavailability of those ingredients.
When is it added?
- Added to a powder blend for direct compression or encapsulation.
- Generally added dry, and in the final blending stages.
Recommended concentration: 0.5 5%.
- Best to use in lowest effective concentration.
- Blending time should be limited as overblending causes compaction problems.
* Problems associated with incorrect lubrication in tablet compression:
- Under-lubricating a powder blend leads to adherence of material on the metal surfaces of the punches and die walls of
the tablet press.
- Over-lubrication leads to soft tablets and poor disintegration and/or dissolution.
EXCIPIENTS USED IN TABLETS
Wetting Agents
Wetting Agents in tablet formulation aid water uptake and thereby enhancing disintegration and assisting in drug
dissolution. Incorporation of anionic surfactant like Sodium Lauryl Sulphate (SLS) is known to enhance the dissolution.It
has been established that SLS improves permeation of drug through biological membrane since it destroys the path
through which drug has to pass and thus minimizing the path length for the drug to travel. Wetting agents are mainly
added when hydrophobic drug is to be formulated into tablet. SLS, Sodium diisobutyl sulfosuccinate are used as wetting
agent in tablet formulation.
Dissolution Retardants
Dissolution Retardants are incorporated into tablet formulation only when controlled release of drug is required. Waxy
materials like stearic acid and their esters can be used as dissolution retardants.
Dissolution Enhancers
They are the agents that alter the molecular forces between ingredients to enhance the dissolution of solute in the solvent.
Fructose, Povidone, Surfactants are used as dissolution enhancer.
Adsorbents
Adsorbents are the agents that can retain large quantities of liquids. Therefore liquids like Vitamin E can be incorporated
into tablets by addition of adsorbents .Most commonly used adsorbents in pharmaceuticals are anhydrous calcium
phosphate, starch, magnesium carbonate, bentonite, kaolin, magnesium silicate, magnesium oxide and silicon dioxide.

Generally the liquid to be adsorbed is first mixed with the adsorbent prior to incorporation into the formulation. Silicon
dioxide when added can play as both glidant and an adsorbent role in the formula.
Buffers
Buffers are added to maintain a required pH since a change in pH may cause significant alteration in stability. Most
commonly used buffering agent in tablet formulation includes sodium bicarbonate, calcium carbonate, and sodium citrate.
Antioxidants
Antioxidants are added in tablet formulation to protect drug from undergoing oxidation. Antioxidants undergo oxidation in
place of drug or they block the oxidation reaction or they act as synergists to other antioxidants. Chelators may also act as
antioxidant. Most commonly used antioxidants include ascorbic acid and their esters , alpha-tocopherol , ethylene diamine
tetra acetic acid , sodium metabisulfite , sodium bisulfite , Butylated Hydroxy Toluene (BHT) , Butylated Hydroxy
Anisole (BHA) , citric acid , and tartaric acid .
Chelating Agents
Chelating agents tend to form complexes with trace amount of heavy metal ions inactivating their catalytic activity in the
oxidation of medicaments. Ethylenediamine tetracetic acid and its salts, Dihydroxy Ethyl Glycine, Citric Acid and Tartaric
Acid are most commonly used chelators.
Preservatives
Preservatives may be a part of tablet formulation in order to prevent the growth of microorganisms in tablet formulation.
Parabens like methyl, propyl, benzyl, butyl p-hydroxy benzoate are used as preservatives.
Colourants
Colourants neither contribute to therapeutic activity nor do they improve product bioavailability or stability but are
incorporated into tablets for purposes like to facilitate identification of similar looking products with in a product line to
avoid mix ups, to facilitate identification of products of similar appearance that exist in the lines of different
manufacturers, to overcome colour change on aging, disguising of off-colour drugs, for brand image in the market, to
enhance the aesthetic appearance of the product to have better patient acceptance. While employing wet granulation, care
should be taken to prevent colour migration during drying .
Flavours
Flavors are commonly used to improve the taste of chewable tablets as well as mouth dissolved tablets. Flavors are
incorporated either as solids (spray dried flavors) or oils or aqueous (water soluble) flavors. Solids that is dry flavors are
easier to handle and generally more stable than oils. Oil is usually added at the lubrication step because of its sensitivity to
moisture and their tendency to volatilize when heated during drying. It may also be adsorbed onto an excipient and added
during the lubrication process. Aqueous flavors are less used because of its instability on aging.
Sweeteners
Saccharin is 500 times sweeter than sucrose. Its major disadvantages are that it has a bitter aftertaste and is carcinogenic.
Even cyclamate is carcinogenic .Aspartame is about 180 times sweeter than sucrose. The primary disadvantage of
aspartame is its lack of stability in the presence of moisture. When aspartame is used with hygroscopic components, it will
be necessary to determine its stability under conditions in which the manufactured and marketed product can adsorb
atmospheric moisture. Aspartame is available in market under the brand Nutrasweet by Nutrasweet Company.
Antiadherents
Antiadherents are used to reduce the adhesion between the powder (granules) and the punch faces and thus prevent
sticking to tablet punches. They are also used to help protect tablets from sticking. Most commonly used is magnesium
stearate.
TYPES OF TABLETS
Types of tablet:
Tablet may be uncoated or coated. Uncoated tablets are chewable tablet, effervescent tablet, lozenge tablet, soluble tablet,
and sublingual tablet. Coated tablets are enteric coated tablet, film coated tablet, implant, sugar coated tablet, and
modified-release tablet. A broken section of a coated tablet shows a core which is surrounded by a continuous layer of a
different texture. The reasons for coating a tablet are:

a) to protection of the active ingredients from air, moisture, light,


b) to mask the unpleasant tastes and odor; and
c) to improve appearance
Chewable tabletThe tablet which is intended to be broken and chewed in between the teeth before ingestion. Antacid and vitamin tablets
are usually prepared as chewable tablets. It is given to the children who have difficulty in swallowing and to the adults
who dislike swallowing.
Effervescent tabletThe tablet that contains acid substances and carbonate or hydrogen carbonate that react rapidly in the presence of water to
release carbon dioxide. Sodium bicarbonate, citric acid and tartaric acid are added to the active ingredients to make the
tablet effervescent. This preparation makes the tablet palatable.
Lozenge tabletThe tablet that is intended to produce continuous effect on the mucous membrane of the throat. There is no disintegrating
agent. The quality of the binding agent is increased so as to produce slow dissolution. Suitable sweetening (sugar),
coloring and flavoring agents must be include in this formulation. Gum is used to give strength and cohesiveness to the
lozenge and facilitating slow release of the active ingredient.
Soluble tabletThe tablet that dissolves completely in liquid to produce solution of definite concentration. Mouth wash, gargle, skin
lotion, douche; antibiotic, certain vitamins, and aspirin are given in this formulation.
Sublingual tabletThe drug which is destroyed or inactivated within the gastrointestinal tract but can be absorbed through the mucosal tissue
of the oral cavity is usually given in this formulation. The tablet is required to be placed below the tongue for the slow
release of drug. But for immediate effect some medicaments are formulated in such a way to dissolve within 1 to 2
minutes. Nitroglycerin is prepared in this formulation.
Enteric coated tabletSome drugs are destroyed by gastric juice or causes irritation to the stomach. These two factors can be overcome by
coating the tablet with cellulose acetate phthalate. This polymer is insoluble in gastric contents but readily dissolves in
intestinal contents. So there is delay in the disintegration of dosage form until it reaches the small intestine. Like coated
tablet, enteric coated tablet should be administered in whole form Broken or crushed form of the enteric coated tablet
causes destruction of the drug by gastric juice or irritation to the stomach. Enteric coated tablet is comparatively
expensive.
Film coated tabletThe tablet that is covered with a thin layer or film of polymeric substance which protects the drug from atmospheric
conditions and mask the objectionable taste and the odor of drug.
ImplantA small tablet that is prepared for insertion under the skin by giving a small surgical cut into the skin which is stitched
after the insertion of the tablet. This tablet must be sterile one. The drug used in this preparation is usually water insoluble
and the tablet provides a slow and continuous release of drug over prolonged period of time ranging from 3 to 6 months or
even more Contraceptive tablet is formulated as implant.
Sugar coated tabletThe tablet that contains active ingredient(s) of unpleasant taste may be covered with sugar to make it more palatable. This
type of tablet should be administered in whole form, otherwise the patient will experience the unpleasant taste of the
active ingredient.
Modified release tabletModified-released tablet is either uncoated or coated. This contains special additives or prepared by special procedure
which, separately or together, is intended to modify the rate of release of the drug into the gastrointestinal tract. It
prolongs the effect of drug and also reduces the frequency of administration of drug. Several drugs are available in
modified release tablet such as indomethacin.
Factors Affecting Poor Drug Release:
1. Water content Increasing water content in the granulation liquid leads to an increase in the hardness of the tablets.
2. Hardness Increase of hardness leads to poor drug release.
3. Binders used Different binders contribute to different drug release profile. If using Avicel PH-101, a gel-like
structure will not form. It will remain unchanged in the aqueous dissolution medium, resulting in a greater
release rate.

4. Suppliers The use of similar products but different suppliers could change the characteristics of the tablets formed.
Avicel PH-101, Emcocel and Unimac MG are three examples of microcrystalline cellulose from different
manufacturers. Tablets prepared with these materials had differences in sizes and in roundness when processed under
same conditions.
Specifications of Raw Materials:
Physical properties of raw materials affect the manufacturing process, resulting in poor quality products. Changes in
particle size or polymorphism will influence flow properties and moisture uptake, which in turn affect blend and
compression behavior. This can result in the poor content uniformity. So, in order to avoid this problem, the raw materials
can now be identified and be tested for manufacturing suitability. Nearinfrared (NIR) spectroscopy is a wellknown tool for
identifying raw materials in the pharmaceutical industry. It is a very sensitive, non-destructive technique using overtones
and combination of bands of fundamental vibrations derived from the mid-infrared. NIR spectra are sensitive to the
physical changes.
Storage of Raw Materials Contamination of raw materials by microorganisms. This will result in the formation of soft
tablets. Microbial deterioration of tablets has serious pharmaceutical implication as it affects therapeutic efficacy of drugs.
During storage, transporatation or handling, the soft tablets may break up since they are not able to withstand minimal
shocks. Therefore, the amount of active drug is reduced. So, the raw materials should be stored in a quarantine area.
*Examples of Specification of Raw Materials:
Major excipients required in direct compression
Diluents
Selection of direct compression diluent is extremely critical, because the success or failure of direct compression
formulation completely depends on characteristics of diluents. There are number of factors playing key role in selection of
optimum diluent. Factors like- Primary properties of API (particle size and shape, bulk density, solubility), the
characteristics needed for processing (flowability, compressibity), and factors affecting stability (moisture, light, and other
environmental factors), economical approach and availability of material. After all, one can say that raw material
specifications should be framed in such a way that they provide an ease in manufacturing procedures and reduce chances
of batch to batch variation.
Binders
Binders are the agents used to impart cohesive qualities to the powdered material. The quality of binder used has
considerable influence on the characteristic of the direct compression tablets. The direct compression method for
preparing tablets requires materials which are not only free flowing but also sufficiently cohesive to act as binder.
Factors affecting disintegration :
Effect of fillers
The solubility and compression characteristics of fillers affect both rate and mechanism of disintegration of tablet. If
soluble fillers are used then it may cause increase in viscosity of the penetrating fluid which tends to reduce effectiveness
of strongly swelling disintegrating agents and as they are water soluble, they are likely to dissolve rather than disintegrate.
Insoluble diluents produce rapid disintegration with adequate amount of disintegrants. Chebli and cartilier proved that
tablets made with spray dried lactose (water soluble filler) disintegrate more slowly due to its amorphous character and
has no solid planes on which the disintegrating forces can be exerted than the tablet made with crystalline lactose
monohydrate.
Effect of binder
As binding capacity of the binder increases, disintegrating time of tablet increases and this counteract the rapid
disintegration. Even the concentration of the binder can also affect the disintegration time of tablet.
Effect of lubricants

Mostly lubricants are hydrophobic and they are usually used in smaller size than any other ingredient in the tablet
formulation. When the mixture is mixed, lubricant particles may adhere to the surface of the other particles. This
hydrophobic coating inhibits the wetting and consequently tablet disintegration.
Lubricant has a strong negative effect on the water uptake if tablet contains no disintegrants or even high concentration of
slightly swelling disintegrants. On the contrary, the disintegration time is hardly affected if there is some strongly swelling
disintegrants are present in the tablet. But there is one exception like sodium starch glycolate whose effect remains
unaffected in the presence of hydrophobic lubricant unlike other disintegrants.
Effect of surfactants
Sodium lauryl sulphate increased absorption of water by starch or had a variable effect on water penetration in tablets.
Surfactants are only effective within certain concentration ranges. Surfactants are recommended to decrease the
hydrophobicity of the drugs because the more hydrophobic the tablet the greater the disintegration time. Aoki and fukuda
claimed that disintegration time of granules of water-soluble drugs did not seem to be greatly improved by the addition of
nonionic surfactant during granulation , but the desired effect of a surfactant appeared when granule were made of slightly
soluble drugs. The speed of water penetration was increased by the addition of a surfactant.
Other problems
Weight variation between granules
Proportion between fines and granules influence the die filling capacity and the results in weight variation of tablets. If
large granules are use to fill small die cavities, even a small differences in granules results in high percent of weight
variation of tablets
Solution- uniform size distribution (narrow range) and smaller granular size is preferable
Poor flow of granules
Solution
- using glidants like talc, colloidal silica
-Preparing uniform- sized and shaped granules
Poor mixing
Improper mixing of ingredient such as glidant and lubricant, which is useful for proper flow and punching
Insufficient or inadequate time of mixing
Solution: - proper mixing by maintaining adequate time and using suitable mixer.
Hardness variation
Due to weight variation in granules when filled in die
Space between the two punches
Solution: proper tooling of machine
Factors Affecting Tablet Production
Wet Granulation
-More than 70 % of world granule manufacturing uses this method to produce pharmaceutical granules.
-process of adding a liquid solution to powders, is one of the most common ways to granulate.
-involves the massing of a mix of dry primary powder particles using a granulating fluid.
The fluid contains a solvent which must be volatile so that it can be removed by drying, and be non-toxic. Typical liquids
include water, ethanol and isopropanol either alone or in combination. The liquid solution can be either aqueous based or
solvent based. Aqueous solutions have the advantage of being safer to deal with than solvents.
Water mixed into the powders can form bonds between powder particles that are strong enough to lock them together.
However, once the water dries, the powders may fall apart. Therefore, water may not be strong enough to create and hold
a bond. In such instances, a liquid solution that includes a binder (pharmaceutical glue) is required. 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. When PVP and a solvent/water are mixed with powders, PVP forms a bond with the
powders during the process, and the solvent/water evaporates (dries). Once the solvent/water has been dried and the

powders have formed a more densely held mass, then the granulation is milled. This process results in the formation of
granules.
The process can be very simple or very complex depending on the characteristics of the powders, the final objective of
tablet making, and the equipment that is available. In the traditional wet granulation method the wet mass is forced
through a sieve to produce wet granules which is subsequently dried.
Dry 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).
When a tablet press is used for dry granulation, the powders may not possess enough natural flow to feed the product
uniformly into the die cavity, resulting in varying degrees of densification. The roller compactor uses an auger-feed
system that will consistently deliver powder uniformly between two pressure rollers. The powders are compacted into a
ribbon or small pellets between these rollers and milled through a low-shear mill. When the product is compacted
properly, then it can be passed through a mill and final blend before tablet compression.
Manufacture of the tableting blend
In the tablet pressing process, the main guideline is to ensure that the appropriate amount of active ingredient is in each
tablet. Hence, all the ingredients should be well-mixed. If a sufficiently homogenous mix of the components cannot be
obtained with simple blending processes, the ingredients must be granulated prior to compression to assure an even
distribution of the active compound in the final tablet. Two basic techniques are used to granulate powders for
compression into a tablet: wet granulation and dry granulation. Powders that can be mixed well do not require granulation
and can be compressed into tablets through direct compression.

Wet granulation
Wet granulation is a process of using a liquid binder to lightly agglomerate the powder mixture. The amount of liquid has
to be properly controlled, as over-wetting will cause the granules to be too hard and under-wetting will cause them to be
too soft and friable. Aqueous solutions have the advantage of being safer to deal with than solvent-based systems but may
not be suitable for drugs which are degraded by hydrolysis.
Low shear wet granulation processes use very simple mixing equipment, and can take a considerable time to achieve a
uniformly mixed state. High shear wet granulation processes use equipment that mixes the powder and liquid at a very
fast rate, and thus speeds up the manufacturing process. Fluid bed granulation is a multiple-step wet granulation process
performed in the same vessel to pre-heat, granulate, and dry the powders. It is used because it allows close control of the
granulation process.

Dry granulation
Dry granulation processes create granules by light compaction of the powder blend under low pressures. The compacts soformed are broken up gently to produce granules (agglomerates). This process is often used when the product to be
granulated is sensitive to moisture and heat. Dry granulation can be conducted on a tablet press using slugging tooling or
on a roll press called a roller compactor. Dry granulation equipment offers a wide range of pressures to attain proper
densification and granule formation. Dry granulation is simpler than wet granulation, therefore the cost is reduced.
However, dry granulation often produces a higher percentage of fine granules, which can compromise the quality or create
yield problems for the tablet. Dry granulation requires drugs or excipients with cohesive properties, and a 'dry binder' may
need to be added to the formulation to facilitate the formation of granules.

Granule lubrication
After granulation, a final lubrication step is used to ensure that the tableting blend does not stick to the equipment during
the tableting process. This usually involves low shear blending of the granules with a powdered lubricant, such as
magnesium stearate or stearic acid.
Manufacture of the tablets
Whatever process is used to make the tableting blend, the process of making a tablet by powder compaction is very
similar. First, the powder is filled into the die from above. The mass of powder is determined by the position of the lower
punch in the die, the cross-sectional area of the die, and the powder density. At this stage, adjustments to the tablet weight
are normally made by repositioning the lower punch. After die filling, the upper punch is lowered into the die and the
powder is uniaxially compressed to a porosity of between 5 and 20%. The compression can take place in one or two stages
(main compression, and, sometimes, pre-compression or tamping) and for commercial production occurs very fast (500
50 msec per tablet). Finally, the upper punch is pulled up and out of the die (decompression), and the tablet is ejected from
the die by lifting the lower punch until its upper surface is flush with the top face of the die. This process is simply
repeated many times to manufacture multiple tablets.
Common problems encountered during tablet manufacturing operations include:

poor (low) weight uniformity, usually caused by uneven powder flow into the die
poor (low) content uniformity, caused by uneven distribution of the API in the tableting blend

Liquid Requirement. High-shear mixers may exhibit a narrow margin between the liquid required to obtain granule growth
and the amount that results in an over-wetted mass. Because of the intensive wet massing and densification of the
granules, less liquid is normally required with high- than with low-shear mixers [5]. In addition, impeller rotation speed
influences the liquid requirements, as does evaporation of the solvent, usually water, in the binder solution. Especially
with high-shear mixers, intense agitation results in a temperature rise and loss of solvent by evaporation.
Effects of Raw Material Properties. The following properties influence granule formation and growth:

Contact angle of the binder liquid to the solids

Solubility of the particles in the binder liquid

Mean particle size and size distribution of the solids

Particle shape and surface morphology

Packing properties of the solids


Raw materials must have good wetting properties if there is to be uniform liquid distribution and, hence, controlled
granule growth. The smaller the particle size of the raw material, the more binder liquid required.
Factors affecting
granules
Amount of fines
Moisture content

Excipient related
problem

Reason

Problems caused

Solution

Too high amount of fines


Too dry

Capping
Capping, chipping,
cracking, binding,
sticking, picking
Capping
Capping,

Remove fines through mesh screen


Moisten suitably, control the
moisture properly

Not dry enough


Insufficient or improper
binder
Insufficient or improper
lubricant
Too much binder

Capping, sticking,
picking, binding
Chipping ,
sticking, picking

Dry thoroughly
Increase amount of binder or add
dry binder
Increase amount of lubricant or
change type of lubricant, can use
colloidal silica too
Optimize binding or use dry
binders

Temperature

Types of ingredient and


excipients

Granules too warm when


compressing
Too low when compressing
Oily and waxy materials in
granules
Hydrophobic lubricant
Stick on punch faces

Picking
Capping, cracking
Lamination ,
sticking
Lamination,
sticking
Chipping

Size of granules

Too large
Tablets expand

Cracking

Hardness

Granules too hard

Binding

Granules too soft

Sticking

Low mp substance soften by


heat of compression
Low melting point
medicament in high
concentration
Granules too coarse

Picking

Granular material too


abrasive and cuts the dies
Granular material too warm
and sticks to die

Binding

Compress at room temp. Cool


sufficiently before compress
Compress at room temperature
Modify mixing process. Add
adsorbent or absorbent
Use less amount of lubricant
Dry the granules properly or
increase lubricant
Reduce granule size. Add fines
Improve granulation by add dry
binders
Reduce granular size, add more
fines, use more effective lubricant
Optimize anount of binder and
granulation technique
Add high mp material and high mp
lubricant
Refrigerate granules

Reduce granular size, add more


fines, use more effective lubricant
Reduce size of coarse granules/ use
wear-resistance dies
Reduce temperature

In Process Quality control (Q. C.) tests for tablets


These factors must be controlled during production (in-process control) and verified after production. Some test methods
are described in the pharmacopeias; others are not and thus are referred to as "non-compendial" tests
Official Quality control tests for tablets (Compendial tests)
British Pharmacopoeia (B.P.) & US Pharmacopoeia (USP)
1- Uniformity of content of active ingredient (Uniformity of weight & Content uniformity)
2- Disintegration test.
3- Dissolution test.
4- Friability test.
Non-Compandial tests
There are many tests are frequently applied to tablets for which there are non-pharmacopoeial requirements but will form
a part of manufacture's owner product specifications.
1- Tablet thickness.
2- Tablet hardness.
1. Tablet thickness
Tablet thickness is important for tablet packaging; very thick tablets affect packaging either in blisters or plastic
containers. The tablet thickness is determined by the diameter of the die, the amount of fill permitted to enter the die and
the force or pressure applied during compression. The thickness of the tablet may be measured manually or by automatic
equipment.
2. Hardness tests/ Crushing strength
Tablet Hardness: Hardness of tablets depends on the nature of drug, amount of binder and applied compression force. It
dictates the rate of disintegration and dissolution. A tablet of appropriate hardness ensures its ability to withstand shock of

handling, packing and shipping. It is tested by mechanical hardness testers, which measure resistance to crushing of a
tablet.
The test measures crushing strength property defined as the compressional force applied diametrically to a tablet which
just fractures it. Among a large number of measuring devices, the most favored ones are Monsanto tester, Pfizer tester, and
Strong cobb hardness tester. All are manually used. So, strain rate depends on the operator. Heberlein Schleuniger,
Erweka, Casburt hardness testers are motor driven.

1- Uniformity of active ingredient:


(WHY?) To ensure a constant dose of drug between individual tablets.
Traditionally, dose variation between tablets is tested in two separate tests;
1- Weight uniformity
2- Content uniformity
If the drug forms greater part of the tablet, any variation in the tablet weight obviously indicates a variation in the active
ingredient. (Weight uniformity test)
If the drug is potent (USP specifies 50 mg of the active ingredient or less), the excipients form the greater part of the tablet
weight and the correlation between the tablet weight and amount of the active ingredient can be poor, in this case another
test (Content uniformity) must be performed.
Pharmacopoeial requirement:
A. Weight uniformity
B.P. design:
Not more than two of the individual tablet weights deviate
- Weigh 20 tablets individually
from the average weight (X) by more than 7.5% according
- Calculate the average weight of tablets
to the following table and none deviate by double this %:
Percentage deviation Tablets
80 mg or less 10
> 80- < 250 mg 7.5
250 mg or more 5
% Error for a tablet=
Difference between Actual tablet weight & Average tablet weight x 100
Average tablet weight
B. Content uniformity
USP defines content uniformity test for tablets containing 50 mg or less of drug substance in case of uncoated tablets and
for all sugar coated tablets regardless to the drug content.
USP design:
Ten tablets are individually assayed for their content (according to the method described in the individual monograph) The
requirements for content uniformity are met if the amount of the active ingredient in each tablet lies within the range of
85- 115 % of the label claim.
(If one or more tablet does not meet these criteria, additional tests as prescribed in the USP are required)
1- Uniformity of active ingredient:

2. Disintegration test:
The disintegration test is a measure of the time required under a given set of conditions for a group of tablets to
disintegrate into particles which will pass through a 10 mesh screen. Generally, the test is useful as a quality assurance
tool for conventional dosage forms. The disintegration test is carried out using the disintegration tester which consists of a
basket rack holding 6 plastic tubes, open at the top and bottom, the bottom of the tube is covered by a 10-mesh screen.
The basket is immersed in a bath of suitable liquid held at 37 o C, preferably in a 1L beaker. For compressed uncoated
tablets, the testing fluid is usually water at 37 o C but some monographs direct that simulated gastric fluid be used. If one
or two tablets fail to disintegrate, the test is repeated using 12 tablets. For most uncoated tablets, the BP requires that the
tablets disintegrate in 15minutes (although it varies for some uncoated tablets) while for coated tablets, up to 2hours may
be required 3 . The individual drug monographs specify the time disintegration must occur to meet the Pharmacopoeial
standards.
The tablet disintegration test is limited to manufacturing control of lot-to-lot variations in individual products and is not a
measure of bioavailability 27 .
Applications of Disintegration test :
1.Disintegration test is a simple test which helps in the preformulation stage to the formulator.
2.It helps in the optimisation of manufacturing variables, such as compressional force and dwell time.
3.This test is also a simple in-process control tool to ensure uniformity from batch to batch and among different tablets
4.It is also an important test in the quality control of tablets and hard gelatine capsules.
Advantages of Disintegration tests:
This test is simple in concept and in practice.
It is very useful in preformulation, optimisation and in quality control.
Disadvantages:
Disintegration test cannot be relied upon for the assurance of bioavailability
3. Dissolution test :
Dissolution is the process by which a solid solute enters a solution. In the pharmaceutical industry, it may be defined as
the amount of drug substance that goes into solution per unit time under standardized conditions of liquid/solid interface,
temperature and solvent composition. Dissolution is considered one of the most important quality control tests performed
on pharmaceutical dosage forms and is now developing into a tool for predicting bioavailability, and in some cases,
replacing clinical studies to determine bioequivalence. Dissolution behaviour of drugs has a significant effect on their
pharmacological activity.
In fact, a direct relationship between in vitro dissolution rate of many drugs and their bioavailability has been
demonstrated and is generally referred to as in vitro-in vivo correlation, IVIVC1.
In spite of IVIVC, dissolution is not really a predictor of therapeutic efficiency. Rather, it is a qualitative and quantitative
tool which can provide valuable information about biological availability of a drug as well as batch-to-batch consistency
of products. Dissolution tests are therefore used to confirm compliance with compendial specifications and are needed as
part of a product license application. Additionally, they are used during product development and stability testing as part
of the specifications for the product. However, no universal dissolution test has been designed that gives the same in vitro
dissolution and in vivo bioavailability for different formulations and batches. Thus, different compendial specifications
have been developed for different formulations and dosage forms.
Tablet Dissolution is a standardised method for measuring the rate of drug release from a dosage form. The principle
function of the dissolution test may be summarised as follows:
Optimisation of therapeutic effectiveness during product development and stability assessment.
Routine assessment of production quality to ensure uniformity between production lots.
Assessment of bioequivalence, that is to say, production of the same biological availability from discrete batches of
products from one or different manufacturers.
4. Friability test:

The friability test is closely related to tablet hardness and is designed to evaluate the ability of the tablet to withstand
abrasion in packaging, handling and shipping. It is usually measured by the use of the Roche friabilator. A number of
tablets are weighed and placed in the apparatus where they are exposed to rolling and repeated shocks as they fall 6 inches
in each turn within the apparatus. After four minutes of this treatment or 100 revolutions, the tablets are weighed and the
weight compared with the initial weight. The loss due to abrasion is a measure of the tablet friability. The value is
expressed as a percentage. A maximum weight loss of not more than 1% of the weight of the tablets being tested during
the friability test is considered generally acceptable and any broken or smashed tablets are not picked up 3 . Normally,
when capping occurs, friability values are not calculated. A thick tablet may have less tendency to cap whereas thin tablets
of large diameter often show extensive capping, thus indicating that tablets with greater thickness have reduced internal
stress 2 . Most effervescent tablets and some chewable tablets undergo high friability weight loss which is an indication for
the special stack packing that is required for these types of tablets.
In case of hygroscopic tablets a humidity-controlled environment (relative humidity less than 40%) is required for testing.
Tablets prone to capping during the test are considered unfit for commercial use.
Friability is affected by various external and internal factors like:
1) Punches that are in poor condition or worn at their surface edges, resulting in whiskering at the tablet edge and show
higher than normal friability values.
2) Friability test is influenced by internal factors like the moisture content of tablet granules and finished tablets. Moisture
at low and acceptable level acts as a binder
Quality Control for finished product:
Packaging: Upon completion of processing, the product is inspected by QC for appearance, broken tablets, damaged or
overfilled capsules and a sample is withdrawn for testing. A product found to contain minor defects is further inspected
and a determination for corrective procedures is made and effected before released for packaging. Products released by
QC are either bulk packaged in polyethylene lined fiber boxes, and labeled with complete product information or bottled
and labeled as per customer specifications. An expiration date, based on appropriate testing by the customer, is also
printed on the finished product. Inspection and packaging records are maintained and samples are withdrawn to be
retained by QC for at least one year past the expiration date of the product.
Sampling & Inspection: The tablets are checked and tested on half-hour intervals for their physical properties and, if
necessary, corrective action is taken to maintain those properties. Representative samples of 100 units are collected for
both the core and the finished product for Quality Control testing, customer approval and as Reference Samples, a set for
each need.
Storage of Finished Goods: The product shall be quarantined and stored under controlled temperature conditions until
approval and shipping to the customer.
The QC group also maintains calibration records of all instruments at suitable intervals and in addition checks
conformance of all operations to the set procedures. In-process testing is performed by the QC chemists to determine
whether the product being manufactured conforms to specifications. The Quality Control Unit also retains samples of raw
materials (for one year past the expiration date of the last product they are used in) arid finished products (for one year
past the product expiration date) are maintained under control conditions
Tabletting problems
Types of
problem
Capping

Description
Separation of upper/lowers
segment of tablet and
come off as a cap, during

Causes
1) Large quantity of fines
2) Too dry
3) Binder factor

Solution
1) Filter through 100-200
mesh
2) Add hydroscopic agent

manufacturing or
subsequent handling.

4) Lubricant factor

3) Increase amount of
binder/add dry binder
4) Increase amount of
lubricant or change the type

Lamination

Separation of a tab into 2


or more distinct horizontal
layers.

1) Oily granules
2) Excess lubricant
3) Rapid decompression

Chipping

Breaking of tablet edges,


during ejection or coating
process
Small, fine cracks
observed on upper and
lower central surface of
tablets
Adherence of tablet
material to the die wall

1) Stick to punch faces


2) Too dry granules
3) Excess binding

1) Add absorbent
2) Reduce lubricant amount
3) Reduce turret speed and
reduce final compression
pressure
1) Increase lubrication
2) Add hydroscopic agents
3) Use dry binders

Cracking

Sticking

Picking

Mottling

Adherence of tablet
material to upper punch tip

Unequal distribution of
colour of a tablet

Problems
BLISTERI
NG

Definition
It is local
detachment of film
from the substrate
forming blister

CHIPPING

It is a defect where
the film becomes
chipped and
dented, usually at
the edges of the
tablet

CRATERI
NG

It is a defect of film
coating whereby
volcanic-like
craters appears

1) Large size granules


2) Too dry granules

1) Add fines
2) Moisten granules and add
proper amount of granules

1)
2)
3)
4)
1)
2)

1)
2)
3)
4)
1)

Too moist granules


Improper lubrication
Excess binder
Oily granules
Same causes as above and
Low mp substances soften
from heat of compression

1) Coloured drug with


colourless excipients
2) Migration of dyes to
surface of granules while
drying
3) Improper mixing of
coloured binder solution

2)
1)
2)
3)

Dry granules properly


Increase/change lubricant
Reduce amount of binder
Add absorbent
Refer to sticking solution
and
Use high melting point
lubricant
Use proper colourants
Reduce drying temp and
particle size
Add dry colour additive
during powder mixing and
addd adhesives like acacia

Reasons
Entrapment of gases in
or underneath the film
due to overheating either
during spraying or at
the end of the coating
run
Decrease in fluidizing
air or speed of rotation
of the drum in pan
coating

Causes
Effect of temperature on
the strength, elasticity
and adhesion of the film

Remedy
Use mild drying condition

High degree of attrition


associated with the
coating process

increase hardness of the


film by increasing the
molecular weight grade of
polymer

The coating solution


penetrates the surface of
the tablet, often at the
crown where the surface

1.Inefficient drying

1. Use efficient and


optimum drying conditions
2. Increase viscosity of

exposing the tablet


surface

is more porous, causing


localized disintergration
of the core and
distribution of the
coating

2.Higher rate of
application of coating
solution

coating solution to decrease


spray application rate

It is a defect where
isolated areas of
film are pulled
away from the
surface when the
tablet sticks
together and then
part
It is a defect
whereby pits occur
on the surface core
without any visible
disruption of the
film coating

Conditions similar to
cratering that produces
an overly wet tablet bed
where adjacent tablets
can stick together and
then break apart

1.Inefficient drying

1. Use efficient and


optimum drying conditions

2.Higher rate of
application of coating
solution

2. Increase viscosity of
coating solution to decrease
spray application rate

Temperature of the
tablet core is greater
than the melting point of
the materials used in the
tablet formulation

Inappropriate drying
(inlet air )
temperature

Dispensing with preheating


procedures at the initiation
of coating
and modifying the drying
(inlet air) temperature such
that the
temperature of the tablet
core is not greater than the
melting point of the batch
of additives used

BLOOMIN
G

It is defect where
coating becomes
dull immediately or
after prolonged
storage at high
temperatures.

It is due to collection on
the surface of low
molecular weight
ingredients included in
the coating formulation.
In most circumstances
the ingredient will be
plasticizer.

High concentration and


low molecular weight of
plasticizer

Decrease plasticizer
concentration and increase
molecular weight of
plasticizer

ORANGE
PEEL/ROU
GHNESS

It is a surface
defect resulting in
the film being
rough and non
glossy. Appearance
is similar to that of
an orange.
A defect which
involves variation
in color of the film

Inadequate spreading of
the coating solution
before drying

1. Rapid Drying

1.Use mild drying


conditions

2. High solution viscosity

2. Use additional solvents


to decrease viscosity of
solution

Improper mixing, uneven


spray pattern,
insufficient coating,
migration of soluble
dyesplasticizers and other
additives during drying

geometric mixing,
reformulation with
different plasticizers and
additives or mild
drying conditions can be
used.

PICKING

PITTING

COLOUR
VARIATIO
N

Alteration of the
frequency and duration
of appearance of tablets
in the spray zone or the
size/shape of the spray
zone

Tableting process
1. Dispensing (weighing and measuring)

Dispensing is the first step in any pharmaceutical manufacturing process. During this step, the weight of each ingredient
in the mixture is determined according to dose.
Dispensing may be done by:

Purely manual by hand scooping from primary containers and weighing each ingredient by hand on a weigh scale.

Automated dispensaries with mechanical devices such as vacuum loading system.

Consideration during dispensing:

weighing accuracy

dust control (laminar air flow booths, glove boxes)

during manual handling

material movement into and out of dispensary

Proper humidity and temperature control.


2. Sizing

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. This provides a greater uniformity of dose. A fine
particle size is essential in case of lubricant mixing with granules for its proper function.
The ranges of equipment employed for this process:

Fluid energy mill

Colloidal mill

Ball mill

Hammer mill

Cutting mill

Roller mill

Conical mill
3.

Powder 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. In special cases of mixing a lubricant, over
mixing should be particularly monitored.
The various blenders used:

Tumbling mixer

High speed mixer granulator

Fluidized bed mixer

Agitator mixer

4.

Granulation

Granulation is the process in which primary powder particles are made to adhere to form larger, multi particle entities

called granules. Pharmaceutical granules typically have a size range between 0.2 and 4.0 mm.
Reasons for granulation:
To prevent segregation of the constituents of the powder mix.
To improve the flow properties of the mix
To improve the compaction characteristics of the mix
Types of granulation:
Wet granulation
- Involves the massing of a mix of dry primary powder particles using a granulation fluid.
- In the traditional wet granulation method, the wet mass is forced through a sieve to produce wet granules which are then
dried. A subsequent screening stage breaks agglomerates of granules and removes the fine material which can be recycled.
Dry granulation
Steps:
1. The primary powder particles are aggregated at high pressure.
2. There are two main processes either a large tablet (slug) is formed in a heavy duty tabletting press (slugging) or
the powder is squeezed between two rollers to produce a sheet of material (roller compaction).
3. In both cases, these intermediate products are broken using a suitable milling method to produce granular material
which is usually sieved to separate the desired fraction range.
4. The unused fine powder may be reworked to avoid waste.
Types of granulator:

1.

Dry granulators

Slugging
2.

Roller compaction

Wet granulators

Shear granulators

High-speed mixer/granulators

Fluidized-bed granulators

Spray driers

Spheronizers/pelletizers

Extrusion-spheronization

Drying
1. Drying is a most important step in the formulation and development of pharmaceutical product.
2. Drying is defined as the removal of small amounts of water or other liquids from a material by the application of
heat.
3. In drying process both heat and mass transfer takes place.
4. The drying process must provide the latent heat without significant temperature rise because it would enhance the
thermal degradation of the product.
Types of dryer:

Convective Dryers (Fluidized-bed dryer)

Conductive Dryers (Vacuum oven)

Radiation Dryers (Microwave)

Spray dryer

Freeze dryer

Consideration:
In case of overnight drying there should be installment of a temperature limit alarms.
Tablet formation
1. The physical principle involved in the tablet formation is compression. Tablets are formed by forcing particles (powder,
granules) into close proximity to each other thus
enabling the particles to cohere into porous, solid specimen of definite geometry.
2. Compression is carried out in a die by the action of two punches namely the lower punch and upper punch. Theses
punches are brought together to provide the compression force.
3. Compression: the reduction in volume of a powder owing to the application of a force. Bonds are formed between
particles which provide the coherence to the powder (compact).
4. Compaction: The formation of a solid specimen of definite geometry as a result of powder compression.
Mechanics of tablet formation
1. Die filling
This is normally accomplished by gravitational flow of the particles (powder, granules, and pellets) from a hopper via the
die table into the die. The presses based on centrifugal die filling are also available. The die is closed at its lower end by
the lower punch.
2. Tablet formation
- The upper punch descends and enters the die and the powder is compressed under a fixed compression force till the
tablet is formed.
- During the compression phase, the lower punch can be stationery or can move upwards in the die.
- After the maximum applied force is reached, the upper punch leaves the powder, i.e. the decompression phase.
3. Tablet ejection
- During this phase the lower punch rises until its tips reaches the level of the top of the die.
- The tablet is subsequently removed from the die and die table by a pushing device.
The sequence of events involved in the tabletting
It consists of 4 events:
1. Upper punch is raised while lower one is dropped to create a space in the die.
2. Hopper shoe is moved forward over die to transfer the particles (powder, granules, pellets) into the die.
3. Hopper shoe moves back while the upper punch is brought down so as to compress the particles into tablet.
4. The upper punch moves upward and same is true for the lower punch to eject the formed tablet. The cycle is repeated
then
Problem encountered in tablet formation:
1. Poor flow
- Improper design of hopper
- Bridging of granules at the bottom of hopper
- Solutions
Glidants (talc, colloidal silica
Flow enhancing devices (vibrator)
Uniform sized and shaped granuler
- Poor mixing
Improper mixing of ingredients
Insufficient or inadequate time of mixing

Solution
Proper mixing
Maintain adequate mixing time
Use suitable mixer

2. Punch variation
- Unequal length of lower punches
- Variations of granular volume filled in die

Solution
Use good and uniform sized punches

PROBLEMS ASSOCIATED WITH PACKAGING:


Glass Containers
Flaking
o Alkali is extracted from the surface of glass and a silica rich layer is formed which is sometimes detached
form the surface
o can be seen in the form of shining flakes in the product.
Weathering or blooming
o Occurs when glassware is stored in damp atmosphere or with extreme temperature variations for several
months
o The wetting of the surface by condensing moisture results in salts being dissolved out of the glass.
o It gives the appearance of fine crystals on the glass in early stage
Plastic Containers
Permeation
o Transmission of gases or liquids that can affect products shelf life.
Leaching
o Release of constituent from container that may contaminate the product.
Sorption
o removal of component of product by the packaging material.
o may cause loss of preservatives.
Chemical reactivity
o Certain components of packaging material may react chemically with one or more components of product.
Modification
o The physical or chemical alteration of the packaging material by the product.
Blister packing
Film shrinkage
o most films shrink to certain level, accepted shrinkage level is 2-3% and excessive shrinkage leads to curl
Film sticking
o occurs at molds or heating plates due to excessive heating of the film
Incomplete blister cavities
o Indicates insufficient heat to films.
o Heating temperature needs to be controlled
Incomplete blister forming
o Due to temporary or actual lack of air pressure to the line
Poor lid stock sealing
o Sealing temperature normally is identical for PVC, PVDC/PVC and PE/PVC, so carelessness in selecting
temperature leads to this problem
PROBLEMS ASSOCIATED WITH STORAGE:
Increased moisture content and temperature will also disrupt the inter-particulate bonds of granules formed during
compaction and alter the tablet strength.
Moisture as liquid or water vapour may cause physical changes(eg softening and hardening) or chemical changes.
Extremes of temperature can cause deterioration to product and/or pack.
Tablets will become more friable on aging as they suffer from moisture loss.
Thus, tablets should be stored at reasonable temperature and humidity in order to maintain their hardness and
friability.
Expiry Date

The therapeutic effect of the tablet may deteriorate and the strength of the ingredients can drop to 60% or maybe even
50% of what it originally was.
There was there are also possible harmful effects. The ingredients may start to break down into a chemical that is
more harmful than the original substance.
There may be uneven consistency of the ingredients especially in liquid medications. This unbalanced medication
may increase the risk of using excessive dose or insufficient dose.

Machines:
During mixing: Powder mixers
1. Tumbling mixer
2. High speed mixer granulator
3. Fluidized bed mixer
4. Agitator mixer (ribbon mixer)
5. Nautamixer
Nautamixer: Cone mixer (http://www.1985blender.com/videoDSH2.html)
1. Depends on the principle of rotation and revolution, conveying the material along with the axle by means of
rotation.
2. The material is upward and downward cycled by gyratory stirring along wall surface of cone, with the central
revolution. The even mixing can be performed in the shortest time.
3. Besides used for gentle mixing action and minimal heat generation, it can also be used for high shear mixing
using lump breakers, which is driven separately.
Mechanisms:
Cone screw mixer consists of a conical container which houses a continuous flight/ rotating screw.
The screw rotates about it's own axis and revolves along the walls of the cone.
The screw conveys the material to near the top, where it cascades back in to the mass
Mixer combines convective mixing and shear and diffusive mixing
The material of widely differing densities and particle shapes and sizes are mixed homogenously without any
degradation.

Nautamixer

ribbon mixer

tumbler mixer high speed mixer granulator

Drying of granules:
Working principle:
Upon purified and heated, the air is
introduced through the air inlet. It will pass
through the screening plate at the bottom of
the hopper. In the hopper, the materials that
have been stirred will tumble under the
action of the air currents flowing at a high
speed with the water content to be
evaporated and brought away and materials
dried fast.

Coating:

Coating pan
Working principle of auto coater:

Auto Coater

The tablet to be coated make continuous complicated orbital motion the closed rotating Drum under the action of a
streamline of Baffles. During the motion coating medium automatically sprays according to the technological process and
rational technological parameters, at the same time hot filtered air supplied under a negative pressure. The hot air
penetrates through the tablets core layers and is discharged from the bottom of the layers, so that the coating medium
sprayed on the surface of the tablet cores will dry rapidly and evenly, thus forming a solid and smooth surface film on
tablet.
Ways to control faulty of machines:
(a) Auxiliary Equipments:
I. Granulation Feeding Device:
In many cases, speed of die tablet is such that the time of die under feed frame is too short to allow adequate or consistent
gravity, filling of die with granules, resulting in weight variation and content uniformity. These also seen with poorly
flowing granules. To avoid these problems, mechanized feeder can employ to force granules into die cavity.
II. Tablet weight monitoring devices:High rate of tablet output with modern press requires continuous tablet weight monitoring with electronic monitoring
devices like Thomas Tablet Sentinel,
Pharmakontroll and Killan control System-MC. They monitor force at each
compression station by starin gage technology which is then correlated with
tablet weight.
III. Tablet Deduster: In almost all cases, tablets coming out of a tablet machine bear excess powder on its surface and are run through the tablet
deduster to remove that excess powder.
IV. Fette machine
Fette machine is device that chills the compression components to allow the compression of low melting point substance
such as waxes and thereby making it possible to compress product with low meting points.

Granulation Feeding Device

Tablet weight monitoring devices

Tablet Deduster

Fette machine

Prevention:
In order to prevent the tablet problems, batch to batch variation and release of defect product into the market, several
prevention measures must be carried out against the:
o Errors involving instruments
o Errors involving raw materials and products
o Human errors
o Environmental errors
1. Prevention against errors involving instruments:
Calibration
Maintenance
2. Prevention against errors involving raw materials and products:
Product specifications:
- Quality of tablets should fulfill certain specifications:
o Weight and content uniformity, dissolution test, hardness test, friability test, visual observation, thickness and
diameter of the tablets, Packaging
3. Prevention against the human errors:
i.
Requirements for personnel:
Attitude:
- Should be responsible for their duties.
- Should not smoking, eating, drinking in production, laboratory, storage or other area where they might adversely
influence product quality.
- Should in good health, capable of handing their duties properly.
Experiences:
Enable them to have professional judgments to the practical problem encountered in the manufacture and quality
control of pharmaceutical products.
Professionalism:
- All personnel should wear clean full garments appropriate to the duties they perform, including appropriate hair
covers and shoes.
- All personnel should practice good hygiene. For example, wear glove while handling the raw materials.
Qualifications:
- Key personnel responsible for supervising the manufacture and quality control of pharmaceutical products
should possess the qualifications of a scientific education and practical experience required by nation
legislation.
- Their education should include the study of an appropriate combination of:
-Chemistry, biochemistry, chemical engineering, microbiology, pharmaceutical science and technology,
pharmacology and toxicology, physiology.

ii.

iii.

No drugs or medical supplies shall be manufactured except under the supervisions of a licensed pharmacist,
chemist or other qualified personnals.
Training:
- All the personnel who are directly engaged in the manufacturing activities should be trained in the
particular operations and in the principles of Good Manufacturing Practice (GMP).
- Individual responsibilities should be clearly defined and understood by the persons concerned and
recorded as written description.
- After training, their performance should be appraised to determine whether they have proper experience
for jobs assigned to them.
Role of supervisors:
Monitor and frequent checking of the machines.
Identify the problems in tableting process and solve it.
Address productivity improvement.
Motivate employee and improve their attitude.
Role of Heads of production and quality control:
Authorization of written procedures and other documents.
Monitor and control of the manufacturing environment
Approval and monitoring of suppliers of materials
Approval and monitoring of contract manufacturers.
Designation and monitoring of storage conditions for materials and products,
Performance and evalution of in- process controls
Monitoring of compliance with GMP requirements.

4. Prevention of environmental errors:


Storage areas:
- Should be clean, dry and maintained within acceptable temperature limits.
- Should be of sufficient capacity to allow orderly storage of the various categories of material and
products.
- Temperature, relative humidity and days stored at rest should be optimized.
Receiving areas:
- Should be designed and equipped to allow containers of incoming materials to be cleaned if necessary
before storage.
Manufacturing areas:
- Use of automated vacuum conveyer to
Transfer powder products to blending and tableting machinery.
- Reduce the amount of heavy lifting and manual labor performed by employees.
- Prevent contamination.