Tablets

TABLETS
Mr. Sagar Kishor Savale
[Department of Pharmaceutics]
avengersagar16@gmail.com
2015 - 016
Department of Pharmacy (Pharmaceutics) | Sagar savale
112-07-2016 Sagar Kishor Savale

INTRODUCTION
 Tablet is defined as a compressed solid dosage
form containing medicaments with or without
excipients. According to the Indian Pharmacopoeia
Pharmaceutical tablets are solid, flat or biconvex
dishes, unit dosage form, prepared by compressing a
drug or a mixture of drugs, with or without diluents.

Definition according to the BP
Tablets are dosage forms that are circular in shape
with either flat or convex faces and prepared by
compressing the medicament or mixture of
medicaments usually with added substances
Tablets are now the most popular dosage form ( 70%
of all ethical pharmaceutical preparations produced)

Tableting machine
Click to figure video was started 512-07-2016 Sagar Kishor Savale

Click to figure video was started

The Advantages of the Tablet dosage form
 They are unit dosage form and offer the greatest capabilities of all oral
dosage form for the greatest dose precision and the least content
variability.
 Cost is lowest of all oral dosage form.
 Lighter and compact.
 Easiest and cheapest to package and strip.
 Easy to swallowing with least tendency for hang-up.
 Sustained release product is possible by enteric coating.

 Objectionable odour and bitter taste can be masked by coating
technique.
 Suitable for large scale production.
 Greatest chemical and microbial stability over all oral dosage
form.
 Product identification is easy and rapid requiring no additional steps
when employing an embossed and/or monogrammed punch face.

Disadvantages of Tablet dosage form are:
 Difficult to swallow in case of children and unconscious patients.
 Some drugs resist compression into dense compacts, owing to
amorphous nature, low density character.
 Drugs with poor wetting, slow dissolution properties, optimum
absorption high in GIT may be difficult to formulate or manufacture
as a tablet that will still provide adequate or full drug bioavailability.
 Bitter testing drugs, drugs with an objectionable odor or drugs that are
sensitive to oxygen may require encapsulation or coating. In such
cases, capsule may offer the best and lowest cost.

Different types of Tablets
(A) Tablets ingested orally:
1. Compressed tablet, e.g. Paracetamol tablet
2. Multiple compressed tablet
3. Repeat action tablet
4. Delayed release tablet, e.g. Enteric coated Bisacodyl tablet
5. Sugar coated tablet, e.g. Multivitamin tablet
6. Film coated tablet, e.g. Metronidazole tablet
7. Chewable tablet, e.g. Antacid tablet
(B) Tablets used in oral cavity:
1. Buccal tablet, e.g. Vitamin-c tablet
2. Sublingual tablet, e.g. Vicks Menthol tablet
3. Troches or lozenges
4. Dental cone

(c) Tablets administered by other route:
1. Implantation tablet
2. Vaginal tablet, e.g. Clotrimazole tablet
(D) Tablets used to prepare solution:
1. Effervescent tablet, e.g. Dispirin tablet (Aspirin)
2. Dispensing tablet, e.g. Enzyme tablet (Digiplex)
3. Hypodermic tablet
4. Tablet triturates e.g. Enzyme tablet (Digiplex)

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TYPES OF TABLETS
1. COMPRESSED TABLETS
• In addition to the medicinal agent or agents, compressed tablets
usually contain a number of pharmaceutical adjuncts, including
the following:
Diluents or fillers: which add the necessary bulk to a formulation
to prepare tablets of the desired size.
Binders or adhesives: which promote adhesion of the particles
of the formulation, allowing a granulation to be prepared and
maintaining the integrity of the final tablet.

Disintegrants or disintegrating agents: which promote breakup of the tablets after
administration to smaller particles for ready drug availability.
Antiadherents, glidants, lubricants, or lubricating agents: which enhance the flow
of the material into the tablet dies, minimize wear of the punches and dies, prevent
fill material from sticking to the punches and dies, and produce tablets with a sheen.
Miscellaneous adjuncts: such as colorants and flavorants.
After compression, tablets may be coated with various materials as described later.
Tablets for oral, buccal, sublingual, or vaginal administration may be prepared by
compression.

MULTIPLY COMPRESSED TABLETS
• Multiply compressed tablets
are prepared by subjecting
the fill material to more than
a single compression.
• T h e re s u l t m ay b e a
multiple-layer tablet or a
tablet within a tablet, the
inner tablet being the core
and the outer portion being
t h e s h e l l . .

• Layered tablets are prepared by initial compaction of a portion of fill material
in a die followed by additional fill material and compression to form two-
layered or three- layered tablets, depending on the number of separate fills.
• Each layer may contain a different medicinal agent, separated for reasons
of:
1. chemical or physical incompatibility
2. staged drug release
3. for the unique appearance of the layered tablet.
• Usually, each portion of fill is a different color to produce a distinctive-
looking tablet.
• In preparation of tablets within tablets, special machines are required to
place the preformed core tablet precisely within the die for application of
surrounding fill material.

SUGARCOATED TABLETS
• Compressed tablets may be coated with a colored or
an uncolored sugar layer.
• The coating is water soluble and quickly dissolves
after swallowing.
1. The sugarcoat protects the enclosed drug from
the environment and provides a barrier to
objectionable taste or odor.
2. The sugarcoat also enhances the appearance of
the compressed tablet and permits imprinting of
identifying manufacturer’s information.
• Among the disadvantages to sugarcoating tablets are
the time and expertise required in the coating
process and the increase in size, weight, and shipping
costs.
• Sugarcoating may add 50% to the weight and bulk of
the uncoated tablet.

FILM-COATED TABLETS
• Film-coated tablets are compressed tablets coated with a thin
layer of a polymer capable of forming a skin-like film.
The film is usually colored and has the advantage over
sugarcoatings in that it is:
1. more durable
2. less bulky
3. less time- consuming to apply.
• By its composition, the coating is designed to rupture and expose
the core tablet at the desired location in the gastrointestinal
tract.

GELATIN-COATED TABLETS
• A recent innovation is the gelatin-coated
tablet.
• The innovator product, the gelcap, is a
capsule- shaped compressed tablet that allows
the coated product to be about one-third
smaller than a capsule filled with an
equivalent amount of powder.

ENTERIC-COATED TABLETS
• Enteric-coated tablets have delayed-release
features.
• They are designed to pass unchanged through the
stomach to the intestines, where the tablets
disintegrate and allow drug dissolution and
absorption and/or effect.
• Enteric coatings are employed when the drug
substance:
is destroyed by gastric acid or
is particularly irritating to the gastric mucosa or
when bypass of the stomach substantially
enhances drug absorption.

BUCCAL AND SUBLINGUAL TABLETS
• Buccal and sublingual tablets are flat, oval tablets intended
to be dissolved in the buccal pouch (buccal tablets) or
beneath the tongue (sublingual tablets) for absorption
through the oral mucosa.

• They enable oral absorption of drugs that
are destroyed by the gastric juice and/or
are poorly absorbed from the
gastrointestinal tract.
• Buccal tablets are designed to erode
slowly, whereas those for sublingual use
(such as nitroglycerin) dissolve promptly
and provide rapid drug effects.
• Lozenges or troches are disc-shaped solid
dosage forms containing a medicinal agent
and generally a flavoring substance in a
hard candy or sugar base.
• They are intended to be slowly dissolved in
the oral cavity, usually for local effects,
although some are formulated for systemic
absorption.

CHEWABLE TABLETS
• Chewable tablets, which have a
smooth, rapid disintegration
when chewed or allowed to
dissolve in the mouth, have a
creamy base, usually of specially
flavored and colored mannitol.
• Chewable tablets are especially
useful for administration of large
tablets to children and adults
who have difficulty swallowing
solid dosage forms.

EFFERVESCENT TABLETS
• Effervescent tablets are prepared by
compressing granular effervescent
salts that release gas when in contact
with water.
• These tablets generally contain
medicinal substances that dissolve
rapidly when added to water.
• The “bubble action” can assist in
breaking up the tablets and
enhancing the dissolution of the
active drug.

MOLDED TABLETS
• Certain tablets may be prepared by molding rather than by
compression. The resultant tablets are very soft and soluble
and are designed for rapid dissolution.

TABLET TRITURATES
• Tablet triturates are small, usually cylindrical, molded or compressed tablets
containing small amounts of usually potent drugs.
• Today, only a few tablet triturate products are available commercially, with
most of these produced by tablet compression.
• Since tablet triturates must be readily and completely soluble in water, only a
minimal amount of pressure is applied during their manufacture.
• A combination of sucrose and lactose is usually the diluent.
• The few tablet triturates that remain are used sublingually, such as
nitroglycerin tablets.
• Pharmacists also employ tablet triturates in compounding. For example,
triturates are inserted into capsules or dissolved in liquid to provide accurate
amounts of potent drug substances.

HYPODERMIC TABLETS
• Hypodermic tablets are no longer available in the United States.
• They were originally used by physicians in extemporaneous
preparation of parenteral solutions.
• The required number of tablets was dissolved in a suitable vehicle,
sterility attained, and the injection performed.
• The tablets were a convenience, since they could be easily carried in
the physician’s medicine bag and injections prepared to meet the
needs of the individual patients.
• However, the difficulty in achieving sterility and the availability of
prefabricated injectable products, some in disposable syringes, have
eliminated the need for hypodermic tablets.

DISPENSING TABLETS
• Dispensing tablets are no longer in use.
• They might better have been termed compounding tablets
because the pharmacist used them to compound
prescriptions; they were not dispensed as such to the
patient.

IMMEDIATE-RELEASE TABLETS
• Immediate-release tablets are designed to disintegrate and
release their medication with no special rate-controlling
features, such as special coatings and other techniques.

EXTENDED-RELEASE TABLETS
• Extended-release tablets (sometimes called controlled-
release tablets) are designed to release their medication in a
predetermined manner over an extended period.

VAGINAL TABLETS
• Vaginal tablets, also called vaginal inserts, are uncoated, bullet-
shaped or ovoid tablets inserted into the vagina for local effects.
• They contain :
antibacterials for the treatment of nonspecific vaginitis caused
by Haemophilus vaginalis
antifungals for the treatment of vulvovaginitis candidiasis caused
by Candida albicans and related species.

INSTANTLY DISINTEGRATING OR DISSOLVING
TABLETS
• Instant-release tablets (rapidly dissolving tablets, or RDTs) are characterized by
disintegrating or dissolving in the mouth within 1 minute, some within 10 seconds
• Tablets of this type are designed for children and the elderly or for any patient who
has difficulty in swallowing tablets.
• They liquefy on the tongue, and the patient swallows the liquid.
• A number of techniques are used to prepare these tablets, including:
Lyophilization
soft direct compression
• These tablets are prepared using very water- soluble excipients designed to wick
water into the tablet for rapid disintegration or dissolution. They have the stability
characteristics of other solid dosage forms.

• The original fast-dissolving tablets were molded tablets for sublingual
use.
• They generally consisted of active drug and lactose moistened with an
alcohol–water mixture to form a paste.
• The tablets were then molded, dried, and packaged.
• For use, they were simply placed under the tongue to provide a rapid
onset of action for drugs such as nitroglycerin.
• Also, they have been used for drugs that are destroyed in the
gastrointestinal tract, such as testosterone, administered sublingually
for absorption to minimize the first-pass effect.

• These RDTs are more convenient to carry and administer
than an oral liquid.
There are no standards that define an RDT, but one possibility is dissolution in the mouth
within approximately 15 to 30 seconds; anything slower would not be categorized as
rapidly dissolving.
Packaging
• They are generally packaged in cards or bubble-type packaging with
each individual tablet in its own cavity.

• Not withstanding these advantages, there are a number of
disadvantages and difficulties associated with formulating RDTs,
including:
drug loading
taste masking
friability
manufacturing costs
stability of the product

COMPRESSED TABLETS
The physical features of compressed tablets are well known:
Round, oblong or unique in shape
thick or thin
large or small in diameter
flat or convex
unscored or scored in halves, thirds, or quadrants
engraved or imprinted with an identifying symbol and/or code
number
coated or uncoated
colored or uncolored
one, two, or three layered.

• Tablet diameters and shapes are determined by the die and punches
used in compression.
The less concave the punches, the flatter the tablets; conversely
The more concave the punches the more convex the resulting tablets.
Punches with raised impressions produce recessed impressions on the
tablets
Punches with recessed etchings produce tablets with raised impressions
or monograms.
Monograms may be placed on one or on both sides of a tablet,
depending on the punches

Tablet Ingredients
In addition to active ingredients, tablet contains a number of inert materials known
as additives or excipients. Different excipients are:
1. Diluent
2. Binder and adhesive
3. Disintegrents
4. Lubricants and glidants
5. Colouring agents
6. Flavoring agents
7. Sweetening agents

EXCIEPIENTS- functions
 Impart weight, accuracy, & volume(its allow acccuracy of dose)
 Improve solubility
 Increase stability
 Enhance bioavailability
 Modifying drug release
 Assist pdt identification
 Increase patient acceptability
 Facilitate dosage form design

Excipient functions

1. Diluent: Diluents are fillers used to make required bulk of the tablet when
the drug dosage itself is inadequate to produce the bulk. Secondary reason is
to provide better tablet properties such as improve cohesion, to permit use of
direct compression manufacturing or to promote flow.
A diluent should have following properties:
1. They must be non toxic
2. They must be commercially available in acceptable grade
3. There cost must be low
4. They must be physiologically inert
5. They must be physically & chemically stable by themselves & in
combination with the drugs.
6. They must be free from all microbial contamination.
7. They do not alter the bioavailability of drug.
8. They must be color compatible.

Commonly used tablet diluents
1. Lactose-anhydrous and spray dried lactose
2. Directly compressed starch-Sta Rx 1500
3. Hydrolyzed starch-Emdex and Celutab
4. Microcrystalline cellulose-Avicel (PH 101and PH 102)
5. Dibasic calcium phosphate dehydrate
6. Calcium sulphate dihydrate
7. Mannitol
8. Sorbitol
9. Sucrose- Sugartab, DiPac, Nutab
10. Dextrose

2. Binders and Adhesives: These materials are added either dry or in wet-
form to form granules or to form cohesive compacts for directly
compressed tablet.
Example:
 Acacia, tragacanth- Solution for 10-25% Conc.
 Cellulose derivatives- Methyl cellulose, Hydroxy propyl methyl cellulose,
Hydroxy propyl cellulose
 Gelatin- 10-20% solution
 Glucose- 50% solution
 Polyvinylpyrrolidone (PVP)- 2% conc.
 Starch paste-10-20% solution
 Sodium alginate
 Sorbitol

3. Disintegrants: Added to a tablet formulation to facilitate its breaking or
disintegration when it contact in water in the GIT.
Example:
 Starch- 5-20% of tablet weight.
 Starch derivative – Primogel and Explotab (1-8%)
 Clays- Veegum HV, bentonite 10% level in colored tablet only
 Cellulose
 Cellulose derivatives- Ac- Di-Sol (sodium carboxy methyl cellulose)
 Alginate
 PVP (Polyvinylpyrrolidone), cross-linked

4. Superdisintegrants: Swells up to ten fold within 30 seconds when contact
water.
Example:
 Crosscarmellose- cross-linked cellulose, Crosspovidone- cross-linked povidone
(polymer), Sodium starch glycolate- cross-linked starch. These cross-linked
products swells with in 30 seconds when in contact with water.
 A portion of disintegrant is added before granulation and a portion before
compression, which serve as glidants or lubricant.

5. Lubricant and Glidants: Lubricants are intended to prevent adhesion of
the tablet materials to the surface of dies and punches, reduce inter
particle friction and may improve the rate of flow of the tablet granulation.
Glidants are intended to promote flow of granules or powder material by
reducing the friction between the particles.
Example:
 Lubricants- Stearic acid, Stearic acid salt - Stearic acid, Magnesium stearate,
Talc, PEG (Polyethylene glycols), Surfactants
 Glidants- Corn Starch – 5-10% conc., Talc-5% conc., Silica derivative - Colloidal
silicas such as Cab-O-Sil, Syloid, Aerosil in 0.25-3% conc.

6. Coloring agent: The use of colors and dyes in a tablet has three purposes:
(1) Masking of off color drugs
(2) Product Identification
(3) Production of more elegant product
 All coloring agents must be approved and certified by FDA. Two forms of colors
are used in tablet preparation – FD &C and D & C dyes. These dyes are applied
as solution in the granulating agent or Lake form of these dyes. Lakes are dyes
absorbed on hydrous oxide and employed as dry powder coloring.
Example:
 FD & C yellow 6-sunset yellow,FD & C yellow 5- Tartrazine ,FD & C green 3-
Fast Green,FD & C blue 1- Brilliant Blue ,FD & C blue 2 - Indigo carmine

7. Flavoring agents: For chewable tablet- flavor oil are used
8. Sweetening agents: For chewable tablets: Sugar, mannitol.
 Saccharine (artificial): 500 time’s sweeter than sucrose
 Disadvantage: Bitter aftertaste and carcinogenic
 Aspartame (artificial)
 Disadvantage: Lack of stability in presence of moisture.

9. Wetting Agents
• Water molecules attract each other equally in all directions. Water molecules on
the surface, however, can only be pulled into the bulk water by water molecules
underneath, since there are no water molecules to pull in the opposite
direction. The surface tension of water is strong enough to support the weight
of tiny insects such as water striders.
• The surface tension in action can be visualized by placing a small drop of alcohol
on a thin layer of water. Alcohol with lower surface tension mixes with water
causing reduction in the surface tension in the local region. Owing to the higher
surface tension of water in the neighbor, water is pulled from the alcohol
dropped region into the neighbor, and this leads to the formation of a dry spot
in the middle of the water layer. 5412-07-2016 Sagar Kishor Savale

API
Filler Mixing of
granulation blend
GranulationBinder(s)
Preparation of
binder solution
Drying
Milling
LOD
Disintegrant
screening
screening Initial Blending
lubricant screening
Final Blending
Compression
Solvent
Film coating agent Preparation
Film Coating of Tablets
Packaging
and Labelling
Weight
Hardness
Friability
Flow Chart

Lactose
 Non-reactive in anhydrous or hydrous form
 Hydrous form undergoes maillard reaction leading to browning and
discoloration of certain drugs, hence anhydrous form is preferred.
 But anhydrous form picks up moisture when exposed to humidity.
 In wet granulation, hydrous lactose of two varieties are used 60-80 mesh
(coarse) and 80-100 mesh (regular) grade.
 Lactose formulation show good release.
 Low cost diluent.
 But may discolor in presence of amine drug bases or salts of alkaline
compounds

Spray dried lactose
 Lactose is placed in aqueous solution, removed impurities and spray
dried
 Mixture of large alpha monohydrate crystals and spherical aggregates
of smaller crystals
 Good flowability but less compressibility
 Poor dilution potential
 Less compressibility upon initial compaction
 Problem of browning due to contamination of 5-hydroxyfurfural which
was accelerated in the presence of basic amine drugs and catalyzed by
tartarate, citrate and acetate ions

– Fast-Flow lactose (early 1970s)
• Spherical aggregates of microcrystals lactose monohydrate
• Held together by a higher concentration of glass (amorphous lactose)
• Much more compressible
• Highly fluid
• Non hygroscopic
• Tablets are three to four times harder than regular spray dried
– Tabletose: aggromerate form of lactose
• More compressible than spray dried but less compressible than Fast Flo
lactose

Starch
 Can be corn, wheat or potato source
 USP grade of starch has poor flow & compression characteristics
 Also has high moisture content between between 11 & 14 %.
 Specially dried starches also have standard moisture level of 2-4%
 Therefore used in wet granulation

Sta 1500:
 Intact starch grains and ruptured starch grains that have been partially
hydrolyzed and subsequently aggromerated
 Free flowing, self lubricating, containing slightly high MC (10 %)
 Due to which does not form hard compacts
 Dilution potential is minimal, not generally used as filler-binder but as filler
disintegrant
 Retains the disintegrant properties of starch without increasing the fluidity
and compressibility of the total formulation
 Flow promoters like colloidal silicon dioxide is needed.
 Lubricants tend to dramatically soften tablets containing high concentrations
of Starch 1500

Dextrose
 90-92% dextrose, 3-5% maltose and the remainder higher glucose
polysaccharides
 Available both anhydrous and a hydrate product
 Excellent compressibility and good flow
 Contain 8-10% moisture and may increase hardness after compression
 Largest particle size, therefore blending problem may occur
 Cerelose is also avilable

Stages of pharmaceutical manufacturing
PI
Excipients
Primary
Packaging
Seco
Packa
API Finished
Product
ng Materials
micals) 6212-07-2016 Sagar Kishor Savale

ug product manufacture
Dosage Form
milling
Fluid Bed Dryer
lubrication
tableting
impr
combines the drug and excipients
dosage form
Excipients
API
filtration
oven drying
Dry granulation
/ milling
Direct
compression

Tableting methods

Manufacturing Methods

Powders intended for compression into tablets must possess two essential
properties
 Powder fluidity or flowability
• The material can be transported through the hopper into the die
• To produce tablets of a consistent weight
• Powder flow can be improved mechanically by the use of vibrators, incorporate
the glidant
 Powder compressibility
• The property of forming a stable, intact compact mass when pressure is applied
is called powder compressibility
 Easily mixed with other particles
 Homogenous colouring etc
 Friction and adhesion properties

Slugging (dry granulation)
a. Blend is forced into dies of large capacity tablet press and
compacted using flat faced punches.
b. compacted masses are called slugs and process is called
slugging.
c. Slugs milled or screened to produce good free flowing granules
for compression.

Dry compaction/Roller compaction
 On a large scale compression granulation can also be performed on a roller
compactor.
 Granulation by dry compaction can also be achieved by passing powders
between two rollers that compact the material at pressure of up to 10 tons per
linear inch.
 Materials of very low density require roller compaction to achieve a bulk
density sufficient to allow encapsulation or compression.
 One of the best examples of this process is the densification of aluminum
hydroxide.
 Roller compactor is capable of producing as much as 500 kg/hr of compacted
ribbon like materials which can be then screened and milled in to granules for
compression.

Limitations of dry granulation
1- Dry granulation often produces a higher percentage of fines or
non compacted products, which could compromise the quality or
create yield problems for the tablet.
2- It requires drugs or excipients with cohesive properties.

Wet granulation
The most popular method (over 70% )
Granulation is done
 To prevent segregation of the constituents of the powder blend.
 To improve flowability of the powder mixture.
 To improve the compaction characteristics of the powder mixture due to
better distribution of the binder within the granules.
 To improve homogeneity and thus ensure content uniformity
Wet granulation is a process of using a solution binder to the powder mixture. The
amount of liquid can be properly managed; overwetting = the granules to be
too hard, underwetting =too soft and friable.
Aqueous solutions are safer than other solvents.

Procedure of Wet Granulation
Step 1: Weighing and Blending
Step 2: wet granulate prepared by adding the binder solution
Step 3: Screening the damp mass into pellets or granules (6-8mesh)
Step 4: Drying the granulation in thermostatically controlled ovens
Step 5: Dry screening:
Step 6: Mixing with other ingredients: A dry lubricant, antiadherent and glidant is
added to the granules either by dusting over the spread-out granules or by
blending with the granules. Dry binder, colorant or disintegrant may be also
added in this step.
Step 7: Tableting: Last step in which the tablet is fed into the
die cavity and then compressed.

• Single punch machine
• Multi-station rotary presses
• The head of the tablet machine that holds the upper punches, dies and lower
punches in place rotates
• As the head rotates, the punches are guided up and down by fixed cam tracks,
which control the sequence of filling, compression and ejection.
• The portions of the head that hold the upper and lower punches are called the
upper and lower turrets
• The portion holding the dies is called the die table

Compression cycle
 Granules from hopper empty in the feed frame (A) containing several
interconnected compartments.
 These compartments spread the granulation over a wide area to provide time
for the dies (B) to fill.
 The pull down cam (C) guides the lower punches to the bottom, allowing the
dies to overfill
 The punches then pass over a weight-control cam (E), which reduces the fill in
the dies to the desired amount
 A swipe off blade (D) at the end of the feed frame removes the excess
granulation and directs it around the turret and back into the front of the feed
frame
 The lower punches travel over the lower compression roll (F) while
simultaneously the upper punches ride beneath the upper compression roll (G)

 The upper punches enter a fixed distance into the dies, while the lower
punches are raised to squeeze and compact the granulation within the dies
 After the moment of compression, the upper punches are withdrawn as they
follow the upper punch raising cam (H)
 The lower punches ride up the cam (I) which brings the tablets flush with or
slightly above the surface of the dies
 The tablets strike a sweep off blade affixed to the front of the feed frame (A)
and slide down a chute into a receptacle
 At the same time, the lower punches re-enter the pull down cam (C) and the
cycle is repeated

• The principle modification from earlier equipment has been an increase in
production rate which is regulated by
– Number of tooling sets
– Number of compression stations
– Rotational speed of the press
High speed
rotary machine
Multirotary
machine

Processing problems
 Capping is the partial or complete separation of the top or bottom crowns of a
tablet from the main body of the tablet.
 Lamination is separation of a tablet into two or more distinct layers. Both of
these problems usually result from air entrapment during processing.
 Picking is removal of a tablet’s surface material by a punch.
 Sticking is adhesion of tablet material to a die wall. These two problems result
from excessive moisture or substances with low melting temperatures in the
formulation

 Mottling is an unequal color distribution on a tablet, with light or dark areas
standing on otherwise uniform surface. This results from use of a drug with a
color different from that of the tablet excipients or from a drug with colored
degradation products.
 Weight variation-granule size distribution, poor fiow,punch variation
 Hardness variation
 Double impression-monograms or engraving on punch

Background
Basic
Problems
Weight
Variation
Mechanical
Strength
Related
Hardness Friability
Content
Uniformity
Release
Profile
Altered
Visual defects

Visual
Defects
Process
Related
Capping
Lamination
Cracking
Chipping
Formulation
Related
Sticking
Picking
Binding
Machine
Related
Double
Impression 8412-07-2016 Sagar Kishor Savale

Tablets Defects
Capping
Lamination
Sticking &
Picking
Hardness
variation
Chipping
Splitting
Erosion
Thickness
variation
Black Spots
Double Impressions

Capping

Lamination

Sticking & Picking

The Causes and Remedies of Capping related to
‘Formulation’
Sr.
No.
CAUSES REMEDIES
1. Large amount of fines in the
granulation
Remove some or all fines through 100 to 200 mesh screen
2. Too dry or very low moisture content
(leading to loss of proper binding
action).
Moisten the granules suitably. Add hygroscopic substance
e.g.: Sorbitol, Methylcellulose or PEG-4000.
3. Not thoroughly dried granules. Dry the granules properly.
4. Insufficient amount of binder or
improper binder.
Increasing the amount of binder OR
Adding dry binder such as pre-gelatinized Starch, Gum
acacia, powdered Sorbitol, PVP, hydrophilic Silica or
powdered Sugar.
5. Insufficient or improper lubricant. Increase the amount of lubricant or change the type of
lubricant.
6. Granular mass too cold to compress
firm.
Compress at room temperature.

The Causes and Remedies of Capping related to ‘Machine’
Sr.
No.
CAUSES REMEDIES
1. Poorly finished dies Polish dies properly. Investigate other steels
or other materials.
2. Deep concave punches or beveled-edge
faces of punches.
Use flat punches.
3. Lower punch remains below the face of die
during ejection.
Make proper setting of lower punch during
ejection.
4. Incorrect adjustment of sweep-off blade. Adjust sweep-off blade correctly to facilitate
proper ejection.
5. High turret speed. Reduce speed of turret (Increase dwell time).

The Causes and Remedies of Lamination related to ‘Formulation’
Sr.
No.
CAUSES REMEDIES
1. Large amount of fines in the
granulation
Remove some or all fines through 100 to 200 mesh screen
2. Too dry or very low moisture content
(leading to loss of proper binding
action).
Moisten the granules suitably. Add hygroscopic substance
e.g.: Sorbitol, Methylcellulose or PEG-4000.
3. Not thoroughly dried granules. Dry the granules properly.
4. Insufficient amount of binder or
improper binder.
Increasing the amount of binder OR
Adding dry binder such as pre-gelatinized Starch, Gum
acacia, powdered Sorbitol, PVP, hydrophilic Silica or
powdered Sugar.
5. Insufficient or improper lubricant. Increase the amount of lubricant or change the type of
lubricant.

The Causes and Remedies of Lamination related to ‘Machine’
Sr.
No.
CAUSES REMEDIES
1. Rapid relaxation of the peripheral
regions of a tablet, on ejection from a
die.
Use tapered dies, i.e. upper part of the die
bore has an outward taper of 3° to 5°.
2. Rapid decompression Use pre-compression step. Reduce turret
speed and reduce the final compression
pressure.

The Causes and Remedies of Chipping related to ‘Formulation’
Sr.
No.
CAUSES REMEDIES
1. Sticking on punch faces Dry the granules properly or increase lubrication.
2. Too dry granules. Moisten the granules to plasticize. Add
hygroscopic substances.
3. Too much binding causes chipping
at bottom.
Optimize binding, or use dry binders.

The Causes and Remedies of Chipping related to ‘Machine’
Sr.
No.
CAUSES REMEDIES
1. Groove of die worn at compression
point.
Polish to open end, reverse or replace the
die.
2. Barreled die (center of the die wider
than ends)
Polish the die to make it cylindrical
3. Edge of punch face turned
inside/inward.
Polish the punch edges
4. Concavity too deep to compress powder
blend.
Reduce concavity of punch faces. Use flat
punches.

The Causes and Remedies of Cracking related to ‘Formulation’
Sr. No.
CAUSES REMEDIES
1. Large size of granules. Reduce granule size. Add fines.
2. Too dry granules. Moisten the granules properly and add proper amount of
binder.
3. Tablets expand. Improve granulation. Add dry binders.
4. Granulation too cold. Compress at room temperature.

The Causes and Remedies of Cracking related to ‘Machine’
Sr. No.
CAUSES REMEDIES
1. Tablet expands on ejection due to air entrapment. Use tapered die.
2. Deep concavities cause cracking while
removing tablets
Use special take-off.

The Causes and Remedies of Sticking related to ‘Formulation’
Sr.
No.
CAUSES REMEDIES
1. Granules not dried properly. Dry the granules properly. Make moisture analysis to
determine limits.
2. Too little or improper
lubrication.
Increase or change lubricant.
3. Too much binder Reduce the amount of binder or use a different type of
binder.
4. Hygroscopic granular
material.
Modify granulation and compress under controlled
humidity.
5. Oily or way materials Modify mixing process. Add an absorbent.

The Causes and Remedies of Sticking related to ‘Machine’
Sr. No.
CAUSES REMEDIES
1. Concavity too deep for granulation. Reduce concavity to optimum.
2. Too little pressure. Increase pressure.
3. Compressing too fast. Reduce speed.

The Causes and Remedies of Picking related to ‘Formulation’
Sr.
No.
CAUSES REMEDIES
1. Excessive moisture in granules. Dry properly the granules, determine optimum limit.
2. Too little or improper lubrication. Increase lubrication; use colloidal silica as a
‘polishing agent’, so that material does not cling to
punch faces.
3. Low melting point substances, may soften
from the heat of compression and lead to
picking.
Add high melting-point materials. Use high meting
point lubricants.
4. Low melting point medicament in high
concentration.
Refrigerate granules and the entire tablet press.
5. Too warm granules when compressing. Compress at room temperature. Cool sufficiently
before compression.
6. Too much amount of binder. Reduce the amount of binder, change the type or use
dry binders.

The Causes and Remedies of Picking related to ‘Machine’
Sr.
No.
CAUSES REMEDIES
1. Rough or scratched punch faces. Polish faces to high luster.
2. Embossing or engraving letters on punch
faces such as B, A, O, R, P, Q, G.
Design lettering as large as possible.
Plate the punch faces with chromium to
produce a smooth and non-adherent face.
3. Bevels or dividing lines too deep. Reduce depths and sharpness.
4. Pressure applied is not enough; too soft
tablets.
Increase pressure to optimum.

The Causes and Remedies of Binding related to ‘Formulation’
Sr.
No.
CAUSES REMEDIES
1. Too moist granules and extrudes
around lower punch.
Dry the granules properly.
2. Insufficient or improper lubricant. Increase the amount of lubricant or use a more
effective lubricant.
3. Too coarse granules. Reduce granular size, add more fines, and
increase the quantity of lubricant.
4. Too hard granules for the lubricant
to be effective.
Modify granulation. Reduce granular size.
5. Granular material very abrasive
and cutting into dies.
If coarse granules, reduce its size.
Use wear-resistant dies.
6. Granular material too warm, sticks
to the die.
Reduce temperature.
Increase clearance if it is extruding.

The Causes and Remedies of Binding related to ‘Machine’
Sr.
No.
CAUSES REMEDIES
1. Poorly finished dies. Polish the dies properly.
2. Rough dies due to abrasion,
corrosion.
Investigate other steels or other materials or modify
granulation.
3. Undersized dies. Too little
clearance.
Rework to proper size.
Increase clearance.
4. Too much pressure in the tablet
press.
Reduce pressure. OR
Modify granulation.

The Causes and Remedies of Mottling
Sr.
No.
CAUSES REMEDIES
1. A coloured drug used along
with colourless or white-
coloured excipients.
Use appropriate colourants.
2. A dye migrates to the surface
of granulation while drying.
Change the solvent system,
Change the binder,
Reduce drying temperature and
Use a smaller particle size.
3. Improperly mixed dye,
especially during ‘Direct
Compression’.
Mix properly and reduce size if it is of a larger size to
prevent segregation.
4. Improper mixing of a coloured
binder solution.
Incorporate dry colour additive during powder blending
step, then add fine powdered adhesives such as acacia
and tragacanth and mix well and finally add granulating
liquid.

The Causes and Remedies of Double Impression
Sr.
No.
CAUSE REMEDIES
1. Free rotation of either upper
punch or lower punch during
ejection of a tablet.
-Use keying in tooling, i.e. inset a key alongside of
the punch, so that it fits the punch and prevents
punch rotation.
-Newer presses have anti-turning devices, which
prevent punch rotation.

Tablet coating

Objectives of Coating/why coating
1. Reduce influence of atmosphere
2. Mask: taste odor & color of drug
3. Control or Modify drug Release: CR, SR …….
4. Protect drug against GI environment : Enteric coating
5. Avoid irritation of esophagus and stomach
6. Incompatibility: Drug & drug
7. Improve elegance : color imprinting & patient
acceptance
8. Increases the mechanical strength of the core tablet
9. To prevent direct contact with the drug substance

Types of coating processes
The main types are used in the pharmaceutical industry
today
Coating
Functional coating
Non Functional coating
- Sugar coating Compression coating

The main steps involved in the coating of tablets are as
follows:
The tablets (or granules) are placed within the coating apparatus
and agitated.
The coating solution is sprayed on to the surface of the tablets.
Warm air is passed over the tablets to facilitate removal of the
solvent from the adsorbed layer of coating solution on the
surface of the tablets.
When the solvent has evaporated, the tablets will be coated
with the solid component of the original coating solution.

Sugar coating
• Description of tablets: Smooth, rounded and polished to a high gloss.
• Process: Multistage process involving 6 separate operations

Sugar coating
• Sealing tablet core: application of a water impermeable polymer such as
Shellac, cellulose acetate phthalate and polyvinyl acetate phthalate,
which protects the core from moisture, increasing its shelf life.
• Sub coating After the tablets are waterproofed if needed, three to five
subcoats of a sugar-based syrup are applied. This bonds the sugar coating
to the tablet and provides rounding. The sucrose and water syrup also
contains gelatin, acacia, or PVP to enhance coating.
• Smoothing process -remove rough layers formed in step 2 with the
application of sucrose syrup. This syrup is sucrose based, with or without
additional components such as starch and calcium carbonate.

Sugar coating
• Colouring - for aesthetic purposes often titanium based
pigments are included.
• Polishing - effectively polished to give characteristic
shine, commonly using beeswax, carnauba wax.
• Printing -permanent ink for characterization

Film coating
• Coating tablets, capsules, or pellets by surrounding them
with a thin layer of polymeric material.
• Process: Single stage process, which involves spraying a
coating
The solution or suspension is sprayed to a rotating
tablet bed followed by drying, which facilitates the
removal of the solvent leaving behind the
deposition of thin film of coating materials around
each tablet

Film coating
Film coating contains the following;
1. Film forming Polymer
2. Solvent
3. Plasticizer
4. Colourant

Film-coating machine

Film forming Polymer

Plasticizer
LOW MOLECULAR WEIGHT ORGANIC MOLECULES, CAPABLE OF
MODIFYING THE PHYSICAL PROPERTIES OF A POLYMER
- Better mechanical properties
– Resistance to deformation
– Flexible, elastic films (high modulus of elasticity)
– Continuous film

Solvent
Solvent
organic
Environmental
 Safety
 Financial
 Solvent residues
P. WaterProduct – Stability

Film-coating solutions may be nonaqueous or aqueous.
• The nonaqueous solutions contain the following types of
materials to provide the desired coating to the tablets:
1. A film former capable of producing smooth, thin films
reproducible under conventional coating conditions and
applicable to a variety of tablet shapes. Example: cellulose
acetate phthalate.
2. An alloying substance providing water solubility or
permeability to the film to ensure penetration by body
fluids and therapeutic availability of the drug. Example:
polyethylene glycol.

3. A plasticizer to produce flexibility and elasticity of the coating and thus
provide durability. Example: castor oil.
4. A surfactant to enhance spreadability of the film during application.
Example: polyoxyethylene sorbitan derivatives.
5. Opaquants and colorants to make the appearance of the coated tablets
handsome and distinctive. Examples: Opaquant, titanium dioxide;
colorant, FD&C or D&C dyes.
6. Sweeteners, flavors, and aromas to enhance the acceptability of the
tablet by the patient. Examples: sweeteners, saccharin; flavors and
aromas, vanillin.
7. A glossant to provide luster to the tablets without a separate polishing
operation. Example: beeswax.
8. A volatile solvent to allow the spread of the other components over the
tablets while allowing rapid evaporation to permit an effective yet
speedy operation. Example: alcohol mixed with acetone.

• One commercial water-based colloidal coating dispersion called Aquacoat
(FMC Corporation) contains a 30% ethyl cellulose pseudolatex.
• Pseudolatex dispersions have a high solids content for greater coating ability
and a relatively low viscosity.
• The low viscosity allows less water to be used in the coating dispersion,
requiring less evaporation and reducing the likelihood that water will
interfere with tablet formulation.
• In addition, the low viscosity permits greater coat penetration into the
crevices of monogrammed or scored tablets.
• A plasticizer may be added to assist in the production of a dense, relatively
impermeable film with high gloss and mechanical strength.

A typical aqueous film-coating formulation contains the
following:
1. Film-forming polymer (7% to 18%). Examples: cellulose ether
polymers such as hydroxypropyl methylcellulose,
hydroxypropyl cellulose, and methylcellulose.
2. Plasticizer (0.5% to 2.0%). Examples: glycerin, propylene
glycol, polyethylene glycol, diethyl phthalate, and dibutyl
subacetate.
3. Colorant and opacifier (2.5% to 8%). Examples: FD&C or D&C
lakes and iron oxide pigments.
4. Vehicle (water, to make 100%).

Film coating Sugar coating
Film coating
•Tablet appearance
 Retains shape of original core
Small weight increase of 2-10 %
due to coating material
 logo or ‘break lines’ possible
No Wait & size variation
•Tablet appearance
Rounded with high degree of polish
Larger weight increase 30-100 %
due to coating material
 Logo or ‘break lines’ are Impossible
Wait & size variation within the batch or from
batch to batch
Sugar coating
•Process
Can be automated
 Easy training operation
Single stage process
 Less Time
 Easily adaptable for controlled
release allows for functional
coatings.
•Process
Difficult to automated
Considerable training operation
 Multi stage process
 More time
 Not able to be used for controlled Release

Problems of Film Coating
PICKING/ STICKING: small holes pulled
in film or small amount of the film
flaking from the tablet surface
PEELING: the coating peels away from
the tablet surface or large amount of
the film flaking from the tablet surface

Twinning: two or more tablets that stick
together. Common problem with flat or
capsule shaped tablets
Roughness or orange peel : film not
smooth

CRACKING: Torn or cracked films
CORE EROSION: loss of material from
tablet surface

Color Variation or mottling
LOGO BRIDGING: the coating fills
in the logo on the tablets

Functional coatings
Functional coatings are coatings, which perform a
pharmaceutical function
• Enteric coating
• Controlled release coating

ENTERIC COATING
 The technique involved in enteric coating is protection of the tablet core from
disintegration in the acidic environment of the stomach by employing pH
sensitive polymer, which swell or solubilize in response to an increase in pH to
release the drug.
Aims of Enteric protection:
1. Protection of active ingredients, from the
acidic environment of the stomach.
2. Protection from local irritation of the
stomach mucosa.
3. Release of active ingredient in specific
target area within gastrointestinal tract.

Among the materials used in enteric coatings are:
1. Pharmaceutical shellac
2. Hydroxypropyl methylcellulose phthalate
3. Polyvinyl acetate phthalate
4. Diethyl phthalate
5. Cellulose acetate phthalate.

FLUID BED COATER

Press coating
• Press coating process involves compaction of coating
material around a preformed core
for creating modified-released products
involves the compaction of granular materials
around preformed tablet core using specially
designed tableting equipment. Compression
coating is a dry process

COMPRESSION COATING
• Compared to sugarcoating using pans, compression
coating is more uniform and uses less coating
material, resulting in tablets that are lighter, smaller,
and easier to swallow and less expensive to package
and ship.

CHANGES ON SOLID DOSAGE FORM
Starting materials
Manufacturing process

PACKAGING AND STORING TABLETS
Tablets are stored in tight containers, in places of low
humidity, and protected from extremes in temperature.

• Products that are prone to
decomposition by moisture generally
are packaged with a desiccant packet.
• Drugs that are adversely affected by
light are packaged in light-resistant
containers.
• With a few exceptions, tablets that are
properly stored will remain stable for
several years or more.

Upon aging
• Hardness - The increase in tablet hardness can
frequently be attributed to the increased adhesion of
the binding agent and other formulative components
within the tablet

• In tablets containing volatile drugs, such as nitroglycerin,
the drug may migrate between tablets in the container,
resulting in a lack of uniformity among the tablets.
• Also, packing materials, such as cotton and rayon, in
contact with nitroglycerin tablets may absorb varying
amounts of nitroglycerin, reducing potency of the tablets.
The USP directs that nitroglycerin tablets be preserved in
tight containers, preferably of glass, at controlled room
temperature.

Also, migration within tablets can occur resulting in
unequal distribution within a single tablet; this can be
problematic if the tablet is scored and designed to be
broken in half where the two halves may not contain
equal portions of the drug.
Storage of a container next to a heat source may
result in greater loss or movement of the volatile drug
in the portion of the bottle closest to the heat.

• The USP further directs that nitroglycerin tablets be
dispensed in the original unopened container,
labeled with the following statement directed to the
patient. “Warning: to prevent loss of potency, keep
these tablets in the original container or in a
supplemental nitroglycerin container specifically
labeled as being suitable for nitroglycerin tablets.
Close tightly immediately after use” (4).

Pan coating
• Benefits
• Mask taste
• Chemical barrier
• Controlled release
• Appearance
• Critical Parameters
• Air flow
• Spray
• Drum dynamics
• Rotational speed
• Fill fraction
Air+Moisture
Rotation Spra
Air Flow
Inlet Filter
SteamInlet
Temperature
Inlet Air
Outlet Air
Outlet Filter
Outlet
Temperature

OTHER SOLID DOSAGE FORMS FOR ORAL
ADMINISTRATION
• LOZENGES
• LOLLIPOPS

Chewable tablets
• Chewable tablets are pleasant-tasting tablets formulated
to disintegrate smoothly in the mouth with or without
chewing.
• They are prepared by wet granulation and compression,
using only minimal degrees of pressure to produce a soft
tablet.
• Generally, chewable tablets do not contain disintegrants,
so patients must be counseled to chew the tablets
thoroughly and not swallow them whole.

• Mannitol, a white crystalline hexahydric alcohol, is used as the excipient in
most chewable tablets.
• Mannitol is about 70% as sweet as sucrose, with a cool feel in the mouth.
• Mannitol accounts for 50% or more of the weight of many chewable tablet
formulations.
• Sometimes other sweetening agents, such as:
sorbitol
lactose
dextrose
crystalline maltose
glucose
may be substituted for part or all of the mannitol.
Xylitol may be used in the preparation of sugar- free chewable tablets.

Among the types of products prepared as chewable
tablets are:
1. antacids (e.g., calcium carbonate)
2. antibiotics (e.g., erythromycin)
3. anti-infective agents (e.g., didanosine)
4. anticonvulsants (e.g., carbamazepine)
5. vasodilators (e.g., isosorbide dinitrate)
6. analgesics (e.g., acetaminophen)
7. various vitamins
8. Cold– allergy combination tablets.

The following is a formula for a typical
chewable antacid tablet
Aluminum hydroxide 325.0mg
Mannitol 812.0mg
Sodium saccharin 0.4mg
Sorbitol (10% w/v solution) 32.5mg
Magnesium stearate 25.0mg
Mint flavor concentrate 4.0mg

QUALITY STANDARDS AND COMPENDIAL
REQUIREMENTS
• In addition to the apparent features of tablets, tablets must meet other physical
specifications and quality standards.
These include criteria for:
Weight
Weight variation
Content uniformity
Thickness
Hardness
Disintegration
Dissolution
These factors must be controlled during production (in-process controls) and verified
after the production of each batch to ensure that established product quality
standards are met

1. Tablet Weight and USP Weight Variation Test
• The quantity of fill in the die of a tablet press determines the weight of the
tablet.
• The volume of fill is adjusted with the first few tablets to yield the desired
weight and content.
• For example, if a tablet is to contain 20 mg of a drug substance and if
100,000 tablets are to be produced, 2,000 g of drug is included in the
formula.
• After the addition of the pharmaceutical additives, such as the diluent,
disintegrant, lubricant, and binder, the formulation may weigh 20 kg, which
means that each tablet must weigh 200 mg for 20 mg of drug to be present

• Thus, the depth of fill in the tablet die must be adjusted to hold a
volume of granulation weighing 200mg.
• During production, sample tablets are periodically removed for visual
inspection and automated physical measurement.
The USP contains a test for determination of dosage form uniformity
by weight variation for uncoated tablets.
• In the test, 10 tablets are weighed individually and the average weight
is calculated.
• The tablets are assayed and the content of active ingredient in each of
the 10 tablets is calculated assuming homogeneous drug distribution.

2. Content Uniformity
• By the USP method, 10 dosage units are individually assayed for
their content according to the method described in the
individual monograph.
• Unless otherwise stated in the monograph, the requirements for
content uniformity are met if the amount of active ingredient in
each dosage unit lies within the range of 85% to 115% of the
label claim and the standard deviation is less than 6%.
• If one or more dosage units do not meet these criteria,
additional tests as prescribed in the USP are required.

3. Tablet Thickness
• The thickness of a tablet is determined by:
1. The diameter of the die
2. The amount of fill permitted to enter the die
3. The compaction characteristics of the fill material
4. The force or pressure applied during compression.
• To produce tablets of uniform thickness during and between
batch productions for the same formulation, care must be
exercised to employ the same factors of fill, die, and pressure.
• The degree of pressure affects not only thickness but also
hardness of the tablet; hardness is perhaps the more important
criterion since it can affect disintegration and dissolution.

4. Tablet Hardness and Friability
• It is fairly common for a tablet press to exert as little as 3,000 and as
much as 40,000lb of force
• In production of tablets. Generally, the greater the pressure applied,
the harder the tablets, although the characteristics of the granulation
also have a bearing on hardness.
• Certain tablets, such as lozenges and buccal tablets, that are intended
to dissolve slowly are intentionally made hard; other tablets, such as
those for immediate drug release, are made soft.
Tablets should be sufficiently hard to resist breaking during normal
handling and yet soft enough to disintegrate properly after
swallowing.

• Special dedicated hardness testers or multifunctional
systems are used to measure the degree of force (in
kilograms, pounds, or in arbitrary units) required to break a
tablet.
• A force of about 4kg is considered the minimum
requirement for a satisfactory tablet.
• A tablet’s durability: may be determined through the use of
a friabilator.
A maximum weight loss of not more than 1% generally is
considered acceptable for most products.

5. Tablet Disintegration
• For the medicinal agent in a tablet to become fully available for absorption, the
tablet must first disintegrate and discharge the drug to the body fluids for
dissolution.
• Tablet disintegration also is important for tablets containing medicinal agents (such
as antacids and antidiarrheals) that are not intended to be absorbed but rather to
act locally within the gastrointestinal tract.
• In these instances, tablet disintegration provides drug particles with an increased
surface area for activity within the gastrointestinal tract.
• All USP tablets must pass a test for disintegration, which is conducted in vitro using a
testing apparatus.
• The apparatus consists of a basket and rack assembly containing six open-ended
transparent tubes of USP-specified dimensions, held vertically upon a 10-mesh
stainless steel wire screen.

• Tablets must disintegrate within the times set in the individual
monograph, usually 30 minutes, but varying from about 2 minutes for
nitroglycerin tablets to up to 4 hours for buccal tablets.
• If one or more tablets fail to disintegrate, additional tests prescribed
by the USP must be performed.
• Enteric-coated tablets are similarly tested, except that the tablets are
tested in simulated gastric fluid for 1 hour, after which no sign of
disintegration, cracking, or softening must be seen.
• They are then actively immersed in the simulated intestinal fluid for
the time stated in the individual monograph, during which time the
tablets disintegrate completely for a positive test.

6. Tablet Dissolution
• In vitro dissolution testing of solid dosage forms is important for
a number of reasons :
• It guides formulation and product development toward product
optimization.
• Dissolution studies in the early stages of a product’s
development allow differentiation between formulations and
correlations identified with in vivo bioavailability data.
• Consistent in vitro dissolution testing ensures bioequivalence
from batch to batch.

The goal of in vitro dissolution testing is to provide insofar as is possible a reasonable prediction of or
correlation with the product’s in vivo bioavailability.
• The system relates combinations of a drug’s solubility (high or low) and its intestinal permeability (high or
low) as a possible basis for predicting the likelihood of achieving a successful in vivo–in vitro correlation
(IVIVC).

Using this system, drugs are placed into one of four categories as follows:
1. Category I drug (high-solubility and high-permeability)
2. Category II drug, dissolution may be the rate-limiting step for absorption,
and an IVIVC may be expected. - dissolution rate is slower than the rate of
gastric emptying -
1. Category III drug (In the case of a high-solubility and low- permeability ),
permeability is the rate-controlling step, and only a limited IVIVC may be
possible.
1. Category IV drug (low solubility and low permeability)  significant
problems are likely for oral drug delivery

• Tablet disintegration is the important first step to the dissolution of
the drug in a tablet.
A number of formulation and manufacturing factors can affect the
disintegration and dissolution of a tablet, including
1. particle size of the drug substance
2. solubility and hygroscopicity of the formulation
3. type and concentration of the disintegrant
4. binder
5. lubricant
6. manufacturing method
7. particularly the compactness of the granulation
8. compression force used in tableting
9. any in-process variables

COMPRESSED TABLET MANUFACTURE
• Compressed tablets may be made by three basic methods:
wet granulation
dry granulation
direct compression
• Most powdered medicinal agents require addition of excipients such as:
diluents
binders
disintegrants
Lubricants
 to provide the desired characteristics for tablet manufacture and efficacious
use.

• One important requirement in tablet manufacture is that
the drug mixture flows freely from the hopper of the tablet
press into the dies to enable high-speed compression of the
powder mix into tablets.
• Granulations of powders provide this free flow.
• Granulations also increase material density, improving
powder compressibility during tablet formation.

Reasons for Granulation
1. To avoid powder segregation
2. To enhance the flow of powder
3. Granules have higher porosity than powders
4. To improve the compressibility of powders.
5. Avoid dustiness , The granulation of toxic materials will reduce the hazard of generation of toxic dust,
which may arise during the handling of the powders.
6. Materials, which are slightly hygroscope, may adhere & form a cake if stored as a powder.
7. Granules, being denser than the parent powder mix, occupy less volume per unit weight.

WET GRANULATION
Wet granulation is a widely employed method for the production
of compressed tablets.
The steps required are
(a) weighing and blending the ingredients
(b) preparing a dampened powder or a damp mass
(c) screening the dampened powder or damp mass into pellets or
granules
(d) drying the granulation
(e) sizing the granulation by dry screening
(f) adding lubricant and blending
(g) forming tablets by compression.

Weighing and Blending
Specified quantities of active ingredient, diluent or filler, and disintegrating agent are mixed by mechanical
powder blender or mixer until uniform.
Fillers include:
1. lactose
2. microcrystalline cellulose
3. starch
4. powdered sucrose
5. calcium phosphate.
The choice of filler usually is based on:
1. the experience of the manufacturer with the material
2. its relative cost
3. its compatibility with the other formulation ingredients.

EXAMPLE
For example, calcium salts must not be used as fillers with tetracycline
antibiotics because of an interaction between the two agents that
results in reduced tetracycline absorption from the gastrointestinal
tract.
Among the fillers most preferred are:
lactose, because of its solubility and compatibility,
microcrystalline cellulose, because of its easy compaction,
compatibility, and consistent uniformity of supply

Disintegrating agents include:
1. croscarmellose
2. corn and potato starches
3. sodium starch glycolate
4. sodium carboxymethylcellulose
5. polyvinylpyrroli-done (PVP)
6. crospovidone
7. cation exchange resins
8. alginic acid
9. other materials that swell or expand on exposure to moisture
and effect the rupture or breakup of the tablet in the
gastrointestinal tract.

Croscarmellose (2%) and sodium starch glycolate (5%) are often
preferred because of their:
high water uptake
rapid action.
One commercial brand of sodium starch glycolate is reported to swell
up to 300% of its volume in water
When starch is employed, 5% to 10% is usually suitable, but up to
about 20% may be used to promote more rapid tablet disintegration.
The total amount of disintegrant used is not always added in
preparing the granulation.

Preparing the Damp Mass
• A liquid binder is added to the powder mixture to facilitate
adhesion of the powder particles.
• A good binder results in appropriate tablet hardness and
does not hinder the release of the drug from the tablet.

Among binding agents:
solutions of povidone, an aqueous preparation of
cornstarch (10% to 20%)
glucose solution (25% to 50%)
molasses
methylcellulose (3%)
carboxymethylcellulose
microcrystalline cellulose.
If the drug substance is adversely affected by an aqueous
binder, a nonaqueous solution, or dry binder, may be used.

The amount of binding agent used is part of the operator’s
art; however, the resulting binder–powder mixture should
compact when squeezed in the hand.
The binding agent contributes to adhesion of the granules to
one another and maintains the integrity of the tablet after
compression.

• Overwetting can result in  granules that are too hard for
proper tablet formation
• Underwetting can result in  tablets that are too soft and
tend to crumble.
• When desired, a colorant or flavorant may be added to the
binding agent to prepare a granulation with an added
feature.

Screening the Damp Mass into Pellets or
Granules
• The dampened powder granules are screened or the wet
mass is pressed through a screen (usually 6 or 8 mesh) to
prepare the granules.
• This may be done by hand or with special equipment that
prepares the granules by extrusion through perforations in
the apparatus.
• The resultant granules are spread evenly on large lined trays
and dried to consistent weight or constant moisture
content.

Drying the Granulation
• Granules may be dried in
thermostatically cotrolled
ovens that constantly record
the time, temperature, and
humidity.

Sizing the Granulation by Dry Screening
• After drying, the granules are passed through a screen of a smaller mesh
than that used to prepare the original granulation.
• The degree to which the granules are reduced depends on the size of the
punches to be used.
• In general, the smaller the tablet to be produced, the smaller the granules.
• Screens of 12- to 20-mesh size are generally used for this purpose.
• Sizing of the granules is necessary so that the die cavities for tablet
compression may be completely and rapidly filled by the free-flowing
granulation.
Voids or air spaces left by too large a granulation result in the production of
uneven tablets.

Adding Lubrication and Blending
• After dry screening, a dry lubricant is dusted over the spread-out
granulation through a fine- mesh screen.
• Lubricants contribute to the preparation of compressed tablets
in several ways:
1. They improve the flow of the granulation in the hopper to the
die cavity.
2. They prevent adhesion of the tablet formulation to the
punches and dies during compression.
3. They reduce friction between the tablet and the die wall
during the ejection of the tablet from the machine.
4. They give a sheen to the finished tablet

Among the more commonly used lubricants are:
magnesium stearate
calcium stearate
stearic acid
talc,
sodium stearyl fumarate.
Magnesium stearate is most used.
• The quantity of lubricant used varies from one operation to
another but usually ranges from about 0.1% to 5% of the weight
of the granulation.

ALL-IN-ONE GRANULATION
METHODS
• Technologic advances now
allow the entire process of
granulation to be completed
in a continuous fluid bed
process, using a single piece
of equipment, the fluid bed
granulator.

The fluid bed granulator performs the following steps:
(a) preblending the formulation powder, including active
ingredients, fillers, and disintegrants, in a bed with
fluidized air
(b) granulating the mixture by spraying onto the fluidized
powder bed, a suitable liquid binder, such as an aqueous
solution of acacia, hydroxypropyl cellulose, or povidone
(c) drying the granulated product to the desired moisture
content.

• Another method, microwave vacuum processing, also allows the
powders to be:
mixed
wetted
agglomerated
dried within the confines of a single piece of equipment.
o The wet mass is dried by gentle mixing, vacuum, and microwave.
o The use of the microwave reduces the drying time considerably, often
by one fourth.
o The total batch production time is usually in the range of 90 minutes.
o After adding lubricants and screening, the batch is ready for tablet
formation or capsule filling.

Advantages of wet granulation
Advantages
• Reduced segregation of formulation components during
storage and/or processing
• Useful technique for the manufacture of tablets containing
low and or high concentrations of therapeutic agent
• Employs conventional excipients and therefore is not
dependent on the inclusion of special grades of excipients

Disadvantages of wet granulation
Disadvantages
1. Often several processing steps are required
2. Solvents are required in the process: this leads to a
number of concerns:
Drug degradation may occur in the presence of the solvent
The drug may be soluble in the granulation fluid
Heat is required to remove the solvent

DRY GRANULATION
• By the dry granulation method, the powder mixture is
compacted in large pieces and subsequently broken down or
sized into granules.
For this method, either the active ingredient or the diluent must
have cohesive properties.
• Dry granulation is especially applicable to materials that cannot
be prepared by wet granulation because they degrade in
moisture or the elevated temperatures required for drying the
granules.

Slugging
• After weighing and mixing the ingredients, the powder mixture is
slugged, or compressed, into large flat tablets or pellets about 1
inch in diameter.
• The slugs are broken up by hand or by a mill and passed through
a screen of desired mesh for sizing.
• Lubricant is added in the usual manner, and tablets are prepared
by compression.
• Aspirin, which is hydrolyzed on exposure to moisture, may be
prepared into tablets after slugging.

Roller Compaction
• Instead of slugging, powder compactors may be used to increase the density
of a powder by pressing it between rollers at 1 to 6 tons of pressure.
• The compacted material is broken up, sized, and lubricated, and tablets are
prepared by compression in the usual manner.
• The roller compaction method is often preferred to slugging.
• Binding agents used in roller compaction formulations include
Methylcellulose
hydroxy methylcellulose (6% to 12%),
which can produce good tablet hardness and friability.

Advantages of dry granulation
1. These methods are not generally associated with
alterations in drug morphology during processing.
2. No heat or solvents are required.

Disadvantages of dry granulation
1. Specialist equipment is required for granulation by roller compaction.
2. Segregation of components may occur mixing.
3. There may be issues regarding powder flow.
4. The final tablets produced by dry granulation tend to be softer than those
produced by wet granulation
5. Slugging and roller compaction lead to the generation of considerable dust

DIRECT COMPRESSION TABLETING
• Some granular chemicals, like potassium chloride, possess free-flowing and cohesive
properties that enable them to be compressed directly in a tablet machine without any need
of granulation.
• For chemicals lacking this quality, special pharmaceutical excipients may be used to impart
the necessary qualities for the production of tablets by direct compression.
• These excipients include fillers, such as:
 spray-dried lactose
 microcrystals of alpha-monohydrate lactose
 sucrose–invert sugar–corn starch mixtures
 microcrystalline cellulose
 crystalline maltose
 dicalcium phosphate

Disintegrating agents, such as:
direct compression starch
sodium carboxymethyl starch
cross-linked carboxymethylcellulose fibers
cross-linked polyvinylpyrrolidone
lubricants, such as:
magnesium stearate
 talc
Glidants, such as
 fumed silicon dioxide

Advantages and disadvantages of direct
compression
Advantages:
1. Low labour input
2. A dry process
3. Fewest processing steps
Disadvantages:
1. Stratification (layers) may occur due to differences in particle size and bulk
density which results poor content uniformity.
2. A large dose drug may cause problem in direct compression. It requires diluents.
The tablet becomes large in size which is difficult to swallow and also costly.
3. During handling of dry materials static charge may form which may present
uniform distribution of drug.
4. Direct compression diluent may interact with the drug. For example, amine drug
with Lactose produce discoloration of tablet

WET GRANULATION DRY GRANULATION DIRECT COMPRESSION
1. Milling and mixing of drugs and
excipients
1. Milling and mixing of drugs
and excipients
1. Milling and mixing
of drugs and excipients
2 .Preparation of binder solution 2. Compression into slugs or roll
compaction
2. Compression of
tablet
3. Wet massing by addition of
binder solution or granulating
solvent
3. Milling and screening of slugs
and compacted powder
4. Screening of wet mass 4. Mixing with
disintegrant/lubricant
5. Drying of the wet granules 5. Compression of tablet
6. Screening of dry granules
7. Blending with disintegrant /
lubricant and
8. Compression of tablet

Compression process
Filling: By gravitational flow (or mechanical conveyors) of powder from
hopper via the die table into die. The die is closed at its lower end by
the lower punch.
Compression: The upper punch descends and enters the die and the
powder is compressed until a tablet is formed. During the
compression phase, the lower punch can be stationary or can move
upwards in the die. After maximum applied force is reached, the
upper punch leaves the powder
Ejection: During this phase, the lower punch rises until its tip reaches
the level of the top of the die. The tablet is subsequently removed
from the die and die table by a pushing device.

Tablet compression machine
1. Hopper for holding and feeding granulation to be compressed
2. Dies that define the size and shape of the tablet
3. Punches for compressing the granulation within the dies
4. Cam tracks for guiding the movement of the punches
5. Feeding mechanisms for moving granulation from the hopper into
the die
6. Tablet ejector

Solid dosage processing
• Dosage forms
• Quality factors
• Excipients
• Particle properties
• Processing routes
• Unit operations
• Size reduction (milling)
• Blending
• Dry granulation (roll compaction)
• Wet granulation
• Drying
• Tablet compaction
• Coating

Models at different scales

Product and process functions
• Product function
• Product property: Content uniformity, dissolution, flowability, dust formation
• Particle Properties: Particle size, particle shape, surface characteristics
• Process function
• Process parameters: Type of unit operation, operational parameters

Particle properties
Product property = F(particle properties, formulation)

Mean particle size and flowability

Size distributions for various powders

Powder flow and tablet weight variations

Processing routes
Fill die
Coating, Packaging etc..
Compress Tablet
ct Compression
nt
Mixing
Mixing
Dry Granulation
Disintegrant
Glidant
Lubricant
Drug
Diluent
Lubricant
Mixing
Compression
Comminution
Screening
Mixing
Mixing
Wetting
Granulation
Drying
Screening
Mixing
Drug
Diluent
Binder
Solvent
Disintegrant
Glidant
Lubricant
Wet Granulation
Other Rout
Fluidized bed gra
Extrusion / rotary gr
ssion

Unit operations
• Unit Operation
Every separate manufacturing step.
• Unit Dose Operations
Determined by what manufacturing steps are needed to combine the active
ingredient with other needed ingredients to make a quality finished product.
• Type of unit operation
• Dispensing
• Milling/Screening
• Blending
• Granulation
• Drying
• Compression
• Coating
• Packaging

Dispensing
• One of the most critical steps in pharmaceutical manufacturing
• manual weighing on a weight scale with material lifting assistance like vacuum
transfer and bag lifters
• automated weighing
• Issues:
• dust control (laminar air flow booths, glove boxes)
• weighing accuracy
• multiple lots of active ingredient with different assays, moisture and residual
solvent content
• cross contamination

• Dispensing is the first step in any pharmaceutical manufacturing
process. Dispensing is one of the most critical steps in pharmaceutical
manufacturing;
• during this step, the weight of each ingredient in the mixture is
determined according to dose.
Issues like:
• weighing accuracy,
• dust control (laminar air flow booths, glove boxes), during manual
handling,
• lot control of each ingredient,
• material movement into and out of dispensary should be considered
during dispensing.

Raw Material Dispensing Record

Considerations
Theoretical quantity of API [100% assay (anhydrous) and nil water] = 30 Kg

Milling/Screening

Particle size reduction
• The sizing (size reduction, milling, crushing, grinding, pulverization) is an impotent
step (unit operation) involved in the tablet manufacturing.
• In manufacturing of compressed tablet, the mixing or blending of several solid
ingredients of pharmaceuticals is easier and more uniform if the ingredients are
approximately of same size.
Advantages associated with size reduction in tablet manufacture are as follows:
i) It increases surface area, which may enhance an actives dissolution rate and hence
bioavailability.
ii) Improved the tablet-to-tablet content uniformity by virtue of the increased number of
particles per unit weight.
iii) Improved flow properties of raw materials.
iv) Improved colour and/or active ingredient dispersion in tablet excipients.

• Excessive heat generation can lead to degradation, change in polymorphic form
• Increase in surface energy can lead to agglomeration
• May result in excessive production of fines or overly broad particle size distribution

Forces in milling
• Shear (cutting forces)
• Compression (crushing forces)
• Impact (high velocity collision)
Y
T
c


Griffith theory
• T = Tensile stress
• Y = Young’s modulus
• ε = Surface energy
• c = fault length

Milling equipment – screen mills
• Critical parameters for a conical screen mill
• Screen Hole Size/Shape
• Impeller Type
• Impeller Clearance
• Speed
• Evaluate impact on aspirin granulation
• Particle size reduction
• Milling time and energy requirements
• Overall milling performance
• Milling Work Index = Size reduction / Milling work
• Milling Time Index = Size reduction / Milling time

• Screen hole size has largest impact on particle size reduction, milling
time and energy requirements
• Milling work index significantly lower for smaller screen hole sizes
• Impeller type has largest effect on overall milling performance
• Impeller clearance not significant at small clearances
• Milling work index lower at higher mill speeds
• Deflection of material away from screens

Milling equipment – impact mills
• Significant wear on surfaces
• Hammer mills
• Medium to coarse size reduction
• Peripheral speed 20-50 m/sec
• Pin mills
• Peripheral speed up to 200 m/sec
• Capable of fine grinding
• Can be used to mill sticky materials

Milling equipment – jet mill
• Superfine to colloid size reduction
• Can be used for heat sensitive products
• Different configurations
• Pancake (spiral) jet mill
• Fines exit from center
• Loop/oval jet mill
• Fines exit from top
• Opposing jet mills
• Particles impact each other in opposing jets
• Fluidized bed jet mill
• Particles are jetted towards center (low wear on equipment)
• Fixed/moving target jet mills
• Particles impact on surface of target (wear can be significant)

Milling equipment – stirred media mill
• Critical parameters
• Agitator speed
• Feed rate
• Size of beads
• Bead charge
• Density of beads
• Design of blades
• Mill chamber
• Residence time

Mill selection

Energy based analysis – ball mill
• Macroscale energy-size relationships (Chen et al., 2004)
• Calculate specific energy for a given size reduction
• Functional form derived from theoretical considerations
• Rittinger’s model
• Energy required for particle size reduction is proportional to the area of new surface created
• Kick’s model
• Energy required to break a particle is proportional to the ratio of the particle volume before
reduction to the volume after reduction
1 1P
R R
P F
m t
E C
W x x
 
   
 
lnP F
K K
P
m t x
E C
W x
 
   
 

Energy based analysis – ball mill
Size Reduction of α–Lactose Monohydrate in a Ball Mill 23412-07-2016 Sagar Kishor Savale

Milling/Screening
• Principle: Mixing or blending is more uniform if ingredients are of similar size

Manufacturing Instructions screening

Blending

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.
Blending step prior to compression is normally achieved in a simple
tumble blender.
• The various blenders used include blender, Oblicone blender,
Container blender, Tumbling blender, Agitated powder blender, etc.

Blending – diffusion mixing
• Critical parameters
• Blender load
• Blender speed
• Blending time
V-Blender
Cross Flow
Blender
Bin Blender
Double Cone
Blender

Blending – convective mixing
on Blenders Orbiting Screw Blenders
Planetary Blender
Horizontal Double Arm Blenders
Forberg Blenders
al High Intensity Mixers
ntal High Intensity Mixers
Diffusion Mixers with Intensifier/Agitator24012-07-2016 Sagar Kishor Savale

Blending
• Blending is the most difficult operation in the manufacturing process since perfect
homogeneity is practically impossible due to differences in size, shape and density of
particles

Mixer and blender

Granulation

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).

Advantage:
• Avoid exposure of the powder to moisture and heat.
• Used for powders of very low bulk density to ↑ their bulk density.
Disadvantage:
• Tablet disintegration and dissolution may be retarded due to double
lubrication and compaction

Steps of Dry Granulation
• The blend of finely divided powders is forced into the dies of
a large capacity tablet press.
• Then, compacted by means of flat faced punches
(Compacted masses are called slugs and the process is
slugging) or roll
compactor to produce sticks or sheets.
• Slugs or sheets are then milled/screened to produce
granules (flow more than the original powder mixture).

Methods of Dry Granulation
A. Slugging technique
If a tablet press is used for the compaction process, the term slugging is
used. But since particles with a small particle size do not flow well into
the die of a tablet press, the results are weight differences from one
tablet (slug) to another.
This in turn causes large fluctuations in the forces applied onto the
individual slugs, with translates in variations of the slug’s mechanical
strength. Therefore, the properties of these granulates obtained by
milling the slugs cannot be controlled well either. This is one of the main
reasons why slugging is hardly used any more as a dry granulation
method.

B. Roller compaction technique
A Roller compactor generally consist of three major units:
• A feeding system, which conveys the powder to the compaction area
between the rolls
• A compaction unit, where powder is compacted between two
counter rotating rolls to a ribbon by applying a force
• A size reduction unit, for milling the ribbons to the desired particle
size.

Roll compaction
Critical parameters
• Roll speed and pressure
• Horizontal and vertical feed speed,
deaeration
• Roll diameter and surface
Advantages
• Improve powder flow
• Reduce segregation potential
• No moisture addition, drying

Johanson’s theory
Slip region
Nip region
Compressibility
Eff. angle of friction Wall angle of friction

Eff. angle of friction and peak pressure (Johanson’s
theory)

Eff. angle of friction and nip angle (Johanson’s theory)
Eff. Angle of Friction
Nip Angle

Eff. angle of friction and nip angle (Johanson’s theory)

Effect of lubrication on peak roll pressure

Effect of lubrication on nip angle

Effect of entrained air on feeding and discharging

Characterization of flowability
• Hausner ratio = tapped density / bulk density
• Excellent 1.05–1.10
• Good 1.11–1.15
• Fair 1.15–1.20
• Passable 1.21–1.25
• Poor 1.26–1.31
• Very Poor 1.32–1.37
• Extremely Poor 1.38–1.45

Roll compaction and flow properties
Soares et al. (2005), Dry granulation and compression of spray dried plant extracts, AAPS PharmSciTech
Before
Compaction
(poor)
After Compaction
(excellent)

Recent Advances in Granulation Techniques
• Steam Granulation: Modification of wet granulation; steam
is used as a binder instead of water; granules are more
spherical and exhibit higher rate of dissolution
• Melt Granulation / Thermoplastic Granulation: Granulation
is achieved by the addition of meltable binder i.e. binder is in
solid state at room temperature but melts in the
temperature range of 50 – 80˚C [e.g. PEG (water soluble),
stearic acid, cetyl or stearyl alcohol (water insoluble)] -
drying phase unnecessary since dried granules are obtained
by cooling them to room temperature
• Moisture Activated Dry Granulation (MADG): Involves
distribution of moisture to induce agglomeration – drying
time is reduced

• Moist Granulation Technique (MGT): A small amount of
granulating fluid is added to activate dry binder and to
facilitate agglomeration. Then a moisture absorbing
material like Microcrystalline Cellulose (MCC) is added to
absorb any excess moisture making drying step
unnecessary. Mainly employed for controlled release
formulations
• Thermal Adhesion Granulation Process (TAGP): Granules
are prepared by moisturizing excipient mixtures with very
little solvent in a closed system (tumble mixing) with low
heating – mainly employed for preparing direct
compression formulations
• Foam Granulation: Binders are added as aqueous foam

Drying
Tray dryerFluid bed dryer

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