Granules flow better than powders.

The easy flow characteristics are important in supplying

drug materials from the hopper or feeding container into the tableting presses. For this reason
powder mixtures are usually granulated if they are intended to be compressed into
tablets. Granules also eliminate or control dust.
2. Granules increase compressibility.
3. Granules have smaller surface area than a comparable volume of powders. This makes
granules more stable physically and chemically than the corresponding powders. Granules are
less likely to cake or harden upon standing than are powders.
4. Granules are more easily wetted by a solvent than are certain powders, so that granules are
also preferred in making solutions. Example: Principen (ampicillin) for Oral Suspension
(Squibb). Ampicillin is unstable in aqueous solution, so it is usually prepared as granules and
reconstituted by a pharmacist with purified water just prior to dispensing. The granules also
contain colorants, flavorants, and other pharmaceutical ingredients, so the resulting solution or
suspension has all the desired medicinal and pharmaceutical features of a liquid pharmaceutical.
5. Granules produce particle size uniformity, thus content uniformity.
6. Can mask the bitter taste of powder when these powders are granulated with flavoured
excepients

34 Cards in this Set
Front

Back

What are powders?
mixtures of dry, finely divided drugs
intended for internal or external use.

What are the advantages and
disadvantages of powders?
A) faster dissolution and absorption,
easier to swallow, improved dry stability

D) undesirable taste, poor flow

How have powders been historically
used?
orally, through nose as snuffs,
insufflation, externally to compromised
area.

How are particle sizes differentiated?
Very coarse, Coarse, Moderately
Coarse, Fine, or Very Fine
How are particles characterized? by morphology, purity, stability, and size
6 methods to determine particle size? Sieving, Microscopy, Sedimentation,
light scattering, laser holography, and
cascade impactor

What is a cascade impactor?
multi-stage impaction device for
separating airborne particles by size.

How can particle sizes be reduced?
MANUALLY by trituration or levigation,
good for small pharmacy

Mechanically by blade grinders which
are good for industry

Describe methods of small scale
blending
1)spatulation - using spatula, not good
for large quantities or potent drugs

2) trituration - mortar and pestle, good
for community pharmacy

3) levigation - mortar and pestle, a paste
is formed by combining powder and
liquid

Describe methods of large scale
blending
1) Sifting - results in light, fluffy product

2) Tumbling - rotating chamber,
thorough mixing

3) Twin Shell Blender - rolling rather
than sliding, simple cleaning

4) Vertical Impeller - little floor space,
screw-type impeller

5) Fluidized Mixer - air stream enters
bottom and powder is fluidized
34 Cards in this Set
Front

Back

What are powders?
mixtures of dry, finely divided drugs
intended for internal or external use.

What are the advantages and
disadvantages of powders?
A) faster dissolution and absorption,
easier to swallow, improved dry stability

D) undesirable taste, poor flow

How have powders been historically
used?
orally, through nose as snuffs,
insufflation, externally to compromised
area.

How are particle sizes differentiated?
Very coarse, Coarse, Moderately
Coarse, Fine, or Very Fine
How are particles characterized? by morphology, purity, stability, and size

6 methods to determine particle size?
Sieving, Microscopy, Sedimentation,
light scattering, laser holography, and
cascade impactor

What is a cascade impactor?
multi-stage impaction device for
separating airborne particles by size.

How can particle sizes be reduced?
MANUALLY by trituration or levigation,
good for small pharmacy

Mechanically by blade grinders which
are good for industry

Describe methods of small scale
blending
1)spatulation - using spatula, not good
for large quantities or potent drugs

2) trituration - mortar and pestle, good
for community pharmacy

3) levigation - mortar and pestle, a paste
is formed by combining powder and
liquid

Describe methods of large scale
blending
1) Sifting - results in light, fluffy product

2) Tumbling - rotating chamber,
thorough mixing

3) Twin Shell Blender - rolling rather
than sliding, simple cleaning

4) Vertical Impeller - little floor space,
screw-type impeller

5) Fluidized Mixer - air stream enters
bottom and powder is fluidized
When are oral powders
useful?
1) local (laxative, antacid)
or systemic (analgesic)
effects

2) patients with difficulty
swallowing

3) for large dose meds too
bulky for tablets

4) easily mixed with
food/beverage

Describe topical powders
contain micronized
particles mostly used for
anti fungal or antibacterial.
stored in a sifter-type
container

Describe insufflated
powders
used to deliver drug to ear,
nose, throat, tooth socket
or skin but with difficulty in
proper dose delivery

Describe aerosol powders
uses a dry-powder
metered inhaler with
particles 1-6 micrometers

Describe problems with
Eutectic powders. How is
this overcome?
- some powders may
become sticky, pasty, or
may even liquefy when
mixed
-to overcome, mix powders
with a bulky powder
absorbent (Magnesium
Carbonate) and triturate
very lightly with a spatula

What are Hygroscopic and
Deliquescent powders?
How are the problems with
these overcome?
Hygroscopic - absorb
moisture
Deliquescent - absorb
moisture from air and
liquefy

To overcome, disperse in
tight containers with
dessicant, and instruct to
store in a dry place.

What are bulk powders?
powders dispersed in bulk
and measured out doses
by the patient, limited to
non-potent meds

Examples of Bulk Powders
1)antacids (sodium
bicarbonate)
2)Laxatives (metamucil)
3)Douche powders
(mussengill)
4)Topical anti-infectives
(bacitracin zinc)

What are divided powders?
commonly used for potent
drugs, blended by
geometric dilution and over
dose is divided into
individual dosing units

Describe the process of
preparing charts for divided
powders
For potent drugs: weigh
each powder quantity

For non-potent drugs:
block and divide method
When are oral powders
useful?
1) local (laxative, antacid)
or systemic (analgesic)
effects

2) patients with difficulty
swallowing

3) for large dose meds too
bulky for tablets

4) easily mixed with
food/beverage

Describe topical powders
contain micronized
particles mostly used for
anti fungal or antibacterial.
stored in a sifter-type
container

Describe insufflated
powders
used to deliver drug to ear,
nose, throat, tooth socket
or skin but with difficulty in
proper dose delivery

Describe aerosol powders
uses a dry-powder
metered inhaler with
particles 1-6 micrometers

Describe problems with
Eutectic powders. How is
this overcome?
- some powders may
become sticky, pasty, or
may even liquefy when
mixed
-to overcome, mix powders
with a bulky powder
absorbent (Magnesium
Carbonate) and triturate
very lightly with a spatula

What are Hygroscopic and
Deliquescent powders?
How are the problems with
these overcome?
Hygroscopic - absorb
moisture
Deliquescent - absorb
moisture from air and
liquefy

To overcome, disperse in
tight containers with
dessicant, and instruct to
store in a dry place.

What are bulk powders?
powders dispersed in bulk
and measured out doses
by the patient, limited to
non-potent meds

Examples of Bulk Powders
1)antacids (sodium
bicarbonate)
2)Laxatives (metamucil)
3)Douche powders
(mussengill)
4)Topical anti-infectives
(bacitracin zinc)

What are divided powders?
commonly used for potent
drugs, blended by
geometric dilution and over
dose is divided into
individual dosing units

Describe the process of
preparing charts for divided
powders
For potent drugs: weigh
each powder quantity

For non-potent drugs:
block and divide method
When are oral powders
useful?
1) local (laxative, antacid)
or systemic (analgesic)
effects

2) patients with difficulty
swallowing

3) for large dose meds too
bulky for tablets

4) easily mixed with
food/beverage

Describe topical powders
contain micronized
particles mostly used for
anti fungal or antibacterial.
stored in a sifter-type
container

Describe insufflated
powders
used to deliver drug to ear,
nose, throat, tooth socket
or skin but with difficulty in
proper dose delivery

Describe aerosol powders
uses a dry-powder
metered inhaler with
particles 1-6 micrometers

Describe problems with
Eutectic powders. How is
this overcome?
- some powders may
become sticky, pasty, or
may even liquefy when
mixed
-to overcome, mix powders
with a bulky powder
absorbent (Magnesium
Carbonate) and triturate
very lightly with a spatula

What are Hygroscopic and
Deliquescent powders?
How are the problems with
these overcome?
Hygroscopic - absorb
moisture
Deliquescent - absorb
moisture from air and
liquefy

To overcome, disperse in
tight containers with
dessicant, and instruct to
store in a dry place.

What are bulk powders?
powders dispersed in bulk
and measured out doses
by the patient, limited to
non-potent meds

Examples of Bulk Powders
1)antacids (sodium
bicarbonate)
2)Laxatives (metamucil)
3)Douche powders
(mussengill)
4)Topical anti-infectives
(bacitracin zinc)

What are divided powders?
commonly used for potent
drugs, blended by
geometric dilution and over
dose is divided into
individual dosing units

Describe the process of
preparing charts for divided
powders
For potent drugs: weigh
each powder quantity

For non-potent drugs:
block and divide method




With the development of technology, the production process
had become more simplified and more mechanized; the complexity of a tablet
punching process has increased. But relatively reducing the problems associated
with the manufacturing process
In olden days tablets were initially punched on
small scale with hand operated machines, which suffered the problem of varied
strength and integrity,
(1)hand
operated small scale production machine
(2)medium scale
production automated tablet punching machine
(3)
(large scale automated fast tablet punching machine.)
but now the
tablet punching machines are all mechanized, the mechanical feeding of feed
from the hopper into the die, electronic monitoring of the press, but still tablet
process problem still persist.
Tablet processing problems can be due to the problem
in the formulation or in the compression equipment, or both of them.
Thus we can classify the problems into following
three types(4,5,6):
1.
Problem
due to excipient: chipping, picking, binding, sticking,
mottling,
2.
Problems
during process: capping, lamination.
3.
Problem
due to machine: double impression.
So at ever y step of the tablet manufacturing
process, utmost care should be taken to avoid defected tablet.
1) Problems due to excipient:
This
can arise due to the inaccurate addition of excipients or errors in the
granulation process. It includes: sticking, picking, binding, mottling.
O Picking:
o
Picking happens when a part of the
tablets gets sticks to the punch surface and gets eroded from the tablet
surface
o
This mostly happens with the upper
punch. And if this is left unchecked then this may lead to weight
variation
too.
Sno Cause Remedy
1.
Due
to engraving or embossing
on the upper punch
The
letters to be embossed should be in
large size particularly on small
punches,
or the size of the tablet be increased.
2.
Rough
punch surface
The
punch surface should be coated with
chromium so as to get a smooth non
adherent face of punch.
3.
Sticky
surface of tablet
Colloidal
silica may be added in the formula as
polishing agent to avoid sticking to
the punch
4.
Too
deep dividing lines
Reduce
the depth of the division.
5.
Excess
moisture.
Proper
drying of granules.
6.
Hot
granules while compression
The
granules are to be dried so that they
do not stick.
7.
Excess
binder.
Reduce
the amount or change the binder so
that the adhesive force is reduced and
more cohesive it becomes.
OSticking:
o
It refers to the sticking of the tablet
material with the die walls.
o
Due to this sticking with the die walls,
additional force is required to eject the tablet form the die walls.
o
Sticking also causes production of
tablets with rough edges.
o
If this problem persists, then this can
cause chipping of the tablet.
o
It produced unusual stress on the cam
track and punch heads resulting in their damage!
Sno Cause Remedy
1.
Low
pressure
Increase
the pressure of punching
2. Fast compression
Increase
the contact time by reducing the
speed
3.
Greater
concavity of the punch
Reducethe
concavity of the punch to optimum
level.
OBinding:
o
Binding is sticking of the tablet to the
die and does not eject properly out of the die.
o
It may be mainly due to lack of proper
lubricant or less quantity of lubricant, or may be due to excess
moisture in
the tablet.
Sno Cause
Remedy

1.
Less
or incorrect lubricant
Increase
the conc of lubricant or use
appropriate lubricant
2.
High
moisture content of the
tablet
material
The
granules are to be properly dried.
3.
Hard
granules reducing the
effectiveness of lubricant
Reduce
the size of the granules by passing
through 30 mesh so that increased
surface
area can increase the chances of even
binding of the lubricant.
4.
Worn
out dies walls
Polish
the dies properly
5.
Excess
pressure in the die
Reduce
the pressure with in the die.
OChipping:
o
Chipping usually happens around the
tablet surface, small pieces are broken out or chipped out of the tablet.
o
It is mainly due to improper machine setting, like
ejection of the tablet.
Sno Cause Remedy
1.
Too
much drying
Moistane
the granule with an hygroscopic
substance
2.
Worn
out punches
Polish
the punch surface to get a smooth
finish
3.
Sticking
of the tablet material to the
Addition
of proper lubricant and properly dry
punch the granules.
4.
Non
cylindrical dies with gap in
the edges
Polish
the dies so that they become
cylindrical shape.
OMottling:
o
Mottling is uneven distribution of the
colour on the surface of the tablet, with dark and light patches on it.
o
It is mainly due to different
colouration of the excipient or the degradation product of the tablet is
coloured.
(7)
Sno Cause Remedy
1.
A
dye may cause mottling
when it migrates to the
surface during the
granulation
process
The
formulator is intended to change the
solvent system, binder system, drying
temperature.
2.
When
coloured binder solution is
not evenly distributed
during mixing process
The
addition should in the sequence of
First the powder colorant is added
followed by the binder like acacia or
tragacanth, followed by the addition
of
granulating liquid, and properly
mixed.
3.
A
colored active ingredient
used along with colourless
excipients.
Addition
of appropriate colouring agent.
OCapping:
o
Capping is a complete or partial
separation of the upper or lower surface of the tablet horizontally,
when the
tablet comes out of the die.
o
When the air is entrapped in between the
tablet material in a die, and when the material gets compressed
between the two
punches, the air entrapped also gets compressed, but when the
pressure is released
on the tablet I.e. when the two punched move apart and the tablet
ejects out of
the die, the compressed sir expands and leads to capping.
Sno Cause Remedy
1.
Large
number of fines in the
material
To
remove the excess of fines the
granulation material should bee
passed through
100 to 200 mesh.
2.
Improperly
dried granules
Dry
the granules properly.
3.
Inadequate
or improper binder
Increase
the quantity of binder or use and
appropriate one.
4.
Compression
may not be firm due to cool
temperature
Compress
the tablet material at higher
temperature.
5.
Improper
setting of the lower
punch,which
causes the sweep off blade
to cut the surface
Correct
height of the lower punch should be
adjusted so that the tablet is smoothly
ejected out.
OLamination:
o
It is similar to capping but here the
tablet gets separated into layers.
o
It can once again occur due to the air
entrapment or due to the high speed of turret
Sno Cause Remedy
1.
Fast
decompression of the tablet
Precompression
step should be included in the
process, so that the pressure at the
final compression
is reduces.
2.
Granules
may contain oily or waxy
material
Suitable
adsorbent or absorbent should be
added.
(8)
(tablet capping and lamination)
O Double impression:
o
It is seen when the tablet punches have
engraving or monograms on it to be embossed on the tablet.
o
When the tablet material comes into the
die for the compression both the punches come in contact with the
tablet
material and compress it, the next step is ejection of the tablet from
the die,

o
During ejection process the lower punch
travels a small distance down and then comes up to give a gentle push
to the
tablet, at this point when the lower punch moves down and comes up
it moves in
a swirlling motion, due to the free rotation when it comes in contact
with the
tablet for the second time to push it up it leaves another impression on
the
tablet. Which is leads to double impression.
o
To avoid this key are to be used along
the sides of the punches, so that it prevents rotation of the punches.
deal properties of API (drug) for formulating tablets
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1.6 Ideal Properties of Active Pharmaceutical Ingredient (API) for formulating
tablets
(46)

What will you gain?
The desirable properties of API for formulating tablets :
1.6.1 High purity
1.6.2 High stability
1.6.3 Good compatibility with excipients
1.6.4 Optimum bulk powder properties
1.6.5 Optimum and uniform particle size - particle size distribution
1.6.6 Spherical shape
1.6.7 Good flowability
1.6.8 Optimum moisture content
1.6.9 Good compressibility
1.6.10 Absence of static charge on surface
1.6.11 Good organoleptic properties
1.6.12 Miscellaneous
1.6.1 High Purity
API has to be in pure form otherwise impurities can catalyze series of chemical reactions,
e.g. in case of hydrocortisone impurity of cupric ion causes oxidation of ketone functional
group. API should meet specifications given in the respective Pharmacopoeia.
1.6.2 High stability
The API should be stable against photolysis, oxidation, hydrolysis, etc. to keep the
formulation a simple one. Sensitive particles require careful handling during manufacturing.
1.6.3 Good compatibility with excipients
(47)

In order to formulate a tablet one need to add excipient along with API. There should not be
any kind of interaction between excipient and API. Excipients have to be inert in nature.
However there are some reported examples of API-excipient interactions like Lisinopril
reacts with lactose and undergoes browning reaction leading to darkening on storage. So,
avoid the use of lactose and use other fillers for API containing primary amine. To ascertain
drug and excipient interaction, 1:1 mixture is prepared and stored under accelerated/ICH
conditions. The amount of drug degraded shall be determined to select the most suitable
excipient.
1.6.4 Optimum bulk powder properties
Bulk powder properties have to be optimum to:
i) Prevent segregation.
ii) Have optimum size tablet particularly for low potency-low density API.
iii) Have good flow.
1.6.5 Optimum and Uniform particle size-particle size distribution
API should have uniform particle size and close particle size distribution because it has
pronounce effect on uniformity of content, uniformity of weight, disintegration time, granule
friability, drying rate kinetics of wet granulation, flowability, compressibility, stability,
dissolution, bioavailability, etc. The flow and compression characteristics are important from
the viewpoint of industrial pharmacist. Strong tablets are obtained if fine particles are used
due to increase in surface area and surface energy.
1.6.6 Spherical shape
The shape of particles decides flowability. Spherical shaped particles exhibit good flow as
compared to needle shaped particles. Particles with irregular shape may exhibit hindered
flow due to interlocking between particles. This point is very important since it is directly
related with weight of tablet and uniformity.
1.6.7 Good flowability
(48-50)

Flow is important for having uniformity of weight and uniformity of drug content. It can be
measured using angle of repose, Carr's index and Hausner ratio.
The methods used to improve flow are summarized below
i)Addition of glidants
ii) Addition of fines: Addition of fines up to certain extent improves flow. This is because of
filling of void space and decrease in surface roughness.
iii) By wet granulation: Wet granulation gives regular sphere shaped granules and removes
static charge if present on particle surface. Thus, flow property improved.
iv) By densification with help of slugging.
1.6.8 Optimum moisture content
(51-53)

Moisture content has to be optimum because of the following reasons:
i)Total lack of moisture results into brittle tablet.
ii) Moisture affects flow, which in turn affects uniformity of content.
iii)High amount of moisture gives stickiness, which will affect compaction.
iv)Picking/sticking may be observed.
Moisture content can be controlled by:
i)Use of anhydrous salts.
ii)Use of non-aqueous solvent.
iii) Optimum drying time.
iv) Addition of finely powdered adsorbent like magnesium oxide.
1.6.9 Good compressibility
(1,2,4,5,54)

API should exhibit good compressibility. However this depends upon its intrinsic nature like:
(A) Elasticity:
The particles deform under the effect of pressure in a die but they revert back to original state
on removal of applied pressure i.e. on ejection. Such tablets may exhibit capping and or
lamination. The intrinsic nature of particle can be changed by:
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i)Wet massing
ii)Pre-compression
iii)Plastic tabulating matrix (micro crystalline cellulose)
Elastic material is less suitable for direct compression.
(B)Plasticity:
Plastic material gets bonded after viscoelastic deformation. Viscoelastic deformation is time
dependent. Hence, the crushing strength is dependent on the time that tablet spends in a die.
Changing the turret speed can change dwell time. Plastic materials may exhibit viscoelastic
deformaiton.
(C) Brittle fracture:
A particle fractures into small particles on application of pressure in a die. Brittle fracture
also promotes tableting. Brittle materials are less lubricant sensitive as compared to plastic
materials. A blend of lactose and MCC is widely used in industry to get advantages of brittle
materials and plastic materials.
1.6.10 Absence of static charge on surface
(55)

It is important because of the following reasons:
i)Affects uniformity of dose and weight variation (flow worsen if attractive forces
generated).
ii) During mixing it may cause segregation and lead to non-uniformity of content if API and
excipients are charged.
iii) Charged API may adhere to feed frame and result into serious damage to tablet
equipment.
In order to remove charge certain treatments can be given like granulation, addition of
diluents or lubricant, surface coating with help of colloidal silica, etc.
1.6.11 Good organoleptic properties
Many API are unpalatable and unattractive in their natural form. In such cases, tablet
formulation require certain care. API has to be checked for colour and taste.
I. Colour
Ideally API should be colourless. For coloured API, the following steps shall be considered:
i)Select appropriate excipient to avoid mottling.
ii)Incorporate API in smallest particle size.
iii)Incorporate colour in dry form along with binder and activate mixture by addition of water
or other activator.
iv)Coating can be applied to conceal non-uniform colour (sugar coated multivitamin tablet).
II. Taste
It is very important for tablets because they come in contact with taste buds. Ideally API
should have no taste. But sometimes it might have unpleasant taste like bitter e.g.
Chloramphenicol, Clindamycin, etc. The following taste masking options can be tried:
i)Use of prodrug to decrease API solubility in saliva or to reduce affinity for taste receptor
e.g. Chloramphenicol Palmitate.
ii)Sugar coating or film coating.
iii)Addition of sweeteners like mannitol in cause of fast dissolving tablet or chewable tablet.
iv) Use of drug-ion exchange adsorbent in formulation.
v)Drug v-cyclodextrin complex may exhibit good taste profile and good compressibility as
well.
1.6.12 Miscellaneous points
i)API should not exhibit sublime characteristics
ii)Liquid APIs are less suitable for tablet formulation. One of the options is conversion of
liquid in pseudosolid (mix liquid API with adsorbents). A combination of Valproic acid and
Sodium Valproate is a typical example of converting a liquid into pseudosolid.
iii)BCS class IV drugs are difficult to formulate if dissolution and bioavailability
requirements are to meet as per regulatory agencies.
Key Phrases
OHigh Purity to avoid contamination and degradation.
OHigh stability against photolysis, oxidation, hydrolysis, etc.
OGood compatibility with excipients. For example, avoid use of lactose with drugs with
primary amine functional group.
OOptimum bulk powder properties to prevent segregation and to have good flow.
OOptimum particle size and size distribution to have uniformity of weight, uniformity of
content, good flow and compressibility.
OSpherical shape to avoid interlocking between the particles and thus to aid flow.
OGood flow to have uniformity of weight and uniformity of drug content
OOptimum amount of moisture to avoid problems like brittle tablet, picking/sticking, etc.
OGood compressibility to have nicely bonded tablet.
OAbsence of static charge on the surface to prevent demixing and damage to tableting
equipment by adhering to feed frame.
OGood organoleptic properties to have better patient acceptance.
OMiscellaneous: Convert liquid API to pseudosolid e.g. Valproic acid and Sodium valproate,
etc.