TECHNOLOGY OF SOLID DOSAGE FORMS

UNIT 1 POWDERS AND GRANULES

ADVANTAGES AND DISADVANTAGES OF POWDERS

ADVANTAGES OF POWDERS
 Powder form is the most versatile and convenient to prescribe, compound
and administer.
 A physician has the option to deviate from the conventional dose of a
medicament according to the requirement of the patient.
 Powders are stable and do not enter into reaction in solid state, lesser
difficulties are experienced in compounding them together,
 It is possible to reduce them in the desired particle size range and thus
facilitate rapid absorption.
 Less incompatibility as compared to liquid dosage form.
 Powders are in the form of small particles; they offer a large surface area
and are rapidly dissolved in the gastrointestinal (GI) tract minimizing the
problems of local irritation. Drugs that have to be given in bulk can be
best administered in powder form by mixing them with foods or drinks.
 Whenever effervescence is desired, accurate quantities of the two reacting
powders are mixed with water.
 It is difficult for children and infants to swallow tablets and capsules and
under such circumstance’s drugs may be administered in powder form
making them palatable by mixing with milk, fruit juice or honey.
 Manufacturing of powder is economic hence product cost is quite
economic as compare to other dosage form.
DISADVANTAGES OF POWDERS

 Patient may misunderstand the correct method of use. Without clear

instruction, patients may inhale through the nose a drug intended for oral
administration. In oral administration, it may have to be clear whether
the drug has to be dissolved first in water or taken as is.
 It is undesirable to take bitter or unpleasant tasting drugs by oral
administration. Many herbal drugs (mainly infusions in boiling water)
have very bitter tastes. To overcome the unpleasant taste of the extracts,
it was often told that “bitter medicine is better medicine.” This may not
necessarily be true.
  It is difficult to protect powders containing hygroscopic, deliquescent
(tending to melt or dissolve in humid environment), or aromatic materials
from decomposition.
 Uniform, individually wrapped doses of powders (sachets) are required
and this may increase the manufacturing expense. (It is possible to
include a spoon in a packet of powder drug. This may result in inaccurate
amount of drug delivered).
 Powder must be a homogeneous blend of all of the components and must
be of the most advantageous particle size. The particle size of a drug
influences the rate of solubility in water. It may also influence the
biological activity of a drug.

ADVANTAGES AND DISADVANTAGES OF GRANULATED

PRODUCTS
ADVANTAGES
 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.
 Granules increase compressibility.
 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.
 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.
 Granules produce particle-size uniformity, thus content uniformity.
DISADVANTAGES
  The masking of bitter tastes may be a problem with this type of
preparation.
 Granules are not a good method of administering potent drug with low
dose.
 Instability in presence of moisture,
 Problems in packaging and storage.

MIXING OF POWDERS
METHOD
 Mechanical mixing
 Hand mixing
o Spatulation (spatula+tile)
o Trituration (mortar+pestle)
o Tumbling (wide mouth closed container)
The ideal mixer
 Produce a complete blend rapidly to avoid product damage.
 It should be cleaned and discharged easily.
 Be dust tight.
 Require low maintenance and low power consumption.
MORTAR AND PESTLE
The pharmacist most generally employs the mortar and pestle for the
small-scale mixing.
The mortar and pestle method are a single operation. Thus, it is
particularly useful where some degree of particle-size reduction as well as
mixing is required as in the case of mixtures of crystalline material.
SPATULATION
The blending of powders with a spatula on a tile or paper used sometimes
for small quantities or when the mortar and pestle technique is undesirable.
It is not suitable for large quantities of powders or for powders containing
one or more potent substance because homogenous blending may not occur.
SIEVING
 Sieving usually is employed as a pre or post mixing method to reduce
loosely held agglomerates and to increase the overall effectiveness of blending
process.
TUMBLING
Powder is mixed in rotating chamber. Mixing is thorough but time
consuming. Mostly used in industry.
DIVIDED POWDERS
After a powder has been properly blended (using the geometric dilution
method for potent substances), it may be divided into individual dosing units
based on the amount to be taken or used at a single time. Each divided portion
of powder may be placed on a small piece of paper (Latin chartula; abbrev.
chart.; powder paper) that is folded to enclose the medication. A number of
commercially prepared premeasured products are available in folded papers or
packets, including headache powders (e.g., BC powders), powdered laxatives
(e.g., psyllium mucilloid, cholestyramine resin), and douche powders (e.g.,
Massengill powder packets).
Divided powders may be prepared by the pharmacist as follows.
Depending on the potency of the drug substance, the pharmacist decides
whether to weigh each portion of powder separately before enfolding in a paper
or to approximate each portion by using the block-and-divide method. By the
latter method, used only for nonpotent drugs, the pharmacist places the entire
amount of the prepared powder on a flat surface such as a porcelain or glass
plate, pill tile, or large sheet of paper and, with a large spatula, forms a
rectangular or square block of the powder having a uniform depth. Then, using
the spatula, the pharmacist cuts into the powder lengthwise and crosswise to
delineate the appropriate number of smaller, uniform blocks, each representing
a dose or unit of medication. Each of the smaller blocks is separated from the
main block with the spatula, transferred to a powder paper, and wrapped.
The powder papers may be of any size convenient to hold the amount of
powder required, but the most popular commercially available sizes are 2.75 ×
3.75 inch, 3 × 4.5 inch, 3.75 × 5 inch, and 4.5 × 6 inch. The papers may be (a)
simple bond paper; (b) vegetable parchment, a thin, semi opaque paper with
limited moisture resistance; (c) glassine, a glazed, transparent paper, also with
limited moisture resistance; and (d) waxed paper, a transparent waterproof
paper. The selection of the type of paper is based primarily on the nature of the
powder. If the powder contains hygroscopic or deliquescent materials,
waterproof or waxed paper should be used. In practice, such powders are double
wrapped in waxed paper, and then for esthetic appeal, they are wrapped in bond
paper. Glassine and vegetable parchment papers may be used when only a
limited barrier against moisture is necessary. Powders containing volatile
components should be wrapped in waxed or glassine papers. Powders
containing neither volatile components nor ingredients adversely affected by air
or moisture are usually wrapped in a white bond paper.
Today, compounded powder papers are rarely used on an out-patient,
community practice basis. Their use is usually limited to institutional and
research practice. Commercial drug products that are provided in this drug
delivery form include polyethylene glycol 3350 (i.e., MiraLAX),
cholestyramine resin, pectin, l-glutamine, sodium phenylbutyrate, and wheat
dextrin (i.e., Benefiber).
PROBLEMS IN MANUFACTURING POWDERS
1. Hygroscopic and deliquescent powder
Problem:
Absorption of moisture from air leading to potential or partial or
complete liquefication.
Solution:
 Applied in a granular form to decrease the exposed surface to air.
 Packed in aluminum foil or in plastic film packets.
 Addition of light magnesium oxide to reduce the tendency to damp.
 Addition of adsorbent materials such as starch.
Examples:
 Halide salts (sodium iodide)
 Certain alkaloids (physostigmine HCl)

2. Efflorescent powders
Problem:
Crystalline substances which during storage loose their water of
crystallization and change to powder (to be efflorescent). The liberated
water converts the powder to a paste or to a liquid.
Solution:
Using the anhydrous form, and treating it in a manner similar to
hydroscopic powders.
Examples:
Alum, atropine sulfate, citric acid, codeine phosphate.
3. Eutectic mixtures
 Problem:
Mixture of substances that liquefy when mixed, rubbed or
triturated together. The melting points of many eutectic mixtures are
below room temperature.
Solution:
 Using inert adsorbent such as starch, talc, lactose to prevent
dampness of the powder.
 Dispensing the components of the eutectic mixture separately.
Examples:
Menthol, thymol, phenol, camphor
4. Potent drug
Problem:
Limited precision and accuracy of the used balances to weight
small amounts of potent drugs.
Solution: drug triturates:
 suitable diluents like lactose are mixed with the potent drug to
form 10-20% w/w drug triturates.
 Very fine powders should be used in the triturates.
5. Incompatible salts
Problem:
Chemically incompatible salts when triturated together produce
discoloration, chemical deterioration or loss of potency.
Solution:
 Compounding such substances with minimum pressure.
 Use a convenient method for mixing the powder like tumbling in a
jar or spatulation on a sheet of paper.
 Each substance should be powdered separately in a clean mortar
and then combined with other ingredients gently.
 Powder and dispense separately.
6. Explosive mixtures
Problem:
Oxidizing agents (potassium salts of chlorate, dichromate,
permanganate and nitrate, sodium peroxide, silver nitrate and silver
oxide) explore violently when triturated in a mortar with a reducing agent
(sulfides, sulfur, tannic acid, charcoal).
Solution:
 Comminute each salt separately.
 Subject to a minimum pressure.
EFFERVESCENT GRANULATED SALTS
 An effervescent dosage form, frequently tablets or granules, contains
ingredients that, when in contact with water, rapidly release carbon dioxide. The
dosage form is dissolved or dispersed in water to initiate the effervescence prior
to ingestion.
Effervescent salts are granules or coarse to very coarse powders
containing a medicinal agent in a dry mixture usually composed of sodium
bicarbonate, citric acid, and tartaric acid. When added to water, the acids and
the base react to liberate carbon dioxide, resulting in effervescence. The
resulting carbonated solution masks undesirable taste of any medicinal agent.
Using granules or coarse particles of the mixed powders rather than small
powder particles decreases the rate of solution and prevents violent and
uncontrollable effervescence. Sudden and rapid effervescence could overflow
the glass and leave little residual carbonation in the solution.
Using a combination of citric and tartaric acids rather than either acid
alone avoids certain difficulties. When tartaric acid is used as the sole acid, the
resulting granules readily lose their firmness and crumble. Citric acid alone
results in a sticky mixture difficult to granulate.
EFFERVESCENT GRANULES
Effervescent granules are prepared by two general methods: (a) the dry or
fusion method and (b) the wet method
Dry or fusion method
In the fusion method, the one molecule of water present in each molecule
of citric acid acts as the binding agent for the powder mixture. Before mixing
the powders, the citric acid crystals are powdered and then mixed with the other
powders of the same sieve size to ensure uniformity of the mixture. The sieves
and the mixing equipment should be made of stainless steel or other material
resistant to the effect of the acids. The mixing of the powders is performed as
rapidly as is practical, preferably in an environment of low humidity to avoid
absorption of moisture and a premature chemical reaction. After mixing, the
powder is placed on a suitable dish in an oven at 34°C to 40°C. During the
heating process, an acid-resistant spatula is used to turn the powder. The heat
releases the water of crystallization from the citric acid, which, in turn,
dissolves a portion of the powder mixture, setting the chemical reaction and
consequently releasing some carbon dioxide. This causes the softened mass of
powder to become somewhat spongy, and when it has reached the proper
consistency (as bread dough), it is removed from the oven and rubbed through a
sieve to produce granules of the desired size. A No. 4 sieve produces large
granules, a No. 8 sieve prepares medium size granules, and a No. 10 sieve
prepares small granules. The granules are dried at a temperature not exceeding
54°C and are immediately placed in containers and tightly sealed.
Wet method
The wet method differs from the fusion method in that the source of
binding agent is not the water of crystallization from the citric acid but the water
added to alcohol as the moistening agent, forming the pliable mass for
granulation. In this method, all of the powders may be anhydrous as long as
water is added to the moistening liquid. Just enough liquid is added (in portions)
to prepare a mass of proper consistency; then the granules are prepared and
dried.
REASONS FOR GRANULATION
 To enhance the flow properties.
 To prevent the problems of dust during compression.
 To produce uniform size particles.
 To improve drug compression ability.
 For regulate the drug releasing from the tablet.
 It is use full to densifying the material.
 The granulation of toxic materials will reduce the hazard associated with
the generation of toxic dust that may raise when handling powders.
 Materials which are slightly hygroscopic may adhere and form a cake if
stored as a powder. Granulation may reduce this hazard, as the granules
will be able to absorb some moisture and retain their flow ability because
of their size.
 Granules, being denser than the parent powder mix, occupy less volume
per unit weight. They are therefore more convenient for storage.
GRANULATION MECHANISM
Granules are formed by the binding together of powder particles.
Sufficiency strong bonds much be formed between particles so that they adhere
and do not break. There are five recognized bonds that form between particles:

 adhesive and cohesive forces in the immobile liquid between particles

 interfacial forces in mobile liquid films within granules
 formation of a solid bridge after subsequent solvent evaporation – the
main mechanism in dry granulation
 attractive forces between solid particles – presence of liquid not required
 mechanical interlocking of particles often between fibrous or flat particles
There are two broad methods employed for granulating pharmaceutical
formulations: dry granulation and wet granulation.

Dry granulation

Dry granulation is used to form granules without using a liquid solution

because the materials 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 has fewer process stages than wet granulation.

Compacting the powder for dry granulation can be done either using a
heavy duty tabletting press, or the powder is squeezed between two counter-
rotating rollers, in what is referred to as a Chilson compactor, to produce a
continuous sheet or ribbon of materials.

In the case of the roller compactor, the different ingredients are first
weighed and mixed in the required proportions. The resulting mixture is
conveyed to the compaction area and compaction rollers, normally with a screw
feeder or auger. It is then compressed by roller compaction (slugging) for the
first time. This results in sheets of compressed material, which are then milled
into granules of exactly the agreed density, before being lubricated and
compressed into the desired final form. Roller compacted particle are usually
dense, with sharp-edged profiles. When a tablet press is used for dry
granulation, the powders may not possess enough natural flow to feed the
product uniformly into the die cavity, resulting in varying degrees of
densification.

In dry granulation there are two types of irresistible attractive physical forces
between particles that cause them to bind them together

 Electrostatic forces – there are generally weak but may cause cohesion
when the material is mixed initially.
 Vander Waals forces – these are stronger than electrostatic forces and
they increase as the inter-particulate distances decrease during the
compression of powders.

In dry granulation the pressure applied increases the contact area between the
adsorption layers of particles and decreases the inter-particulate distances,
thereby contributing to the final strength of the material. The pressure applied
during dry granulation may also melt low melting-point materials where the
particles touch and high pressures are developed. When this happens the
particles will bind together and crystallization may take place when the pressure
is relieved.
Wet granulation

In wet granulation, granules are formed by the addition of a granulation

liquid (usually an aqueous solution) onto a powder bed which is under the
influence of an impeller (in a high-shear granulator), screws (in a twin screw
granulator) or air (in a fluidized bed granulator). Agitation of the particles along
with the added liquid produces bonding between the primary powder particles
to produce wet granules. The liquid must be volatile so that it can be removed
by drying and typically water, ethanol or isopropanol is used either alone or in
combination. Aqueous liquids are safer to use than organic solvents. Although
water may initially bind particles together, when it evaporates the powder may
disintegrate so a binder is added, which is a type of glue. Typically povidone
(polyvinyl pyrollidone (PVP) is used.

Once the water or solvent evaporates from the mixture, the binder locks
powder particles together in granules which may then be milled to the desired
dimensions.

The process can be very simple or very complex depending on the

characteristics of the powders, the final objective of tablet making, and the
equipment that is available. In the traditional wet granulation method the wet
mass is forced through a sieve to produce wet granules which is subsequently
dried.

The mechanism of wet granulation begins when liquid is added to the

powder causing a thin and immobile film of liquid to form between particles.
This causes an effective decrease in inter-particulate distance and an increase in
contact area between particles. The shortening of the inter-particulate distance
increases the Van der Waals forces of attraction. More liquid is usually added in
wet granulation to form a mobile liquid film. As a result, there are three states
that can describe the distribution of liquid between particles:

 Pendular state – usually at low moisture level, this is when the particles
are held together by lens-shaped rings of liquid, but it is mainly air
between the particles.
 Funicular state – this is an intermediary state where air starts to displace
from between particles
 Capillary state – this is when all air has been displaced from between the
particles.

In the capillary state liquid penetrates the pores of the particles and will form a
solid bridge between particles, giving the strongest form of adhesion, when the
liquid evaporates.
 Nucleation of granules in wet granulation starts with a number of
particles joining together in the pendular state. Agitation of the mixture causes
the particles to adopt the capillary state and at this point the particles act as
nuclei for further granule growth. As the mixture is agitated, further granular
growth occurs forming a large number of small granules with a fairly wide size
distribution. This is the ideal composition. Two or more granules may coalesce
to form larger granules, or they may break into fragments that can adhere to
other granules. There may also be some mechanical interlocking of powder
particles. If agitation is continued too far, the granules will coalesce to form
unusable over-massed spheres of material. The amount of liquid added and the
nature of the starting materials will affect the required mixing time, as well as
the type of mixer. High shear mixers often require less liquid than low–shear
mixers, and high impeller rotation speeds can cause local heating of the mixture
and loss of solvent by evaporation.

PHARMACEUTICAL GRANULATION EQUIPMENTS

1. RAPID MIXING GRANULATOR
 Rapid mixer granulator is designed to achieve excellent mixing and
consistent granules at lower operating cost along with higher
productivity.
 Better mixing and closed control of granule size leads to faster
tableting speeds with improved quality and least rejections.

Impellers: impellers are fixed at the bottom of dome shaped stainless

steel bowl. It has fully length and two half length blades. Impellers are
designed such a way that small blade lift the material and full length
blades push the material to mix well. These impellers break up the wet
mass into small pieces and granules.

Chopper: these are specially designed small blades located at the bottom
of the dome. The primary function of chopper is to cuts the lumps into
smaller fragments those are mixed equally by the impeller and aids the
bowl or sprayed onto the powder to achieve a more homogeneous liquid
distribution. It rotates at high speed RPM to give easy and uniform
granulation. The speed of chopper is responsible for the size of granule.

Discharge port: the discharge port is mounted horizontally into the dome
with vertical downward opening. Granules are unloaded in the container
through the discharge port. Opening of discharge port is operated by
pneumatic cylinder (compressed air cylinder) that requires 3-5 kg/cm2
pressure of compress air.
2. FLUIDIZED BED DRYER

Fluidized bed dryer (also called fluid bed dryer) is a kind of

equipment used extensively in the pharmaceutical industries to reduce the
moisture content of pharmaceutical powder and granules. The equipment
works on a principle of fluidization of the feed materials. In fluidization
process, hot air is introduced at high pressure through a perforated bed of
moist solid particulate. The wet solids are lifted from the bottom and
suspended in a stream of air (fluidized state). Heat transfer is accomplished
by direct contact between the wet solid and hot gases. The vaporized liquid
is carried away by the drying gases. Sometimes to save energy, the exit gas
is partially recycle.

Components

 Air preparatory unit

 Product container
 Exhaust filter
 Exhaust blower
 Control panel
 Air distribution plate
 Spray nozzle
 Solution deliver

Parameters to be controlled in fluidized bed dryers

Process/operating parameter

 Temperature: increased temperature leads to increased moisture

diffusivity and hence increased drying rate and decreased drying
time. The nature of the material plays an important role in choosing
the operating temperature.
 Humidity: faster drying is achieved when the moisture content of
the inlet air is maintained at its minimum.
 Air flow rate/gas velocity: increasing gas velocity increases
drying rate but should be maintained at an optimized rate (not to
fast or too slow). Gas velocity has no effect on particles with high
internal resistance to moisture transfer.

Product parameters
  Moisture content of the feed material.
 Feed rate/batch size.
 Product moisture content.
 Particle size, shape and diameter.

Types of fluidized bed dryers

Conventional fluidized bed dryers

 Batch fluidized bed dryers.

 Semi- continuous fluidized bed dryers.
 Well-mixed, continuous fluidized dryers.
 Plug flow fluidized bed dryer.

Modified fluidized bed dryers

 Hybrid fluidized bed dryers

 Fluidized bed dryer with immersed heat exchange
 Vibrated fluidized bed dryer
 Agitated fluidized bed dryers/wirl fluidizers
 Fluidized bed dryers of inert particles
 Spouted bed dryer
 Recirculating fluidized bed dryer
 Fluidized bed freeze dryer

Advantages of fluidized bed dryer

 High rates of moisture removal due to excellent gas particle

constant which results in high heat and mass transfer rates.
 Lower capital and maintenance cost.
 Reduced contact time for drying.
 Ease of control.

Disadvantages of fluidized dryer

 High pressure drops results as a result of the need to suspend the

entire bed in gas which equally leads to high energy consumption.
 Requires increased gas handling due to extensive recirculation of
exhausts gas for high thermal efficiency operation.
 Poor fluidization and low flexibility especially if the feed is too
wet.
  Not the best choice of equipment when organic solvents need to be
removed during drying.
 Non uniform product quality for certain types of fluidized bed
dryer.

3. VIBRATORY SIFTER
Working principle
Vibratory shifter works on gyro principle. The required gyratory
motion is obtained from specially designed gyro motor, which is fitted
underneath the vibrating assembly. The complete vibrating assembly is
isolated from the base by means of specially designed rugged springs.
Gyro motor is fitted with top & bottom eccentric weights designed as per
required centrifugal force.
Adjustable flow patterns
Flow patterns of material can be fine tuned for screening efficiency
by repositioning the bottom eccentric weight relative to the top eccentric
weight.
 0 ͦin phase
From a central feed, material flows to screen periphery in a straight
line.
 30 ͦout of phase
Material spirals slightly from the centre to periphery, increasing
retention time. Recommended for general purpose screening.
 45 ͦout of phase
Material flows from center in a distinct spiral pattern, further
increasing retention time. Recommended for classification of
particles and screening of wet material.
 90 ͦout of phase
Prevents oversize material from discharging.

4. MULTIMILL
Multi mill machines are widely used for wet and dry granulation,
pulverization etc. these machines find application in pharmaceutical,
chemical, bulk drug, cosmetic, dyestuffs and food processing industries.
The unit consists of vibrato sifter, tablet coating pan, spray coating
machine and dust extractor. Our multi mill machines can be customized
based on the specific requirements of the clients.

5. DOUBLE CONE BLENDER

 Double cone blender is an efficient and versatile machine for
mixing of dry powders and granules homogeneously. Double cone
blenders are most often used for dry blending of free flowing solids. The
solids being blended in these units can vary in bulk density and in
percentage of the total mixture.

6. TUMBLING GRANULATORS
 Particles are set in motion by the tumbling action caused by the
balance between gravity and centrifugal forces
 Includes discs, drum, pans and a range of similar equipment

Characteristics

 Product granule size in the range of 2 to 20mm

 Not suitable for producing very small granules
 Good for producing high density balls or pallets
 Capable of handling very large throughputs
 Extensively used in mineral processing and fertilizer granulation
7. DISC GRANULATOR
 rotating disc with a rim to hold the tumbling granules
 powder feed continuously fed to the disc, typically at the edge of
the rotating granulator bed
 liquid binder is added through a series of single fluid nozzles
distributed across the face of the bed
8. DRUM GRANULATOR
 Typically used for high capacity applications and usually requires
some type of recycle depending on the product specification
 Granulation where the only feed or the majority of the feed is a
liquid or melt such as urea granulation
 Feeds may be either pre moistened by mixers to form granule
nuclei or liquid may be sprayed onto the tumbling bed via nozzles
or distributor pipe system
 Scrapers are often but not always used to limit build up on the
drum wall

REFERENCES:
 Ansel’s pharmaceutical dosage forms and drug delivery systems by Loyd
V. Allen, Jr. and Howard C. Ansel, tenth edition.
 [Link]
 [Link]
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