PCT 401: Solid Dosage Technology / Industrial Pharmacy Introduction /Characteristic of Powders

PHARM. J. A. BWALA

DEPARTMENT OF PHARMACEUTICS, GOMBE STATE UNIVER

Introduction

Whether as raw materials, intermediates, or final products, powders are integral to the
pharmaceutical industry. However, despite their ubiquity, powders continue to present
challenges, with scientists and engineers constantly striving for better, and more relevant,
information to support every step of the product lifecycle: from R&D through formulation and
into process development, for equipment design and day-to-day operation, for troubleshooting,
and for quality control of raw materials, intermediates, and final products.

Powders are generally considered to be composed of solid particles that have the same or
different chemical composition, with equivalent diameters generally less than 1000µm.

The term powders can also be used to describe a group of particles that are used to form granules
having equivalent diameters greater than 1000µm.

The word ‘powder’ refers to a chemical or mixture that is solid in physical state.

In pharmacy, pharmaceutical powders are used to produce tablets and capsules and as such, it is
critical that we study their properties

PARTICLE PROPERTIES OF POWDERS

Powders are usefully thought of as bulk assemblies consisting of particles, (most usually) air and
low levels of moisture. Particle properties often define critical aspects of product performance:
the dissolution rate of a drug; catalytic activity; or the surface finish delivered by an abrasive.

However, particle properties also impact bulk powder behavior including flowability,
compressibility, permeability and ease of fluidization. These properties, in turn, correlate directly
with product and process performance: the fluidization performance of a catalyst; tablet
hardness; and the feasibility of recycling an additive manufacturing metal powder.

Molecular forces are present in powders and they produce tendencies for solid particle to stick
together or to surfaces. Cohesion and Adhesion forces are two important parts of these forces
that produce these tendencies and they are two forces of the same phenomena.

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Cohesion: This occurs between the same surfaces such as component particles of bulk solid of
the same particles.

Cohesion forces are composed of short range, nonspecific Vander weal’s forces and these forces
increase as the particles size decreases It also changes with relative humidity. Electrostatic
forces, which occurs from fractional charges and have very short half-life.

Cohesion forces provides a useful means of measuring the fractional forces that prevent powder
flow.

Adhesion: This occurs between two unlike surfaces E.g. forces between hopper and particles or
forces between particles and die wall. These forces can be accurately measured using specially
adopted ultra-centrifuge.

PARTICLE SIZE

Since cohesion and adhesion are phenomena that occur at surfaces, particle size will influence
flowability of a powder.

Pharmaceutical particles are usually very minute and they are measured as hypothetical spheres.
The particles size is a reflection of the particle dimension, which can be derived from various
characters for example a diameter may be expressed in terms of weight, volumes, surface areas
project areas or sedimentation velocities of particles. This means therefore that the ‘particles
size’ quoted is the diameter of a sphere equivalent to the particle in weight, volume, surface area,
project areas, or sedimentation velocity.

The more asymmetric a particle is, the greater the surface area per unit volume. As the particles
become more asymmetric, it becomes increasingly difficult to assign a meaningful diameter to
the particle hence the need for equivalent spherical diameters. The equivalent spherical diameter
is obtained by choosing one diameter that is characteristics of the surface area or volume of
relating this to the surface area or volume of the particle through a ‘correction factor’ which in
reality is the ratio of one diameter to another. The equivalent spherical diameter relates the size
of the particle to the diameter of a sphere having the same surface areas, volume, or diameter

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thus, the surface diameter is a diameter of a sphere having the same surface area as the particle in
question.

N.B: The type of diameter used to retest the particles size points at the method used to obtain the
diameter. E.g. project diameter (microscopic) or Stoke’s diameter (sedimentation)

PARTICLE SIZE DISTRIBUTION

A collection of particles as seen in the powders is usually polydispersed. It is therefore necessary

to know not only the size (diameter) of a certain particle but also how many particles of the same
size exist in the sample. This therefore point to the need to estimate the size range present and
the number or weight fraction of each particle size. This is the particle size distribution and from
this we can calculate the average particles size for the sample.

The various parts or fractions of the polydispersed system (powder in this case) are divided
according to various sizes of spheres and presented as graphs or usually frequency represented in
histograms, distribution tables.

Cumulative Frequency Distribution Table

% Cumulative
% Cumulative
Sieve % Frequency frequency
Particles frequency
of particles (Oversized) of
Size (µm) retained (g) (undersized) of
retained particles
particles retained
retained
500 3.22 6.45 6.45 100
250 5.2 10.41 16.86 88.34
150 13.57 27.16 44.02 66.44
90 11.2 22.42 66.44 44.02
75 10.95 21.92 88.34 16.86
45 5.82 11.65 100 6.45
49.96

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Cumulative Percent Frequency Distribution Curves (undersize and oversize)

120

100

80
Cumulative % frequency

% Cumulative frequency
60 (undersized) of particles re-
tained

% Cumulative frequency
40 (Oversized) of particles re-
tained

20

0
0 100 200 300 400 500 600
Sieve Size (µm)

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Histogram Showing Frequency of Particles Retained

30

25
WEIGHT OF PARTICLES RETAINED (%)

20

15

10

0
500 250 150 90 75 0
SIEVE SIZE (MICROMETER)

CG EG

The mean particle size has been defined using the arithmetic mean. This arithmetic mean is
achieved by summating the particular parameter for all the individual particles in a sample and
dividing the value by the total number of the particles.

Frequency distribution curves give a visual representation of the distribution that an average
diameter cannot achieve. This is important as it is possible to have two samples with the same
average diameter but different distributions. Also, it is immediately apparent from a frequency
distribution curve what particle size occurs most frequently within the sample. This is termed the
mode.

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METHODS FOR PARTICLE SIZE DETERMINATION

Many method are available for determining particle size but only those that are widely used in
pharmaceutical practice and are typical of a particular principle will be discussed. The great
variety of methods arises from endeavors to fine solution to the problem of expressing the size of
an irregular, three dimensional particle in terms of one linear dimensions.

Although there is no upper limit to the size of particles, the analysis will be confirmed to
powders with a particle size less than 1000µm. the test is essentially carried out on a simple
representative of the whole.

>Microscopy

>Sieving

>Sedimentation and

>The determination of Particle Volume will be discussed here.

1. Optical Microscopy :
Using the optical microscope, particles size range of 0.2 to 100µm can be measured. According
to this method an emulsion or suspension, dilute or undiluted, is mounted on a slide or ruled cell
and placed on a mechanical stage. The microscope eyepiece is fitted with a micrometer by which
the size of the particle can be estimated. The field can be projected onto a screen where the
particles are measured more easily, or a photograph can be taken from which a slide is prepared
and projected on a screen for measurement.
Particles are measured along an arbitrarily chosen fixed line, generally made horizontally across
the center of the particle. This method requires counting 300 – 500 particles to obtain a good
estimation of the distribution.
Disadvantages of this method include the shape, particle position, aggregation, speed of method
and sampling.

Shape – it is necessary to decide on one linear dimension to represent the particle usaually, it is
preferable to estimate the diameter of a circle of the same area as the projected area of the
particle.

Particle position – a particle will assume the position of maximum stability on the microscope
slide. This means that particles that are laminar or plate-like in shape will appear to be
considerably larger than they would be if tested by other methods.

Aggregation – if particles aggregate on the slide, anomalous results will be obtained, the effect
being greater than it is with other methods.

Speed of method – the method is very slow, since large numbers of particles must be measured
and many fields examined in order to obtain reliable results.

Sampling – a further effect of measuring a relatively small number of particles is that special
sampling techniques must be used and, like the counting and measuring procedures, must be
rigidly standardized to ensure that the few particles measured are representative of the bulk.

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2. SIEVING
This involves the use of a set of standard sieves that calibrated by the National Bureau of
Standards. The typical sieve is a cylindrical open container constructed for particle size analysis
with a base of wire mesh of known aperture size. The sieves are arranged in a nest of at least five
with the coarsest at the top and a closed collection pan placed below the small sieve size. A
carefully weighed sample of the powder is placed on the top sieve, and after the sieves are
shaken for a predetermined period of time (say 10 – 15 minutes), Using the sieve shaker, the
powder retained on each sieve is weighed.

Result are presented at cumulative percent undersize for the aperture diameter of the
given stage. Sieving results may vary as a function of sieve load, particle shape, agitation
method, physical properties and overall size distribution.

This method describes the sieve diameter of the particle. The particle size determined by
sieving ranges from 45 µm-1000 µm and it is usually carried out on dry powders, although for
powders in liquid suspension or which agglomerate during dry sieving a process of wet sieving
can be used. It is still largely a non-automated process.

LIMITATION

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 I. Particle can be attracted electrostatically to form aggregates that will not pass through the
mesh.
II. Humidity can affect particles of hygroscopic material leading to the aggregation.
III. Particle shape affects passage of the particles through the mesh. The further a particle
depart from the spherical shape the greater the difficulty it will have in Passing through the
aperture.
IV. The sieving process is affected by the particle size distribution. Some particles can block
the aperture preventing the passage of other particles.
V. Shape of the aperture
VI. Shaking or vibration disturbance affects the way in which the material passes through the
meshes.
VII. Standardization of technique since it is virtually impossible to sieve to completion.
It should be borne in mind that prolong sieving is likely to lead to the formation of some fine
particles by attrition of the coarser particles between each other and against the sieve.

3. SEDIMENTATION
The particle size in the sub sieving range can be obtained by gravity sedimentation as expressed
in Stoke’s law.
2
h d st ⟨ ⍴ −¿ ⍴ ⟩
v= = s 0
g
t 18 Ƞ 0

Or d st =

Where V= rate of setting

√ 18 Ƞ0 h
( ⍴ s−¿ ⍴0 ) > ¿
¿

h= distance of fall in time t

dst= mean diameter of the particles based on the velocity of the sedimentation
⍴s =¿Density of the particles
⍴0 = density of dispersion medium
g=¿Acceleration due to gravity, and
Ƞ 0=viscosity of the medium.

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In this method, the particles must not be clumped together in the suspension because such
clumps would fall more rapidly than the individual particles and erroneous results would be
obtained.

The proper deflocculating agent must be found for each sample that will keep the particles free
and separate as they fall through medium.

Also, for the Stoke’s law to hold, the flow of dispersion medium around the particles as it
sediments should be laminar or streamline.

The Andreasen apparatus consist of a 500 ml vessel containing a 10 ml pipette sealed into a
ground glass stopper. When the pipette is in place in the cylinder, its lower tip is 20cm below the
surface of the suspension. A 1% or 2% suspension of the particles in a medium containing a
suitable deflocculating agent is introduced into the vessel and bought to the 55ml mark, The
stoppered vessel is shaken to distribute the particles uniformly through the suspension, and the
apparatus, with pipette in place, is clamped securely in a constant temperature bath, At various
time intervals, 10ml samples are withdrawn and discharge by means of the two-way stopcock.

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 The samples are evaporated and weighed or analyzed by other appropriate means correcting for
the deflocculating agent that has been added.

The particle diameter corresponding to the various time periods is calculated from stoke’s law,
with h in equation above being the height of the liquid above the lower end of the pipette at the
time each sample is removed. The residue or dried sample obtained at a particular time is the
weighed fraction having particles of size less than the size obtained by the stoke’s law
calculation for that time period of setting. The weighed of each sample residue is therefore called
the weighed undersize, and the sum of the successive weights is known as cumulative weighed
undersize. It can be expressed directly in weight unit or as percentage of the total weight of the
final sediment. This method can be used to measure particle size from 0.8 to 300µm.

4. PARTICLE VOLUME MEASUREMENT

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The Coulter Counter is a popular instrument used for measuring the volume of particles. This
instrument operate on the principle that when a particle suspended in a conducting liquid passes
through a small orifice on either side of which are electrodes, a change in electric resistance
occurs. In practice a known volume of a dilute suspension is pumped through the office.
Provided the suspension is sufficiently dilute, the particles pass through essentially one at a time.
A constant voltage is applied across the electrodes to produce a current. As the particle travels
through the orifice, it displaced its own volume of electrolyte, and this in an increased resistance
between the two electrodes. The change in resistance, which is related to the particles volume,
causes a voltage pulse that is amplified and fed to a pulse height analyzer calibrated in terms of
particle size. The instrument record electronically all those producing pulses that are within two
threshold setting and counting the numbers in a constant sample size, it is possible to obtain a
particle size distribution. The instrument is capable of counting particles at the rate of
approximately 4000 per second, and so both gross counts and particles size distributions are
obtained in a relatively short period of time. The data may be readily converted from a volume

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 distribution to a weight distribution. Particles in size range between 0.5µm to 300µm are
effectively analyzed with this instrument.

Advantages

 The results are expressed in terms of particle volume from which it is simple to calculate the
diameter of the sphere of equivalent volume.
 The instrument can measure particle sizes ranging from 0.5 and 1000 µm.
 Operation is very rapid, a single count usually taking less than 30 seconds.
 Results are more reliable since a large number of particles are counted.
 The operational simplicity of the method reduces operator variables, enabling reproducible result
to be obtained.

Disadvantages

The major disadvantage is that the material must be suspended in the electrolytic liquid, but non-
aqueous electrolytes are available for water soluble materials.

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 PARTICLE SHAPE AND SURFACE AREA
The shape of particles affect the flow and packing properties of powders as well as having an
influence on the surface area. The surface area per unit weight or volume is an important
characteristics of a powder when one is undertaking surface adsorption and dissolution rate
studies

Particle Shape
As particles becomes more asymmetric, it becomes more challenging to assign a meaningful
diameter to the particles hence, as said earlier, the need for equivalent spherical diameters. It is a
sample matter to obtain the surface area or volume of a sphere because for such a particle,
3
πd
surface area = πd 2 and Volume = ; where d=diameter of particles
6
The specific surface is the surface area per unit volume or per unit weight.

METHOD FOR DETERMINING SURFACE AREA

The surface area of a powder sample can be computed from knowledge of the particle size
distribution obtain using one of the methods outlined previously.
Two methods are commonly available that permit direct calculation of surface area;

1. Adhesion method: Here the amount of a gas or liquid that is absorbed onto the sample of
powder to form a monolayer is a direct function of the surface area of the sample.
Particles with a large surface are good adsorbents for adsorption of gases and of solutes from
solution. In determining the surface of the adsorbent, the volume in cubic centimeters of gas
adsorbed per gram of adsorbent is plotted against the pressure of the gas at constant temperature
to give an isotherm.
2. The Air Permeability Method: This depends on the fact that the rate at which a gas or
liquid permeates a bed of powder is related, among other factors, to the surface area exposed to
the permanent. The principal resistance to the flow of a fluid such as air through a plug of
compacted powder is the surface area per grand of powder. So the greater is the resistance to
flow. Hence, for a given pressure drop across the plug, permeability is inversely proportional to
specific surface; measurement of the former provides a means of estimating this parameter.

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 A plug of powder can be regarded as a series of capillaries whose diameter is related to the
average particle size. The internal surface of the capillaries is a function of the surface area
particles.

BULK PROPERTIES OF POWDERS

Apart from size-distribution and surface areas of powders which are the major fundamental
properties of any collection of particles, there are other derived properties that are based on these
two fundamentals and those of particular relevance to pharmacy are;

1. Porosity
2. Packing arrangements
3. Densities of particles

1. POROSITY: The porosity or voids Ԑ, of powder is defined as the ratio of the void volume to the
bulk volume of the packing. Take for instance a powder, such as zinc oxide, is placed in a
graduated cylinder and the total volume is noted. The volume occupied is known as the bulk
volume, Vb. If the powder is nonporous, that is, has no internal pores or capillary space, the bulk
volume of the powder consist of the true volume of the solid particles plus the volume of the
space between the particles The volume of solid particles plus the volume of the spaces, known
as the void volume, V is given by the equation V=V b−V where V P= True volume of particles.
p

V b−V VP
Ԑ= =1 -
p

Vb Vb
Porosity, Ԑ is expressed in percent, Ԑ x 100

2. Packing arrangements:
Packing geometry is what causes particles in a powder bed to occupy less space by
rearrangement, when slight vibration is applied.
Powder beds of uniform sized spheres can assume two ideal packing arrangements;
a. Closest or rhombohedral packing

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b. Most open, loosest, or cubic packing

The particles in real powders are neither spherical in shape nor uniform in size. It is to be
expected that particles of ordinary powders may have any arrangement intermediate between the
two ideal packing shown above, and most powders in practice have porosities between 30% and
50%. If the particles are of greatly different sizes, however, the smaller ones may shift between
the larger ones to give porosities below the theoretical minimum of 26%. In powders containing
flocculates or aggregates, which lead to the formation of bridges and arches in the packing, the
porosity may be above the theoretical maximum of 48%. In real powder systems then, almost
any degree of porosity is possible.

3. Densities of particles:

Density is universally defined as weight per unit volume. Three types of densities can be defined.
They are;

a. True density of the material itself

b. The granule density as determined by the displacement of mercury
c. The bulk density.

a. True density, ⍴
This is the density of the actual solid material as determined by the liquid displacement method,
the true density is the weight of the body divided by the weight of the liquid (usually xylene) it
displaces. A pycnometer is used for this determination.

b. Granule density, ⍴g
This can be determined by a method similar to the liquid displacement method but here, mercury
is used.

c. Bulk density, ⍴b
This is defined as the mass of a powder divided by the bulk volume. This is obtained by
transferring a known weight of powder sample into a measuring cylinder and the volume

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 occupied (the bulk volume) noted. The bulk density is then determined by dividing the weight of
the sample in grams by the volume occupied in the cylinder in cm 3. The bulk density of a powder
depends primarily on particle –size distribution, particle shape, and the tendency of the particles
to adhere to one another.

m mass of powder
ρb = =
v volume occupied

The tapped density is found to be related to the interparticulate space. It is measured in the same
way as the bulk density only that here, the final volume occupied by the sample powder is
obtained after dropping the cylinder from a height of 2 cm or at intervals of 2 seconds onto a
hard wood surface three times (though tapped density does not actually reach a maximum until
the cylinder has been dropped or tapped some 500 times; however, the three tap method has been
found to give the most consistent results among various laboratories).

POWDER FLOW
A bulk powder is somewhat analogous to a non-Newtonian liquid which exhibits plastic flow
and sometimes dilatancy, the particles being influenced by attractive forces to varying degrees.
Powders may be free-flowing or cohesive (“sticky”). To evaluate the flowability of powders, the
following tests can be carried out;

1. ANGLE OF REPOSE, Ø:
The frictional forces in a loose powder can be measured by the angle of repose. The angle of
repose is the maximum angle possible between the surface of a pile of powder and horizontal
plane, µ. It can also be said to be the coefficient of friction, between the particles in a powder.
h
tan∅ =μ=
r

Where h = height of powder pile

d= diameter of the pile

d
r = radius of the pile =
2

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To obtain the angle of repose, the sample is poured onto a horizontal surface from a funnel of
known orifice diameter, whose tip is held 10 cm above the horizontal surface by a retort stand
and the angle of the resulting pyramid is calculated.

Angle of repose < 20˚ (Excellent flow)

Angle of repose between 20 - 30˚ (good flow)

Angle of repose between 30 - 34˚ (pass flow)

Angle of repose > 40 (poor flow)

The rougher and more irregular the surface of the particles, the higher will be the angle of
repose.

2. CARR’S COMPRESSIBILITY INDEX:

To obtain this, it is necessary to first obtain the bulk and tapped densities of the powder sample.

' tapped density−bulk density

Car r s Index(%)= x 100
tapped density

weight
Where, Bulk density=
bulk volume

weight
Tapped density =
true volume

% Compressibility range Flow description

5 – 15 excellent flow

16 – 18 good flow
19 – 21 fair flow
22 – 35 poor flow

36 – 40 very poor flow

> 40 extremely poor flow

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 3. HAUSNER RATIO:

Tapped density
Hausner Ratio=
Bulk density

Hausner Ratio was related to interparticle friction. Value < 1.25 indicates good flow and this is
seen with powders with low interparticle friction such as coarse spheres. Value > 1.5 indicates
poor flow. This is seen with more cohesive, less free-flowing powders such as flakes. Between
1.25 and 1.5, added glidant normally improves flow. Greater than 1.5, added glidant doesn’t
improve flow.

4. FLOW RATE:

The flow rate is the measurement of particle flow in grams per second.

RELEVANCE OF POWDER FLOW TO PHARMACY

1. Uniform feed from the bulk storage into punch and die or capsules depends on the powder flow.
If packing volume is constant then mass ratio is constant and this helps to maintain a uniform
tablet or capsule weight.
2. An uneven powder flow results in excess entrapped air which results in capping and lamination
of tablets.
3. Uneven powder flow increases particle’s friction with die wall, causing lubrication problems and
increase dust contamination risks during powder transfer.
4. Uneven powder flow leads to segregation in blending.

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 GRANULATION

Granulation is the act or process in which primary powder particles are made to adhere to form
larger, multiparticle entities called granules. Granulation involves the forming of bonds between
particles by compression or by using a binding agent. Granules typically have a size range
between 0.2 to 4.0 mm depending on their subsequent use. Granulation is a way of increasing the
proportion of coarser particles of a powder to improve the powder flow, prevent segregation and
to improve the characteristics of powder mix (uniform weight, uniform quantity). Granules can
be used in the production of tablets and capsules or can be used on their own as solid dosage
form. Granulation come after mixing the necessary powder additives (excipient and active
pharmaceutical ingredients).

Reasons for granulation

1. To prevent powder segregation: this occurs after mixing mainly due to difference in size
and densities of the component. Smaller particles settle at the bottom and bigger ones at
the top or vice versa. Ideally, granules will contain all the necessary ingredients in the
same volume after mixing therefore, to control segregation, particles size and density
must be controlled because the hopper is filled by volume, not by weight.
2. Granulation of a toxic material reduces hazard due to dust.
3. Materials which are slightly hygroscopic form cake when stored as powder thus,
granulation reduces caking.
4. Granules being denser than the parent compounds occupies less space (volume per unit
weight) thus easier to transport.

Methods of Granulation

The method of granulation is chosen based on the ingredient’s individual characteristics and
ability to flow, compress, eject and disintegrate.

1. Dry granulation: here, the primary powder particles are aggregated under high pressure.
Either by producing a large tablet (known as slug) in a heavy-duty tableting press (a
process called slugging) or the powder is squeezed between two rollers to produce a sheet
of material (roller compaction). In either cases, these intermediate product are broken
using a suitable milling technique to produce granular material, which is usually sieved to

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 separate the desired size fraction. The unused fine material may be reworked to avoid
waste. This dry method may be used for drugs that do not compress well after wet
granulation or those moisture sensitive.
2. Wet granulation: this involves the massing of a mix of dry primary particles using a
granulating fluid. The fluid contains a solvent which must be volatile so that it can be
removed by drying and be nontoxic. Typical liquids include water, ethanol and
isopropanol, either alone or in combination. The granulation liquid may be used alone or,
more usually as a solvent containing a dissolved adhesive (also referred to as binder or
binding agent) which is used to ensure particle adhesion once the granules is dry. The wet
mass is forced through a sieve to produce wet granules which are then dried. A
subsequent screening stage breaks agglomerates of granules and removes the fine
materials which can be recycled.

Classification of granules

Granules are classified according to particles dimension.

1. Coarse granules, which must be milled.

2. Fine granules, which must be re-granulated.
3. Optimum granules with optimum dimensions, which are ready for used.

Quality controls

1. Weight uniformity tests

2. Dissolution profile
3. Friability test

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 CAPSULES

Capsules are dosage forms in which one or more medicinal and/ or inert substances are
enclosed within a small shell generally prepared from a suitable formulation of gelatin.

In pharmacy, encapsulation refers to a range of dosage forms or techniques used to enclose

medicines in a relatively stable shell known as a capsule, allowing them to, for example, be
taken orally or be used as suppositories.

Gelatin is a translucent, colourless, brittle (when dry), flavourless substance derived by

hydrolysis of collagen, obtained from various animal raw materials (bones, skin and
connective tissues). Type A gelatin is produced by acid hydrolysis and is suitable when being
prepared from skin. Type B gelatin is produced by base hydrolysis and is suitable when being
prepared from bones.

Properties of gelatin that makes it suitable for capsule manufacture include;

1. It is non-toxic as it is used in good stuff and acceptable world-wide.

2. It is readily soluble in biological fluids at body temperature.
3. It has good film forming ability.
The components of capsule shell are;
1. Gelatin – major component
2. Plasticizers – to soften the shell
3. Colourants – a. soluble dyes – synthetic dyes

b. insoluble pigments e.g. titanium dioxide (to whiten)

4. Preservatives

Types of capsules/formulation

I. Hard Gelatin Capsules (HGC)

II. Soft Gelatin Capsules (SGC)

I. HARD GELATIN CAPSULE SHELLS:

HGC Shells are manufactured in two sections – body and a shorter cap. The two
overlap, cap fitting snuggly over the open end of the capsule body.

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 Production of shells
1. Mechanical dipping of pins or pegs of desired shape and diameter into reservoir of
melted gelatin mixture maintained at constant temperature to achieve desired fluidity.
2. Pegs are submerged to desired depth for desired period of time for proper length and
thickness of coating, slowly lifted from gelatin bath, gently dried by flow of temperature
and humidity controlled air.
3. When dry, each capsule part is trimmed mechanically to proper length, removed from
pegs and bodies and caps fitted together.
4. Control the thickness of the gelatin shell wall so body and cap can fit snuggly.
5. Pegs forming caps are bigger in diameter than those forming body.
Flow chart of HGC shell manufacture

Preparing
Dipping Spinning Drying Stripping Cutting Joining Packaging
gelatin
of pegs
mixture

During production, continuous dipping, drying, removing (trimming) and joining of caps and
bodies occurs as the peg containing plates rotate in and out of the gelatin bath.

HGC Shells are made in a range of 8 sizes, from size 000, the largest to size 5, the smallest.

Size Volume (ml)

5 0.13
4 0.20
3 0.27
2 0.37
1 0.48
0 0.67
00 0.95
000 1.36
The most popular sizes are from 0 to 4.

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Determination of capsule fill weight

Capsule fill weight = Tapped density of formulation x Capsule volume

Example:

A preliminary mixture has a fill weight of 500mg and tapped density of 0.80g/ml. what is the
shell size required?

Answer:

Capsule fill weight 0.5 g

Capsule volume= = =0.63 ml
Tapped density 0.8 g /ml

The closest shell size is 0, with 0.67 ml as volume.

However, there is need to add more diluent to capsule content so as to enhance or improve
capsule performance and proper fill. Therefore,

Volume unoccupied=0.67−0.63=0.04 ml

g
The weight of additional diluent needed=0.04 ml x 0.8 =0.032 g=32 mg
ml

Thus, to use size 0 shell, 32 mg of a diluent will need to be added to improve the capsule
performance.

NB: HGC Shells are mostly filled with powder, granules, pellets, tablets, thermosoftening
mixtures, thixotropic mixtures (solid when shearing force is absent but fluid when shear force is
applied such as shaking and rubbing) and pastes.

Materials to be filled into HGC shell should not react with gelatin (e.g. Aldehyde) or interfere
with the integrity of the shell (e.g. water).

Formulation to be incorporated into HGC shell must possess these two basic requirements;

1. be able to be accurately dosed into the capsule shell.

2. be able to release active content in a form available to patient.

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HGC Shell Filling

To fill the shell, body and cap are taken apart, body is filled with required quantity of
formulation blend before cap is replaced. Capsule filling can be carried out on an industrial scale
or on a bench scale.

A. Industrial Scale filling of HGC

Machines here vary in shapes and sizes, from semi-automatic to fully automatic, and continuous
to intermittent motion. Output ranges from 5000 – 150000 capsules per hour. The machines
generally have the same basic method of capsule filling but differ only in their powder dosing
system. Three basic methods used for dosing materials into shell are available; Auger or screw,
The Dosator, The tamping finger and dosing disc

1. The auger or screw method: this is principally used on semi-automatic machines. The empty
shells are fed into a pair of ring holders with the caps retained in one half and bodies in the other.
The bodies in their holders are passed under a powder hopper inside which is a revolving auger
or screw. The materials are transferred into the bodies by the movement of auger. The quantity of
the powder depends on the speed of revolution and design of the auger, quantity of powder in the
hopper and the time the body is under the hopper. The body is filled as completely as possible so
as to get the best uniformity of fill weight. Operation is semi-automatic because it requires
someone to transfer the capsules from one operation to the other – capsule feeding, filling and
closing.

Example is Model No 8 machine supplied by Elanco and Parke Davis, with output between
15,000 and 25,000 capsules per hour.

2. The dosator: this is used on fully automatic machine which may be continuous with output
between 30,000 – 150,000 capsules per hour or Intermittent with output of 5,000 – 60,000
capsules per hour. The dosator consist of a dosing tube inside which is a spring loaded piston.
The tube is plugged into powder bed formulation, open end first. Material rises up in the tube to
the piston to form a plug of powder, further consolidated by application of compression force to
the piston. Assembly is raised and positioned over the capsule body. The piston is lowered,

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ejecting powder plug into the capsule shell. The fill weight can be varied by adjusting the
position of the piston inside the dosing tube, or by altering the depth of the powder bed.

3. The Tamping finger and Dosing Disc: this is used on fully automatic machines having
intermittent motion. The dosing disc forms the base of a revolving powder hopper, with a series
of accurately drilled holes in it. The powder plugs are formed in these holes by sets of metal
rods; tamping fingers, which are lowered into them through the powder bed. The plug is formed
in 5 positions as each one of the finger push materials into the holes before they index onto the
next position. At the 6th position, the powder plugs are pushed out and into the capsule body.
The fill weight can be varied but the depth of the powder bed and the relative movement of the
tamping fingers, and the thickness of the dosing disc.

Example is the Hofliger Karg, with output of 6000 – 180,000 capsules per hour.

B. Bench-scale filling of HGC.

This is used for special prescription and clinical trials (also in research). The two equipment used
are Feton or Labocaps and Tevopharm Capsule fillers. They have plastic plates with pre-drilled
holes to hold 30 – 100 capsules. Empty shells are fitted into holes manually or using loading
device. The bodies are locked in their plate by a screw and the caps in their holder are removed.
The powder filled into bodies by placing on surface of plate and spreading and levelling it by
means of plastic spatula. The plate holding caps are re-positioned over the one holding bodies
and rejoined using manual pressure. Uniformity of weight depends on good powder flow
properties and pressure applied when spreading and levelling powder over bodies.

The Tevopharm CAP III is a sophisticated fill machine that uses mechanical agitation to increase
powder packing within bodies while others use vibrations.

II. SOFT GELATIN CAPSULES

These shells are prepared from gelatin mixture containing glycerin or a polyhydric alcohol such
as sorbitol (for elasticity). The shapes can be oblong, elliptical or spherical or round. The shells
contains liquids, suspension, pasty materials or dry powders. SGCs are prepared, filled and

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sealed in a continuous operation using specialized equipment. The empty shell may be prepared
and hermetically sealed (to prevent the walls from collapsing and adhering to one another) for
filling at a later time (not usual production method).

SGC is useful when it is desirable to seal the medication within the capsule e.g. for liquid drugs
or materials susceptible to deterioration in presence of air. Also for easy swallowing, better
portability of liquid medication, accuracy and uniformity of dosage, improves physiological
availability of drug being in solution form.

Preparation of SGCs

There are two methods of preparation. They are;

1. Plate Process:

Here, a warm sheet of gelatin (Plain or coloured) is placed on bottom plate of the mould. The
liquid medication is evenly poured on it. A second sheet of gelatin is carefully laid in place on
top. The top plate of mould is put in place and pressure is applied to the entire mould to form, fill
and seal the capsule simultaneously. Capsules are removed and washed with suitable solvent and
dried.

2. Rotary Process:

Here, liquid gelatin flows from overhead tank to form 2 continuous ribbons by rotary die
machine. The two sheets are brought together between twin rotating dies. Metered fill material is
injected between the ribbons precisely at the moment the dies form pockets of the gelatin
ribbons. The pockets of fill-containing gelatin are then sealed by pressure and heat. The capsules
are severed into individual capsules by pressure and heat.

MICROENCAPSULATION

This is a process by which solids, liquids or even gases may be enclosed in microscopic particles
by formation of thin coatings of wall material around the substance in order to reduce dosing
frequency and prevent the degradation of pharmaceuticals. In a relatively simple form, a
microcapsule is a small sphere with a uniform wall around it. The material inside the

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microcapsule is a small sphere with a uniform wall around it. The material inside the
microcapsule is referred to as the core, internal phase or fill, whereas the wall is sometimes
called a shell, coating or membrane. Some materials like lipids and polymers, such as alginate,
may be used as a mixture to trap the material of interest inside. Most microcapsules have pores
with diameters between a few micrometers and a few millimeters. Microspheres are
characteristically free flowing powders with proteins or synthetic polymers that are
biodegradable in nature.

APPLICATIONS OF MICROENCAPSULATION

This technology has been used widely for the design of sustained release and controlled release
dosage forms.

1. To mask the bitter taste of drugs like Nitrofurantoin.

2. To reduce gastric and other G.I. tract irritations.

3. A liquid can be converted to a pseudo-solid for easy handling and storage. Example,
Eprazinone.

4. Hygroscopic properties of core materials may be reduced by microencapsulation. E.g. Sodium

chloride.

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5. Carbon tetrachlorides and a number of other substances have been microencapsulated to
reduce their odour and volatility.

6. Microencapsulation has been employed to provide protection to the core materials against
atmospheric effects. Example, Vit. A. palmitate.

7. Separation of incompatible substance has been achieved by encapsulation.

8. To target the release of drugs.

9. To facilitate accurate delivery of small quantities of potent drugs.

10. To enhance safety of handling toxic materials.

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