

Dr. Kevin C. Garala

ATMIYA INSTITTUE OF PHARMACY, RAJKOT
Capsules

1. Introduction
 The word capsule is derived from the Latin capsula, meaning a small box.
 Capsules are solid dosage forms containing drug and usually appropriate filler(s),
enclosed in a hard or soft gelatin shell.
 Mothes and Dublanc were first got patent for one piece capsule in 1834.
 The two piece capsule was invented by James Merdock in 1848.
1.1. Advantages of Capsules
 Capsules mask the taste and odour of unpleasant drugs and can be easily
administered.
 They are slippery when moist and hence easy to swallow with a draught of water.
 They can be made to alter the release rate of the drug.
 As compared to tablets less adjuncts are required.
 They allow powders to be dispensed in an uncompressed form, thus allowing for
quicker dissolution and absorption of the drug following oral dosing (as compared
with tablets).
 The shells are physiologically inert and easily and quickly digested in the
gastrointestinal tract.
 They are easy to handle and carry.
 The shells can be opacified (with titanium dioxide) or coloured, to give protection
from light.
1.2. Disadvantages of Capsules
 The drugs which are hygroscopic in nature, absorb water from the capsule shell
making it brittle and hence are not suitable for filling into capsules.
 Not used for highly efflorescent or deliquescent material because efflorescent
material may cause the capsule to soften while deliquescent material may dry the
shell.
 The concentrated solutions which require previous dilution are unsuitable for
capsules because if administered as such lead to irritation of stomach.
 They are subject to the effects of relative humidity and to microbial contamination.
 More expensive (commercially).
 Bulk dosage cannot be dispensed in capsule.
 Not used for extremely soluble material like KCl, KBr, NH4Cl because sudden release
of such substances may cause irritation in the stomach.
1.3. Capsule Types
Capsules are of two types
 Hard gelatin capsules (HGC)
 Soft gelatin capsules (SGC)

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2. Hard gelatin capsules (HGC)

 Hard gelatin capsule is also referred as “dry filled capsule” (D.F.C.) as their shell is
hard and consist of two sections used for filling dry materials in body capsule.
 Capsules are solid dosage form in which one or more medicaments are enclosed in a
water- soluble, biodegradable shell made up of gelatin.

 The majority of capsule products are made of hard gelatin capsules.

 Hard gelatin capsules are made of two shells: the capsule body and a shorter cap.
 The cap fits snugly over the open end of the capsule body.
 The basic hard gelatin capsule shells are made from mixtures of gelatin, sugar, and
water.
 They are clear, colorless, and essentially tasteless.
2.1. Capsule Size
 For human use, empty capsules ranging in size from 000 the largest to 5 the smallest.
Generally, hard gelatin capsule are used to encapsulate between 65 mg to 1 gram.
 To accommodate special needs some intermediate sizes are produced, termed
'elongated sizes', that typically have an extra 10% of fill volume over the standard
sizes, e.g. for 500 mg doses of antibiotics elongated size 0 capsules are commonly
used.
 For Powder:
Fill weight = Body volume X Tapped bulk density
 For Liquids:
Fill weight = Body volume X Specific Gravity X 0.8
Typical Fill Weights
Capsule Size Size in mm Volume in mL
(mg)*
000 26.3 1.37 960
00 23.7 0.95 665
0 21.8 0.68 475
1 19.2 0.50 350
2 18.3 0.37 260
3 15.3 0.30 210
4 14.7 0.21 145
5 11.9 0.15 90
* Powder Density = 0.70

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2.2. Capsule Shape

 Patient compliance with medication regimens may be influenced by the size and
shape of a tablet or capsule.
 The standard shape of capsules is traditional, symmetrical bullet shape.

 Narrow oblong shape with no sharp corners which reduced perception of getting
stuck in esophagus.

2.3. Raw Materials

 The raw materials used in the manufacture of both types of capsule are similar.
 Both contain gelatin, water, colourants and optional materials such as process aids
and preservatives; in addition, soft capsules contain various plasticizers.
 Gelatin
 Colourants
 Process aids
2.3.1. Gelatin
 Gelatin is the major component of the capsule and has been the material from which
they have traditionally been made.
Source of Gelatin
 Gelatin is a substance of natural origin that does not occur as such in nature.
 Gelatin is heterogeneous product derived by hydrolytic extraction of animal's
collagen, which is the main protein constituent of connective tissues.
 The sources of gelatins including animal bones, hide portions and frozen pork skin.
Gelatin are of two types: TYPE A and TYPE B
TYPE A
 Derived from acid treated precursor that exhibits an isoelectric point at pH-9.
 It is manufactured mainly from pork skin.
 The acid process takes about 7-10 days and is used mainly for animal skins, because
they require less pretreatment than do bones.
(The isoelectric point, is the pH at which a particular molecule carries no net electrical
charge.)
TYPE B
 Derived from alkali treated precursor that exhibits an isoelectric point at pH-4.7.
 It is manufactured mainly from animal bones.
 The basic process takes about 10 times as long and is used mainly for bovine bones.

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 The bones must first be decalcified by washing in acid to give a soft sponge-like
material, called ossein; calcium phosphates are produced as a byproduct.
 The ossein is then soaked in lime pits for several weeks.
 Extraction of Gelatin

The reason for this is that gelatin possesses five basic properties:
1. It is non-toxic, widely used in foodstuffs, and acceptable for use worldwide.
2. It is readily soluble in biological fluids at body temperature.
3. It is a good film-forming material, producing a strong flexible film. The wall
thickness of a hard gelatin capsule is about 100 μm.
4. Solutions of high concentration, 40% w/v, are mobile at 50°C. Other biological
polymers, such as agar, are not.
5. A solution in water or in a water-plasticizer blend undergoes a reversible change
from a sol to a gel at temperatures only a few degrees above ambient.
This is in contrast to other films formed on dosage forms, where either volatile
solvents or large quantities of heat are required to cause this change of state, e.g.
tablet film coating.
 The properties of gelatin that are most important to the capsule manufacturers are
the Bloom strength and the viscosity.
 The Bloom strength is a measure of gel rigidity. It is determined by preparing a
standard gel (6.66% w/v) and maturing it at 10°C. It is defined as the load in grams
required to push a standard plunger 4 mm into the gel.

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Capsules

 The gelatin used in hard capsule manufacture is of a higher bloom strength (200-250
g) than that used for soft capsules (150 g) because a more rigid film is required for
the manufacturing process.

2.3.2. Colourants
 The colourants that can be used are of two types:
 water-soluble dyes
 insoluble pigments
 To make a range of colours dyes and pigments are mixed together as solutions or
suspensions.
 The dyes used are mostly synthetic in origin and can be subdivided in the azo dyes -
those that have an -N=N- linkage - and the non-azo dyes, which come from a variety
of chemical classes.
 Most dyes used currently are of the non-azo class, and the three most widely used are
erythrosine (El27), indigo carmine (El32) and quinoline yellow (E104).
 Two types of pigment are used: iron oxides (El72), black, red and yellow, and titanium
dioxide (El71), which is white and used to make the capsule opaque.

2.3.3. Process aids

 The USNF describes the use of gelatin containing not more than 0.15% w/w of sodium
lauryl sulphate for use in hard gelatin capsule manufacture.
 This functions as a wetting agent, to ensure that the lubricated metal moulds are
uniformly covered when dipped into the gelatin solution.
 Preservatives were formerly added to hard capsules as an in-process aid in order to
prevent microbiological contamination during manufacture.
 In the finished capsules the moisture levels, 13.0-16.0% w/v, are such that they will
not support bacterial growth because the moisture is too strongly bonded to the
gelatin molecule.

2.4. Manufacturing of hard gelatin capsule (HGC) shell

 The process in use today is the same as that described in the original patent of 1846.
 Metal moulds at room temperature are dipped into a hot gelatin solution which gels
to form a film.
 This is dried, cut to length, removed from the moulds and the two parts are joined
together.
2.4.1 Preparation of Gelatin solution
 The first step in the process is the preparation of the raw materials.
 A concentrated solution of gelatin, 35-40%, is prepared using demineralized hot
water, 60-70°C, in jacketed pressure vessels.

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 This is stirred until the gelatin has dissolved and then a vacuum is applied to remove
any entrapped air bubbles.
 Aliquots of this solution are then dispensed into suitable containers and the required
amounts of dye solutions and pigment suspensions added.
 The viscosity is measured and adjusted to a target value by the addition of hot water.
 The viscosity is the parameter used to control the thickness of the capsule shells
during production: the higher the viscosity the thicker the shell wall produced.
 The prepared mixes are then transferred to a heated holding hopper on the
manufacturing machine.

2.4.2. Manufacturing machines

 The manufacturing machines are approximately 10 m long, 2 m wide and 3 m high.
 They consist of two parts, which are mirror images of each other: on one half the
capsule cap is made and on the other the capsule body.
 The machines are also divided into two levels, an upper and a lower.
 The moulds, commonly referred to as 'pins', are made of stainless steel and are
mounted in sets on metal strips, called 'bars'.
 There are approximately 40 000 mould pins per machine.
 The machines are housed in large rooms where the humidity and temperature are
closely controlled.
 The machines are normally operated on a 24-hour basis 7 days per week, stopping
only for maintenance.
 The output per machine is about 1 million capsules per day, depending upon the size:
the smaller the capsule the higher the output.
Dip pan
 At the front end of the machine is a hopper, called a 'dip pan' or 'pot'.
 This holds a fixed quantity of gelatin at a constant temperature, between 45° and
55°C.
 The level of solution is maintained automatically by a feed from the holding
hopper.

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Capsules

2.4.3. Manufacturing process

Steps involved in making empty gelatin capsules

Dipping Joining Polishing

Cutting
Spinning Sorting
(Trimming)

Drying Stripping Printing

i) Dipping
 Capsules are formed by dipping sets of moulds, which are at room temperature, 22°C,
into this solution.
 A film is formed on the surface of each mould by gelling.
 The moulds are slowly withdrawn from the solution and then rotated during their
transfer to the upper level of the machine, in order to form a film of uniform thickness.

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Capsules

ii) Spinning
 The pins are rotated to distribute the gelatin over the pins uniformly and to avoid the
formation of a bead at the capsule ends.

iii) Drying
 The gelatin is dried by a blast of cool air to form a hard shells.
 Groups of 'pin bars' are then passed through a series of drying kilns, in which large
volumes of controlled humidity air are blown over them.

iv) Stripping
 A series of bronze jaws strip the cap and body portions of the capsules from the pins.
 The mould pins are then cleaned and lubricated for the start of the next cycle.
v) Cutting (Trimming)
 The stripped cap and body portions are trimmed to the required length by stationary
knives.

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vi) Joining
 After trimming to the right length, the cap and body portion are joined and ejected
from the machine.
 The assembled capsules are not fully closed at this stage and are in a 'pre-locked'
position, which prevents them falling apart before they reach the filling machine.

vii) Polishing
 Pan Polishing: Acela-cota pan is used to dust and polish.
 Cloth Dusting: Capsule are rubbed with cloth.
 Brushing: Capsule are feed under soft rotating brush.
viii) Sorting
 The moisture content of the capsule as they are ejected from the machine will be in
the range of15-18% w/w, additional adjustment of moisture content towards the final
desired specification will occur during the sorting step.
 During the sorting, the capsule passing on a lighted moving conveyer are examined
visually by inspector, any defective capsule spotted are thus manually removed.
 The capsules now pass through a series of sorting and checking processes, which can
be either manual, mechanical or electronic, to remove as many defective ones as
possible.
 The quality levels are checked through the process using standard statistical sampling
plans based on the Military Inspection Standards.
 Defects are generally classified according to their nature and potential to cause
problems in use.
 The most serious of these are that could cause stoppage of a filling machine, such as
imperfect cuts, dented capsule or those with holes.
 Other defects may cause problems on use, such as capsule with splits, long bodies or
cracks inside.
ix) Printing
 In general, capsules are printed before filling.
 Empty capsule can be handled faster than filled capsule and should there be any loss
or damage to the capsules during printing, no active ingredient would be involved.

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 Generally, printing is done on offset rotary process, using an edible ink based on
shellac, having through put capacities as high as there-generator machine capsule per
hour.
 The information printed is typically either the product name or strength, a company
name or logo, or an identification code.

2.5. Empty capsule properties

 Empty capsules contain a significant amount of water that acts as a plasticizer for the
gelatin film and is essential for their function.
 The standard moisture content specification for hard gelatin capsules is between
13.0% and 16.0% w/w.
 This value can vary depending upon the conditions to which they are exposed: at low
humidities, they will lose moisture and become brittle, and at high humidities, they
will gain moisture and soften.
 The moisture content can be maintained within the correct specification by storing
them in sealed containers at an even temperature.
 Capsules are readily soluble in water at 37°C. When the temperature falls below this
their rate of solubility decreases.
 At below about 30°C they are insoluble and simply absorb water, swell and distort.
 This is an important factor to take into account during disintegration and dissolution
testing.
 Because of this most Pharmacopoeia have set a limit of 37 ° ± 1°C for the media for
carrying out these tests.
 Capsules made from HPMC have a different solubility profile, being soluble at
temperatures as low as 10°C.

2.6. Capsule Shell Filling

 Hard gelatin capsules can be filled with a large variety of materials of different
physicochemical properties.
 Limitations in properties of materials for filling into capsules
 Must not react with gelatin
 Must not contain a high level of 'free' moisture
 The volume of the unit dose must not exceed the sizes of capsule available
 Gelatin is a relatively inert material. The substances to be avoided are those which are
known to react with it, e.g. formaldehyde, which causes a crosslinking reaction that
makes the capsule insoluble, or those that interfere with the integrity of the shell, e.g.
substances containing free water, which can be absorbed by the gelatin causing it to
soften and distort.

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2.6.1. Types of material for filling into hard gelatin capsules

1. Dry solids

Powders

Pellets

Granules

Tablets

Capsules

2. Semisolids (Thermosoftening mixtures, Thixotropic mixtures, Pastes)

3. Liquids (Non-aqueous liquids)

The reason that such a range of materials can be handled is the nature of the capsule
filling process.

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2.6.2. Capsule Filling Machines

 The basic operations for capsules filling is carried out whether capsules are being
filled on the bench for extemporaneous dispensing or on high-speed automatic
machines for industrial products.
 The major difference between the many methods available is the way in which the
dose of material is measured into the capsule body.

[Link]. Powder Filling

Power filling machines are divided on the basis of quantity of capsules to be filed:
 Bench-scale filling
 Industrial-scale filling
i) Bench-scale filling
 There is a requirement for filling small quantities of capsules, from 50 to 10000, in
community pharmacy, in hospital pharmacy, or in industry for special prescriptions
or trials.
 There are several simple pieces of equipment available for doing this, e.g. the 'Feton‘
from Belgium or the 'Labocaps' from Denmark.
Hand Operated Capsule Filling Machine
 It consist of a bed having 200-300 hole, a loading tray having 200-300 holes, a powder
tray, a pin plate having 200-300 pins, a sealing plate having a rubber top, a lever, a
cam handle.
 Empty capsules are fed into the holes in the loading tray, either manually or with a
simple loading device and it is placed over the bed.
 The cam handle is operated to separate the capsule caps from their bodies.
 The pin plate is lowered and the filled powder is pressed by moving the pin
downwards.
 The powder tray is placed in a proper position and filled with an accurate quantity of
powder with scraper.
 The excess of the powder is collected on the platform of the powder tray.
 After pressing the pin plate is raised and the remaining powder is filled into the bodies
of the capsules.
 The powdered tray is removed after its complete filling.
 The cap holding tray is again placed in position.
 The plate with the rubber top is lowered and the lever is operated to lock the caps and
bodies.
 The loading tray is then removed and filled capsules are collected.
 With a 200 hole machine, about 5000 capsules can be filled in one hour, whereas in a
machine having 300 holes, about 7500 capsules can be filled in one hour.

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ii) Industrial-scale filling

 The machines for the industrial-scale filling of hard gelatin capsules come in great
variety of shapes and sizes, varying from semi - to fully automatic and ranging in
output from 5000 to 15,000 per hour.
 Automatic machines can be either continuous in motion, like a rotary tablet press, or
intermittent, where the machine stops to perform a function and then indexes round
to the next position to repeat the operation on a further set of capsules.
The dosing systems can be divided into two groups:
 Dependent dosing systems that use the capsule body directly to measure the powder.
 Uniformity of fill weight can only be achieved if the capsule is filled completely.
 Independent dosing systems where the powder is measured independently of the
body in a special measuring device.
 Weight uniformity is not dependent on filling the body completely.
 With this system the capsule can be part filled.
a) Dependent dosing systems – Auger
 Empty capsules are fed into a pair of ring holders.
 The caps being retained in one half and the bodies in the other.
 The body holder is placed on a variable-speed revolving turntable; the powder
hopper is pulled over the top of this plate, which revolves underneath it.
 In the hopper a revolving auger forces powder down into the capsule bodies.
 The weight of powder filled into the body is dependent mainly upon the time the
body is underneath the hopper during the revolution of the plate holder.
 These machines are semiautomatic in operation, requiring an operator to transfer
the capsule holders from one operation to the next.

 The contact parts of these machines were originally made from cast iron, but are now
made from stainless steel to comply with GMP requirements.

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 The machines are manufactured by many different makers, but are all based on the
original Colton Model No. 8 design.
 Their output varies between 15,000 and 25,000 per hour and is dependent upon the
skill of the operator.
b) Independent dosing systems
 Most industrial machines in use in Europe and the USA are fully automatic and use
dosing mechanisms that form a 'plug’ of powder.
 This is a soft compact formed at low compression forces - between 10 and 100 N -
which are significantly less than those used in tabletting.
 The reason the plug is soft is because it is not the final dosage form, unlike the tablet,
as the material will be contained inside a capsule shell.
 There are two types of plug-forming machine: those that use a 'dosator’ system and
those that use a 'tamping finger and dosing disc' system.
Dosators
 This consists of a dosing tube inside which there is a movable spring-loaded piston,
thus forming a variable-volume chamber in the bottom of the cylinder.
 The dosator consists of a moveable piston inserted in a cylindrical tube.

Stages of operation:
 A – Initial piston height setting;
 B – Modest plug compression as dosator dips into powder bed;
 C – Active piston compression of the plug;
 D – Plug transport to ejection station;
 E – Ejection of plug into capsule body.
 The position of the piston is preset to a height that defines a volume that would
contain the desired dose of the formulation (A).

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 During the filling process, the open end of the dosator is first pushed down into a
powder bed the depth of which has been pre-set and is maintained at that level by
agitators and scrapers.
 Powder thus enters the open end of the dosing tube where it is slightly compressed
against the piston (B).
 Before the dosator is lifted from the powder bed, the piston may be used to deliver a
tamping blow that further compresses the forming plug (C).
 The dosator bearing the plug is then lifted from the powder bed (D) and positioned
over an empty capsule body where the piston is thrust downward to eject the plug
(E).
 In certain machines, the empty capsule body is moved into position under the raised
dosator to receive the ejected plug.
 For a given size of tooling, the fill weight attained for a given formulation is
determined primarily by the initial height of the piston in the dosing tube, and
secondarily by the height of the powder bed.
 This system is probably the most widely used in the world.
Examples of machines that use this system are:
1. Intermittent motion: Zanasi (IMA), Pedini, Macophar and Bonapace.
 Their outputs range from 5,000 to 60,000 per hour.
2. Continuous motion: MG2, Matic (IMA).
 Their outputs range from 30,000 to 1,50,000 per hour.
Tamping finger and dosing disc
 The dosing disc forms the bottom of a revolving powder hopper.
 This disc has in it a series of sets of accurately drilled holes in which powder plugs are
formed by several sets of tamping fingers – stainless steel rods that are lowered into
them through the bed of powder.

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 At each position the fingers push material into the holes, building up a plug before
they index on to the next position.
 At the last position the finger pushes the plug through the disc into a capsule body.
 The powder fill weight can be varied by the amount of insertion of the fingers into the
disc, by changing the thickness of the dosing disc, and by adjusting the amount of
powder in the hopper.
 The machines that use this system are all intermittent in motion. Examples are the
Hofliger and Karg, manufactured by Robert Bosch, and the Shionogi Qualicaps F-80.
[Link]. Pellet filling
 Preparations formulated to give modified-release patterns are often produced as
granules or coated pellets.
 They are filled on an industrial scale using machines adapted from powder use.
 All have a dosing system based on a chamber with a volume that can easily be
changed.
 Pellets are not compressed in the process and may have to be held inside the
measuring devices by mechanical means, e.g. either by inverting the dosator or by
applying a suction to the dosing tube.
 In calculating the weight of particles that can be filled into a capsule it is necessary to
make an allowance for their size.
 Unlike powders, which have a much smaller size, they cannot fill all the available
space within the capsule because of packing restrictions.
 The degree of this effect will be greater the smaller the capsule size and the larger the
particle diameter.
[Link]. Tablet filling
 Tablets are placed in hoppers and allowed to fall down tubes, at the bottom of which
is a gate device that will allow a set number of tablets to pass.
 These fall by gravity into the capsule bodies as they pass underneath the hopper.
 Most machines have a mechanical probe that is inserted into the capsule to check that
the correct number of tablets has been transferred.
 Tablets for capsule filling are normally film coated to prevent dust, and are sized so
that they can fall freely into the capsule body.
[Link]. Semisolid and liquid filling
 Liquids can easily be dosed into capsules using volumetric pumps.
 The problem after filling is to stop leakage from the closed capsule.
 This can be done in one of two ways, either by formulation or by sealing of the capsule.
 Semisolid mixtures are formulations that are solid at ambient temperatures and can
be liquefied for filling by either heating thermo-softening mixtures, or by stirring
thixotropic mixtures.

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 After filling they cool and solidify, or revert to their resting state in the capsule to form
a solid plug.
 Both types of formulations are filled as liquids using volumetric pumps.
 These formulation are similar to those that are filled into soft gelatin capsules, but
differ in one important respect: they can have melting points higher than 35°C, which
is the maximum for soft gelatin capsules because this is the temperature used by the
sealing rollers during their manufacture
 Non-aqueous liquids, which are mobile at ambient temperatures, require the capsules
to be sealed after filling.
 The industrially accepted method for this is to seal the cap and body together by
applying a gelatin solution around the center of the capsule after it has been filled.
 When this has been dried it forms a hermetic seal that prevents liquid leakage,
contains odors inside the shell and significant reduces oxygen permeation into the
contents, protecting them from oxidation.
 An example of such equipment is the Shionogi Qualicaps Hicapseal machines, which
have outputs ranging from 10000 to 100000 per hour.

2.6.3. Examples of Capsule Filling Machine

 Lilly and Parke-Davis: Lilly capsule filling machine, Lilly ROTOFIL capsule filling
machine.
 Farmatic: Farmatic Model 2000/15, 2000/30 and 2000/60 capsule filling machine.
 Hofliger and Karg: Hofliger and Karg model GKF-303, GKF-602, GKF-1500 and GKF-
2500 capsule filling machine.
 Macofar: MT-12, MT-13/1 and MT-13/2 capsule filling machine.
 mG2: Model G36/4, G36/2, G36, G37N and G38 capsule filling machine.
 Osaka: Osaka Model 180 capsule filling machine.
 Perry: Perry Model CF ACCOFIL capsule filling machine.
 Zanasi: Zanasi Model LZ-64 and AZ-20 capsule filling machine.

2.6.4. Filling Machines Class

 Capsule machine filling may be classified as either intermittent or continuous motion
machines.
Intermittent machine
 It exhibit an interrupted-filing sequence as must stop at various station to execute the
basic operation described earlier.
Continuous motion machine
 Executes these functions in a continuous cycle.
 The limitation of the need to decelerate and accelerate from one station to the next
make greater machine speed possible with continuous motion machine.

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Model Dosing Principal Motion Capacity

Lilly/park Davis Tamping/ I 200000/daily
dosing
Elililh Disk Rotarty I 1200/min
rectification
Farmatic Dosator-type C 160000/hr
Hofliger and karg Tamping/
GKF-303 Dosing Disk I 24000
GKF-602 I 48000
GKF-1500 I 180000
GKF-2500
Macofar
MT-12 Dosator Type C 5000
MT-B/1 C 35000/hr
MT-B/2 C 10,000
MG2 Tamping/
Future dosator C 36000
G37W C 60000
G10C C 1000000
OSAKA - 70000-
R-180 C 165000/hr
Perry - - -
CF ACCOFIL
Zanasi
Z-5000 Tamping/ C 70000/hr
Z-5000-RI dosator
Zunsi-6 I 6000
Zunsi-40 Tamping/ I 40000
Matic-140 dosator C 120000

2.6.5. Difficulties in Capsule Filling

 Deliquescent / Hygroscopic powders
 Remedy: Adsorbent (magnesium carbonate, heavy/light magnesium oxide)
 Eutectics mixture
 Remedy: Use of adsorbent (magnesium carbonate, kaolin)
 Small dose of drug
 Remedy: Addition of inert powder
 Incompatibilities of materials
 Remedy: Use of two capsules – small in large
 Lack of adhesiveness difficult to fill by punch method
 Remedy: moistened with alcohol, granules reduced to powders

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2.7. Formulation for Filling

 All formulations for filling into capsules have to meet the same basic requirements:
 They must be capable of being filled uniformly to give a stable product.
 They must release their active contents in a form that is available for absorption
by the patient.
 They must comply with the requirements of the Pharmacopoeias and regulatory
authorities, e.g. dissolution tests.
 In order to formulate rationally it is necessary to take into account the mechanics of
the filling machines and how each type of product is handled.

2.7.1 Powder formulation

 The majority of products for filling into capsules are formulated as powders.
 These are typically mixtures of the active ingredient together with a combination of
different types of excipients.
Types of excipient used in powder-filled capsules
Diluents, which give plug-forming properties
Lubricants, which reduce powder to metal adhesion
Glidants, which improve powder flow
Wetting agents, which improve water penetration
Disintegrants, which produce disruption of the powder Mass
Stabilizers, which improve product stability
 The ones selected depend upon several factors:
 The properties of the active drug
 Its dose, solubility, particle size and shape
 The size of capsule to be used.
 The latter factor defines the free space inside the capsule that is available to the
formulator.
 The easier active compounds to formulate are low-dose potent ones, which in the
final formulation occupy only a small percentage of the total volume - <20% - and
so the properties of the mixture will be governed by the excipients chosen.
 Whereas those compounds with a high unit dose, e.g. 500 mg of antntibiotic, leave
little free space within the capsule and excipients must be chosen that exert their
effect at low concentrations, <5%, and the properties of the mixture will be
governed by that of the active ingredient.
2.7.2 Formulation for filling properties
 There are three main factors in powder formulation:
 Good flow, (using free-flowing diluent and glidant)
 No adhesion (using lubricant)
 Cohesion (plug-forming diluent).

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 The factor that contributes most to the uniform filling of capsules is good powder flow.
 This is because the powder bed, from which the dose is measured, needs to be
homogeneous and packed reproducibly in order to achieve uniform fill weights.
 Packing is assisted by mechanical devices on the filling machines.
 Low-dose actives can be made to flow well by mixing them with free-flowing diluents,
e.g. lactose.
 The diluent is chosen also for its plug forming properties: the most frequently used
ones are lactose, maize starch and microcrystalline cellulose.
 When space is limited then either glidants, which are materials that reduce
interparticulate friction, such as colloidal anhydrous silica, or lubricants, which are
materials that reduce powder to metal adhesion, e.g. magnesium stearate, are added,
enabling the dosing devices to function efficiently.
 Both of these types of material exert their effect by coating the surfaces of the other
ingredients, and thus the mixing of these into the bulk powder has a significant effect
on their functioning.
 Some excipients, such as lubricants and glidants, are added to formulations to
improve their filling properties, and these can sometimes have an effect on release.
 The important thing to avoid in formulations are materials that tend to make the mass
more hydrophobic. The most commonly used lubricant for both encapsulation and
tabletting is magnesium stearate.
 The increase in the use of dissolution testing for control purposes has led to products
being formulated for this factor.
 This has been achieved in two ways: by the addition of either surfactants or
disintegrants.
 The addition of a wetting agent, sodium lauryl sulphate, has been studied by several
workers.
 For poorly soluble drugs the use of a soluble diluent together with 1% sodium lauryl
sulphate gave the best results.
 Disintegrants were formerly never added to capsule formulations because starch,
which was the most widely used tabletting disintegrant, does not function well in this
context.
 This is because the powder plug is much less compacted than a tablet and the starch
swells insufficiently to disrupt it.
 In more recent times 'superdisintegrants' have been introduced that either swell many
fold on absorbing water, e.g. sodium starch glycolate and croscarmellose, or that act
as wicks, attracting water into the plug, e.g. crospovidone.
 These actions are sufficient to help break up the capsule plug.
 The choice of disintegrant is dependent upon the solubility of the active and the
diluent, which governs whether either swelling or wicking is the main disruptive force
required.

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2.7.3. Formulation for release of active ingredients

 The first stage in active ingredient release is disintegration of the capsule shell.
 When capsules are placed in a suitable liquid at body temperature, (37°C) the gelatin
starts to dissolve and within 1 minute the shell will split, usually at the ends.
 With a properly formulated product the contents will start to empty out before all the
gelatin has dissolved.
 The official tests for disintegration and dissolution were originally designed for
tablets.
 Capsules have very different physical properties, and after the contents have emptied
out the gelatin pieces remaining will adhere strongly to metal surfaces and may
confuse the end-point of the test.
 The literature shows that the rate-controlling step in capsule disintegration and
product release is the formulation of the contents, which ideally should be hydrophilic
and dispersible.
 It has been shown that the particle size influences the rate of absorption for several
compounds.
 The diluent used should be chosen in relationship to the solubility of the active.
 If a soluble diluent such as lactose is added to a poorly or insoluble compound it will
make the powder mass more hydrophilic, enabling it to break up more readily on
capsule shell disintegration.
 The converse is also true: actives that are readily soluble are best mixed with
insoluble diluents such as starch or microcrystalline cellulose, because they help the
powder mass to break up without interfering with their solubility in the medium.
 The main factors in powder formulation release are:
 Active ingredient, optimum particle size
 Hydrophilic mass, relating solubility of active to excipients
 Dissolution aids, wetting agent, superdisintegrant
 Optimum formulation for filling and release.

2.8. Evaluation of Capsules

 Quality control should be carried out during all stages of manufacturing operation
which is the primary requirement of good manufacturing practices.
 Whether capsules are produced on a small scale or large scale all of them are required
to pass through certain tests i.e., quality control tests to test the quality of the finished
product.
 Quality control of capsules should be carried out at four stage:
 Raw materials
 Empty capsules shell
 Fill capsules
 Finished (Packaged) capsules

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2.8.1. Evaluation of Raw materials

The gelatin of the capsule shells should be assayed for
 Physical properties like Bloom strength, Viscosity, Moisture content, Clarity
 Chemical tests like pH, limits for heavy metals like Sulphur dioxide, ash content
 Microbial properties like Total Aerobic Count, E. coli, Salmonella
i) Bloom Strength
 The gelatin of the capsule shells should be evaluated for varies physical properties
like bloom strength , viscosity etc..
 Method for determination of Bloom Strength is follows:
 Step 1) Prepare aqueous solution (6.67%) of gelation and transfer in standard
bloom bottles.
 Step 2) The mixture is then stirred and keep it for 3 hours at room temperature.
 Step 3) Bottles are placed in a 65 °C bath for 20 minutes.
 Step 4) Allow the bloom jars to cool for 15 minutes up to room temperature.
 Step 5) They are then conditioned for 16 hours in water bath at 100 °C.
 Step 6) The bloom jar is centered with the probe just above the sample surface.
 Step 7) The probe penetrates the gelatin to a target depth of 4 mm at a speed of 0.5
mm/s, and then retracts.
 Report: The peak force is noted as the gel (bloom) strength in grams bloom.
 It is between 200-250 gm.

ii) Viscosity
 The viscosity of a 6.67% gelatin solution is determined at 60ºC by measuring the flow
time of 100 mL of the solution through a Ostwald or standard pipette.
 It is a measure of the molecular chain length.
 Standard used: 2.8-4.5 mPa s.
iii) Moisture Content
 A weighed sample of gelatin is maintained for 16 to 18 hours at 105 ± 2ºC and is then
reweighed. The moisture content is defined as the percentage loss in weight of the
sample.

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iv) Clarity
 The clarity of a 6.67% gelatin solution is determined at 45ºC by measuring the percent
transmittance through a 1 cm cuvette at 640 nm.
v) pH
 The pH of a 1.5 % gelatin solution is determined by potentiometry at a temperature
of 35 ± 1°C using a pH meter.
 pH 4.5 -6.5
vi) Ash Content
 Gelatin is ashed in a crucible at 550ºC using a muffle furnace.
 The residue is determined by differential weighing and the result expressed as a
weight percentage of the original sample.
vii) Sulfur Dioxide
 Sulfur dioxide content can be determined using the Monier-Williams test method.
viii) Total Aerobic Count
 Use of plate-count agar media to enumerate in 48 hours at 35ºC the level of
microorganisms, including mesophilic bacteria, yeasts and moulds, by counting the
colony forming units (CFU) per 1 g of gelatin.
ix) E. coli
 The USP Method is a conventional cultural method that is applicable to the detection
of viable E. coli in raw materials, finished products and environmental swabs.
 The entire detection testing protocol may take up to 3 days to complete. The FDA-
BAM method is also applicable.
x) Salmonella
 The Association of Official Analytical Chemists (AOAC) / Bacteriological Analytical
Manual (BAM) Method is a conventional cultural method that is applicable to the
detection of viable Salmonella in raw materials, finished products and environmental
swabs.
 The entire detection testing protocol may take up to 5 days to complete.
2.8.2. Evaluation of Empty Capsule Shell
Empty Capsule Shells should be evaluated for
 Shell integrity Tests
 Purity
 Diameter
 Colour
 Loss on drying
 Sorting of defects
 Printing inspection
 Final inspection
i) Shell integrity Tests
 The capsule manufacturer routinely conducts accelerated stability study on all new
capsule products as an integral part of the product development programmed.

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 These tests known as “shell integrity tests” are used for determination of the effect of
capsule content on the gelatin shell, but not the stability of active ingredients of the
capsule.
 The result of these tests may indicate the reformulation of the capsule content or the
capsule shell and also assist in the selection proper retail package.
 For conducting these tests, sample of the capsules are exposed to the following
conditions over a period of 2 weeks, with periodic observation.
 80% RH at room temperature in an open container.
 40°C in an open container.
 40°C in a closed container (glass bottle with tight screw cap).
 Both gross and subtle effect of the above storage conditions on the capsule shell are
noted and recorded.
 The control capsule (containing mineral oil with Shell Hardness ratio of 0.5:1 and a
water to dry gelatin ratio of 1:1) should not be affected, except under 80 % RH, where
it may become soften, tackier and bloated (swollen).
ii) Purity
 According to Japanese Pharmacopoeia, the test called 'purity' uses five empty hard
gelatin capsules which are tested individually.
 Each is placed in a 100 ml conical flask and shaken vigorously after adding 50 ml of
water at 37 °C throughout the test.
 The capsule passes the test if it completely dissolves within 10 minutes giving
odorless and neutral (or slightly acidic) solution.
iii) Capsule Diameter
 The manufacturing machine's output should be monitored continuously via the
dimensional correctness during each lot production.
 A capsule diameter sorter allows to pass to the next unit of any capsule within ± 0.020
inch of theoretical diameter.
iv) Capsule color
 The capsules are fed to it automatic colour measuring machine from the diameter
sorter by a pneumatic conveyer.
 In this unit, any capsule whose colour does not conform to the reference/standard
colour then that particular product is discarded others passes the test.
 The colour of the capsules should be checked against a standard strip; in case of any
changes the gelatin solution should be adjusted by adding standardized dye solutions
which can be ensured via thin layer chromatography.
v) Loss on Drying
 The Loss on Drying Test is designed to measure the amount of water and volatile
matters in a sample when the sample is dried under specified conditions.
 Between 13 % and 16 %, determined on capsule shells weighing 1.0 g by drying in an
oven at 105 °C for 18 hours.

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 Determination of loss on drying via the oven method consumes more time.
 To prevent this advanced methods like infrared balances, humidity meter etc.
vi) Sorting of Defects
 After electronic or manual inspection, they are sampled by quality control inspectors.
 The results should meet the inspection plan, if not the capsules should be resorted or
rejected depending upon frequency of faults.
vii) Printing Inspection
 Quality inspector sampled the lot and are inspected for quality of print.
 The results will again be compared with the inspection plan and in case if it does not
match then, either capsules should be resorted or rejected depending upon number
of faults present.
viii) Final Inspection
 After the capsules are placed in final containers, samples are checked for various
parameters like dimensions, physical defects and color.
 These samples are also subjected to various microbial tests also.

2.8.3. Evaluation of Fill Capsules

Fill capsules should be evaluated for
 Content uniformity
 Weight variation
 Disintegration test
 Dissolution test
i) Content uniformity
The uniformity of dosage units may be demonstrated by determining weight variation
and/or content uniformity. The content uniformity method is as follows.
 Randomly selected 10 capsules subject to assay.
 Test is passed if,
i. 9 of 10 capsules should be within the range of 85% to 115% (i.e., ±15%) of the label
claim.
ii. With no unit outside the range of 70% to 125% of label claim.
 Additional tests (for 20 capsules) are prescribed when two or three dosage units are
outside of the desired range but within the stated extremes.
 All capsules within range of ± 25% (75-125%).
ii) Weight Variation
 The weight variation method for HGC is as follows:
 Step 1) Weigh 20 intact capsules individually, and calculate the average mass.
 Step 2) The mass of each capsule should be within ±10% of the average mass.

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 Step 3) If all the capsules do not fall within these limits, weigh the 20 capsules
again, taking care to preserve the identity of each capsule,
 Step 4) remove the contents as completely as possible.
 Step 5) Weigh the emptied shells individually and calculate for each capsule the
net mass of its contents by subtracting the mass of the shell from the gross mass.
 Net mass of contents = Gross mass - Mass of shell
 Determine the average net content from the sum of the individual net masses.
 Then determine the difference between each individual net content and the average
net content.
 Deviation of individual net mass from the average net mass should not exceed the
limits given below.
Net mass of capsule contents Deviation (%) Number of capsules
less than 300 mg ± 10.0 minimum 18
± 20.0 maximum 2
300 mg and over ± 07.5 minimum 18
± 15.0 maximum 2
iii) Disintegration test
 The disintegration test determines whether tablets or capsules disintegrate within
the prescribed time when placed in a liquid medium in the experimental conditions
prescribed below.
 Disintegration is considered to be achieved when:
 a) no residue remains on the screen, or
 b) if there is a residue, it consists of a soft mass having no palpably firm,
unmoistened core, or
 c) only fragments of coating (tablets) or only fragments of shell (capsules) remain
on the screen; if a disc has been used (capsules), fragments of shell may adhere to
the lower surface of the disc.
 The disintegration of capsules is different from those of tablets because the
determination of end point is difficult owing to the adhesive nature of shell.
 The shell pieces after disintegration may agglomerate forming large mass of gelatin
taking more time to dissolve and may adhere to the mesh thus, blocking the holes.
 The apparatus consists of
 a basket-rack assembly,
 a 1000 mL, low-form beaker, 138-160 mm in height and having an inside diameter
of 97-115 mm for the immersion fluid,
 a thermostatic arrangement for heating the fluid between 35 °C and 39 °C,
 a device for raising and lowering the basket in the immersion fluid at a constant
frequency rate between 29 and 32 cycles per minute, through a distance of not
less than 53 mm and not more than 57 mm.

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 The volume of the fluid in the vessel is such that at the highest point of the upward
stroke the wire mesh remains at least 15 mm below the surface of the fluid and
descends to not less than 25 mm from the bottom of the vessel on the downward
stroke.
 At no time should the top of the basket-rack assembly become submerged.
 The time required for the upward stroke is equal to the time required for the
downward stroke and the change in stroke direction is a smooth transition, rather
than an abrupt reversal of motion.
 The basket-rack assembly moves vertically along its axis.
 There is no appreciable horizontal motion or movement of the axis from the vertical.
Basket-rack assembly
 The basket-rack assembly consists of six open-ended transparent tubes, each 75.0-
80.0 mm long and having an internal diameter of 20.70-23.00 mm and a wall 1.0-2.8
mm thick.
 The tubes are held in a vertical position by two plates, each 88-92 mm in diameter
and 5.00-8.50 mm in thickness, with six holes, each 22-26 mm in diameter,
equidistant from the center of the plate and equally spaced from one another.
 Attached to the lower surface of the lower plate is a woven stainless steel wire mesh,
which has a plain square weave with 1.8-2.2 mm apertures and with a wire diameter
of 0.570-0.660 mm.
 The parts of the apparatus are assembled and rigidly held by means of three bolts
passing through the two plates.
 A suitable means is provided to suspend the basket-rack assembly from the raising
and lowering device using a point on its axis.
 The design of the basket-rack assembly may be varied somewhat provided the
specifications for the glass tubes and the screen mesh size are maintained.

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Discs
 The use of discs is permitted only where specified or allowed.
 Each tube is provided with a cylindrical disc 9.35-9.65 mm thick and 20.55-20.85 mm
in diameter.
 The disc is made of a suitable, transparent plastic material having a specific gravity of
1.18-1.20.
 Five parallel 1.9-2.1 mm holes extend between the ends of the cylinder.
 One of the holes is centered on the cylindrical axis.
 The other holes are centered 5.8-6.2 mm from the axis on imaginary lines
perpendicular to the axis and parallel to each other.
 Four identical trapezoidal-shaped planes are cut into the wall of the cylinder, nearly
perpendicular to the ends of the cylinder.
 The trapezoidal shape is symmetrical; its parallel sides coincide with the ends of the
cylinder and are parallel to an imaginary line connecting the centres of two adjacent
holes 6 mm from the cylindrical axis.

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 The parallel side of the trapezoid on the bottom of the cylinder has a length of 1.5-1.7
mm and its bottom edges lie at a depth of 1.50-1.80 mm from the cylinder’s
circumference.
 The parallel side of the trapezoid on the top of the cylinder has a length of 9.2-9.6 mm
and its centre lies at a depth of 2.5-2.7 mm from the cylinder’s circumference.
 All surfaces of the disc are smooth.
 If the use of discs is specified, add a disc to each tube and operate the apparatus as
directed under procedure.
Procedure
 Place one dosage unit in each of the six tubes of the basket and if specified add a disc.
 Operate the apparatus using water as the immersion fluid unless another liquid is
specified and maintain its temperature at 37 ± 2 °C (35-39 °C).
 Attach a removable wire cloth with a plain square weave of 1.8-2.2 mm of mesh
aperture and a wire diameter of 0.60-0.655 mm to the surface of upper rack of the
basket assembly.
 At the end of the specified time, lift the basket from the fluid and observe the dosage
units: all of the dosage units have disintegrated completely.
 If one or two dosage units fail to disintegrate, repeat the test on 12 additional dosage
units.
 The requirements of the test are met if not less than 16 of the 18 dosage units tested
are disintegrated.
Disintegration test requirements for HGC
Indian Pharmacopoeia British pharmacopoeia US Pharmacopoeia
1996 (IP) 2009 (BP) 2009 (USP)

Uses disintegration Uses disintegration apparatus Same as uncoated

apparatus with 250 ml or 1 with water or specified liquid tablets. Use a circular
L of specified medium at medium, add a metal disc to cloth mesh of
37±2 °C & for specified prevent capsule from floating diameter 0.60- 0.655
time as per monograph. & operate for 30 min or as per mm & 1.8- 2.2 mm
monograph. square mesh size.
If 1-2 fail, repeat for 12 If 1- 2 fail, repeat for 12 No palpable material
different units. 16 out of 18 different units. 16 out of 18 to remain on the
indicate test is affirmative. indicate test is affirmative. mesh.

iv) Dissolution test

 Dissolution test is an official method to determine the dissolution rate of a solid
dosage form.
 Dissolution rate is defined as the rate at which the drug is released into the systemic
circulation from the dosage from

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Capsules

 It measures the portion (%) of the API that (1) has been released from capsules and
(2) has dissolved in the dissolution medium during controlled testing conditions
within a defined period.
 Generally, dissolution of capsules are performed by USP dissolution apparatus type 1.
USP Dissolution Test Apparatus -I
 The assembly consists of the following:
 a covered vessel made of glass or other inert,
 transparent material;
 a motor;
 a metallic drive shaft; and
 a cylindrical basket.
 The vessel is partially immersed in a suitable water bath of any convenient size or
placed in a heating jacket.
 The water bath or heating jacket permits holding the temperature inside the vessel at
37 ± 0.5 °C during the test and keeping the bath fluid in constant, smooth motion.
 No part of the assembly, including the environment in which the assembly is placed,
contributes significant motion, agitation, or vibration beyond that due to the smoothly
rotating stirring element.
 Apparatus that permits observation of the specimen and stirring element during the
test is preferable.
 The vessel is cylindrical, with a hemispherical bottom and with one of the following
dimensions and capacities:
 for a nominal capacity of 1 L, the height is 160 mm to 210 mm and its inside
diameter is 98 mm to 106 mm;
 for a nominal capacity of 2 L, the height is 280 mm to 300 mm and its inside
diameter is 98 mm to 106 mm; and
 for a nominal capacity of 4 L, the height is 280 mm to 300 mm and its inside
diameter is 145 mm to 155 mm.
 Its sides are flanged at the top.
 A fitted cover may be used to retard evaporation.
 The shaft is positioned so that its axis is not more than 2 mm at any point from the
vertical axis of the vessel and rotates smoothly and without significant wobble.
 A speed regulating device is used that allows the shaft rotation speed to be selected
and maintained at the rate specified in the individual monograph, within ±4%.
 Shaft and basket components of the stirring element are fabricated of stainless steel,
type 316 or equivalent.
 Unless otherwise specified in the individual monograph, use 40 ¬mesh cloth.
 A basket having a gold coating 0.0001 inch (2.5 µm) thick may be used.
 The dosage unit is placed in a dry basket at the beginning of each test.

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 The distance between the inside bottom of the vessel and the basket is maintained at
25 ± 2 mm during the test.

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Procedure
 Place the stated volume of the Dissolution Medium (±1%) in the vessel of the
apparatus specified in the individual monograph, assemble the apparatus, equilibrate
the Dissolution Medium to 37 ± 0.5 °C, and remove the thermometer.
 Place 1 capsule in the apparatus, taking care to exclude air bubbles from the surface
of the dosage form unit, and immediately operate the apparatus at the rate specified
in the individual monograph.
 Within the time interval specified, or at each of the times stated, withdraw a specimen
from a zone midway between the surface of the Dissolution Medium and the top of
the rotating basket, not less than 1 cm from the vessel wall.
 Unless otherwise indicated in the monograph, withdraw samples at 45 minutes.
 Replace the aliquots withdrawn for analysis with equal volumes of fresh Dissolution
Medium at 37 °C or, where it can be shown that replacement of the medium is not
necessary, correct for the volume change in the calculation.
 Keep the vessel covered for the duration of the test, and verify the temperature of the
mixture under test at suitable times.
 Perform the analysis as directed in the individual monograph. Repeat the test with
additional dosage form units.

Dissolution criteria
 The requirements are met if the quantity of active ingredients dissolved conforms the
following:
 At stage 1 (S1): When 6 capsules are tested, amount of each of the dissolved
content should not be less than ± 5% of the mentioned in monograph.
 At stage 2 (S2): when 6 capsules are tested, the average of 12 (both from step 1and
2) should be equal to or greater than 15% and no capsule should be than 15%.
 At stage 3 (S3): when 12 capsules are tested, the average of 24 capsules (all 1, 2
and 3 steps) should be equal to or greater than the amount mentioned in the
monograph, not more than two units are less than 15% and no unit s less than
25%.
 Where capsule shells interfere with the analysis, remove the contents of no fewer than
six capsules as completely as possible and dissolve the empty capsule shells in the
specified volume of dissolution medium.
 Carry out the test as directed in the individual monograph and make any necessary
correction.
 Correction factors should not be greater than 25% of the labelled content.
 "Quality is not the step that can be incorporated at last, it is mandatory and should be
inbuilt into the products" to, make this happen, apart from all these mandatory tests
certain other tests can also be performed.
Evaluation of Finished (Packaged) Capsules

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2.8.4. Finished capsules evaluation

 Moisture Permeation Test
 Stability testing

i) Moisture Permeation Test

The USP requires determination of the moisture permeation characteristics of single-unit
and unit-dose containers to ensure their suitability for packaging capsules.
Method 1
 The degree and rate of moisture penetration is determined by
 Step 1) Packaging the dosage unit together with a color-revealing desiccant pellet,
 Step 2) Exposing the packaged unit to known relative humidity over a specified
time,
 Step 3) Observing the desiccant pellet for color change.
 Report: Any change in colour indicates absorption of moisture.
Method 2
 By measuring pre-test weight and post-test weight of packaged unit, amount of
moisture permeated can be calculated.

ii) Stability test

 Stability tests for capsules are performed to know the integrity of gelatin capsule shell
and for determining the shelf life of capsules.
 It also provide an evidence on how the quality of a drug substance or drug product
varies with time under the influence of a variety of environmental factors such as
 Temperature
 Humidity
 Light
 The tests helps in improving the quality of contents of capsule shell and for choosing
the appropriate retail package.
 Parameters like brittleness, dissolution (or disintegration, if justified), water content,
and level of microbial contamination are required to be determined during stability
testing.
Stability test - Storage Condition

 The effect of temperature and humidity on capsule shell

Temperature Humidity Effect on Capsule shell
21-24±°C 60% Capsules become softer, tackier and
bloated
Greater than 24°C Greater than 45% More rapid and pronounced effects –
unprotected capsules melt and fuse
together

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 The test conditions for such accelerated physical stability tests

Test Conditions Observation
80% RH at room temperature in an open Capsules are observed periodically
container for 2 weeks, both gross and subtle
40°C in an open container effects of the storage conditions
are noted and recorded. The
40°C in a closed container (glass bottle with tight control capsule should not be
screw-cap) affected except at the 80% RH
storage

Study Design
Study Storage condition Minimum time period
covered by data at
submission
Long term* 25°C ± 2°C / 60% RH ± 5% RH 12 months
Or
30°C ± 2°C / 65% RH ± 5% RH
Intermediate 30°C ± 2°C / 65% RH ± 5% RH 6 months
term**
Accelerated 40°C ± 2°C / 75% RH ± 5% RH 6 months
 *It is up to the applicant to decide whether long term stability studies are performed
at 25  2°C/60% RH  5% RH or 30°C  2°C/65% RH  5% RH.
 **If 30°C  2°C/65% RH  5% RH is the long-term condition, there is no intermediate
condition.

2.9. Packaging and Storage of Capsules

 Capsules should be stored in sealed containers at uniform temperatures to maintain
their properties.
 Capsules should be packed in a well-closed glass or plastic containers and stored in a
cool place.
 These type of containers have advantage over cardboard boxes that they are more
convenient to handle and transport and protect the capsules from moisture and dust.
 Empty gelatin capsules have a moisture content between 13% and 16%.
 The water acts as a plasticizer and is essential to maintain the flexibility and strength
of the capsule.
 They will become brittle if the moisture content falls outside of the limits and soften
if it increases above it.
 The water in hard gelatin capsules is tightly bound into the polymer structure and is
insufficient for active bacterial growth.
 To prevent the capsules from rattling a tuft of cotton is placed over and under the
capsules in the vials.

Dr. Kevin C. Garala 34

Capsules

 In vials containing very hygroscopic capsules a packet-containing desiccant like silica

gel or anhydrous calcium chloride may be placed to prevent the absorption of
excessive moisture by the capsules.
 Now a days capsules are strip packaged which provide sanitary handling of medicines,
ease in counting and identification.
 The dimensions of capsules vary slightly as their moisture changes.
 As a general rule, the dimensions of gelatin capsules change by 0.5% for every 1%
change in moisture in the range 13.0–16.0%.
 Thus, higher-speed filling machine must be operated in air-conditioned areas to
achieve their maximum performance.
 The moisture content of capsules depends upon the conditions to which they are
exposed.

Containers for Dispensing Capsules

 The USP lists specifications prescribing the type of container suitable for the
repackaging or dispensing of each official capsule and tablet.
 Depending on the item, the container may be required to be tight, well-closed, and
light resistant.
 Plastic pouch zip locked (for sale via
retail stores or route trucks must be
packed in outer case for shipping).

 Plastic bottle with screw cap (most

popular package in USA)

 Clam shell blister (one piece plastic

that folds over and locks itself; no
heating required)

 Blister pack (heat sealed blister on a

cardboard)

Dr. Kevin C. Garala 35

Capsules

 Plastic pail/bucket( economical bulk

package)

2.10. Vegetable (Non-Gelatin) Capsules

 In recent era, vegetable capsules are new approach which might be replace the usage
of gelatin or non-vegetable capsules.
 Vegetable capsule shell is mostly prepared from the hydroxypropyl methylcellulose
(HPMC), most commonly known as hypromellose.
 It is produced by synthetic modification of the naturally occurring polymer cellulose
and is considered safe for normal consumption, in human.
 Religious, cultural and personal issues may affect patients’ preference towards the
medications presented in capsule dosage forms.
 HPMC capsules is good alternative of gelatin capsules due to its vegetable source.

Structure of HPMC HPMC Capsules

 The first vegetable capsule which is made of HPMC were produced in 1989 by G S
Technologies Inc. with trade name Vegicaps.
 For gelatin capsule alternative, the first patient registered was in 1950 by H W
Murphy of Eli Lilly and Company for methyl cellulose which did not last long in the
market because of in vivo disintegration delay.
 The manufacturing technique remains similar to that of hard gelatin capsules and
involves the use of pins dipping into HPMC solution.
 There are different types of HPMC capsules which may have different in vitro and in
vivo performances among themselves and in comparison to hard gelatin capsules.
 Vegicaps soft capsules are an alternative animal free capsules.
 The shell is made from seaweed extract and gluten free starch and contains no
modified sugars and artificial colors.
 Advantages of vegetable capsules:
 free of all animal derivates i.e., no pork or beef content,
 easy to swallow,
 soft,

Dr. Kevin C. Garala 36

Capsules

 natural,
 perception of a healthier product and
 low shell odor.

2.10.1 Manufacturing of Non-gelatin capsule

 Non-gelatin capsules are prepared by using similar equipments as required for gelatin
capsules manufacturing.
 The manufacturing of HPMC based capsules requires some modification to the
molding machine or to the formulation of the shell materials.
 HPMC gelling from solution occurs when the temperature is increased while it is
converted to its original solution as the temperature is decreased, unlike gelatin
solution.
 It means that the pins immersed in the dip pan containing the HPMC solution must be
of higher temperature (70°C) in order for the film to be formed.
 The temperature of the pins must be further maintained post-dip to facilitate gelation
until the films dry out in the kilns.
 Because HPMC shell walls are much weaker than gelatin made shells, removal of the
capsule from the pins and subsequent handling and filling are difficult.
 To overcome these problems, three approaches were adapted.
 These approaches were
 to use a stripper jaw with depressions on the inner surface,
 increase the formed HPMC film thickness and
 the use of gelling agents.

2.10.2. Properties of hypermellose capsules

 Empty hypromellose capsules have a moisture content of 3% to 6%.
 These capsules can be dried down to less than 1% moisture without losing their
mechanical strength and becoming brittle.
 Hypromellose capsules contain less water than gelatin ones, and their change in
dimensions with moisture content is less.
 Hypromellose does not react with aldehydes or other agents that cause cross-linking
of gelatin.
 Hypromellose capsules start to release their contents slightly slower than gelatin ones
because of the slower rate of diffusion of water through the shell walls.
 However, once dissolution has commenced, the rates are similar and the results are
comparable.

Dr. Kevin C. Garala 37

Capsules

Empty HPMC capsules and their manufacturers

Capsule shell Manufacturer Registered Gelling aid
brand name year in USA
Quali-V Shionogi Qualicaps July, 2002 Carrageenan
Vcaps Capsugel (A division of Pfizer) April, 2003 Gellan gum
VegiCaps G S Technologies Inc. (now R.P. May, 1989 None
Scherer Technologies
ownership)
Embo Caps –Vg Suheung Capsule Co., Ltd - Pectin and
glycerin
Capstech’s HPMC Baotou Capstech Co., Ltd - None
Capsule
Vcaps plus Capsugel (A division of Pfizer) - None

2.11. IP Capsules
Amoxycillin Capsules
 Amoxycillin Trihydrate capsules contain not less than 90.0 per cent and not more
than 110.0 per cent of the stated amount of amoxycillin, C16H19N3O5S.
Amantadine Capsules
 Amantadine Capsules contain not less than 95.0 per cent and not more than 105.0
per cent of the stated amount of amantadine hydrochloride, C10H17N HCl.
Ampicillin Capsules
 Ampicillin Capsules contain Ampicillin or Ampicillin Trihydrate equivalent to not
less than 92.5 per cent and not more than 107.5 per cent of the stated amount of
ampicillin, C16H19N3O4S.
Azithromycin Capsules
 Azithromycin Capsules contain not less than 90.0 percent and not more than 110.0
percent of the stated amount of azithromycin, (C38H72N2OI2).
Other Capsules
Bromocriptine Capsules Etoposide Capsules Piroxicam Capsules
Calciferol Capsules Ethosuximide Capsules Pregabalin Capsules
Cefaclor capsules Indinavir Capsules Ramipril Capsules
Cephalexin Capsules Indomethacin Capsules Rifampicin Capsules
Chloramphenicol Capsules Ketoprofen Capsules Ritonavir Capsules
Clobazam Capsules Levodopa Capsules Stavudine Capsules
Clofazimine Capsules Lincomycin Capsules Temozolomide Capsules
Clomipramine Capsules Lomustine Capsules Tetracycline Capsules
Cloxacillin Capsules Loperamide Capsules Thiocolchicoside Capsules
Cycloserine Capsules Lopinavir and Ritonavir Tramadol Capsules
Danazol Capsules Capsules Triamterene Capsules
Diazepam Capsules Mefenamic Acid Capsules Troxidone Capsules
Didanosine Capsules Mexiletine Capsules ValproicAcid Capsules
Dothiepin Capsules Nifedipine Capsules Vancomycin Capsules
Doxepin Capsules Omeprazole Capsules Vitamins A and D Capsules
Doxycycline Capsules Oseltamivir Capsules Zidovudine Capsules
Efavirenz Capsules Oxytetracycline Capsules
Emtricitabine Capsules Phenytoin Capsules

Dr. Kevin C. Garala 38

Capsules

3. Soft Gelatin Capsule (SGC)

 Soft gelatin (also called softgel or soft elastic) capsules consist of one-piece
hermetically-sealed soft shells.
 Soft gelatin capsules are prepared by adding a plasticizer, such as glycerin or
polyhydric alcohol (e.g., sorbitol), to gelatin.
 The plasticizer makes gelatin elastic.
 Softgels are formed, filled, and sealed in a single operation.
 Soft gelatin capsules come in various shapes such as spherical, elliptical, oblong, and
special tube shapes with and without twist off.
 Softgels offer the possibility of delivering a liquid in a solid oral dosage form.
 The size of the Softgel is represented by a numerical number, which represents its
nominal capacity in minims (1 cc = 16.23 minims). For example, an 11 oblong Softgel
can be filled with 8.5–11.0 minims of fill formulation.
 Softgels are formed, filled, and sealed in a single operation.
 Softgels can be easily manufactured in any shape with a plane of symmetry and any
size (to contain up to 25 ml) via appropriate die design.
 A recent survey has shown that smaller sized Softgels are preferred within each shape
category, with oval being the most popular shape.
 Softgel’s ability to enhance bioavailability not only makes it the preferred dosage form
for new chemical entity with poor bioavailability owing to poor aqueous solubility,
but also for reformulation of marketed drugs with the purpose of life-cycle extension.
 Softgels are a unique drug delivery system that can provide distinct advantages over
traditional dosage forms such as tablets, hard-shell capsules, and liquids.
3.1. Advantages
Improved bioavailability
 More than 40% of the NCEs (new chemical entity) discovered have good membrane
permeability but poor aqueous solubility (i.e., Biopharmaceutics Classification System
II).
 By formulating the NCE in solution inside a Softgel (e.g., lipid based) or in
micro/nanoemulsion, the solubility and hence the bioavailability of the compound
may be improved.
 Enhanced drug stability (protection against oxidation, photodegradation, and
hydrolysis in lipophilic systems).
 Superior patient compliance/consumer preference and pharmaceutical elegance.
 Results of studies done through the years show that consumers expressed their
preference for Softgels in terms of ease of swallowing, perceived speed of delivery,
lack of unpleasant odor or taste and modern appearance.
 Excellent dose uniformity.
 Better tamper evidence (tampering leads to puncturing and visible leakage).

Dr. Kevin C. Garala 39

Capsules

 Safer handling of highly potent or cytotoxic drug compounds.

 Product differentiation (through selection of novel shapes, colors, and sizes).
 Excellent product life-cycle management. For example, product enhancement via
faster onset of action.
3.2. Disadvantages
In comparison, the disadvantages of Softgels are relatively few. These include the
following:
 Specialized manufacturing equipment requirements.
 Higher manufacturing cost as compared to tablets.
 Stability concerns with compounds susceptible to hydrolysis.
3.3. Description of Softgels
 Softgels consist of a liquid or semisolid matrix inside a one-piece outer gelatin shell.
 Ingredients that are solid at room temperature can also be encapsulated into softgels,
provided they are at least semisolid below approximately 45°C.
 The drug compound itself may be either in solution or in suspension in the capsule-
fill matrix.
 The characteristics of the fill matrix may be hydrophilic (for example polyethylene
glycols) or lipophilic (such as triglyceride vegetable oils).
 Indeed, in many formulations, the matrix may be a mixture of both hydrophilic and
lipophilic ingredients.
 Significant advances have been made in recent years in the formulation of softgel fill
matrices.
 These include microemulsions and nanoemulsions encapsulated as preconcentrates
in softgels.
 The term 'preconcentrate' means that the softgel fill matrix is a combination of
lipophilic and hydrophilic liquids as well as surfactant components, which after oral
administration disperse to form, for example, a microemulsion.
 If the dispersion results in even smaller droplets in the nanoparticle range, then the
dispersion is known as a nanoemulsion.
 The softgel capsule shell consists of gelatin, water and a plasticizer.
 It may be transparent or opaque, and can be coloured and flavoured if desired.
 Preservatives are not required owing to the low water activity in the finished product.
 The softgel can be coated with enteric-resistant or delayed-release material.
 Although virtually any shape softgel can be made, oval or oblong shapes are usually
selected for oral administration.

Dr. Kevin C. Garala 40

Capsules

Schematic diagram of different softgel formulations

3.4. Shape of Softgels
 Softgels can be formulated and manufactured to produce a number of different drug
delivery systems.
 Orally administered softgels containing solutions or
suspensions that release their contents in the
stomach in an easy to swallow, convenient unit dose
form. This is the most common type of softgel.

 Chewable softgels, where a highly flavoured shell is

chewed to release the drug liquid fill matrix. The
drug(s) may be present in both the shell and the fill
matrix.
 Suckable softgels, which consist of a gelatin shell
containing the flavoured medicament to be sucked
and a liquid matrix or just air inside the capsule.

 Twist-off softgels, which are designed with a tag to

be twisted or snipped off, thereby allowing access to
the fill material. This type of softgel can be very
useful for unit dosing of topical medication,
inhalations, or indeed for oral dosing of a paediatric
product.

Dr. Kevin C. Garala 41

Capsules

 Meltable softgels, designed for use as 'patient

friendly’ pessaries or suppositories.

Size and Shape of Softgels

3.5. Formulation of Softgels

3.5.1. Gelatin shell formulation
 Typical softgel shells are made up of gelatin, plasticizer, and materials that impart the
desired appearance (colourants and/or opacifiers), and sometimes flavours.
i) Gelatin
 A large number of different gelatin shell formulations are available, depending on the
nature of the liquid fill matrix.

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Capsules

 Most commonly the gelatin is alkali- (or base) processed (type B) and it normally
constitutes 40% of the wet molten gel mass.
 Type A acid-processed gelatin can also be used.
ii) Plasticizers
 Plasticizers are used to make the softgel shell elastic and pliable.
 They usually account for 20-30% of the wet gel formulation.
 The most common plasticizer used in softgels is glycerol, although sorbitol and
propylene glycol are also frequently used, often in combination with glycerol.
 The amount and choice of the plasticizer contribute to the hardness of the final
product and may even affect its dissolution or disintegration characteristics, as well
as its physical and chemical stability.
 Plasticizers are selected on the basis of their compatibility with the fill formulation,
ease of processing, and the desired properties of the final softgel, including hardness,
appearance, handling characteristics and physical stability.
 Plasticizers are selected on the basis of their compatibility with the fill formulation,
ease of processing, and the desired properties of the final softgel, including hardness,
appearance, handling characteristics and physical stability.
 One of the most important aspect of softgel formulation is to ensure that there is
minimum interaction or migration between the liquid fill matrix and the softgel shell.
 The choice of plasticizer type and concentration is important in ensuring optimum
compatibility of the shell with the liquid fill matrix.
iii) Water
 The other essential component of the softgel shell is water.
 Water usually accounts for 30-40% of the wet gel formulation and its presence is
important to ensure proper processing during gel preparation and softgel
encapsulation.
 Following encapsulation, excess water is removed from the softgels through
controlled drying.
 In dry softgels the equilibrium water content is typically in the range 5-8% w/w,
which represents the proportion of water that is bound to the gelatin in the softgel
shell.
 This level of water is important for good physical stability, because in harsh storage
conditions softgels will become either too soft and fuse together, or too hard and
embrittled.
iv) Colourants
 Colourants (soluble dyes, or insoluble pigments or lakes) and opacifiers are typically
used at low concentrations in the wet gel formulation.
 Colourants can be either synthetic or natural, and are used to impart the desired shell
colour for product identification.

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Capsules

v) Opacifiers
 An opacifier, usually titanium dioxide, may be added to produce an opaque shell when
the fill formulation is a suspension, or to prevent photodegradation of light-sensitive
fill ingredients.
 Titanium dioxide can either be used alone to produce a white opaque shell or in
combination with pigments to produce a coloured opaque shell.
Properties of soft gelatin shells
vi) Oxygen permeability
 The gelatin shell of a softgel capsule provides a good barrier against the diffusion of
oxygen into its contents.
𝑃𝐴𝑡(𝑝1 − 𝑝2)
𝑞=
ℎ
 The quantity of oxygen (q) that passes through the gelatin is governed by the area (A),
thickness (h), particle pressure difference (p1 - p2), time of diffusion (t) and the
permeability coefficient (P) of the shell by the following equation:
 The permeability coefficient (P) is related to the diffusion coefficient (D) and the
solubility coefficient (S) by the equation P = DS.
 This relationship, described by Henry's Law, assumes no interaction between the gas
and the polymeric film, but P is clearly affected by the formulation of the gelatin shell.
vii) Residual water content
 Softgels contain little residual water, and compounds which are susceptible to
hydrolysis are protected if dissolved or dispersed in an oily liquid fill material and
encapsulated as a soft gelatin capsule.
 The residual water content of most pharmaceutical compounds stored at 20% relative
humidity (the drying condition for softgels) is low, and the water levels in the fills of
softgels are therefore very small.

3.5.2. Base Adsorption of solids to be suspended in soft gelatin capsules

i) Base Adsorption
 Base adsorption is expressed as the number of grams of liquid base required to
produce a capsulatable mixture when mixed with one gram of solid(s).
 The base adsorption of a solid is influenced by such factors such as the solids particle
size and shape, its physical state (fibrous, amorphous, or crystalline), its density, its
moisture content, and its oleophilic or hydrophilic nature.
 A practical procedure for determining base adsorption and for judging the adequate
fluidity of a mixture is as follows:
 Weigh a define amount of the solid (40g is convenient) into a 150 ml beaker.
 In a separate 150 ml beaker, place about 100 g of the solid base.

Dr. Kevin C. Garala 44

Capsules

 Add small increments of the liquid base to the solid, and using a spatula, stir the base
into the solid after each addition until the solid is thoroughly wetted and uniformly
coated with the base.
 This should produce a mixture that has a soft ointment like consistency.
 Continue to add liquid and stir until the mixture flows steadily from the spatula blade
when held at a 45-degree angle above the mixture.
 The base adsorption is obtained by means of the following formula –
Weight of the base/ Weight of the solid = Base Adsorption
ii) Minim per gram (m/g) factor
 The base adsorption is used to determine the “minim per gram” factor (M/g) of the
solid(s).
 The minim per gram factor is the volume in minims that is occupied by one gram (S)
of the solid plus the weight of the liquid base (BA) required to make a capsulatable
mixture.
 It is calculated by dividing the weight of the base plus the gram of solid base (BA+ S)
by the weight of the mixture (W) per cubic centimeter or 16.23 minims (V).
 A convenient formula is - (BA + S) x V/ W = M/g
 Thus lower the base adsorption of the solid (s) and higher the density of the mixture,
the smaller the capsule will be.
3.5.3. Formulation of softgel fill materials
 In terms of formulation requirements, the softgel should be considered as a biphasic
dosage form: a solid-phase, i.e., capsule shell and a liquid-phase, i.e., fill matrix.
 Although it is possible to incorporate a drug in the shell of a softgel, the overwhelming
majority of products have the active ingredient(s) within the fill matrix.
 The liquid-phase fill matrix is selected from components with a wide range of
different physicochemical properties.
 The choice of components is made according to one or more of a number of criteria,
including the following:
 Capacity to dissolve the drug;
 Rate of dispersion in the gastrointestinal tract after the softgel shell ruptures and
releases the fill matrix;
 Capacity to retain the drug in solution in the gastrointestinal fluid;
 Compatibility with the softgel shell;
 Ability to optimize the rate, extent and consistency of drug absorbed.
Types of softgel fill matrices
i) Lipophilic liquids/oils
 Triglyceride oils, such as soya bean oil, are commonly used in softgels.
 When used alone, however, their capacity to dissolve drugs is limited.

Dr. Kevin C. Garala 45

Capsules

 Nevertheless, active ingredients such as hydroxycholecalciferol and other vitamin D

analogues, plus steroids such as oestradiol, can be formulated into simple oily
solutions for encapsulation in softgels.
ii) Hydrophilic liquids
 Polar liquids with a sufficiently high molecular weight are commonly used.
 Polyethylene glycol (PEG) is the most frequently used, for example PEG 400, which
has an average molecular weight of approximately 400 Da.
 Smaller hydrophilic molecules, such as ethanol or indeed water, can be incorporated
in the softgel fill matrix in low levels, typically below 10% by weight.
iii) Self-emulsifying oils
 A combination of a pharmaceutical oil and a non-ionic surfactant such as
polyoxyethylene sorbitan mono-oleate can provide an oily formulation which
disperses rapidly in the gastrointestinal fluid.
 The resulting oil/surfactant droplets enable rapid transfer of the drug to the
absorbing mucosa and subsequent drug absorption.
iv) Microemulsion and nanoemulsion systems
 A microemulsion of a lipid-surfactant-polar liquid system is characterized by its
translucent single-phase appearance.
 The droplet size is in the submicrometre range, and light scattering by these droplets
results in a faint blue colouration known as the Tyndall effect.
 A nanoemulsion is a similar system but contains emulsion droplets in the 100 nm size
range.

Diagram of proposed nanoemulsion/ microemulsion dissolution mechanism

Dr. Kevin C. Garala 46

Capsules

 Microemulsion and nanoemulsion systems have the advantage of a high capacity to

solubilize drug compounds and to retain the drug in solution even after dilution in
gastrointestinal fluids.
 In order to produce a microemulsion or nanoemulsion in the gastrointestinal tract a
'preconcentrate’ is formulated in the softgel fill matrix.
 The preconcentrate fill matrix contains a lipid component and one or more
surfactants, which spontaneously form a microemulsion or a nanoemulsion on
dilution in an aqueous environment, such as in gastrointestinal fluid.
 The resulting microemulsion or nanoemulsion is often stable for prolonged periods.
v) Suspensions
 Drugs that are insoluble in softgel fill matrices are formulated as suspensions.
 Suspension formulations provide significant advantages for certain low-solubility
drugs which are very poorly absorbed after oral administration.
 With the appropriate choice of excipients, softgel suspensions can have improved
bioavailability compared to compressed tablets or hard-shell capsules, or even dilute
aqueous solutions.
vi) Lipolysis systems
 The advantage of the microemulsion approach lies in the high surface area presented
by the microemulsion particles, which are essentially surfactant micelles swollen with
solubilized oil and drug.
 This high surface area facilitates the rapid diffusion of drug from the dispersed oil
phase into the aqueous intestinal fluids, until an equilibrium distribution is
established.
 Thereafter, as drug is removed from the intestinal fluids via enterocyte absorption, it
is quickly replenished by the flow of fresh material from the microemulsion particles.

3.6. Rationale for the selection of softgels as a dosage form

 Improved drug absorption
 Patient compliance
 Safety for Potent & Cytotoxic drugs
 Oils & low melting point. drugs
 Dose uniformity of low dose drugs
 Product stability
i) Improved drug absorption
 Major advances have been made in the development of softgel formulations to
address particular drug absorption issues.
 One of the best methods is presentation of the drug to the gastrointestinal tract in the
form of a solution from which it can be rapidly absorbed.

Dr. Kevin C. Garala 47

Capsules

 This can be achieved using a drug-solution matrix in a softgel formulation whereby

absorption is significantly faster than from other solid oral dosage forms, such as
compressed tablets.
 This is because absorption of a poorly soluble drug from a tablet formulation is rate-
limited by the need for disintegration into granules, then drug dissolution into
gastrointestinal fluid.
 With the solution-softgel approach, the shell ruptures within minutes to release the
drug solution, which is usually in a hydrophilic or highly dispersing vehicle that aids
the rate of absorption.
 This may be a valuable attribute
 (a) for therapeutic reasons, such as the treatment of migraine or acute pain, or
 (b) where there is a limited absorptive region or 'absorption window' in the
gastrointestinal tract.
 As well as increasing the rate of absorption, softgels were found to improve the extent
of absorption.
 This is particularly effective in case of hydrophobic drugs with high molecular
weight).
 This is achieved by Solutions, Suspensions, and Self-emulsifying drug delivery
systems (SEDDSs).
ii) Patient Compliance and Consumer Preference
 Many consumers prefer softgels over either tablets or hard gelatin capsules because
of its ease of swallowing and absence of objectionable taste.
 Absence of poor taste or other sensory problem.
 Convenient administration of a liquid-drug dosage form.
 Enhanced bioavailability, therefore the dose required to achieve therapeutic
effectiveness is reduced.
 In this way, it is possible to reduce the capsule size.
iii) Safety During Manufacturing
 Mixing, granulation, compression and filling in the case of tablets and hard gelatin
capsules results in the generation of a significant amount of dust.
 In case of highly potent drugs and cytotoxic agents, this may be a risk factor for the
machine operators and the environment.
 Preparation of solutions and suspensions of these drugs for softgel filling reduces
such risks.
 Avoids dust handling problems during dosage form manufacture: better operator
safety and environmental controls.
iv) Oils and Low Melting-Point Drugs
 If the pharmaceutical active is an oily liquid or a solid with a melting point of less than
75 °C, it is difficult to formulate it in a tablet or a hard gelatin capsule.

Dr. Kevin C. Garala 48

Capsules

 In such cases softgels are the obvious alternative.

 Oily liquids can be filled directly into softgels without the addition of any excipients.
 Low melting point drugs may be formulated with a diluent oil to ensure a satisfactory
liquid flow and dosing into softgels.
v) Dose Uniformity of Low-Dose Drugs
 Liquid dosing avoids the difficulties of poor powder flow and therefore poor content
uniformity.
 It is a significant benefit for formulations containing drug doses in the microgram
region.
 Improved homogeneity is achieved by dissolving the drug in a liquid and then
encapsulating the liquid matrix in a softgel.
vi) Product Stability
 By formulating the drug in a lipophilic vehicle and encapsulating it in a gelatin shell
ensures good protection against oxygen and moisture induced instabilities.
 The only concern is the fact that the drug may be in solution (more reactive than in
dry state), thus appropriate preformulation studies regarding choice of excipients and
drug degradation are vital to produce a stable product.
Rationale for the selection of softgels – Summary
 Improved drug absorption: Improved rate and extent of absorption and/or reduced
variability, mainly for poorly water-soluble drugs. Softgel can provide increased
bioavailability and decreased plasma variability.
 Patient compliance and consumer preference: Easy to swallow. Absence of poor taste
or other sensory problem. Convenient administration of a liquid-drug dosage form.
 Safety - potent and cytotoxic drugs: Avoids dust handling problems during dosage form
manufacture: better operator safety and environmental controls.
 Oils and low melting-point drugs: Overcomes problems with manufacture as
compressed tablet or hard-shell capsules.
 Dose uniformity for low-dose drugs: Liquid flow during dosage form manufacture is
more precise than powder flow. Drug solutions provide improved homogeneity over
powder or granule mixtures.
 Product stability: Drugs are protected against oxidative degradation by lipid vehicles
and softgel capsule shells.

3.7. Manufacture of softgels

3.7.1. Rotary die process
 The rotary die process involves continuous formation of a heat seal between two
ribbons of gelatin simultaneous with dosing of the fill liquid into each capsule.
 Before the encapsulation process takes place, there are two sub-processes that are
often carried out simultaneously, yielding the two components of a softgel.

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 These are (a) the gel mass which will provide the softgel shell, and (b) the fill matrix
for the contents.
 The gel mass is prepared by dissolving the gelatin in water at approximately 80°C and
under vacuum, followed by the addition of the plasticizer, for example glycerol.
 The hot gel mass is then supplied to the encapsulation machine through heated
transfer pipes by a method that forms two separate gelatin ribbons, each
approximately 150 mm wide.
 During the casting process the gelatin passes through the sol-gel transition and the
thickness of each gel ribbon is controlled to ± 0.1 mm, in the range of about 0.5-1.5
mm.
 The thickness is checked regularly during the manufacturing process.
 The liquid fill matrix containing the active drug substance is manufactured separately
from preparation of the molten gel.
 Manufacture of the active fill matrix involves dispersing or dissolving the drug
substance in the non-aqueous liquid vehicle using conventional mixer-homogenizers.
 Once the gelatin is fully dissolved then other components, such as colours, opacifier,
flavours and preservatives, may be added.
 Once the gelatin is fully dissolved then other components, such as colours, opacifier,
flavours and preservatives, may be added.
 The hot gel mass is then supplied to the encapsulation machine through heated
transfer pipes by a method that forms two separate gelatin ribbons, each
approximately 150 mm wide.
 During the casting process the gelatin passes through the sol-gel transition and the
thickness of each gel ribbon is controlled to ± 0.1 mm, in the range of about 0.5-1.5
mm.
 The thickness is checked regularly during the manufacturing process.
 The liquid fill matrix containing the active drug substance is manufactured separately
from preparation of the molten gel.
 Manufacture of the active fill matrix involves dispersing or dissolving the drug
substance in the non-aqueous liquid vehicle using conventional mixer-homogenizers.
Parameters to be controlled for active fill matrix preparation
 A number of different parameters are controlled during preparation of the active fill
matrix, depending on the properties of drug substance.
 Oxygen sensitive drugs are protected by mixing under vacuum and/or inert gas.
 In some cases antioxidant component may be added to the formulation.
 If the drug substance is present as suspension in the liquid fill matrix then it is
important to ensure that particle size of the drug does not exceed approximately 200
µm.
 In the rotary die encapsulation process, the gel ribbon and the unit dose of liquid fill
matrix are combined to form the softgel.

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 The process involves careful control of three parameters:

 Temperature: This controls the heat available for capsule seal formation.
 Timing: The timing of the dosing of unit quantities of fill matrix into the softgel
during its formation is critical.
 Pressure: The pressure exerted between the two rotary dies controls the softgel
shape and the final cut-out from the gel ribbon.
3.7.2. Mechanism of softgel formation
 It is done using contra rotating dies and the wedge shaped fill matrix injection system.
 Accurately metered volumes of the liquid fill matrix are injected from the wedge
device into the space between the gelatin ribbons as they pass between the die rolls.
 The wedge shaped injection system is itself heated to approximately 40°C.
 The injection of liquid between the gel ribbons forces the gel to expand into the
pockets of the dies, which govern the size and shape of the softgels.
 The ribbon continues to flow past the heated wedge injection system and is then
pressed between the die rolls.
 Here the two softgel capsule halves are sealed together by the application of heat and
pressure.
 The softgel capsules are cut automatically from the gel ribbon by raised rims around
each die on the rollers.

 After manufacture the capsules are passed through a tumble drier and then, to
complete the drying process, spread on to trays and stacked in a tunnel drier that
supplies air at 20% relative humidity.
 The tunnel drying process may take 2 or 3 days, or possibly as long as 2 weeks,
depending on the specific softgel formulation.
 Finally, the softgels are inspected and packed into bulk containers in order to prevent
further drying and for storage.

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3.7.3. Softgel Manufacturing

i) Inspection
 Capsules should be submitted to a final inspection before packing for malformed,
damaged or improperly filled capsules.
 This can be done visually by hand on trays or tables or semi-automatically on a roller
inspection machine.
ii) Packaging
 Packaging normally includes placing softgels into bulk containers, bottles or blister
packaging.
 Blister packaging can be of PVC (polyvinyl chloride) or PVDC (poly vinylidene
chloride).
 PVDC have higher level of water vapor barrier properties and are used for packaging
medicaments which require especially high moisture resistance.

3.8. Product Quality Considerations

3.8.1 Ingredient specifications
 All of the ingredients of a softgel are controlled and tested to ensure compliance with
pharmacopoeial specifications.
 However, additional specification tests may be added for certain excipients in order
to ensure the manufacture of a high-quality softgel product.
 For example, it is important to limit certain trace impurities, such as aldehydes and
peroxides which may be present in polyethylene glycol.
 The presence of high levels of these impurities gives rise to cross-linking of the gelatin
polymer, leading to insolubilization through further polymerization.
Ingredient specifications
 On prolonged storage this can lead to slow dissolution of the capsule shell and
subsequent retarded drug release.
 The ingredient requiring the most careful control is gelatin itself.
 Once a particular grade of gelatin is used in a softgel formulation the quality is
controlled using parameters such as the viscosity of a hot solution and the bloom
strength of the gel (bloom strength is a measure of the hardness of a gel).
3.8.2. In-process testing
 During the encapsulation process the four most important tests are:
 The gel ribbon thickness;
 Softgel seal thickness at the time of encapsulation;
 Fill matrix weight and capsule shell weight;
 Softgel shell moisture level and softgel hardness at the end of the drying stage.

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 Appropriate control levels for these parameters are established during process
development for each softgel product, and are applied in routine production scale
manufacture.
3.8.3. Finished product testing
 Finished softgels are subjected to a number of tests in accordance with compendial
requirements for unit dose capsule products.
 These normally include capsule appearance, active ingredient assay and related
substances assay, as well as fill weight, content uniformity and microbiological
testing.

3.9. Evaluation of Softgels

 Quality control should be carried out during all stages of manufacturing operation
which is the primary requirement of good manufacturing practices.
 Whether capsules are produced on a small scale or large scale all of them are required
to pass through certain tests i.e., quality control tests to test the quality of the finished
product.
 Quality control of softgels are as follows:
 Weight variation
 Content Uniformity
 Disintegration test
 Dissolution test
 Moisture permeation test
 Physical Stability
3.9.1. Weight Variation
 The weight variation method for SGC is as follows.
 The gross weight of 20 intact capsules is determined individually.
 Then each capsule is cut open and the contents removed by washing with ether or a
suitable solvent.
 The solvent is allowed to evaporate at room temperature over about 30 minutes or to
stand until the odour of the solvent is no longer perceptible, with precautions to avoid
uptake or loss of moisture.
 Other means, such as a jet of compressed air, may be used to remove the contents.
 The individual shells are weighed and the net contents calculated.
 From the results of the assay directed in the individual monograph, the content of
active ingredient in each of the capsules is determined.
 If all the capsules do not fall within these limits, weigh the 20 capsules again, taking
care to preserve the identity of each capsule, and perform the weight variation.
 Deviation of individual net mass from the average net mass should not exceed the
limits given below.

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Net mass of capsule contents Deviation (%) Number of capsules

± 10.0 minimum 18
less than 300 mg
± 20.0 maximum 2
± 07.5 minimum 18
300 mg and over
± 15.0 maximum 2
3.9.2. Content Uniformity
 This test is applicable to all capsules which are meant for oral administration. The
content uniformity method is as follows.
 Randomly selected 10 capsules subject to assay.
 Test is passed if,
 9 of 10 capsules should be within the range of 85% to 115% (i.e., ±15%) of the label
claim.
 With no unit outside the range of 70% to 125% of label claim.
 Additional tests (for 20 capsules) are prescribed when two or three dosage units are
outside of the desired range but within the stated extremes.
 All capsules within range of ± 25% (75-125%).
3.9.3. Disintegration test
 Disintegration is considered to be achieved when:
 a) no residue remains on the screen, or
 b) if there is a residue, it consists of a soft mass having no palpably firm, unmoistened
core, or
 c) only fragments of coating (tablets) or only fragments of shell (capsules) remain on
the screen; if a disc has been used (capsules), fragments of shell may adhere to the
lower surface of the disc.
 Place one dosage unit in each of the six tubes of the basket and if specified add a disc.
 Operate the apparatus using water as the immersion fluid unless another liquid is
specified and maintain its temperature at 37 ± 2 °C (35-39 °C).
 At the end of the specified time, lift the basket from the fluid and observe the dosage
units: all of the dosage units have disintegrated completely.
Disintegration test requirements for SGC
Indian Pharmacopoeia British Pharmacopoeia US Pharmacopoeia
1996 (IP) 2009 (BP) 2009 (USP)
Uses disintegration Uses disintegration Same as uncoated tablets.
apparatus with 250 ml or apparatus with water R or Use a circular cloth mesh of
1 L of specified medium at specified liquid medium, add diameter 0.60- 0.655mm &
37±2 °C & for specified a metal disc to prevent 1.8- 2.2mm square mesh
time as per monograph. capsule from floating and size.
operate for 30 min or as per
monograph.

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If 1-2 fail, repeat for 12 If 1- 2 fail, repeat for 12 No palpable material to

different units. different units. remain on the mesh.
16 out of 18 indicate test 16 out of 18 indicate test is
is affirmative. affirmative.
3.9.4. Dissolution test
Same as per test described in HGC.
3.9.5. Moisture Permeation test
Same as per test described in HGC.
3.9.6. Physical Stability
 Unprotected soft gelatin capsules rapidly reach equilibrium with the atmospheric
conditions under which they are stored.
 This inherent characteristic warrants a brief discussion of the effects of temperature
and humidity on the products.
 General statements relative to the effects of temp and humidity on soft gelatin
capsules must be confined to a control capsule that contains mineral oil with a gelatin
shell having a dry glycerin to dry gelatin ratio of 0.5:1 and water to dry gelatin ratio
of 1:1 and that is dried to equilibrium with 20-30% RH and 21-24 °C.
 The physical stability of soft gelatin capsules is associated primarily with the pick up
or loss of water by the capsule shell.
 If these are prevented by proper packaging, the above controlled capsule should have
satisfactory physical stability at temperature ranging from just above freezing to as
high as 60 °C.
 As the humidity increases the moisture content pickup of capsules increases as shown
below:
 At 30%RH at room temperature shows that gelatin retain about 12% (48 mg) of
water and glycerin 7% (14 mg) of water.
 At 60%RH the moisture content should be 17.4%.
 At high humidity (>60% RH at 21-24°C) produce more lasting effects on the
capsule shell.
 Since as moisture is absorbed, the capsules become softer, tackier, and bloated.
 The capsule manufacturer routinely conducts accelerated stability tests on new
product as an integral part of the production development program.
 The successful results are obtained by conducing at test conditions like
 80%RH at room temp in an open container
 40 °C in open container
 40 °C in closed container (glass bottle with tight screw cap)

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3.10. Comparison between hard gelatin capsules and soft-gels

Parameters Hard gelatin capsules Soft gelatin capsules
Pieces Two Single
Fill material Usually solids, semisolid and Usually semisolid and liquids, solids
liquids possible possible even a tablet can be
encapsulated (Gel-Tab)
Shape Limited Many
PlasticizationNot-Plasticized, moisture Plasticized and highly elastic
makes it not brittle
Closure Traditional friction fit, Hermitically or inherently sealed
interlocking, or liquid sealing (two halves of gelatin are fused
during encapsulation by heat and
pressure)
Manufacturing Shell manufacture and filling Shell manufacture and filling are
are performed in completely performed in one process
two different processes
Fill accuracy 2-5% with modern automatic 1-3%
machines

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4. Microcapsules and Microspheres

 Microspheres are small spherical particles, with diameters in the micrometer range
(typically 1 μm to 1000 μm).
 Microspheres are sometimes referred to as microparticles.
 The term microspheres describe a monolithic spherical structure with the drug or
therapeutic agent distributed throughout the matrix either as a molecular dispersion
or as a dispersion of particles.
 Microspheres are widely applied to Agriculture, Medical, Food, Fragrance and
Cosmetic industries.
 Microcapsules and Microspheres techniques are part of control release technology.
 Active materials are encapsulated to form barriers so that the active substance can be
delivered at an optimum time and rate.
 Specially designed polymers are used to make these shells.
4.1. History
 The concept of packaging microscopic quantities materials within microspheres dates
to the 1930s: “the work of Bungenberg de Jong and co-workers on the entrapment of
substances within coacervates”.
 In the early 1950s Barrett K. Green developed the microencapsulation that used the
process of phase-separation-coacervation.
 The first successful commercial development of a product containing microcapsules
was “carbonless copy paper” developed by the National Cash Register Company that
eliminated the requirement of carbon paper.
 The first pharmaceutical product consisting of microcapsules was a controlled-
release aspirin product.
 In recent years, the microencapsulation processes are used in many industries such
as food, food additives, cosmetics, adhesives, household products and agricultural
materials as well as the aerospace industry and many more.
4.2. Advantages of Microspheres
 Microspheres provide constant and prolonged therapeutic effect.
 Reduces the dosing frequency and thereby improve the patient compliance.
 They could be injected into the body due to the spherical shape and smaller size.
 Better drug utilization will improve the bioavailability and reduce the incidence or
intensity of adverse effects.
 Microsphere morphology allows a controllable variability in degradation and drug
release.
4.3. Limitation of Microspheres
Some of the disadvantages were found to be as follows
 The release rate of the controlled release dosage form may vary from a variety of
factors like food and the rate of transit though gut.
 Differences in the release rate from one dose to another.

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 Controlled release formulations generally contain a higher drug load and thus any loss
of integrity of the release characteristics of the dosage form may lead to potential
toxicity.
 Dosage forms of this kind should not be crushed or chewed.
Microsphere (Micromatrix)
 The core material is homogeneously dispersed in polymer matrix.

Microcapsule
 The polymer encapsulates the core material (drug particle) uniformly.

4.4. Preparation of Microspheres

Preparation of microspheres should satisfy certain criteria:
 The ability to incorporate reasonably high concentrations of the drug.
 Stability of the preparation after synthesis with a clinically acceptable shelf life.
 Release of active substance with a good control over a wide time scale.
 Biocompatibility with a controllable biodegradability and
 Susceptibility to chemical modification.

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4.4.1. Materials
Microspheres usually prepared from polymeric materials. They are classified into two
types:
i) Synthetic Polymers
a) Non-biodegradable polymers
e.g. Poly methyl methacrylate (PMMA)
Acrolein
Glycidyl methacrylate
Epoxy polymers
b) Biodegradable polymers
e.g. Lactides, Glycolides & their co polymers
Poly alkyl cyano acrylates
Poly anhydrides
ii) Natural polymers
e.g. Proteins (Albumin, Gelatin and Collagen)
Carbohydrates (Agarose, Carrageenan, Chitosan, Starch)
Chemically modified carbohydrates (Poly dextran, Poly starch)
 In case of non-biodegradable drug carriers, when administered parenterally, the
carrier remaining in the body after the drug is completely released poses possibility
of carrier toxicity over a long period of time.
 Biodegradable carriers which degrade in the body to non-toxic degradation products
do not pose the problem of carrier toxicity and are more suited for parenteral
applications.
Synthetic Polymer
 Poly alkyl cyano acrylates is a potential drug carrier for parenteral as well as other
ophthalmic, oral preparations.
 Poly lactic acid is a suitable carrier for sustained release microspheres of narcotic
antagonist, anti-cancer agents such as cisplatin, cyclo phosphamide, and doxorubicin.
 Sustained release preparations for anti-malarial drug as well as for many other drugs
have been formulated by using of co-polymer of poly lactic acid and poly glycolic acid.
 Poly anhydride microspheres (40µm) have been investigated to extend the
precorneal residence time for ocular delivery.
 Poly adipic anhydride is used to encapsulate timolol maleate for ocular delivery.
 Poly acrolein microspheres are functional type of microspheres.
 They do not require any activation step since the surfacial free CHO groups over the
poly acrolein can react with NH2 group of protein to form Schiff’s base.
Natural Polymer
 Albumin is a widely distributed natural protein.

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 It is considered as a potential carrier of drug or protiens (for either their site specific
localization or their local application into anatomical discrete sites).
 It is being widely used for the targeted drug for the targeted drug delivery to the
tumour cells.
 Gelatin microspheres can be used as efficient carrier system capable of delivering the
drug or biological response modifiers such as interferon to phagocytes.
 Starch belongs to carbohydrate class.
 It consists of principle glucopyranose unit, which on hydrolysis yields D-glucose.
 It being a poly saccharide consists of a large number of free OH groups.
 By means of these free OH groups a large number of active ingredients can be
incorporated within as well as active on surface of microspheres.
 Chitosan is a deacylated product of chitin.
 The effect of chitosan has been considered because of its charge.
 It is insoluble at neutral and alkaline pH values, but forms salts with inorganic and
organic salts.
 Upon dissolution, the amino groups of chitosan get protonated, and the resultant
polymer becomes positively charged.

4.4.2. Prerequisites for Ideal Microparticulate Carriers

 Longer duration of action  Sterilizability
 Control of content release  Relative stability
 Increase of therapeutic efficacy  Water solubility or dispersibility
 Protection of drug  Bioresorbability
 Reduction of toxicity  Targetability
 Biocompatibility  Polyvalent

4.4.3. Parameters that can be satisfactorily controlled

 Taste and odour masking
 Conversion of oil and other liquids, facilitating ease of handling
 Protection of the drug from the environment
 Delay of volatilization

4.4.4. Methods of Preparations

 Spray Drying  Coacervation phase separation method
 Solvent evaporation method  Spray drying and spray congealing method
 Single emulsion technique  Polymerization method
 Double emulsion technique

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i) Spray Drying
 In Spray Drying the polymer is first dissolved in a suitable volatile organic solvent
such as dichloromethane, acetone, etc.
 The drug in the solid form is then dispersed in the polymer solution under high-speed
homogenization.
 This dispersion is then atomized in a stream of hot air.
 The atomization leads to the formation of the small droplets or the fine mist from
which the solvent evaporate instantaneously leading the formation of the
microspheres in a size range 1-100 µm.
 Microparticles are separated from the hot air by means of the cyclone separator while
the trace of solvent is removed by vacuum drying.
 One of the major advantages of process is feasibility of operation under aseptic
conditions this process is rapid and this leads to the formation of porous micro
particles shown in Figure 2.

Figure 2: Spray Dryer

ii) Phase Separation Coacervation
 Microencapsulation by coacervation phase separation is generally attributed to The
National Cash Register (NCR) Corporation and the patents of B.K. Green et al.
 The process consists of three steps:
 Formation of three immiscible phases; a liquid manufacturing phase, a core material
phase and a coating material phase.
 Deposition of the liquid polymer coating on the core material.
 Rigidizing the coating usually by thermal, cross linking or desolvation techniques to
form a microcapsule.
 In step 2, the deposition of the liquid polymer around the interface formed between
the core material and the liquid vehicle phase. In many cases physical or chemical
changes in the coating polymer solution can be induced so that phase separation of
the polymer will occur.

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 Droplets of concentrated polymer solution will form and coalesce to yield a two phase
liquid-liquid system.
 In cases in which the coating material is an immiscible polymer of insoluble liquid
polymer it may be added directly.
 Also monomers can be dissolved in the liquid vehicle phase and subsequently
polymerized at interface.
 This method is relatively simple; it consists mainly of jacketed tanks with variable
speed agitators.
iii) Complex Coacervation
 This method is based on the ability of cationic and anionic water-soluble polymers to
interact in water to form a liquid, polymer-rich phase called a complex coacervate.
 Gelatin is normally the cationic polymer used.
 A variety of natural and synthetic anionic water-soluble polymers interact with
gelatin to form complex coacervates suitable for encapsulation.
 This technology usually produces single capsules of 20-800 μm diameter that contain
80-90% by weight core material.
 If a water-insoluble core material is dispersed in the system and the complex
coacervate wets this core material, each droplet or particle of dispersed core material
is spontaneously coated with a thin film of coacervate.
 When this liquid film is solidified, microcapsules are formed.
iv) Air Suspension Techniques (Wurster)
 Microencapsulation by air suspension technique consist of the dispersing of solid,
particulate core materials in a supporting air stream and the spray coating on the air
suspended particles.
 Within the coating chamber, particles are suspended on an upward moving air
stream.
 The design of the chamber and its operating parameters effect a recalculating flow of
the particles through the coating zone portion of the chamber, where a coating
material, usually a polymer solution, is spray applied to the moving particles.

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 During each pass through the coating zone, the core material receives an increment
of coating material.

 The cyclic process is repeated, perhaps several hundred times during processing,
depending on the purpose of microencapsulation the coating thickness desired or
whether the core material particles are thoroughly encapsulated.
 The supporting air stream also serves to dry the product while it is being
encapsulated.
 Drying rates are directly related to the volume temperature of the supporting air
stream.
v) Solvent Evaporation
 The processes are carried out in a liquid manufacturing vehicle.
 The microcapsule coating is dispersed in a volatile solvent which is immiscible with
the liquid manufacturing vehicle phase.
 A core material to be microencapsulated is dissolved or dispersed in the coating
polymer solution.
 With agitation the core material mixture is dispersed in the liquid manufacturing
vehicle phase to obtain the appropriate size microspheres.
 The mixture is then heated if necessary to evaporate the solvent for the polymer. Since
the core material is disperse in the polymer solution, due to evaporation of solvent,
polymer shrinks around the core.
 If the core material is dissolved in the coating polymer solution, matrix – type
microcapsules are formed.
 The core materials may be either water soluble or water insoluble materials. Solvent
evaporation involves the formation of an emulsion between polymer solution and an
immiscible continuous phase whether aqueous (o/w) or non-aqueous.

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vi) Single Emulsion technique

 The micro particulate carriers of natural polymers i.e. those of proteins and
carbohydrates are prepared by single emulsion technique.
 The natural polymers are dissolved or dispersed in aqueous medium followed by
dispersion in non-aqueous medium like oil.
 Next cross linking of the dispersed globule is carried out.
 The cross linking can be achieved either by means of heat or by using the chemical
cross linkers.
 The chemical cross linking agents used are glutaraldehyde, formaldehyde, acid
chloride etc.
 Heat is not suitable for thermolabile substances.
 Chemical cross linking suffers the disadvantage of excessive exposure of active
ingredient to chemicals if added at the time of preparation.
 Then resultant system will subject to centrifugation, washing and separation.
 The nature of the surfactants used to stabilize the emulsion phases can greatly
influence the size, size distribution, surface morphology, loading, drug release, and
bio performance of the final multiparticulate product.
vii) Double Emulsion technique
 Double emulsion method of microspheres preparation involves the formation of the
multiple emulsions or the double emulsion of type w/o/w and is best suited to water
soluble drugs, peptides, proteins and the vaccines.
 This method can be used with both the natural as well as synthetic polymers.
 Active principle to be encapsulated is incorporated in an aqueous solution, which is
poured into the casting organic solution of the polymer to form the emulsion of type
w/o.
 The primary emulsion is subjected then to the homogenization or the sonication
before addition to the aqueous solution of the polymer.
 The primary emulsion is itself emulsified in an external aqueous phase leading to
multiple emulsion of the type (w/o/w) (Figure 3).
 The organic phase acts as a barrier between the two aqueous compartment
preventing diffusion of drug towards the external aqueous phase.
 The emulsion is then subjected to solvent removal either by solvent evaporation or
by solvent extraction.
 Number of hydrophilic drugs like leutinizing hormone releasing hormone (LH-RH)
agonist, vaccines, proteins/peptides and conventional molecules are successfully
incorporated into the microspheres using the method of double emulsion solvent
evaporation/ extraction.

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viii) Polymerization techniques

The polymerization techniques conventionally used for the preparation of the
microspheres are mainly classified as:
a. Normal polymerization
b. Interfacial polymerization.
Both are carried out in liquid phase.
a) Normal polymerization
 It is carried out using different techniques as bulk, suspension, precipitation,
emulsion and micellar polymerization processes.
a. In bulk, a monomer or a mixture of monomers along with the initiator or catalyst
is usually heated to initiate polymerization. Polymer so obtained may be moulded
as microspheres. Drug loading may be done during the process of polymerization.
Bulk polymerization has an advantage of formation of pure polymers.
b. Suspension polymerization also referred as bead or pearl polymerization. Here it
is carried out by heating the monomer or mixture of monomers as droplets
dispersion in a continuous aqueous phase. The droplets may also contain an
initiator and other additives.
c. Emulsion polymerization differs from suspension polymerization as due to the
presence initiator in the aqueous phase, which later on diffuses to the surface of
micelles.

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b) Interfacial polymerization
 It involves the reaction of various monomers at the interface between the two
immiscible liquid phases to form a film of polymer that essentially envelops the
dispersed phase.
 Drug is incorporated either by being dissolved in the polymerization medium or by
adsorption onto the nanoparticles after polymerization completed.

ix) Centrifugal force and submerged nozzle process

 A cup perforated with series of fine holes is immersed in an oil bath.
 It is rotated while immersed in oil thereby extruding into the oil phase a stream of
droplets of an oil-in-water emulsion.
 The water phase of this emulsion is a concentrated solution of a water-soluble
polymer that gels on cooling e.g. gelatin.
 By controlling the temperature of oil bath, the external phase of extruded emulsion
droplets is gelled to create oil loaded gel bead lets that can be isolated and dried.
a) Submerged nozzle process
 Capsules are produced by co-extruding an aqueous gelatin solution and oil to be
encapsulated through a two fluid nozzle into a moving fluid stream of an oil solution.
 The gelatin solution surrounds the oil drop to be encapsulated at the point of
extrusion and is gelled thermally before the particles are harvested and dried.

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b) Multi-Orifice Centrifugal Process

 This process utilizes centrifugal forces to hurl a core material particle through an
enveloping microencapsulation membrane, thereby effecting mechanical
microencapsulation.
 The rotating disc flings the particulate the core material towards the orifices.
 The core material arrives at the orifices and encounters the coating material
membrane.
 The impact and centrifugal force generated by the rotating cylinder hurls the core
material through the enveloping coating membrane.
 The embryonic microcapsules upon leaving the orifices are hardened, congealed, or
voided of coating solution.
Processing variables
 Rotating speed of the cylinder
 Flow rate of core and coating material
 The conc. And viscosity of the coating material
 Viscosity and surface tension of core material

x) Centrifugal Extraction
 The core and shell material, two mutually immiscible liquids are pumped through a
spinning two fluid nozzle.
 This produces a continuous two fluid columns or rod liquid that spontaneous break
up into a stream of spherical droplets immediately after it emerges from the nozzle.
 Each droplet contains core region surrounded by a liquid shell.

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 If the shell material is a low viscosity hot melt that crystallizes rapidly on cooling, the
droplets are converted into solid particles as they fall away from the nozzle.
 Core material- polar liquid solution.
 Shell Materials- waxes.
 Droplets emerging from the nozzle may have a shell that is an aqueous polymer
solution able to be gelled rapidly.
 The droplets fall into the gelling bath where they are converted into gel beads.
 Capsules prepared by this process range from 250 m to several mm.

4.5. Characterization of Microspheres

The characterization of the microparticulate carrier is an important phenomenon, which
helps to design a suitable carrier for the proteins, drug or antigen delivery. These
microspheres have different microstructures. These microstructures determine the
release and the stability of the carrier.
i) Particle size and shape
 The most widely used procedures to visualize microparticles are conventional light
microscopy (LM) and scanning electron microscopy (SEM).
 Both can be used to determine the shape and outer structure of microparticles.
 LM provides a control over coating parameters in case of double walled microspheres.
 The microspheres structures can be visualized before and after coating and the
change can be measured microscopically.
 SEM provides higher resolution in contrast to the LM.
 SEM allows investigations of the microspheres surfaces and after particles are cross-
sectioned, it can also be used for the investigation of double walled systems.
 Confocal fluorescence microscopy is used for the structure characterization of multiple
walled microspheres.
 Laser light scattering and multi size coulter counter other than instrumental methods,
which can be used for the characterization of size, shape and morphology of the
microspheres.
ii) Electron spectroscopy for chemical analysis
 The surface chemistry of the microspheres can be determined using the electron
spectroscopy for chemical analysis (ESCA).

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 ESCA provides a means for the determination of the atomic composition of the
surface.
 The spectra obtained using ECSA can be used to determine the surficial degradation
of the biodegradable microspheres.
iii) Attenuated total reflectance Fourier Transform- Infrared Spectroscopy
 FT-IR is used to determine the degradation of the polymeric matrix of the carrier
system.
 The surface of the microspheres is investigated measuring alternated total reflectance
(ATR).
 The IR beam passing through the ATR cell reflected many times through the sample
to provide IR spectra mainly of surface material.
 The ATR-FTIR provides information about the surface composition of the
microspheres depending upon manufacturing procedures and conditions.
iv) Density determination
 The density of the microspheres can be measured by using a multi volume
pycnometer.
 Accurately weighed sample in a cup is placed into the multi volume pycnometer.
 Helium is introduced at a constant pressure in the chamber and allowed to expand.
 This expansion results in a decrease in pressure within the chamber.
 Two consecutive readings of reduction in pressure at different initial pressure are
noted.
 From two pressure readings the volume and hence the density of the microsphere
carrier is determined.
v) Isoelectric point
 The micro electrophoresis is an apparatus used to measure the electrophoretic
mobility of microspheres from which the isoelectric point can be determined.
 The mean velocity at different pH values ranging from 3-10 is calculated by measuring
the time of particle movement over a distance of 1 mm.
 By using this data the electrical mobility of the particle can be determined.
 The electrophoretic mobility can be related to surface contained charge, ionisable
behavior or ion absorption nature of the microspheres.
vi) Angle of contact
 The angle of contact is measured to determine the wetting property of a micro
particulate carrier.
 It determines the nature of microspheres in terms of hydrophilicity or
hydrophobicity.
 This thermodynamic property is specific to solid and affected by the presence of the
adsorbed component.
 The angle of contact is measured at the solid/air/water interface.
 The advancing and receding angle of contact are measured by placing a droplet in a
circular cell mounted above objective of inverted microscope.
 Contact angle is measured at 20˚C within a minute of deposition of microspheres.

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vii) In vitro methods

 There is a need for experimental methods which allow the release characteristics and
permeability of a drug through membrane to be determined.
 For this purpose, a number of in vitro and in vivo techniques have been reported.
 In vitro drug release studies have been employed as a quality control procedure in
pharmaceutical production, in product development etc.
 Sensitive and reproducible release data derived from physico chemically and hydro
dynamically defined conditions are necessary.
 The influence of technologically defined conditions and difficulty in simulating in vivo
conditions has led to development of a number of in vitro release methods for buccal
formulations; however no standard in vitro method has yet been developed.
 Different workers have used apparatus of varying designs and under varying
conditions, depending on the shape and application of the dosage form developed.
 The dosage form in this method is made to adhere at the bottom of the beaker
containing the medium and stirred uniformly using overhead stirrer.
 Volume of the medium used in the literature for the studies varies from 50-500 ml
and the stirrer speed form 60-300 rpm.

4.6. Application of Microspheres

1. Microspheres are used for sustained and controlled release.

E.g. drugs like riboflavin, indomethacin, aspirin, and steroids like progesterone;
testosterone, etc. can be incorporated in it to control their release.
2. It is used in enteric release dosage form.
E.g. drugs like aspirin, salbutamol sulphate which irritant to the stomach and other
side effects can be incorporated in microspheres for their selective release in
intestine.
3. It is used for drug targeting.
E.g. casein and gelatin microspheres containing Adriamycin were magnetically
delivered to the tumor site.

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4. It is used as antigens carrier.

E.g. microspheres prepared from poly (lactic acid) and its copolymer with glycolic
acid (PLGA) of varying composition has been used to improve the ability of the
antigens to provoke a mucosal immune response.
5. To alter the residence time and to improve the bioavailability.
E.g. albumin and gelatin microspheres containing pilocarpine nitrate (ophthalmic
drug delivery) for delivery to eye increase residence time of drug in the eye and
provide improved bioavailability.
6. It is used to protect reactive materials against environment.
E.g. vitamins, aspirin.
7. To separate incompatible substances.
E.g. the stability of incompatible drugs like aspirin and chlorpheniramine maleate
mixture was increased by microspheres of individual components.
8. For isolation from tissues.
E.g. KCl, aspirin.
9. For administration in solid state and dry handling.
E.g. liquids such as eprazine can be converted to a pseudo solid by microspheres as an
aid to handling and storage.
10. It is used to mask bitter or unpleasant taste of the drug.
E.g. quinidine, clofibrate, & paracetamol.
11. It is used as an antidote in the poisoning of heavy metals.
E.g. polymercaptal microspheres on an antidote against mercury poisoning.
12. To facilitate handling of toxic materials.
E.g. microspheres have been used to decrease potential danger in handling toxic
substances like pesticides, fertilizers, and certain pharmaceuticals.
13. It is used as diagnostic tool.
E.g. microencapsulated radio labeled molecules has been used for diagnostic testing
of free drug or hormone concentrations, such as thyroxin estimation.

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5. GTU Questions
 Outline the process of manufacturing gelatin which is used in capsule
 Write a note excipients and additives used in the capsule formulation.
 What is bloom strength? How is it measured?
 What is bloom strength of gelatin? Explain it.
 Explain quality control tests of hard and soft gelatin capsules.
 Comment: Storage condition for capsules is very critical.
HGC
 Explain the formulation of hard gelatin capsule shell.
 Discuss piston tamping principle for filling of hard capsule.
 Define Capsules. Write the quality control tests on Hard Gelatin Capsules.
 Describe the finishing of hard gelatin capsules. Give the approximate fill volume of 00
and 000 size capsules.
 Explain various compositions of hard gelatin capsules.
 What are vegetable capsules? How are they differing from gelatin capsules?
SGC
 Explain rotary die process for manufacturing of soft capsule.
 Write note on base adsorption and M/g factor in capsule Mfg.
 Define & explain “base adsorption” of the solid in soft gelatin capsule.
 What are soft gelatin capsules? Describe rotary die process for their preparation.
 Discuss quality control parameters of soft gelatin capsule.
Microcapsules/microspheres
 Mention the applications of different polymers used in microcapsules /microspheres.
 Explain term microcapsule. Discuss in detail phase coacervation phenomena for
preparation of microcapsules.
 Enumerate various evaluation parameters for microencapsulation. Discuss
application of biodegradable polymer in microcapsules.
 Write note on wurster process for microcapsule.
 Explain the term microsphere and give its importance.
 Enumerate different methods for preparation of microcapsules and explain any one
of them in brief with suitable example.
 Explain the various techniques used in the preparation of microspheres.
 Explain microspheres and microcapsules. Describe their significance in drug delivery.
 What is coacervation phase separation? Which are the techniques to achieve phase
separation?
 Describe biodegradable and non-biodegradable polymers used in microcapsules.
 Enlist advantages and disadvantages of microcapsules giving suitable examples.

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 Enlist various methods of microencapsulation and explain any one in detail.

 Enlist and discuss various evaluation parameters for micro- capsulation.

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