CAPSULE
D.S.T.S MANDALS COLLEGE OF PHARMACY, SOLAPUR
Mr. P.B.Digge
Advantages of Capsules
a) Capsules are tasteless, odourless.
b) They are elegant, attractive in appearance .
c) Drugs with unpleasant odour or taste can be administered as capsule.
d) Capsules specially design for semisolid and liquid state of APIs.
e) Capsules can administerd into the vaginal and anal cavity, because soft gelatin
shell has anti-irritant effect in mucosal layer.
f) Capsule is too easy to handle and carry in ambient environment.
g) They are easily swallowed and quickly dissolved in the stomach,
h) Capsule shells have little or no interaction with Gl contents. (Inert,biocompatible)
Disadvantages of Capsules
a) Capsules are more expensive than tablets.
b) Some hygroscopic drugs absorb moisture from the capsule shell making it more
brittle.
c) Capsules are not air tight thus the shelf life is shorter. (Hard Gelatin Capsule)
d) Unsuitable for concentrated solutions that require dilution prior to administration.
e) Filling operation is performed without compression and thus occupies more
volume.
f) Capsule filling volumes are limited thus limits the dose of the drug.
Hard Gelatin Capsules (HGC)
•Hard gelatin capsules are used for enclosing solid medicament or dry powders of
drug substance.
•It is also known as dry filled capsule.
•They are less flexible and consist of cap and body. The cap is short while body is
long.
•It is available in different sizes, shapes and colours.
•Hard gelatine capsule are hygroscopic in nature.
Primary Ingredients in HGC
Gelatin:
•Gelatin is a tasteless, odourless protein substance which is extracted by boiling
the skin, tendons, ligaments, bones of ox and pig.
•There are two types of gelatine: Type A which is produced by acid-catalyzed
hydrolysis and Type B which is produced by alkali -catalyzed hydrolysis.
•Due to non toxic nature gelatin is widely used in food industry.
•Gelatin is readily soluble in biological fluid and it also has good film forming
properties.
•The molecular weight of gelatin is 15,000-2,50,000.
Plasticizers:
•Plasticizers are additives that increase the plasticity or fluidity of a material.
•It provides structural integrity to the gelatin so the capsule can maintain its
shape.
•The amount of plasticizers determines the rubbery texture of the capsule.
•Sorbitol and glycerin are the most commonly used plasticizers in HGC.
Other components:
•Other components of HGC are colouring agents, preservatives such as methyl
paraben, lubricants such as stearic acid and surface treatment agents.
•Titanium dioxide (TiO₂) may also be included for opacifying effects.
•Opaque capsules are used to provide protection against light or to conceal or
(hide) the contents.
The major component of HGC is gelatin.
Gelatin manufacturing involves organic reactions and thus its preparation is a time
consuming process and may require many weeks to complete the processing.
Previously gelatin capsules were fabricated by pharmaceutical manufacturers but
currently, capsule shell production is done by third party suppliers.
Gelatin solution:
Capsule production is an automated operation that begins with solubilizing the dry
gelatin with a mixture of plasticizer and purified water.
The gelatin solution is heated and transferred to a dip pan or pot which holds specific
amount of hot gelatin at particular temperature.
The amount of gelatin in pot is maintained automatically by controlling flow from hopper.
Dipping:
In this process, stainless steel pins are submerged in the heated gelatin solution to
simultaneously form caps and bodies.
The pins are maintained at 20 – 22°C, whereas the dipping solution is maintained at 50°C
in a heated, jacketed dipping pan.
The contact time of pin to form the film is about 12 sec.
During production, the thickness of the capsule wall is controlled by the viscosity of the
gelatin solution, speed and time of dipping.
Spinning:
After dipping, pins are elevated and spinned to uniformly distribute the gelatin over the
surface to avoid the formation of a bead at the capsule ends.
Drying:
Blasts of cool air, which dry and solidify the capsules, is the next operation.
The viscous gelatin is allowed to dry on the pins and when dry these are removed from
the pins.
Stripping:
A series of bronze jaws are used to strip the cap and body capsules from the pins.
Capsules are rotated on a fixed clamping device to keep them in parts of the place.
Trimming:
Once the capsules are dry, they are separated from the pins by a set of mechanical jaws.
The stripped cap and body parts are further trimmed to the required length using
stationary knives.
The stripped cap and body parts are delivered to a collector where they are firmly held
together.
As collector rotate, knives trims shells to the required length.
Joining:
After trimming to the right length, the cap and body are aligned in channels and the two
portions are slowly pushed together to join them.
The joined whole empty capsule is ejected from the machine.
Polishing:
Empty capsules are polished in pan. Acela-cota pan is used to de-dust and polish.
Capsules are rubbed with cloth to make surface smooth.
Brushing:
Capsules are fed under soft rotating brush to make them free from adsorbed
particles.
Sorting:
The capsules moving on conveyor are examined visually for sorting defective
units by the automated systems or by inspectors .
Printing:
Often capsules are printed before filling operation Printing is done on offer rotary
printing machines having capacities of about 7.5 to 8 lakh capsules per hour.
Size of Capsules and approx. capacity
FORMULATION OF HARD GELATIN CAPSULES
(Powder blend/Granules/Pellets)
The main objective of formulating Powder blend/Granules/Pellets are……….
the good stability, accurate dose, elegance, easy in feeling and better bioavailability.
Excipients used in Capsule manufacturing
(1) Diluents: Improve the physical properties of the contents and increase the volume, and
they often have a certain compressibility. Commonly used diluents are mannitol,
microcrystalline cellulose, lactose, pregelatinized starch 1500, corn starch etc
(2) Lubricants: Prevent the adhesion of powder to metallic part of hopper. Common
materials include magnesium stearate, glyceryl monostearate, stearic acid etc
(3) Glidants: Improve the flow property of the contents. Commonly used glidants are
micro-silica gel and talcum powder.
(4) Disintegrants: Ensure the disintegration of the contents. Common disintegrants include
crosslinked cellulose, corn starch, crosspovidone, pregelatinized starch 1500 etc
(Prepared granules, pellets can easily breakdown )
(5) Protective sorbents: These agents are added to retard the moisture absorption by
hygroscopic agents . e.g. Calcium carbonate, magnesium carbonate, calcium oxide etc
(6) Adhesives: The adhesive binds the drug powder together at the time of granulation, such
as starch slurry, CMC-Na, (Sodium carboxymethyl cellulose) HPC etc
Preparation of Formulation:
A. Dry formulation
i) Powders-The filling of powders into capsules known as accofil or Elancofil
ii) Pellets- The filling of pellets into the capsule known Rotofil. The drug
substances which are designed for modified releases are molded in the form of
pallets and are coated with the suitable coating agents these coated pellets are
then field in the empty capsule shells.
iii) Capsules or tablets- Small capsules or tablets are sometimes placed in the
capsule shell and the remaining capsules body is filled with weighed inert
materials this may help to isolate the chemically incompatible drugs
B) Wet Formulation
Liquid API mixed with absorbents or diluents like Calcium magnesium carbonate
light magnesium oxide. The filling of liquid into capsules is known as
Qualiseal.
Filling of Hard Gelatin capsule:The several type of filling machines in use
in the pharmaceutical industry have in common the following operational
steps or stages.
1. Rectification: The empty capsule are aligned in one direction , i.e Cap end upword
and body end downward. Rectification process happed in the channel which are
placed below the feeder. The vacuum pump helps to rectification.
2. Separation of cap from bodies: In that step Separation of cap from bodies, by
locking the caps into the upper bed plate and body of capsule locked into the
lower bed plate. Separation is due to the decrease the size of bed cavity, cause
capsules hold into the bed cavities.
3. Dosing of fill material: various method like Auger principle, vibratory fill
principle, piston-Tamp principle are employed for powder filling with help of
pins called as piston tamp.
4. Sealing of filled capsule: The cap & body portion are rejoined, by placing the
cap bed plates on to the body bed plates. After sealing, sealed capsules ejected
by compressed air.
Methods of Capsule Filling
(i) Manual filling
(ii) Hand filling or semi-automatic machines
(iii) Fully automatic capsule filling machines
i)Manual filling
The manual filling can be opted when very few numbers of capsules are to be filled.
Principle: Manual filling involves separation of caps and bodies, fillingof bodies
and finally joining of caps and bodies to produce accurately filled capsules.
Method: The ingredients to be encapsulated are triturated to obtain uniform sized
particles and placed on a sheet of clean paper. With the help of a spatula, the
triturated ingredients are made into a cake such that the height of the cake is
almost one third the height of the capsule.
• The required numbers of empty capsules are taken and their caps are separated
from the bodies. The required numbers of empty capsules are taken and their
caps are separated from the bodies. A single body of the capsule is held a
between the thumb and the index finger and is punched into the cake of
powdered drug repeatedly until filled. Finally, the cap is placed over the filled
body.
ii)Hand filling or semi-automatic machines-:
Principle: The principle of hand filling machine is similar to that of manual
filling, except that the rate of capsule filling process is enhanced.
The hand filling machine consists of a fixed lower plate and a movable top plate.
Both the plates have grooves for placing capsule bodies and caps. The lower plate
has clamps which can carry bodies and helps in removal and replacement of caps.
It has the capacity of filling 300 capsules simultaneously. When properly handled,
it can produce about 20000 capsules in a day.
Working: The capsule shells are placed in the lower plate manually with the caps
facing up. The top plate is placed over this lower plate, a slight pressure is applied
and the plate is lifted. It results in separation of caps and bodies (caps in top plate
and bodies in the lower plate). The measured amount of powdered drug is spread
evenly in all the bodies. Finally, the top plate is replaced over the lower plate so
that the caps are placed on the filled capsules bodies i.e., the capsules are sealed
and locked simultaneously.
Capsule Hand filling machine
Finishing of capsule: in order to make capsule more elegant, they under go
the process of finishing. The commonly used step for producing finished capsule
are as follows:
1. Cloth dusting: it is manual method in which small number of capsule are rubbed
with a cloth which may or may not contain inert oil.
2. Polishing: special pan may be used for polishing the the filled capsule. these pan
lined with cheese or polyurethane cloth which remove the dust or other powder
adhere to capsule
3. Brushing: in this method capsule are projected under soft rotating brushes
which remove the dust from capsule shell. This process is assisted under vacuum.
Manufacturing defects of capsule
Major defects
Pin Holes - An irregular opening in the cap or body
Split- A split in the film starting from the cap or body edge
Cracked- A cap or body with many splits
Uncut cap/body -An untrimmed cap or body.
Failure to Cap and body may not be separated properly
Double dip- Extra thick cap due to being dipped twice.
Short Cap - length is 1 mm less than specified length.
Short body - less than specified length
Double cap- A capsule with an additional cap covering the body end
Pinched- Cap or body damage during mechanical collection. Greater than 3mm
pinched or pressed is major defects.
Long joined -Capsule not closed sufficiently to engage the lock
Dye speck- A coloured spot of pigment aggregate different from the colour of cap or
body
Inverted end -A cap or body with the end pushed inwards
Damaged -The edge of the cap is roughly trimmed.
Minor defects
Scrape - A Scratch mark on the surface of a cap or body
Grease – Small marks of grease
Dent- A depression formed in the end of cap or body
Small damaged edge - The edge of the cap is roughly trimmed
Bubble- An air bubble in the cap or body wall which has a diameter greater than 0.4mm
Chips, tails, string- Small fragments of gelatin still attached or free within the capsule from
different color than cap or body
Black speck- A non-contaminant black spot
In Process and Final Quality Control Tests for Capsules
1. Raw material
The gelatin of capsule shell should be assessed for various physical properties like bloom
strength, viscosity, iron content, microbial test etc.
(a) Bloom strength: Bloom strength is defined as an assessment of cohesive strength of
the cross-linking between the molecules of gelatin. It is also known as gel strength or
gel rigidity of gelatin and depends upon its molecular weight. The harder the gelatin,
the higher is its bloom strength.
Determination of bloom strength: A gelatin solution having a concentration, of 6.66%
w/v in kept for 17 hours at a temperature of 10°C. A plastic plunger of 0.5-inch
diameter is taken. The weight (in gram) required to move the plastic plunger 4 mm into
the stored gelatin solution determines the bloom strength of gelatin. Depending upon
the requirements of capsules manufacturers, bloom strength lies in between 150-250 g.
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.
Physical stability of capsule directly proportional to bloom strength of gelatin
i.e. Increasing the bloom strenth ,the physical stability of capsules increases.
(b) Viscosity:
It is defined as the assessment of chain length of gelatin molecules in 6.66% w/v
concentrated gelatin solution in warm water at 60°C. Accordingly, manufacturing
is carried out on a fixed sealing temperature. The gelatin sheets so produced are
pharmaceutically elegant, hard non-viscous and are easy to cut. The required
viscosity of gelatin lies in between 25-45 millipoise.
(c)Iron content: Iron is present in the raw gelatin as well as in the water used for
manufacturing of gelatin capsules shells. Excess quantity of iron in the soft gelatin
capsules can affect the FDC (Food, Drugs and Cosmetics) certified dyes and may
also react with the other organic compounds. Because of this reason iron is not
used in concentration of more than 15 ppm in their manufacturing.
2. Moisture permeation test (I.P. 2007)
The degree and rate of moisture penetration is determined by packaging the
dosage unit together with colour revealing desiccant pellet. Expose the packaged
unit to known relative humidity over a specified time. After some time observe the
desiccant pellet for colour change, any change in colour indicates absorption of
moisture and by measuring pre-weight and post-weight of pellet, the amount of
moisture absorption can be calculated. The standard moisture content specification
for hard gelatin capsule is 12-16%
3. Content uniformity test (I.P. 2007)
Determine the content of active ingredient in each of 10 capsules taken at random using the
method given in the monograph or by any other suitable analytical method of equivalent accuracy
and precision. The capsules comply with the test when all capsules content uniformity within
limit or within the 5% deviation allowed. The capsules comply with the test If Not more than
two capsules outside the limits 85 to 115 % , If three capsule found outside the limits 85 to 115 %
repeat the determination using another 20 capsules. The capsules comply with the test if in the
total sample of 30 capsules not more than three individual values are outside the limits 85 to 115
per cent and none is outside the limits 75 to 125 per cent of the average value.
4. Weight variation test (I.P. 2007)
Weigh an intact capsule. Open the shell and remove the contents as completely as possible.
Weigh the shell. The difference between the weighings gives the weight of the contents. Repeat
the procedure with another 19 capsules.Calculate the average weight. Based on the average
weight calculate upper limit and lower limit. Not more than two of the capsule content weight
deviates from the average weight by more than the percentage shown in the table and none
deviates by more than twice that percentage. Percentage deviation allowed as per I.P.
Disintegration test (I.P. 2007)
Place dosage unit in each of the 6 tubes of the basket and, if prescribed, add a disc. Operate the
apparatus using the specified medium, maintained at 37 ± 2 °C, as the immersion fluid. 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 1 or 2 dosage units fail to disintegrate, repeat the
test on 12 additional dosage units. The passing requirements of the test is out of 18 capsule 16
capsules should be disintegrated .
6. Dissolution test (I.P. 2007)
Apparatus type-1: The capsule sample is allowed to sink to the bottom of the flask before stirring.
The paddle is immersed in a dissolution medium. The flask is maintained at 37 ± 0.5°C by a
constant temperature bath. For dissolution test, I.P. specifies the dissolution test medium and
volume, type of apparatus to be used, rpm of the shaft, time limit of the test and assay procedure.
The tolerance is expressed as % of labelled amount of drug dissolved in the time limit. If single
Capsule shown 25% deviation then fail the test
Apparatus type-2: A single capsule is placed in a small wire mesh basket attached to the bottom
of the shaft connected to a variable speed motor. The basket is immersed in a dissolution medium
(as specified in monograph) contained in the flask. The flask is cylindrical with a hemispherical
bottom. The flask is maintained at 37 ± 0.5°C by a constant temperature bath. The motor is
adjusted to turn at the specified speed and sample of the fluid are withdrawn at intervals to
determine the amount of drug in solutions If single Capsule shown 25% deviation then fail the
test
A softgel or soft gelatin capsule is a solid unit dosage form in which one
or more medicaments are enclosed into the intact body of soft gelatin.
Softgel bodies are hermetically sealed so higher the shelf life of API
A soft gelatin capsules dissolves more quickly than a hard gelatin capsule. Soft gelatin
capsules dissolve readily in the gastric juices of the stomach, and may work faster than
hard gelatin capsules.
Temperature sensitive drug in low dose may incorporate into the outer shell.
The outer shell is composed of a gelatin, Gelatin matrix consists of gelatin, plasticizer,
solvent and optional ingredients such as flavors and colorants.
Rotary die process: Two plasticized gelatin ribbons are continuously formed and
simultaneously fill with the liquid or paste between the rollers of the rotary die
mechanism where the capsule are simultaneously filled, shaped, hermetically sealed and
cut from the gelatin ribbon.
Manufacturing of soft gelatin Capsule by using rotory die
encapsulating machine
