3.1.

1 Introduction
 Capsules are solid unit dosage forms in which one dose of drug or
mixture of the drug is enclosed in a small, water-soluble shell,
practically tasteless, hard or soft shell made up of a suitable form
of gelatin.
 Solid substances are enclosed in hard gelatin capsules.
 Liquid and semisolids are enclosed in soft gelatin capsules.
 Contain a single dose of drugs and are used for oral
administration.
The two main parts of capsules are:
1. Hard capsules
2. Soft gelatin capsules
Hard gelatin capsule
https://www.slideshare.net/MohammedSaleem40/hard-gelatin-
capsules-ppt-b-56523437
 Hard gelatin capsules are also known as Dry Filled Capsules
(D.F.C.), containing dry, powdered ingredients.
 Hard gelatin capsules consist of two parts or two pieces of the
capsule body (The longer part) and the capsule cap (the shorter
part). The drug substances are placed in the body, and the caps
are slid over it, enclosing them.

BODY CAP

Fig: 1 Showing part of hard gelatin capsule

Essential components of hard gelatin capsules
 Gelatin
 Plasticizers
 Colourants
 Opacifying agents
 Preservatives

3.1.2 Production of hard gelatin capsule shells:

https://www.youtube.com/watch?v=wGnTj847Lpc&t=394s
The utterly automatic machine most commonly used for capsules
production consists of a mechanism for automatically the steps
involved :
1. Dipping: capsules shells are manufactured by dipping cool stainless
steel metal bars into an aqueous gelatin solution maintained at about 50
degrees centigrade.
2. Spinning of the dip-coated pins: after absorption of the gelatin solution
onto the surface of the pins, the bar containing the pins are rotated
several times to evenly distribute the gelatin solution around the pins, as
uniform gelatin distribution helps to form the appropriate thickness of the
capsule wall.
3. Drying the gelatin-coated pins: once the gelatin is uniformly distributed
on the mould, a blast of cool air is introduced to set the gelatin on the
mould. During this time, the gelatin is dried, and the pins are moved
through a series of drying stages for attaining an optimum level of
moisture content.
4. Stripping & Trimming: After the gelatin is dried, the capsules are
stripped off the mould by Bronze jaws and trimmed to the desired length.
5. Joining the trimmed capsule shell: Once trimmed, the two halves (the
cap and body) are joined to the pre-closed position using a pre lock
mechanism. During this stage, printing and packing are done and
packed in cartons for shipping.
The suppliers who supply empty capsules are:
Eli Lilly and Company, Indianapolis, IN, capsule, Greenwood, S
R.P Scherer corporation, Troy, MI
Eli Lilly and Parke-Davis -daily output is up to 200,000 capsules.

Fig: 2 sequences of two-piece complex gelatin capsule shell

manufacture

3.1.3 SIZE OF CAPSULE:

https://www.pharmapproach.com/hard-gelatin-capsules-
formulation-and-manufacturing-considerations/
 Empty capsules range from 000, the largest to 5, the most little,
empty capsules sold depending on sizes.
 Generally, hard gelatin capsules are used to encapsulate between
6.5mg to 1gm
 The most common size for humans used is size 0, which has
volume 0.68ml and 21.8mm
Size of Capsule

example of Aspirin and capsule sizes how much Aspirin will get
occupied in each size of a capsule

 Hard gelatin capsules contain about 12-16% water required

storage under controlled conditions of temp humidity.

3.1.4 Filling of Hard Gelatin Capsule:

The filling of hard gelatin capsules is an established technology, with
equipment ranging from small scale manually filling through intermediate
scale, semi-automatic filling to large scale fully automatic filling.

The several types of capsule filling machines used in the pharmaceutical

industry have everyday operations.
1. Rectification: The empty capsules have oriented all points in the
exact directions, i.e. body end downward(placing empty gelatin
capsules on the removable plate with bodies facing downward).
2. Separation of caps from bodies: The rectified capsules delivered
body end first into the upper portion of split bushing; a Vacuum
applied body from below pulls the body down
3. Dosing of fill material: Various methods like the Auger principle,
Vibratory fill principle, Piston-Tamp principle are employed for
filling
4. Replacement of caps/ closing capsule shells and
5. Ejection of filled capsules

Auger Fill Principle: empty capsules-rectifying unit

The rectifier descends the capsules such that caps are turned up and
bodies down. The rectifying unit is placed one by one filling ring is kept
on rotating mode. The lower ring is rotated at a suitable speed, and the
hopper containing powdered drug is held over this ring; the Auger drives
the drug into bodies.
Vibratory fill principle: the feed is placed in the feed hopper, and the
capsule bodies are passed. A perforated resin plate is placed in the feed
hopper. Due to the vibrations of the resin plate, the powder flows freely
through pores into bodies
Piston-Tamp principle: These piston tamps alter powder shape by
compressing the powder to form slugs. These plugs are transferred into
the empty capsule bodies with slight pressure. Finally, the bodies are
ejected from the machine. Compression force 50-200N
a) Dosator machine
b)Dosing disc
Vacuum Fill principle: it consists of an open-ended cylinder. The upper
end of this is fitted with a piston. A perforated resin plate is positioned
and connected to a vibrator in the powder.
The powder blend tends to fluidize by the vibration of the plate; it assists
the powder to flow into the bodies through the holes in the resin plate.
Capsule filling methods:
1. Manual filling
2. Hand filling
3. Semi-automatic machine
 4. Fully automatic capsule filling machine

1. Manual filling method: This method opts when the number of the
capsule to be filled is less
Initially, all powders are triturated and blended, then put on clean paper.
A required number of empty capsules are taken, and caps are separated
from the body. Then each capsule is filled by pressing the body onto the
powder until it is filled. Then cap has to be fitted over it with little
pressure.
2. Hand filling method:
It consists of a bed with 200-300 holes, a loading tray with 200-300
holes, a powder tray, a pin plate with 200-300 pins, a sealing plate with a
rubber top, a lever, and a cam handle.
 The empty capsules are filled into the loading tray, and it is placed
over the bed by operation of hand.
 The cam handle is operated to separate the capsule caps from
their body.
 The powder tray is placed correctly filled with a precise quantity of
powder with a scraper. The excess of the powder is collected on
the platform of the powder tray.
 Lower the pin plate to press the powder in bodies press
 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
robber 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.
There are three stations in this semi-automatic machine
 Orientation of capsule
 Powder filling
 Capsule closing
The functions of the first station include:
1. Capsule feeding
2. Aligning
3. Insertion into bores ring
4. Vacuum is used for separating capsule cap and body in the first
station.
5. After an orientation of the capsule, the capsule cap can stay in an
upper holding ring, and the capsule body can stay lower, holding
ring.
Powder filling: Separate the holding ring, put the lower (body) holding
rotary ring table pull the powder hopper over the lower(body) holding
ring. Auger inside the powder hopper starts to run and fill into the
capsule body.
 Capsule closing:
 put upper holding ring and lower holding ring together then
position, then position intact holding ring in front of peg ring
 Pneumatic pressure is applied to the peg ring, which finally pushes
capsules inside the bores of the holding ring, and the finished
capsules are collected into the container.
Fully Automatic Filling Machine:
 Automatic capsule filling machines have been designed and
developed to fill hard gelatin capsules with powder or pellets. It is a
highly durable and reliable machine that fills dosages to the
highest range accuracy.
 Automatic filling machines employ pistons or tamping pins that
lightly compress the powder into slugs and eject the plugs into the
empty capsule bodies. Automatic machines use dosing.
Fig: 7 Dosing disc type machine
The dosing disc rotates continuously in a circular manner. The stop plate
closes the holes on the dosing plate. The dosing disc rotates below the
powder bed; the material flows into each hole—the pins in the station
compress the powder to a controlled depth.
 The filling and compression process continues until the last
compressing pin, where the dosing machine ejects a compressed
powder through the dosing plate into the capsule.
 This is a continuous process, and the production speed will
depend on the preset machine condition.
3.1.5 Finishing Of Capsule:
 Finished capsules from all filling equipment require some dusting
and polishing before the remaining inspection, bottling, and
labelling are completed.
 Pan polishing: Accela-Cota tablet coating pan used to dust and
polish the capsules
 Cloth dusting: capsule are rubbed with a cloth; this procedure is a
hand operation; it imparts a somewhat improved gloss to the
capsules
 Brushing: capsules are fed under rotating soft brushes, which
serve to remove the dust from the capsule shell
 Rotosort: it is a mechanical sorting device that removes loose
powder, unfilled joined capsules and loose caps

3.1.6 Special techniques of formulation of hard gelatin capsules:

1. Imprinting: imprinting is a method by which company and or product
information or identification can be placed on each capsule. This
operation is best performed on empty capsules.
2. Solubility :
1. Formalin treatment has been employed to modify the solubility of
gelatin capsule exposure to formalin treatment with aq formalin
produces an unpredictable decrease in the solubility of the gelatin
film.
2. Various coatings have been used to provide similarly modified
solubility characteristics. these coatings include salol, shellac,
cellulose acetate phthalate

3. Separation of incompatible materials: This is carried out by using a

two-phase fill in the capsule. One phase consists of either a soft capsule,
more miniature hard capsule, pill or a suitably coated tablet filled into
each capsule. In the second phase, a powder fill is added usually. These
changes would include, at minimum, the necessary changes in the
machine operation to allow materials to be loaded at two points during
the filing cycle.

4. filling of conventional two-piece gelatin capsules with liquid &

semisolid. The formulation used for filling is usually semisolid at ambient
temperature, which is allowed to filling

3.1.7 Manufacturing defects of the hard gelatin capsule:

Fig: 8 manufacturing defect of the hard gelatin capsule

Several defects include

 Shell surfaces are not smooth

 Empty capsules after the filling stage
 The foreign matter inside the capsules
 Capsules fitting is not uniform during filling
 Capsules are not of the specified type
 Colour variation and non-uniformity of appearance
 Surface spots and embedded particles on the capsules
 Capsules may have cracks, breaks, splits and lose their integrity

3.1.8 In-process quality control test for capsules(IPQC):

1. Mfg of the gelatin shell
2. Drying of shells in controlled humidity
 3. Mfg of granules
4. Filling of shells
5. Packing and labelling

IPQC Checks During Gelatin shell Manufacturing :

 % purity of gelatin
 The viscosity of gelatin solution is 25-45 millipore
 Bloom strength of gelatin solution 150-250gm
 Iron content N.M.T. 15ppm
 Film thickness
 Color, surface, the appearance of empty shells
 The temperature of hot air, for drying of shells
 Length of capsule & body of the shell
 Moisture content 12-15%

Inspection of defects like:-

Hardening of shells
Softening of shell
Swelling of shells
Cracking of shells
Discolouration of shells
Misprinting of logo on shells

3.1.9 Finished product quality control test of capsule :

Whether the capsules are produced on a small scale or large scale, all
are required to pass through a specific test, i.e. quality control test to test
the quality of the finished product.
1. Appearance
2. Size and shape
3. Disintegration test
4. Weight variation test
5. Assay
6. Content uniformity
7. Stability testing
8. Moisture permeation test

1. Appearance: A capsule produced on a small or large scale should

be uniform in appearance. Electronic inspection should be undertaken to
detect any flaws in the integrity and appearance of the capsule

2. Size and shape: Hard capsules are made in various sizes; standard
industrial ones today of human medicine range from size 000 (the
largest) to 5 (the smallest) are commercially available. Inspection must
be done for size & shape.

3. Disintegration test: The disintegration determines whether the

capsules have disintegrated with the prescribed time when placed in a
liquid medium under the necessary condition.

Method:
According to B.P. Moreover, which applies to both hard & soft capsules.
1. Introduce one capsule in each tube and suspend the apparatus in
a beaker containing 60ml water at 37℃; if hard capsules float on
the water's surface, the disc may be added.
2. Operate the apparatus for 30 mins, remove the assembly from the
liquid
3. The capsule passes the test if

 No residue remains on the screen of the apparatus or

 If the residue remains, it consists of fragment shell,
 If a soft mass has no palpable core,
 If the disc is used, any residue is remaining on its lower surface
should only consist of fragments of shell
4. Weight variation
test: https://www.slideshare.net/Ramyapriya7/quality-control-of-capsules
The weight variation test denned by USP XX is a sequential test in
which 20 intact capsules are individually weighed, and the average
weight is determined.

 Weigh 20 capsules individually and determine the average weight;

the individual weights should be within the limit of 90-110%, of an
average of eight.
 If not all of the capsules fall within limits, remove the net content of
each capsule with the aid of a small brush, Weigh the empty shells
individually.
 Net weight of contents individually = The weight of Gross shell
weight
 Determine the average net content from the sum of individual net
weight
 Then determine the difference between each net content and
average net content.
 Limits: not more than 2 of the differences are greater than 10% of
the average content; no case is the difference more significant
than the 25% Wt range
  If more than two but less than six net weights determined by the
test deviate by more than 10% but less than 25%, the net contents
are determined for an additional 40 capsules, and the average is
calculated for 60 capsules. Sixty deviations from the new average
are calculated.
 The requirements are met (1) if the difference exceeds 10% of
the average in more than 6 of the 60 capsules.
 and (2) if in no case any difference exceeds 25%
5. Content uniformity: the test applies to all capsules meant for oral
administration. For this test, a content sample is assayed as described in
an individual monograph, and the values calculated must comply with
the prescribed standards.

 In this case, 30 capsules are selected, and 10 of these assayed

individually
 At least 9 of these contain 85-115% drug are & non contain below
75-125% of drug
 If 1-3 of them fall outside 85-115% limits

6. Dissolution test: the dissolution test is carried out using the

dissolution apparatus as per U.S.P.

 The capsule is based in a basket, and the basket is immersed in

the dissolution medium and caused to rotate at a specified speed
 The dissolution medium is held in a covered 1000ml glass and
maintained at 370c +-0.5 C using a constant temperature suitable
water bath.
1. Apparatus - 1 (rotating basket dissolution apparatus)
Small wire mesh size basket - 22
Temperature - 37 +/5°C
Rotated speed 25-150rpm
Dissolution medium-high from the bottom of a vessel: 23-27mm
1. Apparatus -2 (rotating paddle dissolution apparatus)
Small wire mesh size - 22
Dissolution medium-high from the bottom of the vessel: 23-27mm
Temperature - 37 +/5°C
Rotated speed 25-150rpm

7. Moisture permeation Test: The degree and rate of moisture is

determined by packing the dosage unit together with a colour revealing
desiccant pellet

 Capsules packed with coloured pellet.

  Exposed packed unit to known relative humidity for a specific time
 Observe desiccant pellet for colour change
 Any change in the colour indicates absorption of moisture.
 The difference between the pretest weight and weight after the test
indicates the amount of moisture absorbed by the capsule.
)SOFT GELATIN CAPSULE (SGP) :

Soft gelatin capsules are one-piece, hermetically sealed, soft gelatin

shells containing a liquid, a suspension, or a semisolid.
Soft gelatin is mainly composed of gelatin, plasticizers, preservatives,
colouring and opacifying agents and sugars.

Fig: 9 soft gelatin capsules

3.2.1 Nature of capsule shell :
 The capsule shell is composed of gelatin, plasticizer & water.
Additionally, it may contain preservatives, colouring agents,
opacifying agents, flavours, and sweetening agents to achieve the
desired effect.
 The gelatin is USP grade with additional specifications concerning
the bloom strength, viscosity, and iron content of gelatin used.
 Bloom or Gel strength: The bloom or gel strength of the gelatin is a
measure of the cohesive strength of the cross-linking that occurs
between gelatin molecules and is proportional to the molecular
weight of gelatin. Bloom is determined by measuring the weight in
gram required to move a plastic plunger that is 0.5 inches in
diameter 4mm into a six ⅔ % concentration of gelatin gel that has
been held at 10℃ for 17hrs.
 Bloom may vary from 150-250g
Higher bloom gelatins are only used when required to improve a
product's physical stability that requires greater structural strength during
manufacture.
 The viscosity of gelatin: It is a measure that determines the
manufacturing characteristic of the gelatin film. Determined on a 6
⅔ % concentration of gelatin in water at 60℃. the viscosity for
gelatin can range from 25-45 millipores (thickness & film)
 Iron is present in raw gelatin, and the concentration of iron in
gelatin depends on the iron content of water required to Mfg.
gelatin
 The gelatin used in the Mfg. of soft gelatin capsules should not
contain 15ppm.of iron because of its effect on FD&C certified dyes
and its colour reactions with organic compounds
 Fig: 10 [ typical shell Hardness ratio and their uses]

Capsule Content :
 The content of a soft gelatin capsule is a liquid, or a combination of
miscible liquids, a solution of solid in a liquid or suspension of a
solid in a liquid. It can be a liquid like a volatile oil composition. E.g.
vegetable oil like Arachis oil or aliphatic hydrocarbons ether, esters
etc
 Liquids are both water-miscible and volatile can not be included as
a significant constituent of capsule content since liquids they can
migrate into the hydrophilic gelatin shell and volatilize from its
surface. Water, ethyl alcohol, and of course, emulsions fall into this
category.
 Similarly, gelatin plasticizers such as glycerine and propylene
glycol can not be a significant constituent of the capsule content,
owing to their softening effect on the gelatin shell.
 Preparation for encapsulation should have PH 2.5 and 7.5 since
more acidic preparation can cause hydrolysis and leakage of the
shell.
 The maximum capsule size and shape for convenient oral use in
humans is the 20 minim oblong, the 16minim oval, 9 minims
round.