SUBJECT NAME: INDUSTRIAL PHARMACY –I (BP502T)

UNIT-III (CAPSULE) COURSE: B.PHARM SEM: 5TH

Prepared by: Laxmidhar sahoo, Assistant Professor, Roland Institute of Pharmaceutical
Sciences, Berhampur

Abbreviation:

HGC: Hard Gelatin Capsule

SGC: Soft Gelatin Capsule

PEG: Poly Ethylene Glycol

GI: Gastro Intestinal

BA: Base Adsorption

M/g: Minim per Gram factor

MCC: Micro Crystalline Cellulose

CMC: Carboxy Methyl Cellulose

GMS: Glyceryl Mono Stearate

SUBJECT NAME: INDUSTRIAL PHARMACY –I (BP502T)

UNIT-III (CAPSULE) COURSE: B.PHARM SEM: 5TH

Definition:

Capsules are solid dosage forms in which the drug or a mixture of drugs with or without
excipients is enclosed in Hard Gelatin Capsule Shells, in soft, soluble shells of gelatin, or in hard
or soft shells of any other suitable material, of various shapes and capacities. They usually
contain a single dose of active ingredient(s) and are intended for oral administration.

Advantages:

 The drugs having unpleasant odour and taste can be administered by enclosing them in a
tasteless shell.

 They are smooth, become very slippery when moist and can be easily swallowed.
 They are economical
 They are easy to handle and carry.
 The capsules release the medicament as and when desired in gastro-intestinal tract.
 Capsules are made from gelatin and hence they are therapeutically inert.
 Capsule have elegant appearance so that it enhance patient acceptance.
 The drug in the form of solid,liquid & viscous form can be encapsulated in capsule shell.
 Capsule formulation provide better stability of drug as compare to uncoated tablet &

liquid dosage form

Disadvantages:

 Capsule are not usually used for administration of extremely soluble materials such as
potassium chloride, potassium bromide etc. since there is sudden release of such
compound in stomach & causes irritation.

 Capsule should not used for highly efflorescent material as material may cause the
capsule to soften by losing water molecule to shell ,

 Capsule should not used for highly deliquescent powder as powder have tendency to
absorb moisture from capsule shell & make it brittleness.

 The capsule shells can absorb water from the environment and develop problems with
drug stability and capsule shell can become tacky

 it unsuitable for use with liquid formulations

Gelatin as a component of capsule shell:[1]

As the gelatin is the main source for production of capsule shell,we need to understand its source
& process of manufacture .Gelatin is a heterogeneous product derived by irreversible hydrolytic
extraction of treated animal collagen as it never occurs naturally.

The physical & chemical properties of gelatin are the function of parent collagen, method of
extraction,pH value ,thermal degradation & electrolyte content. The main source of collagen
which are required for production of gelatin are animal bones and frozen pork skin.

Generally two type of getatins are used to manufacture capsule shell.

Type A Gelatin:it is derived from the acid treated precursor and exhibit isoelectric point in
region of pH 9.

Type B Gelatin: it is derived from an alkali treated precursor & exhibit isoelectric point in region
of pH 4

[The isoelectric point is the pH at which a molecule carries no net electrical charge or is
electrically neutral ]

Dry bone 5% Hcl ——- Lime 10% ———-Lime removal ——— pH adjustment
10-15 days 4-8 weeks

Bone meal Dicalcium phosphate

Calf skin wash Lime 10%
————————- 6-12 week ———————- water wash (10-30 hours)

Pork skin wash Acid
—————— 1-5% Hcl (10- 30 hrs) ———————– Acid removal

Hot water extraction ———filter ————vacuum conc. ———cool to solidify——- air dry — mill to size

Fig.1 [ The process of manufacturing gelatin ] [1]

Type of capsule ( based on type of shell)

1. Hard Gelatin capsule [HGC]
2. Soft Gelatin capsule [SGC]

Hard Gelatin capsule:it is the capsule in which medicament(s) with or without excipient in the
dry powder form are enclosed in a shell which consist of cap & body.

cap

Body

Fig.2 showing part of hard Gelatin capsule

Production of Hard gelatin capsule shell:[1]

The mechanism involved for production of hard gelatin capsule shell are

 Dipping
 Spinning
 Drying
 Stripping & Trimming
 Joining

Preparation of the gelatin solution (dipping solution): A concentrated solution of gelatin (35-
40%) is prepared by dissolving the gelatin in demineralized water which has been heated to 60–
70°C in jacketed pressure vessels.This is stirred until the gelatin has dissolved and vacuum is
applied to removed entrapped air bubbles. At this stage, other processing aids may be added
like plasticizer, colourant, opaquing agent etc.The viscosity of gelatin preparation has to be
controlled as it may affect downstream manufacturing process & very importantly thickness of
shell.

Dipping: Capsule shells are manufactured under strict climatic conditions by dipping pairs
(body and cap) of standardized steel pins arranged in rows on metal bars into an aqueous gelatin
solution (25 – 30% w/w) maintained at about 50 ° C in a jacketed heating pan.

Spinning of the dip-coated pins: after adsorption of the gelatin solution on to the surface of the
pins, the bar containing the pins is rotated more times to evenly distribute the gelatin solution
around the pins,as uniform gelatin distribution being critical for correct and precise capsule wall
thickness.

Drying of the gelatin-coated pins :once the gelatin is evenly distributed on the mould, a blast of
cool air is used to set the gelatin on the mould. At this point, the gelatin is dried, and the pins are
then passed through several drying stages to achieve the target moisture content.

Stripping & Trimming : After the gelatin is dried, the capsule is stripped off the mould and trimmed to
the proper length

Joining of 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. At this point, printing is done if
needed before packing in cartons for shipping.

Fig.3 Sequence of two piece hard gelatin capsule shell manufacture [2]

Size of capsule:

Size Volume (mL) Fill weight (g) at powder
density of 0.8/cm3

000 1.37 1.096
00 0.95 0.760
0 0.68 0.544
1 0.50 0.400
2 0.37 0.296
3 0.30 0.240
4 0.21 0.168
5 0.13 0.104

Table -1 (capsule size & body fill volume) [3]

Filling of Hard Gelatin capsule:The several type of filling machine in use in the
pharmaceutical industry have in common the following operation.

1. Rectification: The empty capsule are oriented so that all point the same direction, i.e body
end downward. The capsule pass one at a time through a channel just wide enough to
provide a frictional grip at cap end. capsule will always be aligned body end downwards
regardless of which end entered the channel first.

2. Separation of cap from bodies: This process depend on the difference in diameter
between the cap and body. The rectified capsule are delivered body end first into the
upper portion of split brushing .A vacuum applied below pull the bodies down into the
lower portion .the diameter of cap is too large to allow them to bodies into the lower
portion

3. Dosing of fill material: various method like Auger principle, vibratory fill principle,
piston- Tamp principle are employed for filling

4. Replacement of cap and ejection of filled capsule: The cap & body bushing portion are
rejoined. Pins are used to push the filled bodies up into the caps for closure and to push
the closed capsule out of the bushing. Compressed air also used to eject the capsules.

Filling principles:

a) Auger fill principle: The empty hard gelatin capsule are taken from hopper to the

rectifying unit. the rectifier descend the the capsule such that caps are turned up and
bodies are down.

 When vacuum is applied capsule from rectifying unit are placed one by one in the filling
ring kept on rotating mode. The ring consists of upper and lower ring having cavities for
for placing capsule. When all the cavities of ring filled, the upper ring is lifted which
causes separation of bodies from caps.

 The lower ring is rotate with constant speed and the hopper containing powder is held

over the ring. The auger drive the powdered drug into the capsule bodies. After bodies
are completely filled ,the hopper is set aside & rotating ring is stopped. Now ring holding
caps are placed over ring holding the bodies which are then joined together.
b) Vibratory fill principle: in this type of machine ,the feed is placed in the feed hopper

& capsule bodies are pass under it. A perforated resin plate ( connected to vibrator) is
placed in feed hooper.Due to vibration of resin plate the powder flows freely through
the pores into the capsule bodies.
 Pins are present below the capsule bodies for support. Capsule bodies are filled

when the pins are pulled down. but when there is overfilling, The capsule bodies
are pushed up to reach the level of disc plate and excess the powder is forced out
by scrapping

c) Piston-tamp principle: automatic capsule filling machines work on piston-Tamp
principle by using piston or Tamping pins. The piston tapmps alter the shape of
powder by compressing the powder to form plugs (slugs).These plugs are transferred
into empty capsule shell with the application of little pressure. This piston pump
principle can be explained by two type of machine

i)Dosing-disc type machine
ii) Dosator type machine
d) Vacuum fill principle:The machine consist of an open ended cylinder. The upper end

of this cylinder is fitted with piston. The lower end (open end) is placed in bulk
powder. Vacuum is applied and the piston is moved upward by sucking the specific
amount of powder,this result in filling of the cylinder, the powder is filled up to the
piston height and the vacuum is held until the piston is positioned over empty capsule
body. Now the vacuum and pressure in the form of compressed air is applied over the
piston to transfer the powder into the capsule body.

Capsule filling methods:

1. Manual filling
2. Hand filling machine
3. semi-automatic machine
4. Fully automatic capsule filling machine

Manual filling method:

 This method is opted when number of capsule to be filled is less
 Initially the ingredients to be filled are triturated & make is uniform mixing.then

put it on clean paper

 Now the required number of empty capsule are taken and caps are separated from
body. Then individually powder has to be filled with the help of spatula to the
capsule body. Then cap has to be fitted ovet it with little pressure

Hand 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.

 The empty capsules are filled in the loading tray and it is palced over the bed. The cam
handle is operated to separate the capsule caps from their bodies.

 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. The pin plate is lowered and the filled powder is pressed by moving the pin
downwards.

 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.

Fig 4.Hand filling capsule machine

Semi-automatic machine:

There are 3 stations in this semi-automatic capsule filling machine

 orientation of capsule
 powder filling
 capsule closing

The functions of first station include :

1. capsule feeding
2. Aligning
3. insertion into bores of holding ring
4. vacuum is used for separating capsule cap and body in first station.
5. After orientation of capsule, capsule cap can stay in upper holding ring and capsule

body can stay in lower holding ring.

Powder filling:

Separate the holding ring, put the lower (body) holding ring on the rotary table, pull the
powder hopper over the lower (body) holding ring, then auger inside powder hopper starts to
run and fill powder into the capsule body. While Iower holding ring turns one circle, push
powder hopper to its original position.

Capsule closing:

 Put upper holding ring and lower holding ring together, then position intact
holding ring in front of peg ring .closing plate is pivoted to a position
approximately 180 degrees

 Pneumatic pressure is applied to peg ring which finally push capsules inside the
bores of holding ring the finished capsules will be collected into the container.

Fully automatic capsule filling machine:

Most automatic filling machines employs piston or tamping pin that lightly compress the powder
into plugs,(some times referred as slugs) and eject the plugs into the empty capsule bodies.

The compression forces are low, often range from 50-150N, upto 100 fold less than that
employed in typical tablet compression. Often plugs are very soft compacts and not able to
recovered intact from filled capsule.there are two main type of these fillers: Dosator machine and
dosing disc machine.

Fig.4 [ Dosing disc type machine ] [3]

The tamping pin type capsule filling process involves a number of stages. In this case, the
machine has 5 stage tamping technology. This pan rotates continuously in a circular manner
depending on the preset speed. Normally, as the dosing plate rotates below the powder bed, the
filler material flows into each hole. The pins, which are in the tamping stations compress the
powder to a controlled depth. That is, as the filler material flows into the first hole in the disc,
tamping pin 1 compresses it to a predetermined depth. After this first step, the hole moves to the
next stage where the powder again flows into the hole and tamping pin 2 compresses it to a
predetermined depth. The force these tamping pins exert on the powder is just enough to
compact it. That is, it may range from 50N to 150N.

This process continues until the holes with the powder reaches the last tamping pin (no. 5),
where the machine ejects a compacted powder through the dosing plate into the capsule. After
filling the capsule shell, it moves to the next stage (sealing/covering the capsule). This is a
continuous process and the production speed will depend on the preset machine conditions.

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 or gauze 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.

Sorting: This operation is needed to separate the imperfect & damaged capsule. although
in large scale it done manually, some automatic equipment are available e.g-Rotosort

Formulation of powder need to be fill capsule shell:

Ingredients type purpose example
API Produce therapeutic effect Amoxycilin
fillers To increase bulk volume of Starch ,lactose

formulation
Lubricant Reduce powder to metal Magnesium stearate

adhesion
Glidant Improve powder flow Colloidal silica
surfactant Increase the wetting of SLS,sodium docusate

powder mass
Super Disintegrant Disruption of powder mass Crospovidone,Croscarmellose

sodium
Hydrophylic agent Improve the wettability of Methyl cellulose,hydroxyl

poorly soluble drug ethyl cellulose

Table .2[list of excipient used in powder formulation for capsule filling] [3]

Special technique of formulation used in hard gelatin capsule: [1]

1. Imprinting ; is a convenient method by which company and/or product
identification information can be placed upon each capsule. The imprinting
operation is best performed on empty capsule although filled capsule can be printed.

2. Solubility: For special purpose capsule attempt to retard solubility in some manner.

a)formalin treatment has been employed to modify the solubility of gelatin capsule.
exposure to formalin vapour or treatment with aq formalin produce unpredictable
decrease in solubility of the gelatin film.

This result may be noted if product being filled contain aldehyde materials of
aldehyde flavor.it is difficult to control degree of insolubilization.

b) various coating have been used to provide similarity modified solubility character.
These coating include salol,shellac,cellulose acetate phthalate

3. separation of incompatible material: it invoving two phase fill in the capsule. one phase
consist of either a soft capsule,a pill or suitably coated tablet that is filled into the capsule. in
second phase a powder fill is added in usual manner.these changes include ,at minimum the
necessary changes in machine operation to allow material to be loadedat two point during filling
cycle.

4. filling of conventional two piece gelatin capsule with liquid & semisolid.the formulation used
for filling are usually semisolid at ambient temperature, which are melted to allow filling or they
are thixotropic formulation in which the shear developed in filling allows pumping but whose
high viscosity when shear is absent prevent leakage after filling.

Manufacturing defect of hard gelatin capsule:

Fig.5 manufacturing defect of hard gelatin capsule

several defects that include;

 Shell surfaces not smooth
 Opacify not proper
 Empty capsules after the filling stage
 The foreign matter inside the capsules
 Capsules fitting not uniform during filling
 Capsules are not of the specified type
 Color variation and non-uniformity of appearance
 Surface spots and embedded particles on the capsules
 Capsule may have cracks, breaks, pinholes or splits, losing its integrity.

In process Quality control (IPQC) for capsules :

1. Mfg of Gelatin Shell.
2. Drying of shells in controlled humidity.
3. Mfg of granules.
4. Filling of Shells.
5. Packaging & Labeling. •

IPQC Checks During Gelatin Shell Manufacturing:

•% purity of gelatin
•Viscosity of gelatin solution 25-45 millipoise
•Bloom strength of gelatin solution 150-250 gm
•Iron content NMT 15 ppm
•Film Thickness
•Color, surface, appearance of empty shells
•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 shells
Swelling of shells
Cracking of shells
Discoloration of shells
Misprinting of logo on shells

Finished product quality control test of capsule: [4]

1.Appearance:
Capsules produced on a small or a large scale should be uniform in appearance. Visual or
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 a range of sizes,the standard industrial ones in use
today for human medicines range from size from 000 (the largest) to 5 (the smallest) are
commercially available. inspection must be done for size and shape.
3.Unique Identification Markings:
Capsule surfaces may bear symbols or other unique identification markings for better
identification.
4. Uniformity of weight.: Weigh an intact capsule. Open the capsule without losing any part of
the shell and remove the contents as completely as possible. To remove the contents of a soft
capsule the shell may be washed with ether or other suitable solvent and the shell allowed to
stand until the odour of the solvent is no longer detectable. Weigh the shell. The weight of the
contents is the difference between the weighings. Repeat the procedure with a further 19
capsules. Determine the average weight. Not more than two of the individual weights deviate
from the average weight by more than the percentage deviation shown in below and none
deviates by more than twice that percentage.

Average weight of capsule Contents Percentage deviation
Less than 300 mg 10
300 mg or more 7.5
TABLE 3 (percentage deviation for capsule weight)

5.Uniformity of content. This test is applicable to capsules that contain less than 10 mg or less
than 10 per cent w/w of active ingredient.
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 if not more than one of the individual
values thus obtained is outside the limits 85 to 115 per cent of the average value and none is
outside the limits 75 to 125 per cent. If two or three individual values are outside the limits 85 to
115 per cent of the average value repeats 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

6. Disintegration. The disintegration test is not applicable to Modified-release Capsules. For
those Hard Capsules and Soft Capsules for which the dissolution test is included in the
individual monograph, the test for Disintegration is not required..
a) Hard Capsules. Comply with the disintegration test in monograph , Unless otherwise
directed in the individual monograph use water as the medium. If the capsules float on the
surface of the medium, a disc may be added. If the capsules adhere to the discs, attach a
removable piece of stainless steel woven gauze with mesh aperture of 2.00 mm to the upper plate
of the basket rack assembly and carry out the test omitting the discs. Operate the apparatus for 30
minutes unless otherwise directed
b)Soft Capsules. Comply with the disintegration test Unless otherwise directed in the individual
monograph use water as the medium and add a disc to each tube. Operate the apparatus for 60
minutes unless otherwise directed
c) Enteric Capsules. Use the apparatus described under disintegration test (2.5.1), using one
capsule in each tube. Operate the apparatus for 2 hours without the discs in 0.1 M hydrochloric
acid. No capsule shows signs of disintegration or of rupture permitting the escape of the
contents. Replace the medium in the vessel with mixed phosphate buffer pH 6.8, add a disc to
each tube and operate the apparatus for a further 60 minutes. Remove the apparatus from the
medium and examine the capsules. They pass the test if no residue remains on the screen or on
the underside of the discs, or, if a residue remains, it consists of fragments of shell or of a soft
mass with no palpable, unmoistened core.

7. Content uniformity of drug: A sample of 30 capsule is taken and 10 are assayed
individually.The drug content of a capsule should be within the limits of average drug content
±15% and the drug content of none of the capsule fall outside the average drug content ±25%. If
1-3 capsules falls outside the average drug content ±15%, the remaining 20 are assayed. The
drug content of at least 27 out of 30 assayed should be within the average drug content ±15%
limits. and the drug content of none of the capsules falls outside the average drug content ±25%
limits. The test is prescribed for capsules when active ingredient is <10 mg or 10% of fill weight.

8. Dissolution test: The dissolution test is carried out using the dissolution apparatus
as per U.S.P .
• The capsule is placed 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
vessel and maintained at 370 c +-0.50c by means of a constant temperature suitable water bath.
The stirrer speed and type of dissolution medium are specified in the individual monograph

Stage Number of capsule Acceptance criteria

tested
S1 6 Each unit is not less than Q + 5%.
S2 6 Average of 12 units (S1 + S2) is equal to or greater than Q,

and no unit is less than Q – 15%.
S3 12 Average of 24 units (S1 + S2 + S3) is equal to or greater

than Q, not more than 2 units are less than Q – 15%, and
no unit is less than Q – 25%.

Table. 4 [acceptenace criteria for dissolution study][1]

The quantity Q, is the specified amount of dissolved active substance, expressed as a percentage
of the labeled content.

SOFT GELATIN CAPSULE (SGP): Soft gelatin capsules are one piece , hermetically sealed
, and are made up of gelatin in which glycerin or polyhydric alcohol (sorbitol) are added ,
containing liquid , suspension or semisolid enclosed in it.

Advantages:

 Soft gelatin capsules are in sealed form so they protect the inner fill from oxidation and
degradation.

 Opaque soft gelatin capsules also protect the inner fill from UV radiation and photo
sensitive products.

 It enhance patient compliance due to its elegant appearance.
 Suitable for medicaments like semisolid, oils, liquid forms.
 Soft gelatin capsules increase the bioavailability of API.

Disadvantages:
 Few filling equipment available
 Manufacturing expensive
 Drugs from oily vehicle may pass into the shell
 Soft gelatin capsules having difficulties in dealing with water soluble materials.
 Soft gelatin capsules are highly sensitive to moisture.
 Soft gelatin capsules having difficulties in dealing with efflorescent materials.
 Soft gelatin capsules having difficulties in dealing with deliquescent material

Shape of capsule shell:

Fig.6[Size and shape of soft gelatin capsules. number represents the normal capacity in
minims] [1]

Nature of capsule shell:

 The capsule shell is basically composed of gelatin, plasticizer & water.
Additionally it may contain preservative, colouring agent, opacifying agent,
flavor, sweetening agent to achieve desired effect.

 The gelatin is USP grade with additional specification required by the capsule

manufacture. The additional specification concern the bloom
strength,viscosity,iron content of gelatin used.

 Bloom or gel strength: is a measure of cohesive strength of cross linking that
occurs between gelatin molecule 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 6 2/3 % gelatin gel that
has been held at 10oc for 17 hours. Bloom may vary from 150-250g.

 Viscosity: viscosity of gelatin determined on a 6 2/3 % conc of gelatin in water at
600 c, is a measure of molecular chain length and determines the manufacturing
characteristics of gelatin. The viscosity for gelatin can ranges from 25 to 45
millipoise.

 Iron is always present in the raw gelatin and its concentration usually depend on

the iron content of the large quantities of water used in its manufacture.Gelatin
used in manufacture of soft gelatin capsule should not contain more than 15 PPM
of this element.

Hardness Ratio Dry glycerin/Dry Usage

gelatin
Hard 0.4/1 Oral,oil based or shell

softening product,designed
for hot,humidity areas

Medium 0.6/1 Oral,water miscible based
,shell hardening product and
designed for temperate areas

Soft 0.8/1 Tube,vaginal,water miscible
based or shell hardening
product and destined for
cold,dry areas

Table .5 [Typical shell Hardness ratios and their uses] [1]

Capsule content:

 Content may be liquid, or a combination of miscible liquids, Solution of a solid(s)
in a liquid(s) or Suspension of a solid(s) in a liquid. It can be a liquid like a
volatile oil composition E.g. Vegetable oils like arachis oil or aromatic or
aliphatic hydrocarbons, ethers, esters, or alcohols.

 Solids that are not Sufficiently soluble in liquids or in combination of liquids are
capsulated as Suspension. Suspending agents used are Lecithin, Soyabean oil

 Liquids are important part of capsule content. only those liquid that are both water
miscible & volatile cannot be included as major constituent of the capsule content
since they can migrate into the hydrophilic gelatin shell and volatilize from its
surface .water, ethyl alcohol fall inthis category.

 Similarly gelatin plasticizer such as glycerin and propylene glycol cannot be
major constituent of capsule content owing to their softening effect on gelatin
shell.

 Preparation for encapsulation should have a pH between 2.5 and 7.5,since
preparation that are more acidic can cause hydrolysis and leakage of shell and
preparation that are more alkaline can tan the gelatin and affect the solubility of
shell.

 The maximum capsule size and shape for convenient oral use in human is the 20
minim oblong,the 16 minim oval,9 minim round.

Formulation of filling material of SGC:
The various liquid phase filling matrices used in soft gelatin capsule are selected considering
following criteria:
Compatibility with capsule shell
Ability to dissolve the drug
Rate of dispersion in the GI fluid after shell disintegration in the GIT
Ability to optimize the bioavailability of drug
Types of filling/Bases:

1. Hydrophilic Liquids: like PEG 400 having high mol weight are frequently used
2. Lipophilic liquid: soya bean oil commonly used. the drug like steroid, vitamin D are mixed

with these oil
3. Microemulsion system: it consist of oil-surfactant-water system. blend of oil and surfactant

together with the active ingredient is filled into the capsule
4. Emulsifying oil: mixture of pharmaceutical oil & non ionic surfactant like polyoxyethylene

sorbitan mono oleate serve as self emulsifying oil matrix
5. Suspension: the drugs which are insoluble in liquid matrices of capsule & which are poorly

soluble in GI fluid can be formulated as suspension.

Base adsorption:[1]

 In the formulation of suspension for soft gelatin encapsulation, certain basic
information must be developed to determine minimum capsule size. so one of such
tool is Base adsorption of solid(s) to be suspended.

 Base adsorption is expressed as the number of gram of liquid base required to
produce a capsulatable mixture when mixed with one gram of solid(s).

The Base adsorption of solid influenced by
 Particle size & shape
 Its physical state (amorphous or crystalline)
 Density, moisture content, its oleophylic & hydrophilic nature

Determination of Base adsorption:
weigh a definite amount( 40 g is convenient) of solid into 150 ml tared beaker. In a separate
150ml tared beaker , place about 100g of the liquid base. Add small increment of base to the
solid and using the spatula ,stir the base into the solid after each addition until the solid is
completely wetted & uniformly coated with 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 450 angle above the
mixture.

Base adsorption = weight of base/weight of solid

Minim per gram factor(M/g):

 The base adsorptions 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 of the
solid plus the weight of the liquid base(BA) required to make capsulatable mixture.

 The minim per gram factor 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).

 (BA+S) x V/W = M/g
 Thus lower the base absorption of the solids and higher the density of the mixture, the

smaller the capsule will be.

Manufacture of soft gelatin capsule:

1. Plate process
2. Rotary die process
3. Reciprocating die process
4. Accogel capsule filling machine

Plate process:
• Place the gelatin sheet over a die plate containing numerous die pockets.
• Application of vacuum to draw the sheet in to the die pockets.
• Fill the pockets with liquid or paste.
• Place another gelatin sheet over the filled pockets, and
• Sandwich under a die press where the capsules are formed and cut out.

Fig.7 (plate process) [3]

Rotary die process:

1. In this machine the soft gelatin capsules are prepared & then filled immediately with
liquid medicaments it is having two hoppers & two rotating dies

2) Liquid mixture is placed in one hopper & the liquid medicament in other Hooper.
3) The two rotating dies rotate in opposite directions when the fluid gelatin mixture enters

the machine from the hopper it produces two continuous ribbons .
4)These half shell of the capsule is formed.
5) At this stage the measured quantity of the medicament is filled in to it with the stroke
of a pump with the subsequent movement of the dies the other half capsule is formed.
6) The two halves’ of the capsules are sealed together by the heat & pressure of the
rotating dies
7) As the die rolls rotate, the convergence of the matching die pockets seals and cuts out the
filled capsules

Fig .8 (Rotary die process)[1]

Reciprocating die process: This machine produces capsule completely automatically by leading
two films of gelatin between a set of vertical dies. Rows after rows of pockets are formed across
the gelatin film, filled with medicaments and as they process through the dies, are sealed, shaped
and cut out of the film as capsules which drop into a cooled solvent bath

Accogel capsule filling machine: This is another rotary process involving a measuring roll, a
die roll and a sealing roll. The measuring roll rotates directly over the die roll, and the pockets in
the two rolls are aligned with each other. The powder or granular fill material is held in the
pockets of measuring roll under vacuum. A plasticized gelatin sheet is drawn into the die pockets
of the die roll under vacuum. As the measuring roll and die roll rotates, the measured dose are
transferred to the gelatin lined pockets of the die roll.

Fig.9 (Accogel capsule filling machine)

In-process testing :

 During the encapsulation process the four most important tests are:-
 .The gel ribbon thickness;
 Soft gel seal thickness at the time of encapsulation;
 Fill matrix weight & capsule shell weight;
 Soft gel shell moisture level and soft gel hardness at the end of the drying stage.

For the determination of the fill weight each capsule is weighed and the contents removed
by cutting open the capsule. The shell is then washed with petroleum ether, and the
empty shell is reweighed. If necessary, adjustment can be made to obtain the proper fill
weight.

Finished product testing: Test parameter almost same as hard capsule

Special quality control test on soft gelatin capsules:-
•Seal thickness:-Is measured under a microscope and it should one half to two
third of the ribbon thickness.
•Total or shell moisture test:-Moisture content is determined by the toluene distillation
method. Collecting the distillate over a period of one hour.
•Capsule fragility or rupture test:-Force required to rupture the capsule is determined.
•Determination of freezing and high temperature effect:-(>450 c for 30 days)
These are performed similarly to the shell integrity test.

Packaging & store of capsule:
The main aim of packaging of filled capsule is to prevent contamination & loss or gain
of moisture during long term storage.
Many plastic container & various packaging technology such as blister packaging, strip
packaging are used for it.
In some container dehydrating powder(desicants) is placed which retard the excessive
moisture absorption by capsule.

Storage: storage of hard gelatin capsule shell for long time period require proper maintenance of
temp & humidity

Storage condition Relative humidity(%) Temp (0c )
Minimum 35 15
Best possible 50 20
Maximum 65 25
Table .6 (storage condition of capsule)

Very high humidity: capsules soften, stick together and lose shape
Very low humidity: capsules contract in size and become fragile
High or fluctuated temperatures: capsule forms lumps & condensation is seen on the
surface of container.

Capsule 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 temp 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 21-24o 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 temp ranging from just above freezing to as high as 600
c.

• As the humidity increases the moisture content pickup of capsules increases .
• ex- at 30%RH at room temp shows that gelatin retain about12%(48 mg) of water and

glycerin 7%(14 mg) of water. at 60%RH the moisture content should be 17.4%.
• High humidity (>60%RH at 21-240 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
1.80%RH at room temp in an open container
2.400 c in open container
3. 400 c in closed container (glass bottle with tight screw cap)
chemists conducting the physical stability test in their own lab should keep two important points
in mind:
1. prior to testing ,the capsule should be equilibrated to known atm conditions, preferably 20-
30%RH at 21-240 c.
2. evaluation of the results of the previously described heat test should be made only after the
capsules have returned to equilibrium to room temp

Temp Humidity Effect on capsule shell
21-240C 60% Capsule become softer,tackier

& bloated
> 240C > 45% More rapid & pronounced

effect-unprotected capsule
melt & fuse together

Table 7. (Effect of Temp,humidity on capsule shell) [1]

Application of soft gelatin capsule:[1]

1.They permit liquid medications to become easily portable.
2. Accuracy and uniformity of dosage ,capsule to capsule and lot to lot predominant advantage
3.the pharmaceutical availability of drugs formulated for this dosage form ,as measured by
disintegration time or by dissolution rate often shows an advantage over other solid dosage form
4. the physiologic availability of drug is often improved since these capsule contain the drug in
liquid form
5. the biopharmaceutical characterstics of such formulations can altered and adjusted more easily
than those of other solid dosage form
6. orally administered drug ,particularly if used chronically ,can be irritating to the stomach .the
dosage form of such drug can affect gastric tolerance indicated by study.

Pellet [4,5,6]: In the pharmaceutical industry, pellets can be defined as small, free-flowing,
spherical particulates manufactured by the agglomeration of fine powders or granules of drug
substances and excipient using appropriate processing equipment[4]

Pharmaceutical advantages:

 Uniformity of dose
 spheres have excellent flow properties
 Prevention of dust formation
 Controlled release application of pellets due to the ideal low surface area-to-volume ratio
 They can be blended to deliver incompatible bioactive agents simultaneously and/or to

provide different release profiles at the same or different sites in the gastrointestinal (GI)
tract

Disadvantage:
1. It is difficult to compress pellets into tablets as they are too rigid. Therefore, they are often
delivered encapsulated in hard gelatin capsule shells.
2.Pelletization demands highly sophisticated and specialized equipment, thereby increasing
the cost of manufacturing
.3.The control of manufacturing process is complicated with too many process variables as
well as formulation

Formulation:[5]
1) Active Pharmaceutical Ingredient: This multiple unit dosage form technology has the
potential for delivery of variety of APIs. The different drugs can be used to develop immediate
release, sustained release pellets with diversified applications in different areas. Pellets
technology is widely used to delivery GIT drugs at a specific site to release drug in a controlled
manner.
2. Binder: They are also called as agglomerating inducers or bridging agents. These are adhesive
materials that can be incorporated into pellet formulations to bind powders and maintain integrity
on pellet formation and the addition of the binder may be as a solution than the dry form, which
is considered to be more efficient than dry mixing followed by liquid addition. E.g- Gelatin,
HPC, HPMC, MC, PVP, sucrose, starch
3. Granulating fluid: Moisture content of the wet mass prepared is the most crucial parameter
for pellet growth as it imparts the required plasticity and cohesiveness to the wet mass to extrude

it and spheronize it to give a prefect spherical shape. examples are alcoholic or hydroalcoholic
systems, ethyl ether, dilute acetic acid, isopropyl alcohol
4. Spheronizing Enhancer: Spheronization enhancers are formulation aids that improve the
production of spherical pellets, mainly during spheronization and balling processes. They not
only impart plasticity onto the formulation, but also impart binding properties that are essential
for pellet strength and integrity.e.g- MCC ,sodium CMC
5. Filler: These are the excipients used to form the bulk of the material, in the process of
pelletization 70 to 80% of the excipients is formed by fillers. Generally microcrystalline
cellulose is used for this purpose. Avicel PH 101 is considered to be the pelletization aiding
excipient in this process. Glyceryl mono stearate (GMS), Starch RX1500, spray dried lactose.
6. Plasticizer: Plasticizers improve the flexibility of polymers by reducing the tensile strength
and glass transition temperature of the material. examples are Glycerol, Propylene glycol, low
molecular weight polyethylene glycols, phthalate derivatives like dimethyl, diethyl and dibutyl
phthalate
7. Lubricant: In pelletization process, lubricants are rarely used as the high-speed rotary
equipments are being used in the preparation of pellets. However, during compression and
Extrusion-Spheronization, lubricants do play a crucial role in the successful manufacture of
pellets. Their use reduces the friction between the die wall and material mix either during the
compression process or in ejection phase.E.g- Calcium stearate, glycerin, PEG, Mg. Stearate
8. Separating Agents: Separating agents are materials which are adsorbed on the surface and
promote the separation of pellets into individual units during a pelletization process, which are
incorporated initially in the formulation or externally during processing to prevent pellets
attracting one another due to surface charge development during the process.E.g- Kaolin, talc,
silicon dioxide
9. Surfactant: In most pelletization processes, the initial pellet formation and subsequent growth
into fully fledged smooth surfaced spherical pellets depends, to some extent, on the liquid
bridges that hold the primary particles together, therefore, liquid (water in most cases) wetting
the particles effectively is given more attention. Surfactants are added to the liquid to improve
wettability by lowering the interfacial tension between the liquid and drug particles
10) pH adjusters: The pH adjusters are substances that are incorporated in pellet formulations
which influence the microenvironment of drug molecules used for many reasons. Generally acid-
labile drugs are protected from the pH conditions of the GIT by giving an enteric coating. Buffer
systems may also be added to the core formulation to maintain the stability of core in a favorable
range. Examples are Citrate, phosphate.
11. Release modifiers: The main requirement of pelletization process is to manufacture
spherical drug cores that will be subsequently coated in a separate unit operation. It is also
possible to prepare pellet cores that inherently possess specific release profiles in a single step
which can be achieved by the incorporation of release modifiers along with drug during the core
formulation. example are while water insoluble polymers, hydrophobic substances, inorganic
salts, and hydrophilic polymers that swell and/or form gels are incorporated in pellets that retard
release kinetics.( Ethyl cellulose, carnauba wax, shellac.)
12. Flavoring agent: The choice for the flavors changes from individual to individual depending
upon the age, ethnicity and liking which plays a significant role in the taste fondness.
13. Sweetening agent: The sweet taste in formulation is more preferred especially in case of
pediatric population. Natural sweeteners as well as synthetic sweeteners are used to improve the
palatability of the formulations. The traditional source of sweetener is sucrose (derived from

cane or beet in the form of liquid or dry state), dextrose, fructose, glucose, liquid glucose and
maltose.
14. Coloring agents: Coloring agents are generally used in order to improve the appearance and
make it more patient compliance. Pigments such as Titanium dioxide or FD&C approved
coloring agents are used either in the dry form or mixed with the granulating fluid during the
formulation.

Pelletization process : It involves three consecutive regions:

 Nucleation
 Transition and
 Ball growth.

However, based on the experiments on the mechanism of pellet formation and growth, the
following steps were proposed: nucleation, coalescence, layering and abrasion transfer

Nucleation:

 Nucleation is a stage of Pelletization process that occurs whenever a powder is wetted
with solvent system. The primitive particles are drawn together to form three-phase air-
water-liquid nuclei system which are held together by liquid bridges that are pendular in
nature.

 Further the size, the rate and the extent of nuclear formation depends upon the size of the
particles, the moisture content, the viscosity of the binding particles, the wettability of the
substrate and the processing conditions, such as tumbling and drying rates.

Transition phase:
 Nucleation is followed by a transition phase where the growth mechanisms affecting are

coalescence and layering. Coalescence is defined as the formation of large-sized particles
by random collision of well-formed nuclei, this mechanism require slightly excess
moisture on the surface of the nuclei although the number of nuclei is progressively
reduced even though the total mass of the system remains unchanged during this
operation.

 Coalescence causes discrete size changes and leads to decrease in number of
agglomerates but not their mass

 Layering is a slow growth mechanism and with the successive addition of fragments and
fines on an already formed nuclei.

 The fines and the fragments produced through size reduction are taken up by larger
pellets. Production of fines and subsequent coalescence and layering continues until the
number of collisions declines rapidly, thereby leading to a reduction in the rate of growth
of the pellets. At this point the third phase, the ball growth region, is reached.

Ball growth phase:
 The main mechanism in the ball growth phase is the abrasion transfer which involves the

transfer of materials from one granule formed to another without any preference in either
direction.

 This phase does not result in any change in the total number or mass of the particles.
However, the particles undergo a continuous change in their size as long as the conditions
that lead to the transfer of material exist.

Fig.10 showing mechanism of pelettization process

Pelletization Techniques : [6]
Extrusion Spheronization
Layering Technique
Cryopelletization
Hot Melt Extrusion
Freeze Pelletization
MUPS (Multiple unit pellet system)
Extrusion Spheronization :

(a) Dry Mixing: Dry
mixing of ingredients is done to achieve homogeneous powder dispersion using twin
shell blender, planetary mixer, high speed mixer and tumbler mixer

(b) Wet Massing:
Wet massing is done to produce a sufficient plastic mass for extrusion, by employing
normal equipment and processes as employed in wet granulation for compaction. The
most commonly used granulator is planetary mixer or Hobart mixer or sigma blade mixer
and high shear mixer

(c) Extrusion: This is
the third step in the process, which produces rod shaped particles of uniform diameter
from the wet mass. The wet mass is forced through dies and shaped into small cylindrical
particles with uniform diameter.

(d) Spheronization:
consists of a static cylinder and a rotating friction plate where the extrudate is broken up
into smaller cylinders with a length equal to their diameter and these plastic cylinders are
rounded due to frictional forces. During Spheronization process different stages can be
distinguished depending upon the shape

(e) Drying: A drying
stage is required in order to achieve the desired moisture content. Drying rate also
important an increase drying rate gave more porous pellets due to decrease pellet
densification during that drying process

(f) Screening:
Screening may be necessary to achieve the desired size distribution, and for this purpose
sieves are used

Layering Technique :

 This technique is
further of two types: solution/suspension layering and powder layering

 In solution or
suspension layering, powder feed material and other components are dissolved or
suspended in the solvent. These solution or suspension is sprayed on the surface of
the starter core and spread evenly as soon as it impinges on its surface.46 Spraying is
followed by drying phase which allows dissolved material to get crystallized and thus
between core and coating layer of the drug substance and among the consecutive
layers of drug and polymers a solid bridges forms

 It has been
demonstrated that drying method affects the structural and functional properties of
pellets. Like fluidized bed drying increases the dissolution rate of pellets due to
increase pore diameter whereas lyophilized pellets show increase dissolution due to
increase porosity of pellets

 In powder
layering, the seeds (e.g. sugar spheres) are charged into the pelletizer and on its
surface; the binder liquid and the powdered feed material (drug+excipient) is sprayed
tangentially. The powder is properly distributed on to the surface of seed along with
the rolling movement of it which confirms its spherical shape. It involves successive
deposition of fine powder (drug and other components) and on the surface of starting
core with the help of bridging liquid

 Initially the drug
particles get attached to the starter core with the help binding liquid that is sprayed on
it; it forms a liquid bridge. Later on this liquid bridges gets replaced by the solid
bridge which originates either from a binder in the solvent or from any material, that
is soluble in the solvent medium.48 Conventionally coating pan was used for the
manufacturing of pellets

Cryopelletization :
o Pellets were

prepared by the utilization of Freeze drying method in this technique
 Here in this

technique liquid nitrogen at -196°C is used as a fixing medium which causes freezing of
droplet of liquid formulations into solid spherical particles which were then lyophilized to
provide pellets. In this technique material gets freeze immediately and uniformly as a

result of rapid heat transfer between the droplets and liquid nitrogen. In the conventional
freeze drier the pellets were dried. The total quantity of nitrogen required in this
technique depends upon the temperature of the solution being fixed

Hot Melt Extrusion :
This method involves compaction and conversion of blend of powder into uniform shape
product. Polymers were melted and forced these polymers and active ingredients along with
other additives through an orifice or die that were placed under controlled temperature, pressure,
screw speed etc, to form products of different shapes and sizes. Whole process can be classified
into following steps:

1. Feeding of the extruder through a hopper
2. Mixing, grinding and kneading
3. Flow through the die, and
4. Extrusion from the die and further downstream processing

Freeze Pelletization :
 In this technique, a molten-solid carrier in which the drug is uniformly dispersed is

allowed to enter as tiny droplets into an inert column of liquid in which the molten solid
carrier is totally immiscible

 This droplet gets
solidifies into spherical pellets. These pellets can move in either direction i.e. move
upward or downward depending upon the density of the molten solid carrier with respect
to the liquid in the column

 If the density of
the molten-solid carrier is less than that of the liquid in the column then droplets are
introduced from the bottom of the column, which then gets converted into solid pellets at
the top portion of the column. Conversely, if the density of the molten-solid carrier is
more than that of the liquid in the column then the droplets are introduced from the top of
the column, and that gets solidify in the bottom portion of the column

 Melting point of
solid carrier used for this process should be below 100ºC so that it remain in solid form at
room temperature

 In order to prevent
the blockage of the needles and also to maintain the homogeneity in shape and size of the
pellets The viscosity of the drug matrix should be low. The optimum viscosity of the
liquid in the column should range between 4 and 40 cP at 20ºC to obtain spherical pellets

MUPS (Multiple unit pellet system):

MUPS mainly emphasis on the final dosage form, if the multiparticulate were formulated into single-
unit dosage forms such as filling them into hard gelatin capsules or compressing them into tablets
these are called as MUPS

MUPS manufacturing process constitutes of 2 steps: (1) Pellets manufacturing and (2) Tablet
containing pellets manufacturing.

Equipments for manufacture of pellet :

Mixer like sigma blade mixer, hexagonal mixer

Drying equipment like Fluidized Bed Dryer,spray dryer

Fluidized Bed processor

Freeze drying

Spheronizer

Coating pan, compression machine

References:

[1].The theory & practice of industrial pharmacy by Leon Lachman,H.A.Liberman,special
indian edition 2009.

[2]Pharmaceutics, The science of Dosage form Design by Michael E.Aulton,second Edition
2002

[2].Modern Pharmaceutics by Gilbert S.Banker,Christopher T.Rhodes,fourth edition, Revised
& Expanded, volume 121

[3] Indian pharmacopoeia, 2007 Edition

[4]International Research Journal of Pharmacy, 2013,4(4)-91-95

[5]International Journal of pharmaceutical sciences and Research, 2011; Vol. 2(6): 1337-
1355

[6] Indian Journal of Pharmaceutical Education and Research 2016, Vol 50(3),146-160