Download L04 Hard Gelatin Capsule

Hard Gelatin Capsules
Definition


A capsule is an edible package made from gelatin or other suitable
material and filled with a drug(s) to produce a unit dosage, mainly
for oral use.
Hard gelatin capsules: or two-piece capsules which are composed
of two pieces in the form of cylinders closed at one end. The shorter
piece, called the “cap”, fits over the open end of the longer piece,
called the “body”.

Gelatin is the most commonly used material for capsule
manufacturing.

There is no pharmacopoeial (USP) restriction on the use of other
suitable materials for capsule making. In recent years
hydroxypropyl methylcellulose (HPMC) have been used in
manufacturing hard capsules (Vegicap) in order to produce a shell
with low moisture content.
Composition of Hard Gelatin
Capsule shell:

Hard gelatin capsule shell contains the following
ingredients:




Gelatin.
Colourants.
Wetting agents.
Preservatives.
Gelatin


Gelatin is a substance of natural origin. However, it does not occur
as such in nature. It is prepared by the hydrolysis of collagen which
is the main protein constituent of connective tissues.
There are two types of gelatin depending on the preparation
method:
 Type A: Derived from acid hydrolysis of collagen. It is
manufactured mainly from pork skin.

Type B: Derived from alkali hydrolysis of collagen. It is
manufactured mainly from animal bones (calf or beef bones).
Gelatin

Gelatin has been used for more than a hundred years in the
manufacture of capsules. Its widespread popularity is probably due
to:



Safety: it is non toxic, widely used in foodstuffs and
acceptable for use worldwide.
Solubility: it is readily soluble in biological fluids at body
temperature.
Film forming properties: it is capable of producing
strong flexible films (Thickness of the wall of a hard
gelatin capsule is about 100m).
Gelatin

Ease of processing:
• Solutions of ohigh concentrations up to 40% w/v are
mobile at 50 C, other biological polymers, such as
agar, are not.
• A solution of gelatin in water or a water plasticizer
blend undergoes a reversible change from solution to
gel at temperatures only a few degrees above
ambient. Other polymers require large quantities of
organic solvent and thermal energy input to achieve
such a transfer.
Gelatin

Quality Control of Gelatin:
 Viscosity: solution viscosity of a gelatin solution is
dependent on the ratio of the two types of gelatin in
the solution.

Bloom Strength: It is the load in grams required to
push a standard plunger 4 mm into a gel.
It is a measure of the gel rigidity and is measured on a
standard gel (6.66 %W/V) after maturing it at 10oC.
Gelatin

Bloom strength is a test that is borrowed from
the food industry where it is used to quantify the
rigidity of many gels in foodstuff production.

Gelatin used in the manufacture of hard gelatin
capsules has a bloom strength value of (200250 gm) while that used in the manufacture of
soft gelatin capsules has a value of ~ 150 gm.
Gelatin
Standard probes for gelatin testing as shown above, are available for
the assessment of Bloom strength/Gel strength.
Colourants


The colourants are used to give the capsules their
distinct appearance.
Colourants used in gelatin capsules can be either:




Water soluble dyes
Water insoluble pigments
To prepare the range of colours seen in the capsules,
dyes and pigments are mixed together in solutions or
suspensions.
Titanium dioxide is used as an opacifier to make the
capsule opaque.
Wetting agent

According to USNF sodium lauryl sulphate is used at a
level of not more than 0.15% w/w as a wetting agent in
hard gelatin capsule to ensure that the lubricated metal
moulds are uniformly covered when dipped in the gelatin
solution.
o Preservatives !!!
• Preservatives were formerly added to hard capsules as an inprocess aid to prevent microbial contamination.
• Hard gelatin capsules contain between 13 and 16% w/v of
moisture.
• Because the moisture is strongly bound to the gelatin
molecules, gelatin usually doesn’t support microbial growth.
• Manufacturers operating their plants in compliance with GMP do
not have to include preservatives.
Manufacturing

The basic principle of manufacturing hard gelatin capsules
involves metal moulds at room temperature being dipped
into a hot gelatin solution which gels to form a film. This is
dried, cut to length, removed from the moulds and the two
parts are joined together.

The operation nowadays is fully automated, carried out as
a continuous process on large machines housed in airconditioned buildings where temperature and humidity are
closely controlled.
Manufacturing

The first step in the process is the preparation of the raw materials. A
concentrated solution of gelatin 35-40% is prepared using
demineralized hot water 60-70°C in jacketed pressure vessels. This is
stirred until gelatin is dissolved and then a vacuum is applied to
remove any entrapped air bubbles.

Aliquots of this solution are dispensed into suitable containers and the
required amounts of dye solution and pigment suspension are added.

The viscosity is measured and adjusted to a target value by addition of
hot water. Viscosity is important to control the thickness of the capsule
shells during production. The higher the viscosity the thicker the shell
wall produced.
Manufacturing

The machine consists of two mirror image halves (figure next slide), one
for the cap and the other for the body. The moulds which are known as
‘pins’ are made of stainless steel and are mounted in sets on metal
strips, called ‘bars’.

Capsules are formed by dipping sets of moulds, which are at room
temperature 22°C, into a ‘dip pan’ that holds a fixed quantity of gelatin
solution having a constant temperature of 45-55°C.

A film is formed on the surface of each mould by gelling.

The moulds are slowly withdrawn from the solution and then rotated
during their transfer to the upper front level in order to uniform the film
and to avoid the formation of a bead at the capsule ends.
The pin bars are allowed to dry in the upper level of the machine (from
upper front to upper rear). Further drying is achieved by transfer to the
lower level (rear).


Drying is achieved by subjecting the moulds to large volumes of humidity
controlled air.
Manufacturing
Manufacturing

The dried films are removed from the moulds (stripping), cut or trimmed
to the correct length, the two parts joined together and the complete
capsules delivered from the machine.

The capsules then pass through a series of sorting and checking
processes, which can be either manual, mechanical or electronic to
remove the defective capsules.

If required, capsules can be printed using an edible ink based on
shellac.
Once raw materials
have been received and
released by Quality
Control, the gelatin and
hot demineralized water
60-70°C are mixed
under vacuum in
Stainless Steel System
After mixing in stainless steel
receiving tanks, the gelatin
solution is transferred to stainless
steel feed tanks.
Dyes, opacifants, and any needed water
are added to the gelatin in the feed tanks
to complete the gelatin preparation
procedure. The feed tanks are then used
to gravity-feed gelatin into the Capsule
Machine.
From the feed tank, the gelatin is
gravity fed to specially
engineered Dipper section.
Here, the capsules are moulded
onto stainless steel Pin Bars
which are dipped into the gelatin
solution.
The Pin Bars pass through the
Capsule Machine Drying System.
Here gently moving air which is
precisely controlled for volume,
temperature, and humidity,
removes the exact amount of
moisture from the capsule
halves.
Once drying is complete,
the Pin Bars enter the Table
section which positions the
capsule halves for stripping
from the Pins in the
Automatic section.
In the Automatic section,
capsule halves are
individually stripped from
the Pins.
The cap and body
lengths are precisely
trimmed to a ±0.15
mm tolerance.
The capsule bodies
and caps are joined
automatically in the
joiner blocks.
Finished capsules are
pushed onto a conveyer
belt which carries them
out to a container.
Capsule quality is monitored
throughout the production process
including size, moisture content,
single wall thickness, and colour.
Perfect capsules are imprinted
with the logo on high-speed
capsule printing machines.
Properties
1. Capsule Sizes
Eight sizes of capsules are available. The capacity of each size
varies according to the combination of drugs and their apparent densities.
Capsules are available as clear gelatin capsules or in a variety of colors.
Empty Hard Gelatin Capsule Physical Specifications
Size
Outer
Diamete
r (mm)
Height
or
Locked
Length
(mm)
000
9.91
26.14
1.37
960
00
8.53
23.30
0.95
665
0
7.65
21.70
0.68
475
1
6.91
19.40
0.50
350
2
6.35
18.00
0.37
260
3
5.82
15.90
0.30
210
4
5.31
14.30
0.21
145
5
4.91
11.10
0.13
90
Actual
Volume
(mL)
Typical Fill
Weights (mg) 0.70
Powder Density
Capsule Sizes

For a powder, the fill weight is calculated by multiplying
the body volume by the tapped density.

For liquids, the fill weight is calculated by multiplying the
specific gravity of the liquid by the capsule body volume
by 0.8.
2. Shape

The usual shape of the capsule end is round.

To ensure reliable closing of the filled capsules, capsule shells
with locking grooves (or indentations) have been prepared. The
two grooves fit into each other for tight closing and prevent
accidental separation (or splitting) of the capsules.

These capsules have a series of indentations on the inside of
the cap and on the external surface of the body which, when
the capsule is closed after filling, form an interference fit
sufficient to hold them together during mechanical handling.
Capsule Shape
Traditional,
non-inetrlocking
Prefit
Locked
Capsule Shape
3. Moisture Content

Normally, empty capsules have significant
amount (13-16%) of moisture that can act as a
placticizer.

At low relative humidity, moisture is lost and the
capsule becomes brittle. Hygroscopic
formulations can absorb water out of the shell
leading to brittleness and drying-out of the shell.
At high humidity levels they will gain moisture and
soften.

4. Solubility
o Gelatin is soluble at temperature above 30°C.
Below 30°C, hard gelatin capsules absorb
water, swell and distort. In body fluids or during
dissolution at 37°C the shell dissolves and
ultimately disappears. It is worth mentioning
that vegicaps made of HPMC are soluble at
temperature as low as 10°C.
Capsule Filling

Hard gelatin capsules can be filled with a large variety of
materials of different physicochemical properties.

Limitation in properties of materials for filling into
capsules:



Must not react with gelatin (e.g. formaldehyde causes
crosslinking reaction that makes the capsule insoluble).
Must not interfere with the integrity of the shell (materials with
high level of free water, that can be absorbed by gelatin causing
it to soften and distort).
The volume of the unit dose must not exceed the size of capsule
available.
Capsule Filling

Type of materials for filling into hard gelatin capsules:
 Dry solids:
• Powders
• Pellets
• Granules
• Tablets
 Semisolids:
• Thermosoftening mixtures (during filling are in the molten
state and fluid enough to be pumped and filled. On standing
solidification happens. E.g. PEG 4000, solid fat.
• Thixotropic mixtures: thin with low viscosity upon shearing
by mixing and form hard mass with high viscosity upon
standing when shearing ceases. During filling they are fluid
and semisolid during shelf life.
• Pastes
 Liquids:
• Non-aqueous liquids: requires sealing by applying gelatin
solution at the cap-body joint to form sealing gelatin band
upon drying. If not sealed leakage at the joint will happen
during handling. Sealing also reduces oxygen permeation
into the content, protecting them from oxidation.
Filling of Powder Formulations

Bench-scale filling:

Used for small quantities of capsules ranging
from 50 to 10 000 in number.

Usually in community pharmacies, hospital
pharmacies or even in the industry for
special prescriptions or trials.
Filling of Powder Formulations

Bench-scale filling:



Many capsule filling machines may be used for
this purpose “Labocaps  and Feton”.
They consist of sets of plastic plates with
predrilled holes to take from 30-100 capsules
of a specific size.
Empty capsules are fed into the device either
manually or with a simple loading device.
Filling of Powder Formulations

Bench-scale filling:




The bodies are locked in their plate by means of
a screw and the caps in their plate are removed.
The powder is placed onto the surface of the
body plate and is spread with a spatula so that it
is filled into the bodies.
The cap plate is then repositioned over the body
one and the capsules are rejoined using manual
pressure.
The uniformity of fill weight is very dependent
upon good flow properties of the powder.
Filling of Powder Formulations
Filling of Powder Formulations
https://www.youtube.com/watch?v=I3-OHZmklCs

Industrial scale filling:

Machines for industrial scale filling of hard gelatin
capsules come in great variety of shapes and sizes.
The output ranges from 5000-15000/ hour. They
vary from semi- to fully automatic.

They can be continuous in motion like a rotary
tablet press or intermittent where the machine
performs its function on one set of capsules at a
time.
Filling of Powder Formulations

The dosing systems in the industrial scale filling machines may be
divided into two groups:


Dependent systems: which use the capsule body
directly to measure the powder. Uniformity of the fill
weight can be achieved if the capsule is filled
completely.
Independent systems: where the powder is
measured independently of the body in a special
measuring device. Weight uniformity is not dependent
on filling the body completely and the capsule can be
part filled.
Filling of Powder Formulations

Dependent dosing (Auger) Systems:
Consists of three stations
Station 1 : For capsule feeding and opening.
Two rings with holes or bores (upper for caps and lower
for bodies) are combined and placed under capsule
holding hopper. the capsules are sucked by vacuum
into the bores and vacuum is also used for separating
capsule cap and body in a way capsule cap can stay in
upper holding ring and capsule body can stay in lower
holding ring. During feeding, the ring holders are
rotated to allow for row-by-row capsule filling.
Station 2: Powder filling station
The holding rings are separated, and then the lower
(body) holding ring is positioned on the rotary table. The
powder hopper is pulled over the lower (body) holding
ring, then auger inside powder hopper (compulsory
feeder, such as rotating screw) is started to run and fill
powder into the capsule body. Upon the lower holding ring
turns one circle, the powder hopper is pushed to its
original position away from the ring. Upon filling, the
bodies should be completely filled for minimal weight
variation and thus uniformity of fill weight is achieved only
if the capsules are filled completely. Accordingly, the
semiautomatic machines is classified as dosing
dependent system meaning the system use the capsule
body to measure the filled powder. Maximum total fill
weight (with minimal weight variation) can be achieved at
the lowest rotational speed of the turntable and vice
versa. More than one rotational cycle can be applied to
ensure complete filling of the capsules.
Filling of Powder Formulations
Hopper
An Auger capsule filling
machine using the ring
system
Auger
Capsule
body plate
Filling of Powder Formulations
Filling of Powder Formulations

The weight of powder filled into the body is
dependent on the time the body is underneath the
hopper during the revolution of the plate holder.

The dependent dosing systems are semiautomatic
in operation, requiring an operator to transfer the
capsule holder from one operation to the next.

The output from such machines varies between
15,000 and 25,000 per hour and is dependent on
the skill of the operator.
Station 3: for capsule closing and ejection
The upper holding ring and lower holding ring are put together,
and then the holding rings are attached ahead of ejector. The
closing plate is moved 180 degree to that shown in Figure 4
into the closing position. The ejector is aimed at the bores of
holding ring, into which air pressure is applied to press
capsules for closing. Afterward, air pressure is released and
then the closing plate is restored to its original position. Air
Visit
pressure is applied again to expel the capsules through the http://www.youtu
upper portion of the ring. Instead of compressed air, pins can be.com/watch?v
be used for closing and ejection. The capsules upon ejection =r2FYbmwV_iU
are collected through the chute into a collector. Palletized or For video
granular material can be filled on this machine, however, it is
desirable to remove the auger from the hopper in order to
avoid crushing. It may also be desirable to perform closing in a
position other than the vertical position, such as the use of
horizontal ejector. In vertical position, pellets or granules may
escape from the body ring and this may cause damage to
capsules.
Filling of Powder Formulations

Independent dosing systems:




Fully automatic systems.
Use a dosing mechanism that forms a ‘plug’ of
powder that is transferred then to the capsule shell.
Plugs are soft compacts formed at low compression
forces (10-100 N).
Plugs are soft because they are not the final
dosage form, unlike tablets, as they will be
contained inside a capsule shell.
Filling of Powder Formulations

There are two types of plug forming machines:


Dosators.
Tamping finger and dosing disc system.
Filling of Powder Formulations

Dosator systems:
 These consist of a dosing tube inside which there
is a movable spring-loaded piston, thus forming a
variable-volume chamber in the bottom of the
cylinder.
Filling of Powder Formulations





The tube is lowered open end first into a bed of
powder.
As the powder enter the tube and fill the chamber it
forms the plug. The plug may be further consolidated
by applying a compression force with the piston.
The assembly is then raised from the powder bed and
is positioned over the capsule body.
The plug is then ejected by lowering the piston.
The weight of the fill can be adjusted by altering the
position of the piston inside the tube (i.e. increasing or
decreasing the volume) and by changing the depth of
the powder bed.
The dosator system
is the most commonly
used capsule filling
system.



Output could reach
up to 150 000 / hour.
Filling of Powder Formulations

Tamping finger and dosing disc:
 In this system a dosing disc forms the bottom of a
revolving powder hopper.
 The dosing disc has a series of accurately drilled
holes in which powder plugs are formed by several
sets of tamping fingers.
 Sets of tamping fingers (stainless steel rods) are
lowered into them through the powder bed to
compress the plug.
Filling of Powder Formulations



At each position the fingers push material into the
holes, building up a plug before they index on to the
next position.
At the last position the finger pushes the plug through
the disc into a capsule body.
The powder fill weight can be varied by the amount of
insertion of the fingers into the disc, by changing the
thickness of the dosing disc, and by adjusting the
amount of powder in the hopper.
Formulation of Capsule Fillings

Formulations in general should meet some basic
requirements:



Uniformity and stability of drug content.
Ability to release the drug in a form that is
available for absorption by the patient.
Compliance with the requirements of the
regulatory authorities and Pharmacopoeiae
(e.g. dissolution tests).
Powder Formulations:

Majority of products for filling into capsules are
formulated as powders.

These formulations are typically mixtures of the active
ingredient together with different types of excipients.

The choice of the excipients for the powder formulation
depends on:
 The properties of the drug (dose, solubility, particle
size, shape, incompatibilities).
 The size of the capsule to be used.
Powder Formulations:

Types of excipients used in powder-filled
capsules:






Diluents: give plug forming properties.
Lubricants: reduces powder to metal
adhesion.
Glidants: improve powder flow.
Wetting agents: improve water penetration.
Disintegrants: produce disruption of powder
mass.
Stabilizers: improve product stability.
Formulation of Capsule Fillings
A. Drug

Low-dose potent drugs are the easiest to formulate for capsule
filling. In this case the drug occupies only a small percentage of
the total formulation (<20%) and so the properties of the mixture
will be governed by the excipients chosen.

On the other hand, in case of high dose drugs (500mg of an
antibiotic), the excipients must be chosen carefully to exert their
effect at low concentrations (<5%) and the properties of the
mixture will be governed by that of the active ingredient.
Powder Formulations:
B. Diluent:
 Give plug forming properties. Should have the following ideal
properties
 Good flow: obtainable using free flowing diluents and
glidants.
 No adhesion: obtainable using lubricants.
 Cohesion: important for plug formation, using compressible
diluents.
 For drugs that are readily soluble are best mixed with
insoluble diluents such as starch, microcrystalline cellulose,
or calcium sulfate, because they help the powder mass to
break up without interfering with their solubility in the
medium.
 For water insoluble hydrophobic drugs, water soluble diluents, such
as lactose is chosen, because it will improve drug dissolution and
bioavailability.

This was studied for phenytoin (a
hydrophobic drug). When it was
formulated with lactose and given as
capsules for n days, high plasma
concentrations were achieved. When
the same drug was given to the same
patients but using calcium sulfate as a
diluent, the plasma concentrations
continuously dropped. When the
former formulation using lactose was
given for the rest of the study, the
drug plasma concentrations were
restored to their higher values
gradually.
Powder Formulations:
C. Glidants




Uniform filling of capsule bodies is mainly dependent
on good powder flow.
Glidants reduce inter-particulate friction, such as
colloidal anhydrous silica, and talc.
Low dose actives can be made to flow well by mixing
them with free-flowing diluents. And thus glidant is
usualy not necessary.
For high dose drugs, because little space is available
for diluent addition, and flowability is governed by the
drug, glidant addition is usually a must.
Powder Formulations:
D: Lubricants: reduce powder to metal adhesion, such as magnesium
stearate. They exert their effect by coating the surface of other ingredients.
Lubricants are usually hydrophobic materials that achieve their
activity by coating the surface of pharmaceutical powders. At high
levels they can reduce the solid mass wetability and thus reduce
dissolution rate and drug release from pharmaceutical solids.
 However, lubricants are not always disadvantageous. They
were shown to increase the dissolution rate of micronized
powders. This is due to reduction in cohesiveness of the small
particles, thus spreading more rapidly through the dissolution
medium than the unlubricated particles.
 Studies have shown that the inclusion of an optimized level of
magnesium stearate increased the dissolution rate. This was
correlated to reduction in the hardness of the powder plug
(softer plug, therefore easier to break apart).
Effect of lubricant on drug dissolution from capsules
This was demonstrated for the
effect of magnesium stearate
(MS) on rifampicin dissolution at
different particle sizes (Figure to
the right). The addition of MS
reduced drug dissolution from
coarse particles (180-355 m)
due to reduction of wettability.
However, for smaller particles
(less than 75 m), an increased in
dissolution rate was obtained.
This was explained as due to
reduction of particle cohesiveness
leading to faster deagglomeration
and spreading in the dissolution
medium.
Effect of lubricant on drug dissolution from
capsules

In another study the effect of magnesium
stearate on hydrochlorthiazide was
studied by measuring the time for 60%
drug release (t60%). It was found that as
the lubricant concentration increased up
to 1%, t60% was continuously reduced
meaning dissolution was enhanced.
However, further increase in lubricant
concentration beyond1% resulted in
relatively longer t60% (dissolution
retardation). The declining portion of the
plot was attributed to plug softening that
dominated hydrophobic barrier action.
The 2nd portion was attributed to
hydrophobic coating and poor wetting.
When t60% was plotted versus plug
hardness high positive correlation was
obtained meaning as the plug is harder
dissolution rate becomes slower.
Disniegrants



Disntegrants are required to break filled powder mass
into primary powder particles.
Because the powder plug is less compacted than a
tablet, starch swells insufficiently to disrupt it.
Superdisintegrants are more effective, used at much
lower concentration than starch and are best in
breaking the capsule plug. They either swell many folds
on absorbing water (Na starch glycolate and
croscarmellose), or act as wicks, attracting water into
the plug (Crospovidone).
A. Na Starch glycolate: Primojel®, Explotab®
B. Croscarmellose: Ac-Di-Sol®
C. Cross linked PVP: Crospovidone®
Wetting agents

Are used when the drug is poorly soluble and hydrophobic.
They reduce interfacial tension between drug particles and
the aqueous dissolution medium, promoting solvent
penetration and wettability.

Sodium lauryl sulphate at levels of 1% in combination
with a water soluble diluent has been shown to increase
dissolution rate of poorly soluble drugs.