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Hard Gelatin Capsules

Definition
| A capsule is an edible package made from gelatin or other suitable
material
t i l and
d fill
filled
d with
ith a d
drug(s)
( ) tto produce
d a unit
it d
dosage, mainly
i l
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 g
gelatin capsule
p shell contains the following
g
ingredients:

z Gelatin.
z Colourants.
z Wetting agents.
z P
Preservatives.
ti

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Gelatin

| Gelatin is a substance of natural origin. However, it does not occur


as suchh iin nature.
t It is
i prepared
dbby th
the h d l i off collagen
hydrolysis ll which
hi h
is the main protein constituent of connective tissues.

| There are two types of gelatin depending on the preparation


method:
z Type A: Derived from acid hydrolysis of collagen. It is
manufactured mainly from pork skin.

z 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:
z Safety: it is non toxic, widely used in foodstuffs and
acceptable for use worldwide.
z Solubility: it is readily soluble in biological fluids at body
temperature.
z Film forming properties: it is capable of producing
strong flexible films (Thickness of the wall of a hard
gelatin capsule is about 100μm).

٢
Gelatin
z 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

| Qualityy Control of Gelatin:


z Viscosity: solution viscosity of a gelatin solution is
dependent on the ratio of the two types of gelatin in
the solution.

z Bloom Strength: It is the load in grams required to


push a standard plunger 4 mm into a gel 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.

٣
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 (200-
(200
250 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.

٤
Colourants

| The colourants are used to ggive the capsules


p their
distinct appearance.
| Colourants used in gelatin capsules can be either:
z Water soluble dyes
z 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 in-
process aid to prevent microbial contamination
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.

٥
Manufacturing

| The basic p principle


p of manufacturing g hard ggelatin capsules
p
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 air-
conditioned buildings where temperature and humidity are
closely controlled.

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

٦
After mixing in stainless steel
receiving tanks
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.

٧
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
pp into the ggelatin
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.

٨
In the Automatic section,
capsule halves are
individuallyy stripped
pp from
the Pins.

The capp and bodyy


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.

٩
Capsule quality is monitored
throughout the production process
including size, moisture content,
single
g wall thickness,, and colour.

Perfect capsules are imprinted


with the logo
g on high-speed
g p
capsule printing machines.

Properties

1. Capsule Sizes
Eight
g sizes of capsules
p are available. The capacity
p y 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
Height
Outer or Actual Typical Fill
Size Diamete Locked Volume Weights (mg) 0.70
r (mm) Length (mL) Powder Density
(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

١٠
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
b 0.8.
by 08

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.

١١
Capsule Shape

Traditional, Locked
Prefit
non-inetrlocking

Capsule Shape

١٢
3. Moisture Content

| Normally, empty capsules have significant amount


(13-16%) of moisture that can act as a plasticizer.
| 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.

١٣
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:
z Must not react with gelatin (e.g. formaldehyde causes
crosslinking reaction that makes the capsule insoluble).
z 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).
z The volume of the unit dose must not exceed the size of capsule
available.

Capsule Filling
Type of Material for Filling
z Dry solids: Powders, Pellets, Granules, Tablets
z 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
l ti att the
th cap-body
b d jjoint
i t tto fform sealing
li gelatin
l ti b
band
d 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.

١٤
Filling of Powder Formulations
Bench – Scale filling

| Bench-scale filling:

z Used for small quantities of capsules ranging


from 50 to 10 000 in number.

z Usually in community pharmacies, hospital


pharmacies
h i or even iin the
h iindustry
d ffor
special prescriptions or trials.

Filling of Powder Formulations


Bench – Scale filling

z Many capsule filling machines may be used for


this purpose “Labocaps ® and Feton®”.
z They consist of sets of plastic plates with
predrilled holes to take from 30-100 capsules of a
specific size.
z Empty capsules are fed into the device either
manually or with a simple loading device
device.

١٥
Filling of Powder Formulations
Bench – Scale filling

z The bodies are locked in their plate by means of a


screw and d th
the caps iin th
their
i plate
l t are removed.d
z 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.
z The cap plate is then repositioned over the body one
and the capsules are rejoined using manual
pressure.
z The uniformity of fill weight is very dependent upon
good flow properties of the powder.

Filling of Powder Formulations

١٦
Filling of Powder Formulations

| Industrial scale filling:

z 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.

z 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:

z 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.
z I d
Independentd t systems:
t where
h th
the powder
d iis
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.

١٧
Filling of Powder Formulations
Dependent dosing (Auger) Systems:

C
Consists
i t off three
th stations
t ti
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)y) holding
g ring,
g, then auger
g inside p 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
d
dependent
d t system
t meaningi ththe system
t use the
th capsule l b
body
d tto
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.

١٨
Filling of Powder Formulations

Hopper
An Auger capsule filling
machine using the ring
system
Auger

Capsule
body plate

Filling of Powder Formulations

١٩
Filling of Powder Formulations

z The weight
g of ppowder filled into the body y is
dependent on the time the body is underneath the
hopper during the revolution of the plate holder.

z The dependent dosing systems are semiautomatic


in operation, requiring an operator to transfer the
capsule holder from one operation to the next.

z 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.
Th ejector
The j t iis aimed
i d att th
the bores
b off holding
h ldi ring,
i iinto
t which
hi h air
i 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 pressure is applied again to expel the capsules through the upper
portion of the ring. Instead of compressed air, pins can be used for
closing and ejection. The capsules upon ejection are collected through
the chute into a collector. Palletized or granular material can be filled on
this machine,, however,, it is desirable to remove the augerg 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.

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٢٠
Filling of Powder Formulations
Independent Dosing system

z Fullyy automatic systems.


y
z Use a dosing mechanism that forms a ‘plug’ of
powder that is transferred then to the capsule shell.
z Plugs are soft compacts formed at low compression
forces (10-100 N).
z Plugs are soft because they are not the final dosage
form unlike tablets
form, tablets, as they will be contained inside
a capsule shell.

Filling of Powder Formulations

| There are two types


yp of p
plug
g forming
g machines:

z Dosators.
z Tamping finger and dosing disc system.

٢١
Independent Dosing system
Dosator systems

z 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

z The tube is lowered open end first into a bed of powder.


z A the
As th powder
d entert the
th tube
t b and d fill th
the chamber
h b it
forms the plug. The plug may be further consolidated
by applying a compression force with the piston.
z The assembly is then raised from the powder bed and
is positioned over the capsule body.
z The plug is then ejected by lowering the piston.
z 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.

٢٢
z The dosator system
i th
is the mostt commonlyl
used capsule filling
system.

z Output could reach


z up to 150 000 /
hour.

Independent Dosing system


Tamping finger and dosing disc

z In this system a dosing disc forms the bottom of a


revolving powder hopper.
z The dosing disc has a series of accurately drilled
holes in which powder plugs are formed by several
sets of tamping fingers.
z Sets of tamping fingers (stainless steel rods) are
lowered into them through the powder bed to
compress the plug.

٢٣
Filling of Powder Formulations

z At each pposition the fingers


g p
push material into the
holes, building up a plug before they index on to the
next position.
z At the last position the finger pushes the plug through
the disc into a capsule body.
z 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.

٢٤
Formulation of Capsule Fillings

| Formulations in general should meet some basic requirements:

z Uniformity and stability of drug content.


z Ability to release the drug in a form that is available
for absorption by the patient.
z 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:
z The properties of the drug (dose, solubility, particle size,
shape, incompatibilities).
z The size of the capsule to be used.

٢٥
Powder Formulations:

| Types of excipients used in powder-filled capsules:

z Diluents: give plug forming properties.


z Lubricants: reduces powder to metal adhesion.
z Glidants: improve powder flow.
z Wetting agents: improve water penetration.
z Di i t
Disintegrants:
t produce
d di
disruption
ti off powder
d mass.
z Stabilizers: improve product stability.

A. Drug

| Low-dose
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
antibiotic),
effect at low concentrations (<5%) and the properties of the
mixture will be governed by that of the active ingredient.

٢٦
B. Diluent

¾ Give plug forming properties.


properties Should have the following ideal
properties
z Good flow: obtainable using free flowing diluents and glidants.
z No adhesion: obtainable using lubricants.
z Cohesion: important for plug formation, using compressible
diluents.

¾ 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.

C. Glidants

z Uniform filling of capsule bodies is mainly dependent


on good powder flowflow.
z Glidants reduce inter-particulate friction, such as
colloidal anhydrous silica, and talc.
z Low dose actives can be made to flow well by mixing
them with free-flowing diluents. And thus glidant is
usualy not necessary.
z 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.

٢٧
D. Lubricant

z Lubricants reduce powder to metal adhesion, such as magnesium


stearate. They
Th exert their
h i effect
ff by
b coating
i theh surface
f off other
h
ingredients.
z 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.
z However, lubricants are not always disadvantageous. They were
shown to increase the dissolution rate of micronized ppowders. This
is due to reduction in cohesiveness of the small particles, thus
spreading more rapidly through the dissolution medium than the
unlubricated particles.
z 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).

E. Disintegrants

z Disntegrants are required to break filled powder mass into


primary
i powder
d particles.
ti l
z Because the powder plug is less compacted than a tablet, starch
swells insufficiently to disrupt it.
z 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®

٢٨
F. 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.

٢٩