Transcript - iSpatula Pharmacy

Soft Gelatin Capsules (Softgels)
Soft Gelatin Capsules (Softgels)
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They are drug delivery systems made of a liquid or a
semisolid matrix inside a one-piece outer gelatin shell.
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Ingredients that are solid at room temperature can also
be encapsulated into softgels, provided that they are at
least semisolid at approximately 45oC.
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The drug itself may be either in solution or in
suspension in the capsule-fill matrix.
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The fill matrix maybe hydrophilic (polyethylene glycols)
or lipophilic (triglyceride vegetable oils).
Comparison between hard gelatin capsules and softgels
Hard gelatin capsules
softgels
Pieces
Two
Single
Fill material
Usually solids, semisolid and liquids
possible
Usually semisolid and
liquids, solids possible even
a tablet can be encapsulated
(Gel-Tab)
Shape
Limited
Many
Plasticization
Not-Plasticized, moisture makes it not
brittle
Plasticized and highly
elastic
Closure
Traditional friction fit, interlocking, or
liquid sealing
Hermitically or inherently
sealed (two halves of gelatin
are fused during
encapsulation by heat and
pressure
Manufacturin
g
Shell manufacture and filling are
performed in completely two different
processes
Shell manufacture and
filling are performed in one
process
Fill accuracy
2-5% with modern automatic machines
1-3%
Drug delivery systems
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Softgels can be formulated and manufactured to produce
a number of different drug delivery systems:
 Orally administered softgels (easy to swallow,
convenient dosage form).
 Chewable softgels (highly flavoured shell is chewed
to release the drug liquid fill matrix).
 Suckable softgels (gelatin shell contains flavoured
medicament to be sucked and a liquid matrix or just
air inside the capsule).
 Twist-off softgels (designed with a tag to be twisted or
snipped off allowing access to the fill material, it is
very useful for unit dosing of topical medication,
inhalations, or for oral dosing of pediatric product).
 Meltable softgels (pessaries or suppositories).
Soft Gelatin Capsules (Softgels)

Softgel Capsule Shell consists of:
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Gelatin
Water (strongly bound to gelatin)
Plasticizer
Color and/or flavor
Preservatives not usually needed because of
the low water activity in the finished product.
Formulation of Gelatin Shell
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Gelatin
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A large number of different gelatin shell
formulations are available, depending on the
nature of the liquid fill matrix.
Most commonly the gelatin is alkali-(or base-)
processed (type B) and it normally constitutes
40% of the molten gel mass.
Type A acid-processed gelatin can also be used.
Bloom strength ~ 150g.
Formulation of Gelatin Shell
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Plasticizers
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Used to make the shell of the capsule elastic and pliable.
Constitute 20-30% of the wet gel formulation.
Glycerol is the most commonly used one, however,
sorbitol and propylene glycol may be used too in
combination with glycerol.
The amount and choice of plasticizer contribute to the
hardness of the final product and may even affect its
dissolution and disintegration characteristics.
Selection of the type and content of plasticizer is based
on the compatibility with the fill materials, ease of
processing and the desired properties of the final softgel.
It is important to ensure minimum interaction and
migration between the liquid fill matrix and the shell.
Formulation of Gelatin Shell
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Water
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Accounts for 30-40% of the wet gel formulation.
It is important to ensure proper processing during gel
preparation and softgel encapsulation.
After encapsulation, excess water is removed via
controlled drying.
Equilibrium water content in dry softgels is 5-8% w/w.
This portion of water is bound to gelatin in the shell.
The level of water is important for good physical
stability, because in harsh storage conditions softgels
will become either too soft and fuse together, or too
hard and brittle.
Formulation of Gelatin Shell
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Colourants/opacifiers
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Soluble dyes, insoluble pigments or lakes are used
at low concentration in the wet gel formation.
Colourants could either be synthetic or natural.
An opacifier, usually titanium dioxide, may be added
to produce an opaque shell when the fill matrix is a
suspension, or to prevent photo-degradation of lightsensitive fill ingredients.
Titanium dioxide can either be used alone to
produce a white opaque shell or in combination with
pigments to produce a coloured opaque shell.
Rationale for Using Softgels:
1. Improved Drug Absorption and Bioavailability:
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New drug molecules tend to be hydrophobic and therefore
less soluble in aqueous systems.
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Consequently, it is getting more difficult to formulate solid
dosage forms of these drugs that are able to release the
drug in a form that is readily available for absorption
(solution form).
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To overcome disintegration and dissolution steps, these
drugs may be formulated in liquid forms that are included
later in solid dosage forms by encapsulating into softgels.
Rationale for Using Softgels:
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As well as increasing the rate of absorption, softgels
were found to improve the extent of absorption
(hydrophobic drugs with high molecular weight).
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In some cases a drug maybe solubilized in a vehicle that
is capable of spontaneously dispersing into an emulsion
on contact with gastrointestinal fluid. This is known as a
self-emulsifying system.
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In other cases, the drug maybe dissolved in an
oil/surfactant vehicle that produces a microemulsion or a
nanoemulsion on contact with gastrointestinal fluids.
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Softgel formulations may contain excipients (surfactants)
which can aid the stability, wettability and permeability of
the drug.
Rationale for Using Softgels:
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Highly variable plasma levels is a characteristic
of drugs having limited bioavailability. By dosing
the drug optimally in solution, the plasma level
variability of such drugs can be significantly
reduced.
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The cyclic polypeptide drug cyclosporine benefits
from such an approach by using a
microemulsion preconcentrate in a softgel.
Rationale for Using Softgels:
2. Patient Compliance and Consumer Preference:
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Many consumers prefer softgels over either
tablets or hard gelatin capsules because of its
ease of swallowing and absence of
objectionable taste.
Enhanced bioavailability, therefore the dose
required to achieve therapeutic effectiveness is
reduced. In this way, it is possible to reduce the
capsule size.
Rationale for Using Softgels:
3. Safety During Manufacturing:
 Mixing, granulation, compression and filling
in the case of tablets and hard gelatin
capsules results in the generation of a
significant amount of dust.
 In case of highly potent drugs and cytotoxic
agents, this may be a risk factor for the
machine operators and the environment.
 Preparation of solutions and suspensions of
these drugs for softgel filling reduces such
risks.
Rationale for Using Softgels:
4. Oils and Low Melting-Point Drugs:
 If the pharmaceutical active is an oily liquid
or a solid with a melting point of less than
75oC, it is difficult to formulate it in a tablet or
a hard gelatin capsule.
 In such cases softgels are the obvious
alternative.
 Oily liquids can be filled directly into softgels
without the addition of any excipients.
 Low melting point drugs may be formulated
with a diluent oil to ensure a satisfactory
liquid flow and dosing into softgels.
Rationale for Using Softgels:
5. Dose Uniformity of Low-Dose Drugs:
 Liquid dosing avoids the difficulties of poor
powder flow and therefore poor content
uniformity. It is a significant benefit for
formulations containing drug doses in the
microgram region.
 Improved homogeneity is achieved by
dissolving the drug in a liquid and then
encapsulating the liquid matrix in a softgel.
Rationale for Using Softgels:
6. Product Stability:
 By formulating the drug in a lipophilic vehicle
and encapsulating it in a gelatin shell
ensures good protection against oxygen and
moisture induced instabilities.
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The only concern is the fact that the drug
may be in solution (more reactive than in dry
state), thus appropriate preformulation
studies regarding choice of excipients and
drug degradation are vital to produce a
stable product.
Formulation of Softgel Fill Matrix
Formulation of Softgel Fill Materials
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Criteria for the choice of liquid-phase fill matrix:
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Capacity to dissolve the drug.
Ability to disperse in the GI tract after the
softgel shell ruptures and release the fill
matrix.
Capacity to retain the drug in solution in the
GI fluid.
Compatibility with the softgel shell.
Ability to optimize the rate, extent and
improve reproducibility of drug absorbed.
Softgel Fill Matrices
1. Lipophilic liquids / oils:
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Triglyceride oils (Soya bean oil).
Used mostly to prepare simple oily
solutions of Vitamin D (and analogues) and
steroids such as oestradiol.
Softgel Fill Matrices
2. Hydrophilic liquids:
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Polar high molecular weight liquids (PEG
400).
Water or ethanol may be incorporated in
the softgel fill in low levels typically bellow
10% by weight.
Softgel Fill Matrices
3. Self-emulsifying oils:
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A combination of an oil and a non-ionic
surfactant (Polyoxyethylene sorbitan
mono-oleate) can provide an oily
formulation which disperses rapidly in the
GI fluid.
The resulting oil/surfactant droplets enable
rapid transfer of the drug to the absorbing
mucosa and subsequent drug absorption.
Softgel Fill Matrices
4. Self-emulsifying lipidbased formulations
undergoing lipolysis:
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Self-emulsifying drug delivery systems (SEDDSs) have gained
exposure for their ability to increase solubility and
bioavailability of poorly soluble drugs.
SEDDS are isotropic mixtures of oils and surfactants,
sometimes containing cosolvents, and can be used for the
design of formulations in order to improve the oral absorption
of highly lipophilic compounds.
SEDDS can be orally administered in soft or hard gelatin
capsules and form fine, relatively stable oil-in-water
emulsions, microemulsion or nanoemulsion upon aqueous
dilution.
Softgel Fill Matrices
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A microemulsion of a lipid-surfactant-polar
liquid system is characterized by its
translucent single-phase appearance. The
droplet size is in the submicrometre range.
A nanoemulsion is a similar system but
contains emulsion droplets in the 100nm
size range.
Both systems have the advantage of a
high capacity to solubilize drug compounds
and to retain the drug in solution even after
dilution in GI fluids.
Softgel Fill Matrices
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In order to produce a micro/nano emulsion in
the GI tract a ‘preconcentrate’ is formulated
in the softgel fill matrix.
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The ‘preconcentrate’ contains a lipid
component and one or more surfactants,
which spontaneously form a micro/nano
emulsion on dilution in an aqueous
environment such as in GI fluid.
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The resulting micro/nano emulsion is often
stable for prolonged periods.
Softgel Fill Matrices
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The advantage of the microemulsion approach lies
in the high surface area presented by the
microemulsion particles, which are basically
surfactant micelles swollen with solubilized oil and
drug.
The high surface area facilitates the rapid diffusion
of drug from the dispersed oil phase into the
aqueous intestinal fluids, until an equilibrium
distribution is established.
Then as drug is removed from the intestinal fluids
via enterocyte absorption, it is quickly compensated
for by the flow of fresh material from the
microemulsion particles.
Softgel Fill Matrices
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In addition, lipid formulations can also facilitate dissolution and
bioavailability by lipolysis. Lipolysis is achieved by the
pancreatic lipase on triglycerides and partial glycerides to form
monoglycerides and fatty acids known as lipolytic products.
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Lipolytic products interact with bile salts to form small droplets
or vesicles. These vesicles are broken down to smaller and
smaller vesicles, ultimately resulting in the formation of mixed
micelles, that are approximately 3-10 nm in size.
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The hydrophobic drug and lipolytic products reside in the
hydrophobic region of mixed intestinal micelles. If the drug has
higher solubility in the lipolytic products than in triglyceride oil,
drug dissolution is enhanced.
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In addition, the hydrophilic exterior surface of the micelles,
facilitates rapid micellar diffusion across the aqueous GIT fluid
to the intestinal membrane.
Softgel Fill Matrices
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In the microclimate adjacent to the intestinal membrane,
the pH is lower than that in the intestinal lumen. This
promotes demicelization at the membrane and local
drug release at the membrane to supersaturate the
intestinal membrane with drug.
Supersaturation cause rapid absorption by passive
diffusion because of the high concentration gradient
between the supersaturated membrane and the blood.
Softgel Fill Matrices
Softgel Fill Matrices
5. Suspensions:
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Drugs that are insoluble in softgel fill
matrices are formulated as suspensions.
The continuous phase may be any of the
vehicles described above.
Suspension formulations provide
advantages for certain low-solubility drugs
which are very poorly absorbed after oral
administration.
With the right choice of excipients, softgel
suspensions can improve bioavailability
compared to compressed tablets or hard
shell capsules or even aqueous solutions.
Manufacture of Softgels
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The production scale manufacturing of liquid-fill capsules
was achieved when the rotary die encapsulation machine
was invented in 1933. See figure in the next slide.
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The rotary die process involves the continuous formation of a
heat seal between two ribbons of gelatin, simultaneous with
dosing of the fill liquid into each capsule.
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Before the encapsulation process takes place, there are two
sub-processes that are often carried out simultaneously,
yielding the two components of a softgel. These are:
 Preperation and formation of gel mass which will provide
the softgel shell.
 Preperation of the fill matrix of the contents.
Gelatin mass preparation
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The first step in softgel production begins by blending powdered
gelatin with water in a gelatin-melting tank at 80 degrees. Water
accounts for 30-40% in the mixture. During melting and after
hydration takes place the powder becomes a thick "syrup" called
a gelatin mass. The key to mixing gelatin is to heat, blend and
de-aerate (by vacuum to have minimal air in the gelatin) as
quickly as possible, this all takes place in melting tank. After
gelatin is melted and fully dissolved, other ingredients are
blended into to the gelatin mass, it is done so by a high-speed
vacuum mixer again to decrease the amount of added air to the
gelatin.
Plasticizer (glycerol) is then added.
After complete dissolution of the gelatin, the other components
(colours, opacifier and flavours) are added.
The gelatin mass is then transferred from the melting tank
through filters into heated stainless steel feed tanks (FEEDER
TANK).
Fill matrix preparation
The liquid fill matrix containing the active drug substance is
manufactured separately from the preparation of the molten
gelatin mass, which involves dispersing or dissolving the
drug substance in a liquid vehicle using conventional mixerhomogenizer. Protection against oxidation for oxidizable
drug can be achieved by mixing under vacuum and inert
gas, such as nitrogen. When the drug is suspended in the
vehicle, then it is important to ensure that the drug particle
size not exceeding 200 micron. This is to prevent the drug
particles from being trapped within the capsule seal,
potentially leading to loss of integrity of the softgel.
Size reduction of the mixture in a mill, such as the colloid
mill. the purpose of milling is not only to reduce the drug
particle size, but also to make sure that all the solid particles
are wetted inside the liquid carrier, so as to achieve smooth
and homogenous mixture. The medicine preparation is
transferred into the product material tank.
Encapsulation
A. Forming the Gelatin Ribbon
The gelatin mass in the feeder tank is maintained at 57 to 60
degree during encapsulation. The gelatin mass is applied to both
sides of the machine simultaneously by a set of spreader boxes
which regulates the gelatin thickness from 0.5 to 1.5 mm as it is
spread on the cooling drum (casting method). Prior to forming, the
gelatin must be cooled. This is done while the thin layer of gelatin
rotates with the cooling drum. Inside the machine, there is a twostep process: First, the bottom side of the gelatin is cooled to 20°C
with a chilled water circulation system inside the drum. This not only
assists with cooling the gelatin from the bottom side but also
prevents the gelatin from sticking to the drum. Second, the topside
of the gelatin is cooled with blowers (cooling fan). Prior to
encapsulation the gelatin ribbon (sheet) must be coated with a thin
layer of oil to prevent sticking during the filling and sealing process.
Lubrication is done by feeding the chilled rolles over thin layer of
inert oil, such as digestible mineral oil or Fractionated Coconut Oil,
over the oil rolls into the ribbon guide, that guides the ribbon over
the feeder roll.
B. Encapsulation
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After the two halves of gelatin have been cooled and
lubricated, they meet together at the forming and filling
station. Dies that contain small pockets in the shape
and size of the capsule to be made. These dies help
in the formation and sealing of the capsule. The
material to be encapsulated flows by gravity into a
positive displacement pump (FILL PUMP). The pump
accurately meters the material through the leads and
wedge into the gelatin ribbons between the die rolls.
The bottom of the wedge contain small orifices lined
up with the die pockets of the die rolls. The capsule is
about half sealed when the gelatin ribbon is forced by
the pressure of the pumped material into these
pockets with the fill material, which causes the shape
to take place.
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While the capsule is being filled, it is also
simultaneously being sealed and cut from the ribbon.
The sealing of the capsule is achieved by the
application of pressure on the die rolls and the
heating of (37 to 40 degrees) of the ribbons by the
wedge, heated by the wedge heaters. Cutting is
achieved by raised rims around each die on the
rollers.
Fill material
Container
Wedge
Gelatin Ribbon
Die Roll
Softgel
Waste Gelatin
Drying
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Immediately after filling the capsules are transferred by conveyor
and blower to the tumble dryers. At this point, the capsules are
very soft due to the high moisture content (30-40%). The tumble
dryer is used to remove a thin layer of mineral oil from the
surface of the capsule and to accelerate the drying process. In
the tumble dryer, the batch of softgels is rotated in a perforated
drum with blown air of at 20% relative humidity. The tunnel drying
process may take 2 or 3 days or possibly as long as 2 weeks,
depending on the specific softgel formulation. While the tumble
dryer removes most of the moisture from the capsules, additional
drying is needed. The capsules are placed on drying trays then
into drying racks and into rooms where dry air is circulated
around them for a period of up to 48 hours to reach a moisture
level of 5%. The rooms are with air inlet with controlled humidity
of the drying air and outlet for the removal of moist air.
Drying of softgels after encapsulation
Inspection
Capsules should be submitted to a final inspection before
packing for malformed, damaged or improperly filled
capsules. This can be done visually by hand on trays or
tables or semi-automatically on a roller inspection
machine.
 Packaging
Packaging normally includes placing softgels into bulk
containers, bottles or blister packaging. Blister packaging
can be of PVC (polyvinyl chloride) or PVDC (poly
vinylidene chloride). PVDC have higher level of water
vapor barrier properties and are used for packaging medicaments
which require especially high moisture resistance.
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