Soft Gelatin Capsules (Softgels) [627261]

Soft Gelatin Capsules (Softgels)
Soft Gelatin Capsules (Softgels)
/ring4They are drug delivery systems made of a liquid or a
semisolid matrix inside a one-piece outer gelatin s hell.
/ring4Ingredients that are solid at room temperature can also
be encapsulated into softgels, provided that they a re at
least semisolid at approximately 45 oC.
/ring4The drug itself may be either in solution or in
suspension in the capsule-fill matrix.
/ring4The fill matrix maybe hydrophilic (polyethylene gly cols)
or lipophilic (triglyceride vegetable oils).

Comparison between hard gelatin capsules and softge ls
Fill accuracy 2-5% with modern automatic
machines 1-3%Manufacturi
ng Shell manufacture and filling are
performed in completely two
different processes Shell manufacture and
filling are performed in
one process Closure Traditional friction fit, interlocking,
or liquid sealing Hermitically or
inherently sealed (two
halves of gelatin are fused
during encapsulation by
heat and pressure Plasticization Not-Plasticized, moisture makes it no t
brittle Plasticized and highly
elastic Shape Limited Many Fill material Usually solids, semisolid and liquids
possible Usually semisolid and
liquids, solids possible
even a tablet can be
encapsulated (Gel-Tab) Pieces Two Single Hard gelatin capsules softgels
Drug delivery systems
/ring4Softgels can be formulated and manufactured to prod uce
a number of different drug delivery systems:
/circle6Orally administered softgels (easy to swallow,
convenient dosage form).
/circle6Chewable softgels (highly flavoured shell is chewed
to release the drug liquid fill matrix).
/circle6Suckable softgels (gelatin shell contains flavoured
medicament to be sucked and a liquid matrix or just
air inside the capsule).
/circle6Twist-off softgels (designed with a tag to be twist ed or
snipped off allowing access to the fill material, i t is
very useful for unit dosing of topical medication,
inhalations, or for oral dosing of pediatric produc t).
/circle6Meltable softgels (patient friendly pessaries or
suppositories).

Soft Gelatin Capsules (Softgels)
/ring4SoftgelCapsule Shell consists of:
/circle6Gelatin
/circle6Water (strongly bound to gelatin)
/circle6Plasticizer
/circle6Color and/or flavor
/circle6Preservatives not usually needed because of
the low water activity in the finished product.
Formulation of GelatinShell
/ring4Gelatin
/circle6A large number of different gelatin shell
formulations are available, depending on the
nature of the liquid fill matrix.
/circle6Most commonly the gelatin is alkali-(or base-)
processed (type B) and it normally constitutes
40% of the wet molten gel mass.
/circle6Type A acid-processed gelatin can also be used.
/circle6Bloom strength ~ 150g.

Formulation of GelatinShell
/ring4Plasticizers
/circle6Used to make the shell of the capsule elastic and p liable.
/circle6Constitute 20-30% of the wet gel formulation.
/circle6Glycerol is the most commonly used one, however,
sorbitoland propylene glycol may be used too in
combination with glycerol.
/circle6The amount and choice of plasticizer contribute to the
hardness of the final product and may even affect i ts
dissolution and disintegration characteristics.
/circle6Selection 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.
/circle6It is important to ensure minimum interaction and
migration between the liquid fill matrix and the sh ell.
Formulation of GelatinShell
/ring4Water
/circle6Accounts for 30-40% of the wet gel formulation.
/circle6It is important to ensure proper processing during gel
preparation and softgel encapsulation.
/circle6After encapsulation, excess water is removed via
controlled drying.
/circle6Equilibrium water content in dry softgels is 5-8% w/ w.
This portion of water is bound to gelatin in the she ll.
/circle6The level of water is important for good physical
stability, because in harsh storage conditions soft gels
will become either too soft and fuse together, or t oo
hard and brittle.

Formulation of GelatinShell
/ring4Colourants/opacifiers
/circle6Soluble dyes, insoluble pigments or lakes are used
at low concentration in the wet gel formation.
/circle6Colourants could either be synthetic or natural.
/circle6An opacifier, usually titanium dioxide, may be adde d
to produce an opaque shell when the fill matrix is a
suspension, or to prevent photo-degradation of ligh t-
sensitive fill ingredients.
/circle6Titanium 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:
/circle6New drug molecules tend to be hydrophobic and ther efore
less soluble in aqueous systems.
/circle6Consequently, it is getting more difficult to formu late solid
dosage forms of these drugs that are able to releas e the
drug in a form that is readily available for absorp tion
(solution form).
/circle6To overcome disintegration and dissolution steps, t hese
drugs may be formulated in liquid forms that are in cluded
later in solid dosage forms by encapsulating into s oftgels.

Rationale for Using Softgels:
/circle6As well as increasing the rate of absorption, softg els
were found to improve the extent of absorption
(hydrophobic drugs with high molecular weight).
/circle6In some cases a drug maybe solubilized in a vehicle that
is capable of spontaneously dispersing into an emul sion
on contact with gastrointestinal fluid. This is kno wn as a
self-emulsifying system.
/circle6In other cases, the drug maybe dissolved in an
oil/surfactant vehicle that produces a microemulsio n or a
nanoemulsion on contact with gastrointestinal fluids .
/circle6Softgelformulations may contain excipients (surfacta nts)
which can aid the stability, wettabilityand permeab ility of
the drug.
Rationale for Using Softgels:
/circle6Highly 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.
/circle6The cyclic polypeptide drug cyclosporine benefits
from such an approach by using a
microemulsion preconcentratein a softgel.

Rationale for Using Softgels:
2.Patient Compliance and Consumer Preference:
/circle6Many consumers prefer softgels over either
tablets or hard gelatin capsules because of its
ease of swallowing and absence of
objectionable taste.
/circle6Enhanced 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:
/circle6Mixing, granulation, compression and filling
in the case of tablets and hard gelatin
capsules results in the generation of a
significant amount of dust.
/circle6In case of highly potent drugs and cytotoxic
agents, this may be a risk factor for the
machine operators and the environment.
/circle6Preparation of solutions and suspensions of
these drugs for softgelfilling reduces such
risks.

Rationale for Using Softgels:
4. Oils and Low Melting-Point Drugs:
/circle6If the pharmaceutical active is an oily liquid
or a solid with a melting point of less than
75 oC, it is difficult to formulate it in a tablet or
a hard gelatin capsule.
/circle6In such cases softgelsare the obvious
alternative.
/circle6Oily liquids can be filled directly into softgels
without the addition of any excipients.
/circle6Low 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:
/circle6Liquid 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.
/circle6Improved 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:
/circle6By formulating the drug in a lipophilic vehicle
and encapsulating it in a gelatin shell
ensures good protection against oxygen and
moisture induced instabilities.
/circle6The 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
/ring4Criteria for the choice of liquid-phase fill matrix :
/circle6Capacity to dissolve the drug.
/circle6Ability to disperse in the GI tract after the
softgel shell ruptures and release the fill
matrix.
/circle6Capacity to retain the drug in solution in the
GI fluid.
/circle6Compatibility with the softgel shell.
/circle6Ability to optimize the rate, extent and
consistency of drug absorbed.
Softgel Fill Matrices
1. Lipophilic liquids / oils:
/circle6Triglyceride oils (Soya bean oil).
/circle6Used mostly to prepare simple oily
solutions of Vitamin D (and analogues) and
steroids such as oestradiol.

Softgel Fill Matrices
2. Hydrophilic liquids:
/circle6Polar high molecular weight liquids (PEG
400).
/circle6Water or ethanol may be incorporated in
the softgelfill in low levels typically bellow
10% by weight.
Softgel Fill Matrices
3. Self-emulsifying oils:
/circle6A 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.
/circle6The resulting oil/surfactant droplets enable
rapid transfer of the drug to the absorbing
mucosa and subsequent drug absorption.

Softgel Fill Matrices
4. Self-emulsifying lipid-
based formulations
undergoing lipolysis:
•Self-emulsifying drug delivery systems (SEDDSs) hav e gained
exposure for their ability to increase solubility a nd
bioavailability of poorly soluble drugs.
•SEDDS are isotropic mixtures of oils and surfactant s,
sometimes containing cosolvents, and can be used fo r the
design of formulations in order to improve the oral absorption
of highly lipophilic compounds.
•SEDDS can be orally administered in soft or hard ge latin
capsules and form fine, relatively stable oil-in-wa ter
emulsions, microemulsion or nanoemulsionupon aqueous
dilution.
Softgel Fill Matrices
/circle6A microemulsionof a lipid-surfactant-polar
liquid system is characterized by its
translucent single-phase appearance. The
droplet size is in the submicrometre range.
/circle6A nanoemulsion is a similar system but
contains emulsion droplets in the 100nm
size range.
/circle6Both 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
/circle6In order to produce a micro/nano emulsion in
the GI tract a ‘preconcentrate’ is formulated
in the softgelfill matrix.
/circle6The ‘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.
/circle6The resulting micro/nano emulsion is often
stable for prolonged periods.
Softgel Fill Matrices
/circle6The advantage of the microemulsionapproach lies
in the high surface area presented by the
microemulsionparticles, which are basically
surfactant micelles swollen with solubilized oil and
drug.
/circle6The high surface area facilitates the rapid diffusi on
of drug from the dispersed oil phase into the
aqueous intestinal fluids, until an equilibrium
distribution is established.
/circle6Then as drug is removed from the intestinal fluids
via enterocyte absorption, it is quickly compensated
for by the flow of fresh material from the
microemulsionparticles.

Softgel Fill Matrices
/circle6In addition, lipid formulations can also facilitate dissolution and
bioavailability by lipolysis. Lipolysis is achieved by the
pancreatic lipase on triglycerides and partial glyc erides to form
monoglycerides and fatty acids known as lipolytic pro ducts.
/circle6Lipolytic products interact with bile salts to form small droplets
or vesicles. These vesicles are broken down to smal ler and
smaller vesicles, ultimately resulting in the forma tion of mixed
micelles, that are approximately 3-10 nm in size.
/circle6The hydrophobic drug and lipolytic products reside i n 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.
/circle6In addition, the hydrophilic exterior surface of th e micelles,
facilitates rapid micellar diffusion across the aque ous GIT fluid
to the intestinal membrane.
Softgel Fill Matrices
•In the microclimate adjacent to the intestinal memb rane,
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.
•Supersaturationcause rapid absorption by passive
diffusion because of the high concentration gradien t
between the supersaturated membrane and the blood.

Softgel Fill Matrices
Softgel Fill Matrices
5. Suspensions:
/circle6Drugs that are insoluble in softgelfill
matrices are formulated as suspensions.
/circle6The continuous phase may be any of the
vehicles described above.
/circle6Suspension formulations provide
advantages for certain low-solubility drugs
which are very poorly absorbed after oral
administration.
/circle6With 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
/ring4The production scale manufacturing of liquid-fill c apsules
was achieved when the rotary die encapsulation mach ine
was invented in 1933. See figure in the next slide.
/ring4The rotary die process involves the continuous form ation of a
heat seal between two ribbons of gelatin, simultane ous with
dosing of the fill liquid into each capsule.
/ring4Before the encapsulation process takes place, there are two
sub-processes that are often carried out simultaneo usly,
yielding the two components of a softgel. These are :
/circle6Preperationand formation of gel mass which will pro vide
the softgelshell.
/circle6Preperationof the fill matrix of the contents.

Gelatin mass preparation
/ring4The first step in softgel production begins by blen ding 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 "s yrup" called
a gelatin mass. The key to mixing gelatin is to hea t, blend and
de-aerate (by vacuum to have minimal air in the gel atin) as
quickly as possible, this all takes place in meltin g tank. After
gelatin is melted and fully dissolved, other ingred ients 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.
/ring4Plasticizer (glycerol) is then added.
/ring4After complete dissolution of the gelatin, the othe r components
(colours, opacifier and flavours) are added.
/ring4The gelatin mass is then transferred from the melti ng tank
through filters into heated stainless steel feed ta nks (FEEDER
TANK).
Fill matrix preparation
The liquid fill matrix containing the active drug s ubstanceis
manufactured separately from the preparation of the molten
gelatin mass, which involves dispersing or dissolvi ng the
drug substance in a liquid vehicle using convention al mixer-
homogenizer. Protection against oxidation for oxidi zable
drug can be achieved by mixing under vacuum and ine rt
gas, such as nitrogen. When the drug is suspended i n the
vehicle, then it is important to ensure that the dr ug particle
size not exceeding 200 micron. This is to prevent t he drug
particles from being trapped within the capsule sea l,
potentially leading to loss of integrity of the sof tgel.
Size reduction of the mixture in a mill, such as th e colloid
mill. the purpose of milling is not only to reduce the drug
particle size, but also to make sure that all the s olid particles
are wetted inside the liquid carrier, so as to achi eve smooth
and homogenous mixture. The medicine preparation i s
transferred into the product material tank.

Encapsulation
A. Forming the Gelatin Ribbon
The gelatin mass in the feeder tank is maintained a t 57 to 60
degree during encapsulation. The gelatin mass is ap plied to both
sides of the machine simultaneously by a set of spr eader 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 two-
step process: First, the bottom side of the gelatin is cooled to20°C
with a chilled water circulation system inside the drum. This not only
assists with cooling the gelatin from the bottom si de but also
prevents the gelatin from sticking to the drum. Sec ond, the topside
of the gelatin is cooled with blowers (cooling fan) . Prior to
encapsulation the gelatin ribbon (sheet) must be co ated with a thin
layer of oil to prevent sticking during the filling and sealing process.
Lubrication is done by feeding the chilled rolles ov er thin layer of
inert oil, such as digestible mineral oil or Fracti onated Coconut Oil,
over the oil rolls into the ribbon guide, that guid es the ribbonover
the feeder roll.
B. Encapsulation
/ring4After the two halves of gelatin have been cooled an d
lubricated, they meet together at the forming and f illing
station. Dies that contain small pockets in the sha pe
and size of the capsule to be made. These dies hel p
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 an d
wedge into the gelatin ribbons between the die roll s.
The bottom of the wedge contain small orifices line d
up with the die pockets of the die rolls. The capsu le 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 sh ape
to take place.

/ring4While 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.
Softgel Die Roll Gelatin Ribbon Fill material
Container Wedge
Waste Gelatin

Drying
/ring4Immediately after filling the capsules are transfer red 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 softgelsis rotated i n 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 capsule s, additional
drying is needed. The capsules are placed on drying trays then
into drying racks and into rooms where dry air is c irculated
around them for a period of up to 48 hours to reach a moisture
level of 5%. The rooms are with air inlet with cont rolled humidity
of the drying air and outlet for the removal of moi st air.
/ring4Inspection
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 tray s or
tables or semi-automatically on a roller inspection
machine.
/ring4Packaging
Packaging normally includes placing softgels into b ulk
containers, bottles or blister packaging.Blister pa ckaging
can be of PVC (polyvinyl chloride) or PVDC (poly
vinylidenechloride). PVDC have higher level of wate r
vapor barrier properties and are used for packaging medicaments
which require especially high moisture resistance.
Drying of softgels after encapsulation