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34 Soft capsules

Keith G. Hutchison Josephine Ferdinando

CHAPTER CONTENTS • increase the rate of drug absorption, increase

the extent of bioavailability and reduce
Introduction . . . . . . . . . . . . . . . .612
variability in drug plasma levels;
Description of the soft gelatin capsule • improve patient adherence and consumer
dosage form (softgels) . . . . . . . . . . .613 preference;
Rationale for the selection of softgels • improve manufacturing safety for potent and
as a dosage form . . . . . . . . . . . . .614 cytotoxic drugs; and
Improved drug absorption • improve manufacturability of low melting
characteristics . . . . . . . . . . . . . . . . 615 point and low-dose drugs.
Patient adherence and consumer • Careful consideration should be given to any
preference . . . . . . . . . . . . . . . . . . 616 migration of the drug or other formulation
Safety for potent and cytotoxic drugs . . . . 616 components when one is formulating a softgel
Oils and low melting point drugs . . . . . . . 616 so as to achieve satisfactory product stability
Dose uniformity of low-dose drugs . . . . . . 616 and shelf life.
Product stability . . . . . . . . . . . . . . . 616 • There are a number of fill formulation
approaches which can be used, including
Manufacture of softgels . . . . . . . . . .617 suspensions and solutions, using hydrophilic or
Formulation of softgels . . . . . . . . . .619 lipophilic excipients or a mixture of these, to
Gelatin shell formulation . . . . . . . . . . . 619 produce emulsions or self-emulsifying
Properties of soft gelatin shells . . . . . . . . 620 microemulsions or nanoemulsions.
Formulation of softgel fill materials . . . . . . 621
Product quality considerations . . . . . .624 Introduction
Ingredient specifications . . . . . . . . . . . 624
In-process testing . . . . . . . . . . . . . . 624 When pharmaceutical formulation scientists are
Finished product testing . . . . . . . . . . . 624 designing a solid oral dosage form for drug compounds,
References . . . . . . . . . . . . . . . . .624 they have a number of choices which can be influenced
by consumer preference/adherence, economics and
technical feasibility. In recent years, new drug
KEY POINTS molecules tend to be less soluble in aqueous systems,
and if they are intended for oral administration, this
• Soft gelatin capsules (softgels) comprise a
liquid or semisolid preparation inside a capsule can present a considerable formulation challenge for
that is formed in a single-step encapsulation delivering the drug to achieve the desired rate and
process. extent of absorption. One approach is to make a
• They can be used as a formulation approach liquid formulation containing the drug either in
with the potential to: solution or suspended in a matrix that is more readily

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Soft capsules CHAPTER 34

dissolved on contact with gastrointestinal media. In polyethylene glycols), lipophilic (e.g. triglyceride
order to convert a liquid formula into a solid dosage vegetable oils), or a combination of hydrophilic and
form, it may be encapsulated into soft gelatin capsules, lipophilic ingredients (see also Fig. 34.1).
also known as softgels. Significant advances have been made in recent
This chapter explains: years regarding the formulation of softgel fill matrices
• why softgels are selected for formulation (Gullapalli, 2010). These include self-emulsifying
development; microemulsions and nanoemulsions encapsulated as
• how they are formulated; and preconcentrates in softgels. The term ‘preconcen-
trate’ means that the softgel fill matrix which is a
• how they are manufactured and tested.
combination of lipophilic and hydrophilic liquids as
well as surfactant components disperses after oral
administration to form an emulsion, with a droplet
Description of the soft gelatin size in either the micrometre or the nanometre
capsule dosage form (softgels) size range.
The softgel capsule shell consists of gelatin, water
Softgels consist of a liquid or a semisolid matrix and a plasticizer. The shell may be transparent or
inside a one-piece outer gelatin shell (Fig. 34.1). opaque and can be coloured and flavoured if desired.
Ingredients that are solid at room temperature can Preservatives are not normally required owing to the
also be encapsulated into softgels providing they are low water activity in the finished product. The softgel
at least semisolid below approximately 40 °C. The can be coated with enteric-resistant or delayed-release
drug compound itself may be either in solution or coating materials. Although virtually any shape of
in suspension in the capsule-fill matrix. The charac- softgel can be made, oval or oblong shapes are usually
teristics of the fill matrix may be hydrophilic (e.g. selected for oral administration.

Fig. 34.1 • Different softgel formulations.

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PART FIVE Dosage form design and manufacture

Softgels can be formulated and manufactured to medication, inhalations or oral dosing of a

produce a number of different drug delivery systems: paediatric product (Fig. 34.3).
• Orally administered softgels containing solutions • Meltable softgels designed for use as pessaries or
or suspensions that release their contents in the suppositories.
stomach in an easy-to-swallow, convenient unit
dose form (Fig. 34.2).
• Chewable softgels, where a highly flavoured shell
is chewed to release the drug liquid fill matrix.
Rationale for the selection of
The drug(s) may be present in both the shell softgels as a dosage form
and the fill matrix.
• Suckable softgels, which consist of a gelatin shell Some of the reasons why softgels may be selected
containing the flavoured medicament to be as the preferred formulation approach are summarized
sucked and a liquid matrix or just air inside the in Table 34.1, and a more detailed description follows.
capsule. Whilst softgels can solve various technical formulation
• Twist-off softgels, which are designed with a tag challenges not possible with tablets, consideration
to be twisted or snipped off, thereby allowing should be given to the fact that they can be more
access to the fill material. This type of softgel costly than tablet formulations and require specialized
can be used for unit dosing of topical manufacturing equipment.

Fig. 34.2 • Swallowable softgel capsules. Fig. 34.3 • Twist-off softgel capsules.

Table 34.1 Key features and advantages of the softgel dosage form
Features Advantages
Improved drug absorption Increased rate and extent of absorption and/or reduced variability, mainly for poorly water-soluble
drugs
Patient adherence and Easy to swallow. Absence of poor taste or other sensory problems. Convenient administration of a
consumer preference liquid-drug dosage form
Safety – potent and Avoids dust-handling problems during dosage form manufacture; better operator safety and
cytotoxic drugs environmental controls
Oils and low melting Overcomes problems with manufacture as compressed tablet or hard capsules
point drugs
Dose uniformity for Liquid flow during dosage form manufacture is more precise than powder flow. Drug solutions provide
low-dose drugs better homogeneity than powder or granule mixtures
Product stability Drugs are protected against oxidative degradation by lipid vehicles and softgel capsule shells

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Soft capsules CHAPTER 34

Improved drug absorption Increased bioavailability

characteristics As well as increasing the rate of absorption, softgels
may increase the extent of absorption (Aboul-Einien,
Increased rate of absorption 2009). This can be particularly effective for drugs
with poor aqueous solubility and a relatively high
Major advances have been made in the area of
molecular weight. An example of such a product is
developing softgel formulations to address drug
the protease inhibitor saquinavir, which was formu-
absorption issues (Ferdinando, 2000; Perlman et al.,
lated as a solution–softgel product (Perry & Noble,
2008; Aboul-Einien, 2009). For poorly water-soluble
1988). The solution–softgel formulation provided
drugs, ideally the dosage form would present the
approximately three times greater bioavailability than
drug to the gastrointestinal tract in solution form,
a saquinavir nonliquid hard capsule formulation as
from which the drug can be rapidly absorbed. This
measured by the area under the plasma concentration–
can be achieved using a drug-solution matrix in a
time curve.
softgel formulation, and such formulations can provide
In some cases, a drug may be solubilized in vehicles
faster absorption than from other solid oral dosage
that are capable of spontaneously dispersing into an
forms, such as compressed tablets (Lissy et al., 2010).
emulsion on contact with gastrointestinal fluid. This
This is probably because absorption of a poorly soluble
is known as a self-emulsifying drug delivery system
drug from a tablet formulation requires time for
(SEDDS) (Gao et al., 2006). Drug may be dissolved
disintegration of the tablet into granules, then drug
in an oil/surfactant vehicle that produces a microemul-
dissolution into gastrointestinal fluid. With the
sion or a nanoemulsion on contact with gastrointestinal
solution–softgel approach, the shell ruptures within
fluids. A nanoemulsion of progesterone has been
minutes to release the drug solution, which can be
developed whereby the vehicle consists of oils and
in a hydrophilic or highly dispersing vehicle that aids
surfactants in appropriate proportions. On contact
the rate of drug absorption. This may be beneficial
with aqueous fluids, it produces an emulsion with
for (1) therapeutic reasons, such as the treatment
an average droplet size less than 100 nm. The solubil-
of migraine or acute pain, or (2) where there is a
ity of the drug is maintained as long as possible,
limited absorptive region or ‘absorption window’ high
delivering solubilized drug directly to the enterocyte
in the gastrointestinal tract. Fig. 34.4 shows the faster
membrane. This can increase bioavailability compared
absorption that can be achieved using a solution–
with formulations in which the drug is dosed in the
softgel formulation of ibuprofen compared with a
solid state. Fig. 34.5 shows the plasma concentration–
tablet (Saano et al., 1991).
time profile for progesterone absorbed from a softgel
nanoemulsion formulation (Ferdinando, 2000).
Softgel formulations may contain excipients, for
example one or more surfactants that can aid stability,
aid wettability or even enhance the permeability of
the drug (Aungst, 2000).
Mean serum concentration (µg mL −1 )

Decreased plasma variability

High variability in drug plasma levels is a common
characteristic of drugs with limited bioavailability.
By dosing a drug optimally in solution, one can sig-
nificantly reduce the plasma level variability of the
drug, particularly if absorption is limited by drug
solubility. Self-emulsifying drug delivery systems have
been shown to reduce variability of exposure to the
lipophilic drug torcetrapib compared with a formula-
tion in oil (Perlman et al., 2008). The cyclic poly-
peptide drug ciclosporin (Sandimmune Neoral®)
Fig. 34.4 • Pharmacokinetic evaluation of softgels and benefits from such an approach by use of a microemul-
tablets containing 400 mg ibuprofen (in 12 volunteers). sion preconcentrate in a softgel (Drewe et al., 1992;
From Saano et al., 1991. Meinzer, 1993).

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PART FIVE Dosage form design and manufacture

Serum levels of progesterone (mol L −1 )

Fig. 34.5 • Pharmacokinetic evaluation of progesterone comparing a softgel nanoemulsion formulation of

progesterone with a softgel containing a suspension of the drug in an oil following single dose administration in 12
healthy human volunteers. From Ferdinando, 2000.

Patient adherence and Oils and low melting point drugs

consumer preference
When the drug substance is an oily liquid, has a
A number of self-medicating consumer preference melting point lower than approximately 75 °C or is
studies have been conducted to gauge the user’s difficult to compress, liquid filling of softgels (with
perception of softgels relative to hard capsules and or without other diluents) can provide a successful
tablets. The results of the studies showed that approach to presenting it in a solid oral dosage form.
consumers expressed their preference for softgels
in terms of (1) ease of swallowing, (2) absence of Dose uniformity of low-dose drugs
taste and (3) convenience of use (Jones & Francis,
2000). Presentation of low-dose drugs in a solution form
This expressed appeal of the softgel dosage can overcome the challenges of achieving dosage unit
form may have a positive impact on patient adherence. homogeneity compared with other solid oral dosage
Patient adherence may be further enhanced if forms. Where the dose is in the order of micrograms,
the softgel formulation enables dosing of smaller or it can be difficult to mix with other powders suffi-
fewer dosage units, as a result of increased ciently well to ensure an even distribution in the
bioavailability. bulk materials prior to compression of tablets or filling
of hard capsules. This can result in assay variation
Safety for potent and due to content inhomogeneity. By dissolving the drug
in a liquid and encapsulating it in a softgel, such
cytotoxic drugs inhomogeneity concerns can be avoided.
The mixing, granulation and compression/filling
processes used in preparing tablets and hard capsules Product stability
can generate a significant quantity of airborne powders.
This can be a cause of concern for the manufacture If a drug is subject to oxidative or hydrolytic degrada-
of highly potent or cytotoxic compounds because tion, the preparation of a liquid-filled softgel may
of safety considerations for the operator and prove beneficial. The liquid is prepared and encap-
environment. sulated in a protective nitrogen atmosphere and the
If a solution or suspension of the drug is prepared subsequent dried shell has very low oxygen perme-
where the active component is essentially protected ability. By formulating in a lipophilic vehicle and
from the environment by the liquid, these safety packaging in well-designed blister packs using materials
concerns can be reduced. of low moisture transmission, the drug can be

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Soft capsules CHAPTER 34

protected from moisture. As for all dosage forms, the two plates enabled individual capsules to be cut
thorough stability evaluation is required, including out from the die mould, and these capsules were
excipient compatibility studies, to check against subsequently dried.
negative drug stability effects, caused, for example, However, it was not until the invention of the
by component migration between the fill formulation rotary die encapsulation machine by Robert Pauli
and the capsule shell, exposure to moisture during Scherer in 1933 that liquid-fill capsules could be
manufacture or interaction between the drug and manufactured on a production scale. The rotary die
the fill excipients. This may result in the requirement process involves continuous formation of a heat seal
of refrigerated storage (Klein et al., 2007). between two ribbons of gelatin simultaneous with
dosing of the fill liquid into each capsule. Although
the speed and efficiency of the manufacturing process
Manufacture of softgels have improved greatly in recent years, the basic
manufacturing principle remains essentially unchanged.
Softgels were used in the 19th century as a means The overall layout of a soft gelatin encapsulation
of administering bitter-tasting or liquid medicines. machine is shown in Fig. 34.6.
These were manufactured individually by preparing Before the encapsulation process occurs, two
a small sack of gelatin and allowing it to set. Each subprocesses are often performed simultaneously,
sack, or gelatin shell, was then filled with the medica- yielding the two components of a softgel. These are
tion and heat sealed. This method of manufacture (1) the gel mass which will provide the softgel shell
was improved using a process that involved the sealing and (2) the fill matrix for the softgel contents.
of two sheets of gelatin film between a pair of The gel mass is prepared by dissolving the gelatin
matching flat brass dies. Each die contained pockets in water at approximately 80 °C under a vacuum,
into which the gelatin sheet was pressed and which followed by the addition of the plasticizer (e.g.
were filled with the medication. The pressure between glycerol). Once the gelatin has fully dissolved, other

Pump stroke
Pump case indicator Leads

Wedge
assembly Dryer
baskets

Ribbon
guide Green
wash
Spreader Dryer
box console
Die
pressure
gauge

Casting
drum

Yoke

Green wash
Shaker conveyor
Oil bank screens
rolls

Fig. 34.6 • A soft gelatin encapsulation machine.

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PART FIVE Dosage form design and manufacture

Upper lead plate

Pump stroke indicator

Leads
Pump stroke adjusting
knob (coarse)
Wedge arms

Pump stroke adjusting

knob (fine) Fill shut-off valve

Wedge heaters
Lower lead plate Wedge
Dies
Ribbon guide roll
Yoke

Ribbon guide

Yoke tightening
knobs

Die pressure gauge

Die pressure knob Die adapter knobs

Fig. 34.7 • Detail of a soft gelatin encapsulation machine.

components such as colours, an opacifier and flavours oxygen-sensitive drugs are protected by mixing under
may be added. The hot gel mass is then supplied to a vacuum and/or inert gas; in some cases, an anti-
the encapsulation machine through heated transfer oxidant component may be added to the formulation.
pipes by a casting method that forms two separate Additionally, if the drug substance is present as a
gelatin ribbons, each with a width of typically 150 mm. suspension in the liquid fill matrix, then it is important
During the casting process, the gelatin passes through to ensure that the particle size of the drug does not
the sol–gel transition and the thickness of each gel exceed approximately 200 μm. By doing this, it is
ribbon is controlled to ±0.1 mm in the range from possible to ensure that drug particles do not become
0.5 mm to 1.5 mm. The thickness of the gel ribbons entrapped within the capsule seal, potentially leading
is checked regularly during the manufacturing process. to loss of integrity of the softgel.
The two gel ribbons are then carried through rollers In the rotary die encapsulation process, the gel
(at which a small quantity of vegetable oil lubricant ribbon and the unit dose of liquid fill matrix are
is applied) and onwards to the rotary die encapsulation combined to form the softgel. The process involves
tooling (Fig. 34.7). Each gel ribbon provides one half careful control of three parameters:
of the softgel. It is possible to make bicoloured softgels • Temperature. This controls the heat available for
using gel ribbons of two different colours. capsule seal formation.
The liquid fill matrix containing the active drug
• Timing. The timing of the dosing of unit
substance is manufactured separately from the
quantities of liquid fill matrix into the softgel
preparation of the molten gel. Manufacture of the
during its formation is critical.
active fill matrix involves dispersing or dissolving
the drug substance in the nonaqueous liquid vehicle • Pressure. The pressure exerted between the two
using conventional mixer-homogenizers. rotary dies controls the softgel shape and the
A number of different parameters are controlled final cut-out from the gel ribbon.
during preparation of the active fill matrix, depending Fig. 34.8 shows a simplified diagram representing
on the properties of the drug substance. For example, the mechanism of softgel formation using

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Soft capsules CHAPTER 34

of these materials, their functions, their types and

Wedge the amounts most frequently used in manufacturing
Fill material
softgel shells.

Gel ribbon Gelatin

Die roll
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-
processed (or base-processed) (type B) gelatin and
Waste gelatin it normally constitutes 40% of the wet molten gel
Softgels
mass. Type A, acid-processed gelatin can also be used.

Fig. 34.8 • Softgel formation mechanism.

Plasticizers
Plasticizers are used to make the softgel shell elastic
and pliable. They usually account for 20% to 30%
contrarotating dies and the wedge-shaped fill matrix
of the wet gel formulation. The most common
injection system.
plasticizer used in softgels is glycerol, although sorbitol
Accurately metered volumes of the liquid fill matrix
and propylene glycol are also frequently used, often
are injected from the wedge device into the space
in combination with glycerol. The amount and the
between the gelatin ribbons as they pass between
choice of the plasticizer contribute to the hardness
the die rolls. The wedge-shaped injection system is
of the final product and may even affect the final
itself heated to approximately 40 °C. The injection
product’s dissolution or disintegration characteristics,
of liquid between the gel ribbons forces the gel to
as well as its physical and chemical stability. Plasticiz-
expand into the pockets of the dies, which govern
ers are selected on the basis of their compatibility
the size and shape of the softgels. The ribbon con-
with the fill formulation, their ease of processing and
tinues to flow past the heated wedge injection system
the desired properties of the final softgels, including
and is then pressed between the die rolls. Here, the
hardness, appearance, handling characteristics and
two softgel capsule halves are sealed together by the
physical stability.
application of heat and pressure. The softgel capsules
One of the most important aspects of softgel
are cut automatically from the gel ribbon by raised
formulation is to ensure that there is minimum
rims around each die on the rollers.
interaction or migration between the liquid fill
After manufacture, the capsules are passed through
matrix and the softgel shell. The choice of plasticizer
a tumble dryer and then, to complete the drying
type and concentration is important in ensuring
process, they are spread onto trays and stacked in a
optimum compatibility of the shell with the liquid fill
tunnel dryer that supplies air at approximately 20%
matrix.
relative humidity. The tunnel drying process may
take 2–3 days or possibly as long as 2 weeks, depend-
ing on the specific softgel shell formulation. Finally, Water
the softgels are inspected and packed into bulk Water usually accounts for 30% to 40% of the wet
containers in order to prevent further drying, and gel formulation, and its presence is important to
for storage. ensure proper processing during gel preparation and
softgel encapsulation. Following encapsulation, excess
water is removed from the softgels through controlled
Formulation of softgels drying. In dry softgels, the equilibrium water content
is typically in the range of 5% to 8% w/w, which
Gelatin shell formulation represents the proportion of water that is bound to
the gelatin in the softgel shell. This level of water is
Typical softgel shells are made up of gelatin, a important for good physical stability of softgels
plasticizer and materials that impart the desired because in harsh storage conditions softgels will
appearance (colourants and/or opacifiers) and some- become either too soft and fuse together or too hard
times flavours. The following sections describe each and brittle.

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PART FIVE Dosage form design and manufacture

Colourants/opacifiers
Colourants (soluble dyes or insoluble pigments or
lakes) and opacifiers are typically used at low con-
centrations in the wet gel formulation. Colourants
can be either synthetic or natural and are used to
impart the desired shell colour for product identifica-
tion. An opacifier, usually titanium dioxide, may be
added to produce an opaque shell when the fill
formulation is a suspension or to prevent photodeg-
radation of light-sensitive 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.

Properties of soft gelatin shells Fig. 34.9 • Relationship between oxygen permeability
coefficient and the glycerol concentration in the shell of
softgels at room temperature and a range of relative
Oxygen permeability humidities. RH, relative humidity. From Hom et al., 1975.
The gelatin shell of a soft gelatin capsule provides a
good barrier against the diffusion of oxygen into the
contents of the product. The quantity of oxygen (q)
that passes through the gelatin is governed by the
permeability coefficient (P), the area (A), the thickness
(h) of the shell, the pressure difference (p1 – p2) and
the time of diffusion (t) by the following equation:

PAt( p1 − p2 )
q=
h
(34.1)
The permeability coefficient (P) is related to the
diffusion coefficient (D) and the solubility coefficient
(S) by the equation P = DS. This relationship,
described by Henry’s law, assumes no interaction
between the gas and the polymeric film, but P is
clearly affected by the formulation of the gelatin
Fig. 34.10 • Relationship between equilibrium water
shell, as shown in Fig. 34.9. content and the concentration of glycerol in the shell of
Fig. 34.9 shows the relationship between the soft gelatin capsules at room temperature and a range
oxygen permeability coefficient and the glycerol of relative humidities. RH, relative humidity. From Hom
concentration in the gelatin shell of softgels at room et al., 1975.
temperature and relative humidity from 31% to 80%.
The oxygen permeability decreases with the relative
humidity and the glycerol content in the gelatin shell if they are dissolved or dispersed in an oily liquid fill
formulation (Hom et al., 1975). For maximum material and encapsulated as a soft gelatin capsule.
protection against the ingress of oxygen, the gelatin Fig. 34.10 shows the relationship between the
shell should be dry and formulated to contain equilibrium water content and the concentration of
approximately 30% to 40% glycerol. glycerol in the gelatin shell of a softgel, stored at
room temperature and environmental relative humidi-
ties of between 31% and 80%. The data show that
Residual water content minimum water content is found at glycerol levels
Softgels contain little residual water, and compounds in the shell of between 30% and 40%. Such a formula-
which are susceptible to hydrolysis may be protected tion dried at 31% relative humidity has a water

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Soft capsules CHAPTER 34

content in the shell of approximately 7% (Hom et al., approximately 400 Da. Smaller hydrophilic molecules,
1975), and a water content in the fill in equilibrium such as ethanol or indeed water, can be incorporated
with the atmosphere. The residual water content of in the softgel fill matrix in low levels, typically below
most pharmaceutical compounds stored at 20% rela- 10% by weight. If included at higher levels, they may
tive humidity (the drying condition for softgels) is cause physical instability as they can migrate into
low and the water levels in the fills of softgels the shell. Additional excipients may be included with
therefore are very low. hydrophilic liquids to increase the drug solubility in
the matrix, such as polyvinylpyrrolidone, (PVP) or
using a counterion approach as developed for the
Formulation of softgel fill materials enhanced solubility system for drugs such as ibuprofen
(Seager, 1993).
In terms of formulation requirements, the softgel
should be considered as a biphasic dosage form: a Self-emulsifying drug delivery
solid-phase capsule shell and a liquid-phase capsule systems (SEDDS)
fill matrix. Although it is possible to incorporate a
A combination of a pharmaceutical oil and a surfactant
drug in the shell of a softgel, the overwhelming
such as polyoxyethylene sorbitan monooleate can
majority of products have the active ingredient(s)
provide a formulation which emulsifies and disperses
within the fill matrix. The liquid-phase fill matrix is
rapidly in the gastrointestinal fluid. The resulting
selected from components with a wide range of
droplets enable rapid transfer of the drug to the
different physicochemical properties. The choice of
mucosa and subsequent drug absorption. If the droplets
components is made according to one or more of a
formed on contact with aqueous media are in the
number of criteria, including the following:
micrometre size range, then the emulsion formed is
• capacity to dissolve the drug (if a solution fill is known as a microemulsion; if they are in the nanometre
required); range, then it is known as a nanoemulsion.
• rate of dispersion in the gastrointestinal tract In order to produce a microemulsion or a nanoe-
after the softgel shell ruptures and releases the mulsion in the gastrointestinal tract, a ‘preconcentrate’
fill matrix; is formulated in the softgel fill matrix. The precon-
• capacity to retain the drug in solution in the centrate fill matrix contains a lipid component and
gastrointestinal fluid; one or more surfactants, which spontaneously form
• compatibility with the softgel shell; and a microemulsion or a nanoemulsion on dilution in an
• ability to optimize the rate, extent and aqueous environment such as gastrointestinal fluid
consistency of drug absorption. (Fig. 34.11).

Types of softgel fill matrices

Lipophilic liquids/oils
Trigylceride oils, such as soya bean oil, are commonly
used in softgels. When used alone, however, their
capacity to dissolve drugs is limited. Nevertheless,
active ingredients such as hydroxycholecalciferol and
other vitamin D analogues and steroids such as
oestradiol can be formulated into simple oily solutions
for encapsulation in softgels. The drug may also be
suspended in oils with appropriate excipients to ensure
homogeneity during the manufacturing process.

Hydrophilic liquids
Polar liquids with a sufficiently high molecular weight
are commonly used in softgel formulation either to
dissolve or to suspend the drug. Polyethylene glycol
(PEG) is the most frequently used, for example PEG Fig. 34.11 • Proposed nanoemulsion/microemulsion
400, which has an average molecular mass of dissolution mechanism.

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PART FIVE Dosage form design and manufacture

Microemulsion and nanoemulsion systems have lipids in the softgel fill matrix. The quantity of a
the advantage of a high capacity to solubilize drug 1.0 M sodium hydroxide titrant is directly propor-
compounds, and can retain the drug in solution even tional to the extent of lipolysis.
after dilution in gastrointestinal fluids. In addition, The mixed intestinal micelles produced as a result
the microemulsion droplets have a high surface area, of this lipolysis process are of physiological importance
and are essentially surfactant micelles swollen with because these structures can transport high concentra-
solubilized oil and drug. This high surface area tions of hydrophobic molecules across the aqueous
facilitates the rapid diffusion of the drug from the boundary layer which separates the absorptive
dispersed oil phase into the aqueous intestinal fluids, membrane from the intestinal lumen. Thus lipolytic
until an equilibrium distribution is established. products (i.e. fatty acids and monoglycerides) and
Thereafter, as the drug is removed from the intestinal hydrophobic drug, if present, reside in the hydro-
fluids through absorption, it is quickly replenished phobic core regions of mixed intestinal micelles. In
by the flow of fresh material from the microemulsion contrast, the surface of the micelles remains hydro-
droplets. Improved pharmacokinetic characteristics philic, and this facilitates rapid micellar diffusion
may be achieved with this formulation approach. across the aqueous boundary layer to the intestinal
membrane. In the microclimate adjacent to the
Lipolysis systems intestinal membrane, the pH is lower than in the
In addition to promoting the solubility of drug intestinal lumen. This promotes demicellization,
compounds, lipid formulations can also facilitate leading to the formation of a supersaturated solution
dissolution by taking advantage of the natural process of lipolytic products (and hydrophobic drug, if
of lipolysis. Lipid components of a softgel fill matrix, present) close to the enterocyte surface. These
which comprise triglycerides or a partial glyceride materials are then readily absorbed across the cell
(monoglyceride/diglyceride), are often subject to membrane by passive diffusion.
intestinal fat digestion or lipolysis. Lipolysis is the Mixed intestinal micelles comprising bile salts and
action of the enzyme pancreatic lipase on triglycerides lipolytic products can enhance the bioavailability of
and partial glycerides to form 2-monoglycerides and hydrophobic drugs whose absorption is normally
fatty acids. These 2-monoglycerides and fatty acids, dissolution-rate limited. This is because mixed
known as lipolytic products, then interact with bile intestinal micelles can be very potent solubilizing
salts to form small droplets or vesicles. These vesicles agents for a wide range of hydrophobic drugs, much
are broken down into smaller and smaller vesicles, more so than simple bile salt micelles formed in the
ultimately resulting in the formation of mixed micelles absence of lipolytic products. For example, under
that are approximately 3 nm to 10 nm in size. simulated physiological conditions, the aqueous solu-
If a drug substance possesses higher solubility in bility of cinnarizine in simple bile salt micelles is
lipolytic products than in triglyceride oils, then it is 4 μg mL−1, compared with 0.5 μg mL−1 in aqueous
advantageous for lipolysis to occur in the intestinal buffer. However, in the presence of mixed micelles,
lumen. In this way the process of lipolysis promotes the solubility of cinnarizine is further enhanced to
the formation of an excellent dissolution medium approximately 44 μg mL−1 (Embleton et al., 1995).
for the drug, namely lipolytic products. On the other Taking cinnarizine as an example, it would be
hand, the absorption of a drug compound may be advantageous to formulate a softgel fill matrix that
adversely affected by the presence of bile salts, and allows lipolysis to occur in the intestinal lumen
in such a case it may be advantageous for lipolysis because of the high drug solubility in lipolytic
to be reduced or blocked completely. It has been products. If the inhibition of lipolysis by a hydrophobic
found that certain hydrophilic and lipophilic sur- surfactant were allowed to occur, then it is highly
factants have the ability to block or promote lipolysis likely that cinnarizine absorption would be impaired
(MacGregor et al., 1997). These hydrophilic and because of the reduced flow of drug into mixed
lipophilic surfactants are often used in softgel fill micelles. However, if certain lipophilic surfactants
matrix formulations. with a hydrophile–lipophile balance (HLB) less than
Measurement of the rate and extent of lipolysis 10 are added to the formulation, then the inhibitory
for a softgel fill matrix formulation can be achieved effects of hydrophilic surfactants on lipolysis can be
by an in vitro pH stat measurement technique. In reduced or eliminated.
this, lipolysis is quantified by the amount of free Two formulations containing cinnarizine, a hydro-
fatty acids liberated by enzymatic digestion of the phobic drug whose absorption is normally

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Soft capsules CHAPTER 34

Plasma cinnarizine (ng mL−1)

ng h mL−1
[B] Softgel − nonlipolysing AUC(0 −24 h) = 451 ng h mL−1
ng h mL−1

Fig. 34.12 • Plasma concentration versus time curves for three formulations of cinnarizine in the dog (n = 6). AUC,
area under the plasma concentration versus time curve. From Embleton et al., 1995.

dissolution-rate limited, have been compared (Fig. investigated further in an in vivo study. This study
34.12; Embleton et al., 1995). Formulation A was compared the bioavailability of cinnarizine (30 mg)
prepared as a lipolysing formulation and formulation orally administered as a lipolysing formulation
B was prepared as a nonlipolysing formulation, as (formulation A) or a nonlipolysing formulation
demonstrated by the in vitro model. Formulation A (formulation B) to six beagle dogs with a commercially
was composed of a digestible triglyceride oil, a available tablet (formulation C). The area under the
hydrophilic surfactant and a lipophilic surfactant, plasma concentration–time curve (0 h to 24 h) for
which was chosen on the basis of its ability to formulation A compared with the tablet preparation
overcome the inhibitory effects of the hydrophilic was significantly increased by 64% and for formulation
surfactant on the in vitro triglyceride lipolysis. In A compared with formulation B was increased by
vitro, this formulation exhibited 79% lipolysis after 48%. Cmax of formulation A was approximately 75%
60 minutes compared with the digestible oil alone. higher than that of both formulation B and formulation
In contrast, formulation B contained a lipophilic C (Fig. 34.12).
surfactant that did not overcome the inhibitory effects The results of this study have given valuable insight
of the hydrophilic surfactant on the lipolysis of the into the effect of the microemulsion formulation on
triglyceride oil and was shown to exhibit 3% lipolysis. absorption of a hydrophobic drug in the gastrointestinal
It was proposed that the oil in formulation A, which tract, and information as to how the lipolysis process
forms a fine oil-in-water emulsion on aqueous dilution, may influence bioavailability (Lacy et al., 2000).
is rapidly digested, forming mixed intestinal micelles More recently, several studies have been performed
with endogenous bile. These micelles transport the to improve the understanding of drug disposition
drug to the intestinal membrane, where the pH of from lipid-based formulation systems (Porter et al.,
the microclimate promotes micellar breakdown, 2008). A lipid formulation classification system has
facilitating enterocyte transport to the systemic been devised to organize drug–lipid compositions
circulation. In contrast, on dilution with aqueous according to the type of excipients used (Pouton,
fluids, formulation B forms a translucent microemul- 2006):
sion (as indicated by a blue tinge resulting from the
Tyndall effect). As a result of this formulation failing type I: oils (triglycerides or mixed monoglycerides
to undergo lipolysis and thereby remaining unaffected and diglycerides);
by enzymic activity, the drug is maintained within type II: water-insoluble surfactants with HLB <
the oil phase, inhibiting the production of mixed 12;
intestinal micelles, hence restricting absorption of type III: water-soluble surfactants with HLB > 12;
the drug. and
The significance of the lipolysis process in enhanc- type IV: hydrophilic cosolvents such as
ing the bioavailability of hydrophobic drugs was polyethylene glycol.

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PART FIVE Dosage form design and manufacture

The tendency for drugs to precipitate from lipid • the gel ribbon thickness;
formulas in gastrointestinal fluid can be mitigated by • softgel seal thickness at the time of
the presence of polymeric precipitation inhibitors encapsulation;
such as cellulosic excipients (Warren et al., 2010). • fill matrix weight and capsule shell weight; and
• softgel shell moisture level and softgel hardness
Product quality considerations at the end of the drying stage.
Appropriate control levels for these parameters are
established during process development for each
Ingredient specifications softgel product, and are applied in routine production-
scale manufacture.
All the ingredients of a softgel dosage form are
controlled and tested to ensure compliance with
pharmacopoeial specifications. Additional specification Finished product testing
tests may be added for certain excipients to ensure
manufacture of a high-quality softgel product. For Finished softgels are subjected to a number of tests
example, it is important to limit certain trace impuri- in accordance with compendial requirements for
ties such as aldehydes and peroxides that may be unit dose capsule products. These normally include
present in polyethylene glycol. The presence of high capsule appearance, active ingredient assay and
levels of these impurities gives rise to cross-linking related substances assay, as well as fill weight, content
of the gelatin polymer, leading to nonsolubilization uniformity, microbiological testing and dissolution
through further polymerization. On prolonged storage, testing. Development of a dissolution test using
this can lead to slow dissolution of the capsule shell traditional media can be a challenge for certain softgel
and subsequent retarded drug release. formulations, including those with oily fills or those
Gelatin also requires careful control of quality to which rely on physiological conditions to release the
ensure a manufacturable and stable product. The drug. Some have argued that disintegration testing
quality of gelatin is controlled by parameters such may be more suitable for certain softgels (Han &
as the viscosity of a hot solution and the Bloom Gallery, 2006), whilst others use surfactant-based
strength of the gel. The Bloom strength is a measure or enzyme-based media to achieve full dissolution
of gel rigidity (see also Chapter 33). in vitro.

Please check your eBook at https://studentconsult.

In-process testing inkling.com/ for self-assessment questions. See inside
cover for registration details.
During the encapsulation process, tests for the fol-
lowing parameters are performed:

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