CAPSULES PRODUCTION.
MICROCAPSULES.
HARD AND SOFT GELATIN
CAPSULES
Capsules are solid oral dosage forms
in which the drug is enclosed within a hard or soft shell. The shell is
normally made from gelatin and results in a simple, easy - to - swallow formulation
with no requirement for a further coating step. They can be either
hard or soft depending on the nature of the capsule shell, with soft capsules
possessing a fl exible, plasticized gelatin fi lm. Hard gelatin capsules are
usually rigid two - piece capsules that are manufactured in one procedure and
packed in another totally separate operation, whereas the formulation of soft
gelatin capsules is more complex but all steps are integrated.
There is a growing interest in using
non - animal - derived products for formulation of the capsule shells to
address cultural, religious, and dietary requirements. HPMC (e.g., V - caps,
Quali - VC, Vegicaps) and pullulan shells (NPCaps) and starch are alternatives.
Hard - Shell Gelatin
Capsules
Although the challenges of powder
blending, homogeneity, and lubcricity exist for
capsules as for tablets, they are
generally perceived to be a more fl exible formulation as there is no
requirement for the powders to form a robust compact. This means that they may
also be more suitable for delivery of granular and beadlike formulations,
fragile formulations that could be crushed by the normal compaction step. They
are commonly employed in clinical trials due to the relative ease of blinding
and are useful for taste masking.
Capsules are usually more expensive
dosage forms than an equivalent tablet formulation due to the increased cost of
the shells and the slower production rates. Even with modern fi lling
equipment, the fi lling speeds of capsule machines are much slower than tablet
presses. However, increased costs can be offset by avoiding a granulation step.
Capsules, although smoother and easy to swallow, also tend to be larger than
corresponding tablet formulations, potentially leading to retention in the
esophagus. Humidity needs to be considered during manufacture and storage, with
moisture leading to stickiness and desiccation causing brittleness. Cross –
linking of gelatin in the formulation can also lead to dissolution and
bioavailability concerns.
Capsule excipients are similar to
those required for formulation of tablets and include diluents, binders,
disintegrants, surfactants, glidants, lubricants, and dyes or colorants. The
development of a capsule formulation follows the same principles as tablet
development, and consideration should be given to the same BCS issues. The
powder for encapsulation can comprise simple blends of excipients or granules
prepared by dry granulation or wet granulation. There is a reduced requirement
for compressibility, and often the fl ow properties are not as critical as in
an equivalent tablet formulation. The degree of compressibility required is the
major difference, and capsules can therefore be employed when the active
ingredient does not possess suitable compression characteristics.
Manufacture of Hard
Gelatin Shells
Gelatin is a generic term for a
mixture of purifi ed protein fractions obtained either by partial acid
hydrolysis (type A gelatin) or by partial alkaline hydrolysis (type B gelatin)
of animal collagen. Type A normally originates from porcine skin while B is
usually derived from animal bones, and they have different isoelectric points
(7.0 – 9.0 and 4.8 – 5.0, respectively) [6] . The protein fractions consist
almost entirely of amino acids joined together by amide linkages to form linear
polymers, varying in molecular weight from 15,000 to 250,000. Gelatin can
comprise a mixture of both types in order to optimize desired characteristics,
with bone gelatin imparting fi rmness while porcine skin gelatin provides
plasticity. Gelatin Bloom strength is measured in a Bloom gelometer, which
determines the weight in grams required to depress a standard plunger in a
6.67% w/w gel under standard conditions. Bloom strength and viscosity are the
major properties of interest for formulation of capsules, and Bloom strength of
215 – 280 is used in capsule manufacture.
Gelatin is commonly used in foods and
has global regulatory acceptability, is a good fi lm former, is water soluble,
and generally dissolves rapidly within the body without imparting any lag
effect on dissolution. Gelatin capsules are strong and robust enough to
withstand the mechanical stresses involved in the automated fi lling and
packaging procedures.
In addition to gelatin, the shells may
contain colorants, opacifi ers, and preservatives (often parabens esters).
There are eight standard capsule sizes, and the largest capsule size considered
suitable for oral use is size 0 (Table 5 ).
To manufacture the shells, pairs of
molds, for the body and the cap, are dipped into an aqueous gelatin solution
(25 – 30% w/w), which is maintained at about 50 ° C in a jacketed heating pan.
As the pins are withdrawn, they are rotated to distribute the gelatin evenly
and blasted with cool air to set the fi lm. Drying is carried out by
TABLECapsule Size and
Corresponding Volume or Weight of Fill
Size |
Volume (mL) |
Fill weight a (g) |
000 |
1.37 |
1.096 |
00 |
0.95 |
0.760 |
0 |
0.95 |
0.544 |
1 |
0.50 |
0.400 |
2 |
0.37 |
0.296 |
3 |
0.30 |
0.240 |
4 |
0.21 |
0.168 |
5 |
0.13 |
0.104 |
passing dry air over the shell as
heating temperatures are limited due to the low melting point of gelatin. The
two parts are removed from the pins, trimmed, and joined using a prelock
mechanism. The external diameter of the body is usually wider at the open end
than the internal diameter of the cap to ensure a tight fi t. They can be made
self - locking by forming indentations or grooves on the inside of both parts
so that when they are engaged, a positive interlock is formed (e.g., Posilok,
Conicap, Loxit).
Alternatively, they may be
hermetically sealed using a band of gelatin around the seam between the body
and the cap (Qualicaps). This can be applied without the application of heat
and provide a tamper - evident seal. LEMS (liquid encapsulation microspray
sealing) used in Licaps is a more elegant seal in which sealing fl uid (water
and ethanol) is sprayed onto the joint between the cap and body of the capsule.
This lowers the melting point of gelatin in the wetted area. Gentle heat is
then applied which fuses the cap to the body of the Licaps capsule. The moisture
content of manufactured shells is 15 – 18% w/w and levels below 13% will result
in problems with the capsule fi lling machinery. Therefore, capsules are stored
and fi lled in areas where relative humidity is controlled to between 30 and
50%.
Hard - Gelatin Capsule
Filling
The fi lling material must be
compatible with the gelatin shell and, therefore, deliquescent or hygroscopic
materials cannot be used. Conversely, due the moisture content in the capsule
shells, they cannot be used for moisture - sensitive drugs. All ingredients
need to be free of even trace amounts of formaldehyde to minimize cross -
linking of gelatin.
Powders and granules are the most
common fi lling materials for hard - shell gelatin capsules, although pellets,
tablets, pastes, oily liquids, and nonaqueous solutions and suspensions have
been used. Filling machines are differentiated by the way they measure the dose
of material and range in capacity from bench - top to high - output,
industrial, fully automated machines. Those that rely on the volume of the
shell are known as capsule dependent, whereas capsule - independent forms
measure the quantity to be fi lled in a separate operation. The simplest
dependent method of fi lling is leveling where powder is transferred directly
from a hopper to the capsule
TABLE Liquid Excipients
Compatible with Hard Gelatin Capsules
Peanut oil |
Paraffi n oil |
Hydrogenated peanut oil |
Cetyl alchohol |
Castor oil |
Cetostearyl alcohol |
Hydrogenated castor oil |
Stearyl alcohol |
Fractionated coconut oil |
Stearic acid |
Corn oil |
Beeswax |
Olive oil |
Silica dioxide |
Hydrogenated vegetable oil |
Polyethylene glycols |
Silicone oil |
Macrogol glycerides |
Soya oil |
Poloxamers |
body, aided by a revolving auger or
vibration. Additional powder can be added to fi ll the space arising, and the
fi ll weight depends on the bulk density of the powder and the degree of
tamping applied.
Most automated machinery is of the
independent type and compresses a controlled amount of powder using a low
compression force (typically 50 – 200 N ) to form a plug. Most are
piston - tamp fi llers and are dosator or dosing disk machines. The powder is
passed over a dosing plate containing cavities slightly smaller than the
capsule diameter, and powder that falls into the holes is tamped by a pin to
form a plug. This can be repeated until the cavity is full and the plugs (or
slugs) are ejected into the capsule shells. The minimum force required to form
a plug should be used to reduce slowing of subsequent dissolution.
In the dosator method, the plug is formed
within a tube with a movable piston that controls the dosing volume and applies
the force to form the plug. The dose is controlled by the dimensions of the
dosator, the position of the dosator in the powder bed, and the height of the
powder bed. Fundamental powder properties to ensure even fi lling are good
powder fl ow, lubricity, and compressibility. The auger or screw method, now
largely surpassed, uses a revolving archimedian screw to feed powder into the
capsule shell.
A liquid fi ll can be useful when
manufacturing small batches if limited quantities of API are available. Liquid
fi lls also offer improved content uniformity for potent, low - dose compounds
and can reduce dust - related problems arising with toxic compounds. Two types
of liquid can be fi lled into hard gelatin capsules: nonaqueous solutions and
suspensions or formulations that become liquid on application of heat or shear
stress. These require hoppers with heating or stirring systems. For those
formulations that are liquid at room temperature, the capsule shells need to be
sealed after fi lling to prevent leakage of the contents and sticking of the
shells. It is essential to ensure the liquid is compatible with the shell
(Table 6 ).
CAPSULES,
HARD
INTRODUCTION
Hard
or two-piece capsules were first produced on an industrial-scale in
U.S.A. in the 19th century and are now produced throughout the
world.[1] Hard capsules are welcomed by consumers because
of their elegant appearance and shape, which are easy to swallow.
The
majority of capsule fills are dry powder blends, which are typically
simple mixtures. The processing and filling of materials involves
minimum stress and is one of the reasons why products are presented in this form.
The formulator is able to prepare products that have the desired release
characteristics, rapid, controlled, or modified release, because of the
limited number of factors involved. Hard capsules can be filled with
formulation that have a wide range of physical properties from dry
solids to non-aqueous solutions, thus enabling the formulator to use
many different types of excipient to achieve their desired effect. Capsule products
can be formulated to release their active ingredients at many sites along the
gastrointestinal tract and to deliver them to the lungs.
RAW MATERIALS
Gelatin and Alternative
Materials
Gelatin
is a material derived from collagen, a natural protein, which occurs in
the skins, bones, and connective tissues of animals.[2] It is
insoluble in water and is solubilized by hydrolysis. The raw
materials used for its manufacture are obtained mainly from bovine bones
or porcine skins. The reaction can be carried out at an acid pH giving
a type A gelatin (primarily produced from skins) and at a basic
pH giving a type B gelatin (primarily produced from bovine bones). Gelatin
is an ideal material because it is edible, soluble at body temperature,
forms strong thin films and undergoes a gelation process at
temperatures just above ambient.[1] During the 1990s, there were concerns over
the use of bovine materials owing to bovine spongiform encephalopathy, which
originated in U.K. The European Commission (EC) instigated several action
plans to limit the spread of the disease and to control products of
bovine origin. The alkaline hydrolysis process was made the
method choice for bones by the EC because of the pH levels and temperatures used
in the manufacturing process. For human and veterinary pharmaceuticals, the
European Medicines Evaluation Agency (www.emea.eu.int) instituted guidelines
controlling the use of such materials. This led to the European Pharmacopoeia
including requirements for all products that are at risk
and giving rules to minimize this. All manufacturers of materials of bovine
origin need to submit dossiers on their products to the European
Department for the Quality of Medicines (EDQM: www.pheur.org) to obtain
certificates of suitability. These certificates need to be submitted to the
regulatory authorities as part of the marketing authorization for a
product. In addition, the EU scientific steering committee introduced a
system for risk management, which involved assessing countries in terms
of their Geographical BSE Risk (GBR). There are four categories ranging form
GBR I, highly unlikely, to GBR IV, confirmed at a high
level. The GBR category governs the amount of precautions
that have to be taken in handling bovine products.
The
walls of gelatin capsules are homogenous and very robust, and can
readily withstand the mechanical stresses of the filling and
packaging operations. The main draw back in the use of
gelatin is that it contains water, which acts as a plasticizer
to the film. Their properties will change if they are not stored properly, and
when water is lost, they become brittle and thus are not suitable for
hygroscopic formulations. Moisturelabile substances cannot be filled into
them. For certain markets, there are consumer requirements for a capsule of
vegetable origin. The primary problem to overcome in finding a gelatin
substitute is the need to obtain a system that gels in a similar
manner to gelatin so that the same manufacturing machines and processes can
be used. Since 1990, several polymers have been proposed for capsule manufacture:
hypromellose, pullulan, chitosan, and pondac [copolymer of
polyvinyl alcohol (PVA) and methacrylates]. Hypromellose has been the most
successful one because it overcomes the problem of brittleness when the
capsules are exposed to dry conditions.[3] All the other
polymers proposed suffer from this defect to some extent.
Hypromellose solutions are converted into gelling system
for use on standard manufacturing machines by adding a material to act as
a network former, such as carrageenan or gellan gum, and a gel promoter
such as potassium chloride or citric acid. Hard capsules made
from hypromellose have similar but different properties
from gelatin ones. Their main advantage is that their
moisture content is much lower, and even if this is removed,
they retain their mechanical strength.[3] Under International Conference on
Harmonization (ICH)-accelerated storage conditions (40_C, 75% relative
humidity (RH), for six months), they do not undergo cross-linking
reactions like gelatin, and the dissolution rate of products in
hypromellose capsules is unchanged.[4] Another major
difference is that hypromellose capsules from different
manufacturers are not interchangeable like gelatin
capsules, which have the same solubility properties from all
manufacturers. This is because the gelling systems used are patented, and only
the ones containing carrageenan are soluble at pH < 4.0,[3] whereas,
for example, those containing gellan gum are not soluble at acid
pH.[5]
Gelatin
capsules are also produced, which contain 5% Polyethylene glycol (PEG) 4000
as an additional plasticizer. They have improved physical characteristics over
standard gelatin capsules and can loose more moisture before they
become brittle. They were first developed by Shionogi Qualicaps in
Japan, where they are widely used for pharmaceutical products.
CAPSULE MANUFACTURE
Gelatin
capsules are manufactured by a dipping process.[1] The process starts by the
preparation of a concentrated solution of gelatin or other
suitable polymer in hot demineralized water. This solution is subjected to
a low pressure to remove entrapped air bubbles. Small aliquots of this
solution are (20–30 L) are taken. To this are added colorants, either
solutions of soluble dyes or suspensions of pigments, preservatives, process aids,
such as disodium lauryl sulfate solution, and water to adjust the
viscosity. The final solution has a concentration of 25–30 wt% of
gelatin. This solution is then delivered to the
capsule-manufacturing machine.
The
manufacturing machines are housed in rooms supplied with filtered air,
conditioned to 40–45% relative humidity and 22–25_C. The most
commonly used machines are approximately 12m long and 3m high and
are divided down the midline into two parts that are mirror images of
each other (Fig. 1). The machines are divided lengthwise into two
levels, a top and a bottom. The caps are made on the left side
and the bodies on the right side of the machine. The gelatin solutions are
held in temperature-controlled, jacketed hoppers
Fig. A capsule manufacturing machine:
(A) gelatin solution storage tank; (B) dip pan; (C) drying kilns; and (D)
Automatic section. (Reprinted with permission from Eli Lilly & Co. Ltd.)
mold pins are
mounted in a row of 30 on steel bars. Sets of bars are held in a device
operated by a cam, which raises and lowers them. The mold pins, which are at
22_C, are lowered into the gelatin solution, which is at 50–55_C. The gelatin
immediately gels on the mold. The molds are slowly raised, and, as they do, the
excess gelatin runs off (Fig. 2). The quantity picked up by the mold is
proportional to the viscosity. The higher the viscosity of the gelatin
solution, the more the gelatin that is picked up. Thus, the viscosity of the
solution is used to control the thickness of the gelatin film. As the mold
breaks the surface, a blob of gelatin forms on the end of the mold. The sets of
bars are transferred from the bottom to the top level of the machine and, as
they do so, the bars are rotated
Fig. Dip pan, capsule shell formation. (Reprinted
with permission from Qualicaps Europe, S.A.)
to spread the
film evenly over the end of the mold pin. The gelatin film is completely set by
the time the molds reach the upper level of the machine. Sets of bars are
grouped together and mechanically transferred through a series of drying kilns
(Fig. 1C). In these, air at controlled temperature and humidity is blown over
them. When the bars reach the end of the machine, they are transferred to the
lower level and pushed back toward the front of the machine. When the bars
emerge from the drying kilns, the moisture content of the gelatin films has
been reduced from 70%, at dipping to approximately 16 wt%. The molds, which had
been warmed at the start of the drying process, have returned to ambient
machine room temperature before they are dipped again.
The dried
gelatin films are removed from the mold pins and cut to the correct lengths,
and the cap and body pieces are joined together. This is done in the automatic
section of the machine (Fig. 1D). Pairs of bars, one with bodies and one with
caps, are passed into the central section. Metal jaws pull the films off of the
mold pins into collets, which grip them. The collets rotate against a knife,
and the gelatin film is cut. The excess is sucked away and recycled. The two
pieces are transferred to a central joining block and are closed to a set
length, called the unclosed joined length. The capsules are not fully closed,
because the filling machines would have difficulty separating them. They are
closed so that the ‘‘prelock’’ indentations on the cap are engaged by the body,
which provides sufficient holding strength so that they will not separate in
handling.
Hypromellose
capsules are manufactured using the same conditions to similar specifications.
The main difference in the process is that the speed of output is slower
because their gelling system takes longer to set than gelatin solutions, which
rapidly change from the sol to the gel state.
STANDARDS
FOR EMPTY CAPSULES
Two sets of
standards are set for empty capsules, analytical and functional.[1] Capsules, like all other pharmaceutical preparations, must comply with cGMP norms and must be made of materials
that comply with pharmacopeial
chemical and microbiological standards. However,
these tests do not indicate whether a capsule
will run well on a filling machine. Series of functional tests are applied by the manufacturers. The critical dimensions of a capsule
(the lengths and diameters of the
caps and bodies) are checked. It is a continuous
production process, and there will be a very
small proportion of visually defective capsules. Standard statistical sampling methods are used to estimate quality fromsamples. The manufacturers
and users agree on acceptable
quality levels (AQL). The faults are divided
up into three categories depending upon the
likely impact on capsule performance or the filling process. A different AQL is assigned to each category of fault.
STORAGE
OF EMPTY CAPSULES
Capsules should
be stored in sealed containers at uniform
temperatures to maintain their properties. Empty gelatin capsules have a moisture content between 13% and 16%. The water acts as a
plasticizer and is essential to
maintain the flexibility and strength of the capsule. They will become brittle if the moisture content falls outside of the limits and soften if it
increases above it. Empty
hypromellose capsules have a moisture content of 3% to 6%. These capsules can be dried down to less than 1% moisture without losing their
mechanical strength and becoming
brittle.[3] The water in hard gelatin capsules
is tightly bound into the polymer structure
and is insufficient for active bacterial growth.[2]
The dimensions
of capsules vary slightly as their moisture
changes. As a general rule, the dimensions
of gelatin capsules change by 0.5% for every 1% change in moisture in the range 13.0–16.0%.[1] Hypromellose capsules contain less water than
gelatin ones, and their change in
dimensions with moisture content is less.
Thus, higher-speed filling machine must be operated in air-conditioned areas to achieve their maximum performance. The moisture content of capsules
depends upon the conditions to which
they are exposed.[6] Water will be
lost or gained, and the absorption/desorption isotherm follows a marked
hysteresis. In practice, this means
that if capsules lose excessive amounts
of water, they will not fully rehydrate when exposed to standard conditions, RHs between 35% and 55%.
CAPSULE
FILLING
The hard
two-piece capsule can be filled with materials that have a wide range of physical properties. The types of formulations that have been
filled into capsules are shown in
Table . This is possible because of the
Table
Formulation types for filling into hard capsules
Dry solids |
Semisolids |
Liquids |
Powders |
Thixotropic
mixtures |
Oily liquids |
Granules |
Thermosoftening mixtures |
Non-aqueous
solutions and suspensions |
Pellets |
Pastes |
|
Tablets |
|
|
Capsules |
|
|
way in which
filling machines handle empty capsules. First, capsules are orientated so that
they are all pointing in the same direction, with the body downwards. The
capsules are transferred into pairs of bushes: the opening in the base of the
top one only allows the passage of the body, thus retaining the cap. The body
is separated from the cap by means of suction. The open end of the body is then
presented to a dosing mechanism and material transferred into it. The cap is
replaced on the body, and the capsule closed to the correct closed joined
length to ensure that the self-locking mechanism, a series of indentations on
the cap and body, is engaged correctly. This allows filled capsules to be
transported and packaged on automatic equipment without them separating.
Filling machines
are differentiated by the means by which they measure the dose of material.
They are available with a range of outputs, from bench-scale to high-output
industrial scale and from manual to fully automatic.
Powder
Filling
The majority of
formulations that are filled into capsules
are dry powder mixtures. The methods of measuring the dose can be divided up into two groups: dependent and independent. The dependent machines use the capsule body directly to
measure the dose of powder,
whereas the independent machines use a separate device. The literature
available on the mechanics of capsule filling is limited when compared to that
available for tabletting. Part of the reason for this is that tablets, unlike
capsules, are used in a wide range of industries outside the health-care
sector, and thus there have been many more workers in the field.
The first
industrial filling machines were of the dependent type. Powder is transferred
from a hopper directly to the capsule body. The flow of the powder is aided
either by a revolving auger or by a vibrating plate. The powder mass inside
these capsules is a loose fill. The fill weights achievable on an auger
machines are often higher than that obtained on automatic independent type
machines because the body is overfilled, and thus the total internal volume of
the capsule shell is used.[7] The first successful industrial filling machine,
the Model No. 8, was designed by the American doyen of pharmaceutical
engineering, Arthur Colton. This is a semiautomatic auger-filling machine (Fig.
3). The empty capsules are fed, aided by suction, into a pair of
doughnut-shaped plates, which separates them. The upper plate containing the
caps is removed and placed to one side. The lower plate containing the bodies
is transferred manually to a turntable and the powder hopper pulled over the
top of it. Powder is forced by the auger into the bodies as their plate
Fig. Schematic diagram of auger filling system
(Model No. 8): (A) powder hopper; (B) stirrer arm; (C) auger; (D) body ring
holder; (E) turntable; and (F) capsule carrying rings.
revolves under
the hopper. The fill weight is controlled by the speed of rotation of the
turntable and the auger. The only way on these machines to achieve good
uniformity of fill weight is to completely fill the bodies. Partial filling is
not an option. A fully automatic rotary auger-filling machine (LIQFILsuper
JCF40/80TM, Shionogi Qualicaps) has a three-roller system for capsule
orientation and continuous feeding to a revolving disk assembly where the
capsules are separated, filled, and rejoined. Other automaticdependent filling
does not use augers, but vibration to fluidize the powder for filling into the
bodies as they pass underneath the hopper. This system works well only with
dense, free-flowing material. The LIQFILsuper 40 & 80TM (Qualicaps) has
overcome this problem by the use of spring-loaded fingers to further compress
the powder into the capsule body after the initial fill.
Most automatic
machines used in industry are of the independent type and compress the measured
amount of powder to form a plug. There are two types of mechanism: the dosing
tube (or dosator) and the dosing disc and tamping finger.
The dosing tube
is the most widely used type. Current manufacturers are IMA (Zanazi &
Farmatic) (IMA North America Inc.), MG2 (MG America Inc.), Macophar (Romaco
Inc.), and Bonapace (Schaefer technologies Inc.). The plug is formed inside a
tube with a moveable piston that controls the dosing volume and applies a force
to form the plug (Fig. 4). The lower output machines have an intermittent
motion, whereas the higher output machines are rotary. The intermittent
machines tend to apply greater stresses to the powder than the rotary machines,
because there is less time in which to form the plug because a significant
portion of the machine cycle is taken up in indexing the parts. Thus,
formulations for these machines tend to require a higher level of lubricant.
These machines are very versatile because the fill weight can be varied
Fig. Diagram of a dosator or dosing tube system
(Zanasi RM63): (A) compression force platen; (B) piston; (C) dosing tube; (D)
powder hopper; (E) plug ejection platen; (F) capsule body in bush; and (G)
powder plug.
over a wide
range by a simple adjustment to the piston position. The rotary machines can be
linked to checkweighing devices that can control the fill weight automatically,
and allow them to operate unattended.
The dosing disc
and tamping finger machines form a plug in a similar but different manner. They
are produced by a number of companies, Bosch (Robert Bosch Corporation), A. W.
Bohanan Co. and Index Manufacturing Co., Inc. The dosing disc, which forms the
base of the powder hopper, has up to six sets of machined holes (Fig. ). In a
holder, above the powder hopper, there are sets of stainless steel-tamping
fingers corresponding to the holes in the disc. These machines have an
intermittent motion. After the machine has indexed and the turret is
stationary, the tamping fingers are lowered into the powder bed. The fingers
are set to different levels, and they penetrate into the plate and consolidate
the powder in the cavities into plugs. Thus, the plug is formed in a series of
tamps and not in a single action as on the dosator machines. The dosing discs
are produced in a range of thicknesses for each size of capsule. Thus selection
of the correct thickness of disc is important, because if the fill weight
cannot be achieved, the machine has to be dismantled to change it. The
selection of the optimum disc thickness for a formulation can be made either
pragmatically using a simple test rig[8] or systematically by using an Instron
tester to determine plug density and strength of a formulation at known
compression forces.[9] The latest developments on the Bosch series of
Fig. Schematic diagram of a dosing disc and
tamping finger system (Bosch GKF machine): (A) over-load relief spring; (B)
tamp-depth adjuster; (C) tamping finger; (D) powder hopper; (E) powder bed; (F)
dosing disc; (G) suction; (H) support plate; (I) ejection adjuster; (J) guide
block; (K) transfer block; (L) capsule body in bushing; and (M) powder plug.
machines are a
dosing disc with an adjustable thickness, which gives a greater flexibility for
altering fill weights after machine setup, and a weight-checking device that
can weigh every capsule filled, as it exits the machine.
Bench-Scale
Filling Machines
There are a
variety of devices for the manual filling of small numbers of capsules. These typically consist of sets of plastic plates that have sets
of holes drilled in them
corresponding to the size of capsule that can be filled. A device made from stainless steel and other metal alloys is available from Torpac
Inc., which can be autoclaved to
ensure cleanliness without the risk of
distortion. The capsules are fed in to the plates, either manually one at a time or in groups using a feeding device. The bodies are clamped in the
lower plate and the top plate
removed, which separates the caps from
the body. The bodies are released so that they sit below the top of the bottom plate. Powder or pellets are filled into the capsules by
spreading material over the body
plate using a spatula.
A small-scale
automatic machine, the In-cap_, Dott. Bonapace
(Schaefer Technologies Inc.) is available.
This machine measures the dose using a tamping finger and dosing disc device. The output is up to 3000 capsules per hour.
Instrumented
Filling Machines
Instrumented
capsule filling machines are not in widespread use unlike tabletting
machines.[10] This is partly owing to the fact that less basic work has been
done; there is an inherent problem in measuring the low forces (1–100 N) used
in forming and ejecting plugs, and the powder bed is less controlled than in a
tablet die. Most of the published studies have been made on intermittent motion
dosing tube machines. Strain gauges have been applied to the piston and linear
variable displacement transducers (LVDTs) to the moving parts of the system to
measure the work involved in plug formation.[11] Only two groups have published
work on an instrumented dosing disc and tamping finger machine.[11,12] The
problem on these machines is that the plug is formed at up to five different
positions, and full instrumentation would be difficult. Capsulefilling machine
stimulators have been constructed to overcome some of the problems inherent in
putting instrumentation on to actual machines. Rotary operation machines
present the biggest problem because of the movement of the dosing parts. One
solution was to use a machine turret, with a single dosator, held stationary,
and to construct a rig that moved the powder hopper around the dosator,
simulating machine running.[13] A conventional stimulator for an intermittent
motion dosator machine has been built that, in addition to the forces of axial
compression and ejection, can measure the radial compression force.[14] This
has been used to study the consolidation and elastic properties of excipients.
A tablet compaction simulator has been used to investigate plug formation at low
forces, and the results analyzed using standard tabletting physics.[15]
Dry
Solid Filling
Granules,
pellets, and tablets can be filled into capsules using automatic-filling machines. Products are prepared in these forms to modify the release
rates of active ingredients,
separate incompatible components, or
densify a product to achieve the fill weight in a specific size of capsule.
The machines
that can be used to fill pellets and granules
can be divided into the direct and indirect
categories. In the former, the pellets and granules are fed into the body until it is completely full, e.g., Qualifill TM Pellet filler (Schaefer
Technologies Inc.). Indirect machines
have modified dosators that either use suction to hold the material in the tube during transfer or are filled when they pushed up through the
material bed. Other indirect
machines have special chambers with sliding
plates to give a variable volume in which to measure the material, e.g., Bosch GKF and Qualicaps LIQFILsuper machines. Bosch has produced a
pellet-filler based on their
variable thickness dosing disc that uses a slide underneath it to hold the material prior to transfer. Pellets and granules, after
measurement, are transferred to the
capsule bodies either using gravity or assisted by air pressure, e.g., IMA Farmatic 2090 and MG2 G60. Tablets are filled into capsules by
systems that can handle both single
and multiple additions. They have sensing
devices, either mechanical or electrical to check that the correct number of tablets has been dosed.
The physical
properties of these formulations are similar.
Each type must be preferably non-friable;
tablets are usually film coated. Several types of tablets are filled into capsules. Generally
the tablets are convex in shape and
have diameters that enable them to be
introduced easily into the body and with sufficient clearance so that they do not tip onto their side.[16] In U.S.A., after the ‘‘Tylenol_
incident,’’ in the 1980s, there is a
need to fill large single tablets into a
capsule, so that in the shell there is no room for movement. The capsule shell is either banded or
shrunk onto the tablet to prevent
its removal. A recent innovation is the
filling of minitablets, produced on multitip tooling, to produce coated tablets with different release patterns.[17]
Granules and pellets should be regular in
shape so that they flow and pack well. Their size should be related to the size of the capsule. Smaller diameter pellets should be used for
smaller sizes of capsules; otherwise,
lower fill weights than expected will occur
because of the ‘‘wall effect’’ of particle packing.
Liquid
Filling
All the major
machine manufacturers have made machines
that can fill capsules with liquids. There are two types of liquid fills: formulations of non-aqueous solutions and suspensions and
formulations that are liquefied only
for the filling process by either heat or
shear stress.[18] If the formulation is mobile at ambient temperatures, then the capsules will
need to be sealed after filling.
The dose of
material is measured, using volumetric pumps,
and thus the uniformity of fill is, in most cases, better than what be achieved normally on a powderfilling machine. Typically, coefficients of
variation of fill weight less than
1.0% are routinely achievable. This value
will depend upon the physical properties of the liquid, particularly its viscosity.[19] Filling machines have been made, which can handle
materials with viscosities from 0.1
to 20 Pa. Liquid-filling machines operate
mostly at slower speeds than the equivalent powder filling machines. This is because the liquid has to pass through a much smaller orifice than
that for a powder and thus takes
longer. The rates are typically 50–66% of
the rated output of the same size powder-filling machine.
Capsule
Fill Capacity
The fill
capacity of a hard capsule is dependent upon the physical size of the capsule, the type of formulation, and the dosing mechanism on the
filling device (Table 2).[7] The
fill weight for powders has historically
been calculated by multiplying a powder density value by the capsule volume as provided by the capsule manufacturers. This is the capsule body volume and
was derived from practical
experience when capsules were filled
by hand in pharmacies. The relationship gives a reasonably accurate forecast for machine filling, if the volume number is multiplied by the
tapped bulk density (TBD) of the
powder mixture. The relationship holds
because of the machine-dosing mechanisms.
Dependant machines, which can fill the total internal volume of the capsule, are able only to pack the powder in to the bodies at densities less
than the TBD of the fill. Independent
machines, which are able to apply a higher
compressive force to the powder, form plugs whose dimensions must be less than the internal diameter and length of the capsule for them to fit
inside of a closed capsule (Table
2). Thus, although the density of the plug
will be higher than the TBD of the fill, the machines are unable to fill the total internal
capsule volume.
The same rules
of packing apply to pellet and granule filling.
The size of the particles is important because of the increase in voidage caused by large particles in a small diameter tube. The smaller the
capsule size, the smaller the
corresponding size of the particles should
be to achieve uniform fill weights. The liquid-fill capacity of capsules is restricted inorder to
prevent spillage of product, the
maximum fill volume should not exceed 90%
of the body volume.
Capsule
Sealing
Many methods
have been proposed for the sealing of capsules
to prevent the leakage of liquids. The method proven to be the most successful is gelatin banding.[18] Two bands of gelatin solution are
applied around the center of the
filled capsule, e.g., HicapsealTM 40/100
(Shionogi Qualicaps Inc.). This band is dried using air at ambient conditions to prevent moisture loss from the gelatin shells, which would make
them brittle. The band can be
colored, permitting a more complicated appearance
for product branding. This band complies
with the requirements of the Food and Drug Administration (FDA) ‘‘Tamper-Evident Packaging
Requirements for Over-the-Counter
Human Drug Products’’ for
tamper-evident sealed capsules.[20]
Multiple
Contents
Automatic-filling
machines are available, which can have
more than one product-dosing device. Therefore, combinations of materials can be filled into the same capsule, such as mixture of a powder
and a semisolid formulation or a
powder and a tablet. The same formulation
rules apply as to single forms. Combinations of materials allow the formulator to achieve specific goals in terms of product stability
and types of release.
FORMULATION
Powder
Properties
Powder
formulations for capsule filling must have
good flow properties, be non-adhesive, and be cohesive enough to form plugs at low-compression forces. In addition, they must be stable and
release the active ingredient in the
desired manner. There is an interaction between
the formulation, the filling machine, and
the empty capsules, and to devise formulations logically, these need to be understood.[21]
Powder-filling
properties can be assessed on the bench
scale by using a variety of tests ranging from
Table Capsule fill volume data
Size |
Body Volumea (ml) |
Internal Volumeb (ml) |
Maximum Plug Lengthc (mm) |
Maximum Plug Volumed (ml) |
0E |
0.78 |
0.87 |
21.9 |
0.68 |
0 |
0.69 |
0.78 |
19.7 |
0.61 |
1 |
0.50 |
0.56 |
17.7 |
0.44 |
2 |
0.37 |
0.44 |
16.1 |
0.34 |
3 |
0.30 |
0.32 |
14.3 |
0.26 |
4 |
0.21 |
0.25 |
13.2 |
0.19 |
simple to
complex.[7] Successful correlations between powders and filling performance
have been made in several papers by determining various powder property
constants calculated from TBD volumetry.[22–25] For various microcrystalline
celluloses, Lu¨dde–Kawakita’s constant a and Hausner’s ratio were shown to
be good indicators of machine-filling performance.[22] Investigations on the packing
properties of binary mixtures of different shaped particles have shown that
Lu¨dde–Kawakita’s constant a can be used as an indicator of the maximum
volume reduction.[23] Microcrystalline cellulose, an angular particle, and
lactose monohydrate improve packing, whereas spherical or needle-shaped
particles tend to decrease the packing properties. The same methodology was
used to investigate the bulk volume changes of powders after granulation or low
compression.[24] This showed that capsule fill weights could be increased by
high-shear granulation or by the use of machine compression, and that the
outcome was directly related to the initial powder properties. The filling of
capsules with powdered herbs present further challenges because of the range of
tissue materials used. The flow properties of these materials are poor, and a
range of powder property constants was determined to try and find a parameter
that correlated with filling machine performance.[25] It was found that
tamp-filling machines were able to handle a greater variety of herbs than
dosator machines. The flow of powders under active conditions can be measured
using specially constructed rheometers, and these data can be related to other
powder properties.[26]
The flow of
powders on filling machine is aided by machine design. Most machines have
devices to assist flow in the form of moving mechanical parts, vibration, or
suction pads. Adhesion of material to moving parts, particularly the
dose-measuring devices, is a hindrance to obtaining good fill-weight
uniformity. It has been shown that the nature of the surface texture of the
dosator is an important factor.[27] To reduce adhesion, the surface of the
dosing parts can be coated with different metal finishes, similar to that used
for tablet punches and dies.[28]
In
Vitro Testing
Pharmacopeias
require that hard capsules be tested in the
same apparatus as tablets even though they have very different physical properties.[1] Filled capsules contain entrapped air, and most
formulations will float on water.
Devices are required to ensure that they sink, and these can influence the results obtained. Gelatin and hypromellose are adhesive
materials and tend to block wire
meshes that form part of the standard equipment.
The way in which capsules disintegrate and
dissolve is dependent upon several factors such as temperature and nature of the test media.[29] The literature makes reference to the hard
capsule effect; however, the
literature shows that the rate-controlling
step is the nature of the contents and not the shell.[30]
When capsules
are placed in an aqueous solution at body
temperature (37_C), the walls absorb water and swell.[29] The rate of penetration is proportional to the thickness of the wall. In gelatin
capsules, water droplets can be
observed on the inside surface of the shell
after 30–40 sec. The wall ruptures first at the shoulders of the cap and body, which is the
thinnest part of the shell. The rate
of gelatin solubility is dependent upon the
temperature of the solution.[31] There is a significant decrease as the temperature falls below 30_C, and below about 26_C they are completely
insoluble and merely swell and
distort. Hypromellose capsules on the other
hand have a slower but uniform solubility between 10_C and 55_C.[31] The results for both types of capsules are influenced by the nature of the
test media, e.g., the ionic strength
of the ions present and the pH.[29,31]
The rotating
paddle method is the most frequently prescribed
apparatus for measuring the dissolution rate
of products in hard capsules. The test is used for manufacturing control purposes and for assessing product stability. When gelatin capsules are
stored under ICH-accelerated storage
conditions (45_C, 75% RH), their
solubility in water decreases with time. This is owing to the formation of a ‘‘pellicle’’ that slows down release.[32] This effect is called
cross-linking and can be caused
either by interaction between gelatin and compounds containing reactive groups such as an aldehyde [33] or by reorientation of the gelatin molecules to a more collagen-like structure.[2] In
the early 1990s, the FDA became
concerned with this and initiated a test
program to measure whether this had an effect on product efficacy.[34] They filled acetominophen into capsules that had been stressed by
treatment with formaldehyde at two
levels and into unstressed shells. They
measured the dissolution in water and in simulated gastric fluid (SGF) with and without pepsin. This produced three sets of results, those
that pass in all media (unstressed
shells), those that failed in water but
passed in the SGF (low-stress formaldehyde), and those that failed in all media (high-stress formaldehyde). The capsules were tested in human
volunteers. The pharmacokinetic
parameters Cmax, Tmax, and lag times
could be ranked in order and the areas under the curve (AUC) were identical. However, the products were not considered bioequivalent,
because the results from the
capsules that failed all the dissolution tests were outside the 80–125% confidence limits when compared to the unstressed capsules. From this
study, the U. S. Pharmacopeia
introduced a two-tier test for hard capsule
dissolution. If the sample does not comply with the test in the required medium, then the test can be repeated by adding enzymes: in water
or a solution of pH < 6.8 (add
pepsin) or in a solution of pH >
6.8 (add pancreatin). A further study using
gamma scintigraphy showed that there was no difference in disintegration in vivo between untreated and medium-stressed gelatin capsules.[35]
Hypromellose
does not react with aldehydes or other
agents that cause cross-linking of gelatin.[3,4] Hypromellose capsules start to release their contents slightly slower than gelatin ones
because of the slower rate of
diffusion of water through the shell walls.[31] However, once dissolution has commenced, the rates are similar and the results are
comparable.[36]
In
Vivo Performance
Capsule products
can be formulated to deliver active ingredients
to various sites along the gastrointestinal
tract or to the respiratory system.[37] Buccal products can be made by filling standard capsules with semisolid matrix formulations, which give the
product good sensory characteristics
that allow them to be chewed or sucked
and the contents retained in the mouth for
absorption or action.[38] The capsule shape is a good one for swallowing, because one axis is longer than the other. This enables the tongue to
line it up like a torpedo for entry
into the throat. Many large tablets are
made capsule shaped, the so-called ‘‘caplet,’’ to take advantage of this. The literature shows that, providing the patient takes gelatin capsules
with water while upright, they do
not stick in the throat any more than
and, in fact, probably less than any other solid dosage form.[39,40] Capsules can be visualized inside the patient either using radio-opaque
markers and X-rays or using
radioisotopes, such as technetium-99, and
g-scintigraphy. In the stomach, they disintegrate, and the contents spread depending upon the patient’s feeding state, fed or fasting.[41]
Capsule products can be retained in
the stomach by the use of floating formulations. These are based on the use of hydrocolloids that swell on contact with water, forming a gel that releases the active ingredients by
diffusion.[42] Enteric products can
be made either by coating the capsule shell
with a polymer, which has the correct pH solubility characteristics, or by filling the capsule with coated particles. The challenge facing
many formulators is the delivery of
small peptides and proteins to the
colon. This can be achieved by coating capsules with polymers that will only be broken down in the colon, e.g., mixtures of an azopolymer
and a methacrylate polymer[43] or
capsules coated with a mixture of ethylcellulose
and amylose.[44] Delivery to the colon can
also be achieved by using a fill that includes an organic acid and a combination of pH-sensitive coatings, which together deliver the active
ingredients to the proximal
colon.[45] Capsules can be administered rectally.
They can be formulated to give either immediate or a prolonged release.[46] The administration technique is different for other solid rectal
forms and they need to be coated
with a glidant such as liquid paraffin.
The in vivo
performance of gelatin and hypromellose capsules
using gamma scintigraphy has been compared
by several workers.[5,44,47,48] These have shown that hypromellose capsules with carrageenan disintegrate in the stomach in a similar manner to
gelatin capsules.[44,48] Whereas the
disintegration of hypromellose capsules with
gellan gum is delayed.[5]
Capsules
for Inhalation Products
Powders for
inhalation products have been filled into
capsules, which function as an inert biodegradable package, since the early 1970s.[49] The active ingredient is in a micronized state, and it is
either filled directly in to the
capsule or more frequently attached to a carrier particle such as lactose. Originally this delivery system was seen only as a way to treat
pulmonary conditions. There has been
an increased interest in this application
recently, because it is seen as being useful for a wider range of therapeutic applications:
systemic diseases, non-invasive
delivery of peptides and proteins, vaccines, as well as lung diseases.[50] The formulations are filled on automatic machines and because the fill weight is small, i.e., less than 40
mg, microdosators are used. The
product is taken using a special inhalation
device, a dry powder inhaler (DPI). Powder is usually released from the capsule shell through holes that are produced by piercing with
pins or cut with blades. Thus the
physical properties of the capsules especially
under low humidity conditions are important. Hypromellose capsules because of their physical properties are ideally suited for this
application because of their lack of
brittleness when dry and their more
flexible walls that are easier to penetrate.[49] The inhalers are breath actuated. When the patient inhales, there is a turbulent airflow through
the device that carries the active
particles directly into the lungs.
Formulation
for Release
Most products
are formulated to release their contents into the stomach. The rate-controlling
step for release is the nature of the contents inside the capsule. A formulator
in preparing a formulation needs to take into account the physicochemical
properties of the active ingredient, the nature and type of excipients
required, and the filling process.[7,37]
The properties
of the active drug that are most significant are its aqueous solubility and
particle size. The particle size needs to be chosen carefully. Smaller
particles should dissolve faster because of their greater surface area, but
when filled inside a capsule they may aggregate together, and the dissolving
liquid may not be able to reach the individual particles (Fig. 6)[51] Thus the
available surface area of the active ingredient is more important than the
actual surface area. Usually, the excipient that is the largest single quantity
in the formulation is the filler (diluent), which functions both to increase
the amount of fill material for potent active ingredients and to aid in the
formation of the powder plug. They can also play a role in the release of the
active ingredients. People were first alerted to this in the late 1960s by the
diphenylhydantoin incident in Australia, which showed that fillers need to be
selected with solubility properties complimentary to those of the active
ingredients.[52] Poorly soluble active ingredients are best formulated with
soluble excipients. The overall aim should be to make a powder mass that is as
hydrophilic as possible. This can easily be done with potent active
ingredients, because there is space available inside the capsule to accommodate
excipients with the necessary properties, in terms of both flow and solubility.
For higher-dose active ingredients, excipients must be chosen, which are active
at low concentrations. Thus, disintegration and wetting agents need to be
added. Excipients such as starch do not function as disintegrants in capsules
like they do in tablets, because the powder fill is much more porous. Sodium
Starch Glycolate and Croscarmellose are used, because of their greater swelling
and wicking capability.[53]
Certain
excipients that are added to formulations to improve filling-machine
performance can have an adverse effect on release,because they are hydrophobic
in nature. This is true of lubricants, which are added to formulations to
prevent adhesion and to improve flow. The most used excipient in capsule
formulations in both U.S.A. and Europe is magnesium stearate.[53,54] This is
hydrophobic, and there are many reports in the literature concerning its
adverse effect on dissolution rates. However, the relationship between the
concentration of magnesium stearate and release rate is not quite as simple as
for tablets, in which an increase in amount brings a proportional decrease in
release. The reason for this is the very different nature of tablets and
capsules. A tablet is compressed using high forces to form a solid compact of
relatively low porosity and must be if it is to survive subsequent handling. A
hard capsule product, on the other hand, contains a powder mass of high
porosity, which may or may not have been compressed in to plug, and is
contained within the shell that can withstand handling. Magnesium stearate functions
as a lubricant when it is dispersed on the surfaces of other particles. At this
site, it also reduces the cohesion between particles, and thus as its
concentration increases, the powder mass will ecome less cohesive. Several
workers have shown that an increase in magnesium stearate concentration has
increased dissolution rates: small particles are made less cohesive (Fig.
7),[55] and powder plugs are weakened, thus breaking apart more readily when
the capsule shell has dissolved (Fig. 8).[56] If the level in the formulation
is not optimized, then there is a possibility that during the filling
operation, the magnesium stearate will be gradually dispersed to a greater
extent, resulting in changes in dissolution or weight uniformity.[7,57]
The method to
improve the release rate of poorly soluble active ingredients by dissolving or
suspending them in polyethylene glycol was first suggested in 1970.[58] Since
then, the filling of semisolid matrix formulations for filling into hard
capsules has been developed, which enables this simple concept to be turned
into a practical application.[18] This formulation technique gives a different
means to control the release of active ingredients from a capsule, either
improving or delaying release. The technique involves dispersing or dissolving
the active ingredients in excipients that are available in a range of melting
points and hydrophile–lipophile balance values.[18] It is possible to modify
the release rate of an active ingredient from such a matrix capsule by simply
changing the properties of the single excipient. This technique has the added
advantage that when working with potent and toxic material, it significantly
reduces cross-contamination within an area.[59] The active ingredients once
dispersed in a semisolid matrix are safe to handle without resorting to the use
of expensive containment areas, i.e., any material that is spilt does not
spread through the local environment, unlike a powdered material.
Formulation
optimization and expert systems
Product formulations
must meet a number of goals. They
must be able to be filled by machines to give a uniform stable product. They must release the active ingredients in a manner to give the
desired therapeutic effects. They
must comply with the regulatory and compendial
specifications. The excipients used in formulations often have properties that aid in compliance with one aspect but, at the same time, can have a negative effect on another goal. The
relationship between the factors is
complex. There are a variety of statistical
tools that can be used to optimize formulations to achieve the best values of all the factors.[60]
Another method
of obtaining the best formulation is
to use a so-called expert system to devise a formulation. The computer software is based on the use of neural networks and knowledge-based systems.[61–63] They serve two functions. First, they
are able to reduce development time
by suggesting the probable formulations,
and secondly, they act as a teaching tool to pass on the knowledge of experts in the field.
CAPSULES, SOFT
Soft gelatin
capsules (Softgels) offer the possibility of delivering a liquid in a
solid oral dosage form. Softgel’s ability to enhance bioavailability
not only makes it the preferred dosage form for new
chemical entity with poor bioavailability owing to poor aqueous solubility, but
also for reformulation of marketed drugs with the purpose of life cycle
extension. This entry reviews the fundamental requirements and
techniques in Softgel formulation, manufacturing, and
product development. The review of recent advances in this dosage form,
such as non-gelatin-based Softgel, modified release/controlled release Softgel,
and chewable Softgel are also included.
BACKGROUND
Soft gelatin
capsules (also referred to as soft elastic gelatin capsules, Liqui-Gels_, or
Softgels) are a unique drug delivery system that can
provide distinct advantages over traditional dosage forms such
as tablets, hard-shell capsules, and liquids. However,
owing to economic, technological, and patent constraints, there are relatively few
manufacturers of Softgels in the world.[1]
The major
advantages of Softgels include the following:
Ø Improved
bioavailability. More than 40% of the NCEs (new chemical entity)
discovered have good membrane permeability but poor aqueous solubility (i.e.,
Biopharmaceutics Classification System II).[2] By formulating the NCE
in solution inside a Softgel (e.g., lipid based) or in
micro/nano emulsion, the solubility and hence the
bioavailability of the compound may be improved.[3]
Ø Enhanced
drug stability (protection against oxidation, photodegradation, and
hydrolysis in lipophilic systems).
Ø Superior
patient compliance/consumer preference and pharmaceutical elegance.
Results of studies done through the years show that
consumers expressed their preference for Softgels in terms of ease of
swallowing, perceived speed of delivery, lack of unpleasant odor or taste
and modern appearance.[4]
Ø Excellent
dose uniformity.
Ø Better
tamper evidence (tampering leads to puncturing and visible leakage).
Ø Safer
handling of highly potent or cytotoxic drug compounds.
Ø Product
differentiation (through selection of novel shapes, colors, and sizes).
Ø Excellent
product life-cycle management. For example, product enhancement via
faster onset of action.[5–8]
In comparison, the
disadvantages of Softgels are relatively few. These include the
following:
Ø Specialized
manufacturing equipment requirements.
Ø Higher
manufacturing cost as compared to tablets.
Ø Stability
concerns with compounds susceptible to hydrolysis.
Softgels are
formed, filled, and sealed in a single operation. Once production for a
specific product begins, the manufacturing process normally continues 24 hr per
day until the lot of product is completed. This results in a manufacturing
environment that operates around the clock, up to seven days a week.
The standard
Softgel shapes for oral pharmaceutical products are oval, oblong, and round.
The size of the Softgel is represented by a numerical number, which represents
its nominal capacity in minims (1 cc ¼ 16.23 minims). For example, an 11 oblong
Softgel can be filled with 8.5–11.0 minims of fill formulation.
Softgels can be
easily manufactured in any shape with a plane of symmetry and any size (to
contain up to _25 ml) via appropriate die design. A recent survey has shown
that smaller sized Softgels are preferred within each shape category, with oval
being the most popular shape.
Fig.
Examples of Softgels.
DESCRIPTION
The Softgel
(Fig. 1) is a hermetically sealed, one-piece capsule shell with a liquid or semisolid fill without a bubble of air or gas (Fig. 2). The
fill materials can include a wide
variety of vehicles and can be either a solution
or a suspension. Though the Softgels may be
either clear or opaque, it is standard practice to use a clear shell (clear colored or natural
amber) only when the fill is also a
clear solution. In the finished product,
Fig.
Softgel components.
the shell
historically is primarily composed of gelatin, plasticizer, and water.
Recently, shells composed of non-gelatin materials[9–11] (e.g.,
starch/carrageenan) have been developed for Softgel applications. Softgels may
be coated with suitable enteric coating agents, such as cellulose acetate
phthalate, to obtain enteric release of encapsulated material.[12]
Because of their
special properties and advantages, Softgels are used extensively in many
pharmaceutical, cosmetic, and nutritional products. The primary pharmaceutical
applications include oral dosage forms, chewable Softgels, suppositories, and
topical products.
VEGICAP
SOFT_ CAPSULES
VegiCap Soft_
capsules are an alternative patentprotected
Softgels that deliver all of the key attributes of traditional soft gelatin capsules without gelatin. They are made using a modification of the
Scherer rotary die encapsulation
machines.
VegiCap Soft_
capsules provide some technical benefits
that gelatin-based capsules cannot provide. One of the disadvantages with gelatin capsules is the incompatibility with alkaline fill solution. VegiCap
Soft_ shell is compatible with fill
solution with pH value as high as
12.[13]
FORMULATION
DEVELOPMENT
This section
will discuss the formulation principles of
Softgels, including gelatin shell and fill formulations.
Shell
Formulation
Historically,
Softgels have required gelatin as the polymer
basis for the shell. The most frequently used gelatins are derived from bovine source. Gelatins derived from poultry, fish, or other
sources have been reported in the
literature as alterative for bovine and porcine
gelatins. However, they have not gained high commercial interest yet because their availability is limited. In addition to the base
polymer, plasticizer, water, and
materials that impact the desired appearance (colorants and/or opacifiers) and, on occasion, flavors and/or preservatives are
added. For starch/ carrageenan, a
shell buffer (sodium phosphate dibasic) is
also required. When required, enteric or delayed release coatings can also be applied to Softgel capsules. A description of the functions, types,
and amounts of materials most often
used in manufacturing Softgel shell
formulations is detailed in the following
paragraphs.
Gelatin
For
gelatin-based Softgels typically 40–50% of the wet gel formulation can be either Type A (acid processed) or Type B (alkali processed) gelatin.
The selection for the type of
gelatin for a particular Softgel formulation is based on compatibility with the other ingredients (both active and inactive) within the
Softgel and upon manufacturing
experience. The physicochemical properties
of gelatin are largely controlled by the source of collagen, extraction method, pH, thermal history, and electrolyte content.
Plasticizers
Plasticizers are
used to make the Softgel shell elastic and
pliable. The ratio of plasticizer to shell polymer determines the hardness of the shell, assuming there is no effect from the fill.
Plasticizers generally account for
20–30% of the wet gel formulation and are commonly glycerin, sorbitol, or propylene glycol, either individually or in combination. Several
proprietary blends of sugar mixtures
with sorbitol anhydrides can also be
used and are available from excipient suppliers.[14,15] The amount and choice
of the plasticizer help to determine
the hardness of the final product, and may
also affect the dissolution or disintegration of the Softgel, as well as its physical and chemical stability. Plasticizers are selected
on the basis of their compatibility
with the fill formulation, processing (drying) time, and desired properties of the final Softgels, including hardness, appearance,
handling characteristics, stability,
and even the geographical location in which
the product will be sold.
Water
Water usually
accounts for 30–50% of the wet gel formulation and is critical to ensure proper processing during gel preparation and Softgel encapsulation. Following encapsulation, excess water
is removed from the Softgels through
controlled drying, leaving the equilibrium
water content typically at less than 10%.
Colorants/opacifiers
Colorants and
opacifiers are typically used at low concentrations in the wet gel formulation. A wide range of colorants such as FD&C and D&C water-soluble dyes, certified lakes, pigments, and
vegetable colors have been
incorporated into Softgel shells alone or in combination to produce the desired color, tint, or hue for product identification. A general rule in color selection is that the color of the capsule shell
should be similar to or darker than
the fill material to reduce the contrast
with the seams.
An opacifier is
sometimes added to the Softgel shell to
obtain an opaque shell for suspension fills or to protect light sensitive fill ingredients. Titanium dioxide is the most commonly used opacifier.
Flavors such as ethyl vanillin and
essential oils are sometimes included in
the Softgel shell to impart desirable odors or flavors or to offset odoriferous materials that may be contained within the Softgel itself.
Fill
Formulation
Softgels can be
used to dispense active compounds that
are formulated as a liquid or semisolid solution, suspension or microemulsion preconcentrate.
The large groups
of liquids that can be encapsulated into
Softgels fall into one of two categories: watermiscible liquids and water-immiscible liquids.[16]
Water-miscible
liquids include polyethylene glycols (PEG)
and non-ionic surfactants, such as the polysorbates. Low molecular weight grades of PEG (e.g., PEG 400) are used most commonly as they remain liquid at ambient temperatures. Small amounts (up to 5–10%) of other water-miscible
liquids, such as propylene glycol, ethanol,
and glycerin, can also be used.
Water-immiscible
liquids include vegetable and aromatic
oils, aliphatic, aromatic and chlorinated hydrocarbons, ethers, esters, high molecular weight organic acids, and some alcohols.
Liquids that are
likely to cause problems following encapsulation
are low molecular weight water-soluble and
volatile organic compounds, such as some alcohols, acids, ketones, and esters; water (above 5%); emulsions (whether oil in water or water in
oil); liquids with extremes of pH;
and aldehydes.
Drugs that are
not sufficiently soluble in a solvent or
combination of solvents can be formulated into suspensions and encapsulated. Suspension formulae present different challenges to
solutions. Drug solubility in the
excipients should be kept to a minimum to
reduce the chance of particle size or polymorphic changes during the shelf life. In addition, drug particle size needs to be controlled to (i)
provide better process reproducibility
and (ii) for poorly water-soluble drugs,
to reduce the negative effect upon bioavailability.
The particle
size of insoluble drugs should be 180
mm or finer for suspension homogeneity and capsulation equipment requirements. Examples of
suspending agents for water
immiscible vehicles include paraffin
wax, beeswax, and hydrogenated vegetable
oil, and for water miscible vehicles include solid glycol esters (such as higher molecular
weight PEG). Surfactants, such as
polysorbates, are often added to the dispersion to promote wetting of the ingredients and/or dispersion of the fill in vivo. In general, many different materials may be encapsulated;
however, limitations exist for some
compounds owing to high solubility in water
and/or inherent chemical reactivity and the
resultant effect on the shell. These compounds include strong acids and alkalis and their salts, as well as ammonium salts. Some compounds, such
as aldehydes, can react with
gelatin, causing cross-linking and resulting in a product that lacks bioavailability. Some surfactants interfere with the gelatin sealing process, leading to leaking capsules. In
addition, any substance (such as
aspirin) that is unstable in the presence of moisture may also exhibit unacceptable chemical stability in Softgels.
PRODUCT
DEVELOPMENT
This section
will describe the typical stepwise process by which Softgels may be developed. The steps generally include fill formulation development,
shell compatibility, prototype
development (lab scale encapsulation), experimental batch manufacture (process development), clinical supply and conclude with a product performance review of the manufacturing process
and specialized formulation
approaches to enhance pharmacokinetic performance.
Fill
Formulation Development
The Softgel
process relies on the use of a positive displacement
pump for fill dosing. These pumps are capable
of dosing a reasonably wide range of viscosities (up to 10,000 cps or more), though there are several other factors, which may affect the dosing of a particular formulation, most notably
the rheological properties. The fill
liquid is typically either a solution of
drug or a suspension (rather than both in the same capsule), and is generally designed to fit in the smallest possible Softgel with acceptable
chemical and physical stability,
therapeutic effectiveness, and production
efficiency. Solutions are generally the first choice, as they may help reduce the negative
effect of drug particle dissolution
upon bioavailability. For solution formulae, the challenge is generally to develop a solution that is robust enough to remain in solution
throughout manufacturing and shelf
life, whilst concentrated enough to
produce a Softgel size capable of satisfying requirements for patient compliance and economics. It is very important to note that,
when formulating the fill material
for Softgel encapsulation, appropriate consideration
is given to the shell development at the
same time. It is commonly and erroneously assumed by those not skilled in the art of Softgel manufacture, that the shell is inert and undergoes
no changes itself nor imparts any
changes on the encapsulated material.
The first step
in developing a solution containing Softgel
is to determine the solubility of the drug in a range of pharmaceutically acceptable solvents. After the solubility is determined, the
solvents are selected on the basis
of their regulatory acceptability and known
compatibility with Softgel dosage forms. The types of excipient typically include the following:
·
Hydrophilic solvents
·
Lipophilic materials
·
Hydrophilic surfactants
·
Lipophilic surfactant
·
Cosolvents
Solvents that
provide adequate solubility of the drug can be selected, though it may be
necessary to combine them to achieve the desired in vitro or in vivo
characteristics and to ensure good physical stability. It is particularly
important, for solutions of poorly water-soluble drugs, to ensure that the fill
solution is robust enough to withstand the inevitable dynamic changes that take
place within the first 72 hr after encapsulation. This is because of the
migration of components (water, plasticizers, drugs, etc.) within the Softgel
both during and following encapsulation, which do not occur to the same extent
in other ‘‘dry’’ dosage forms. Therefore it is important to conduct moisture,
plasticizer challenge studies and temperature cycling studies to ensure that a
robust fill formulation is achieved.
For Softgels
containing suspension fills, the solubility of the drug in a range of
pharmaceutically acceptable solvents is also determined and excipients in which
the drug shows little or no solubility are then selected. These formulations
generally require viscosity enhancers to provide adequate suspending
characteristics for the drug during processing. This is vital in maintaining
drug homogeneity during manufacture. The type and level of viscosity enhancer
is optimized to provide the best manufacturability. Ideally, the fill material
is designed to set slightly after encapsulation, such that the effects of
long-term migration caused by gravity are reduced. Suspension formulae should
be developed around a drug with controlled particle size, to enable proper
process development. For Softgel suspension formulae, dissolution method
development is a key activity, which requires expert attention to help ensure
that proper interpretation is made.
Shell
Compatibility
Shell
compatibility testing between the fill and shell formulation is an important part of the development process. A variety of problems may
result if the fill is not well
matched to the proper shell formulation.
These may be observed either immediately after encapsulation or after prolonged storage as described earlier. Traditionally, shell
compatibility is performed using
fill material and swatches or samples of gel ribbons. One of the challenges for Softgel development is to decide whether it is even feasible
to determine shell compatibility
without ever making Softgels. For this reason,
it is preferred to perform an encapsulation
trial as soon as possible. To make this easier and more economic, this work may be performed using lab scale equipment.
Prototype
Development
(Lab
Scale Encapsulation)
Traditionally,
one of the features of Softgel manufacture
has been that all the manufacturing encapsulation equipments were designed for commercial production. Whilst this helped reduce the
occurrence of scale-up issues, the
minimum batch size for such machines was
about 2.5–5 L, depending upon the expected yield and capsule quality. This is a large figure for certain NCEs where drug availability is a
restricting factor. Recently, lab
scale equipment has become available at
Cardinal Health that uses as little as 100 ml of fill liquid to produce capsules (Fig. 3). It is now possible to produce first time Softgels in a
laboratory setting, using the same
encapsulation principle as full-scale encapsulation
equipment, and to produce prototypes to
help evaluate whether the Softgel dosage form is viable for a particular drug. This equipment makes the use of air-filled capsules to
perform compatibility studies
obsolete, as the latter, being a dry process, is never able to truly represent the wet capsule process.
Fig.
Lab-scale Softgel encapsulation machine.
Process
Development
Having
identified potential fill and shell formulations at the laboratory scale, a suitable manufacturing process that will enable successful preparation
of the trial batch materials
required for regulatory and clinical studies
must be developed. Such process development
includes selection of equipment and investigating critical processing parameters, such as the order of addition, temperature, mixing
condition, and speed. The
information obtained from these development
batches will provide valuable information for later process ranging and validation studies. For example, the fill moisture and hardness of the
capsules during the drying stages
will be monitored to optimize the drying
process and resulting product stability. Fig. 4 shows the drying profile of a Softgel product. Note that the reduction in fill moisture is
accompanied by an increase in
capsule hardness. As more process development studies are completed, the in-process test data will be reviewed to help develop
preliminary specifications intended
to control product quality. For example,
statistical analysis of in-process fill weight data may be performed to show that the process is capable of meeting the proposed in-process
specification.
Clinical
Supply
Manufacture of
clinical batches will be performed according
to the need for clinical studies (whether
Phase I, II, or III). Process development studies should be carefully coordinated to ensure that the process is robust at the time of the
registration batch manufacture.
Product
Performance Review/Preparation for Process Validation
At the end of
the product development phase and prior to
process validation, a product review should be performed to ensure that the development is complete, and that the various processes for
manufacture are capable of passing
process validation. At this point, any
gaps in the development process may be further studied and attended to, prior to performing process validation (e.g., logo printing
process development), preferably at
full scale. It is advisable to manufacture
two or more process challenge batches to show that the product is acceptable at the upper and lower process ranges. This helps to ensure that validation
will be successful.
METHOD
OF MANUFACTURE
As early as the
1830s, Softgels were used as a method of
drug delivery. Early manufacturing included both a hand-dipping method and a plate-press method. The hand-dipping method created
individual empty Softgel shell that
was subsequently filled with a syringe or
a dropper. The plate-press method was a batch process that involved pressing two sheets of wet gelatin together between two molds. The molds
provided depressions in the gelatin
sheet into which active fill was
then placed. A second gelatin sheet was laid over the first and both were pressed together with fill material sandwiched in between. The pressure of
the plate dies sealed the top and
bottom sheets of gelatin together and
cut out the individual Softgels for subsequent drying. Today, almost every Softgel on the market is made using the rotary die process
patented by Scherer in 1933.[17] The
equipment and manufacturing process has
improved dramatically over the years, but the underlying manufacturing principle remains essentially unchanged. Two independent processes
take place, often simultaneously,
yielding two different materials, the gel
mass and the fill material. Both are united in the encapsulation process that produces wet Softgels.
The wet gel mass
is manufactured by mixing together
and melting, under vacuum, the gelatin shell ingredients (gelatin, plasticizer, water, colorants and sometimes opacifiers, flavors, and
preservatives). At the encapsulation
machine (Fig. 5), molten gel mass flows
through heated transfer tubes and is cast onto
Fig. Encapsulation equipment.
chilled drums,
forming two separate ribbons, each approximately 6 in. wide. The thickness of
the ribbons (usually 0.02–0.04 in.) is carefully controlled and checked periodically
throughout manufacture. The gel ribbons traverse through rollers that provide
proper alignment of the ribbons and apply lubricant to both surfaces of the
ribbons. Each gel ribbon forms one half of the Softgel. Two-toned Softgels are
made using two different colored gel ribbons. Active fill materials are
manufactured in a process separate from the gel mass manufacture. The viscosity
of all fills and the particle size of suspended materials are important
parameters established during development and controlled throughout
manufacture.
Softgels are
formed during the encapsulation part of the process, using the two gel ribbons
and the fill material. Lubricated gel ribbons are fed between a pair of counter
rotating dies, the surface of which contains matching pockets of appropriate
size and shape that serve as molds for forming the Softgels. The die pockets
also seal both sides of the Softgel and cut the formed Softgel away from the
residual gel ribbon. Fig. 6 shows Softgels immediately following encapsulation
as they are being separated from the ribbons. The Softgels are then conveyed to
a tumble dryer to initiate drying.
Situated between
the ribbons and rotating dies is the wedge as shown in Figs. 7 and 8. The wedge
serves three separate functions during the encapsulation process. First, it
heats the gel ribbons close to the gel–sol transition temperature to ensure
that melting (welding) of the two gel ribbons occurs when the ribbons are
pressed together between the dies. Second, the wedge is part of the system that
distributes the fill material from a positive displacement pump to each of the
die pockets. Finally, the wedge, in conjunction with the lubricant, provides a
sealing surface against the ribbons to eliminate air and allows a seal to be
formed
Fig. Newly formed
Softgels.
between the
shell and fill material without the introduction of air into the product. To
properly manufacture the gel mass and form the gel ribbons, the gel mass
formulation contains excess water. Following encapsulation, Softgels must be
dried to obtain a final product that will be durable enough to withstand
subsequent processing, packaging, and shipping, and possess good long-term
physical stability. Drying occurs in two stages. Initial drying takes place in
a rotating basket dryer that tumbles the Softgels in temperature and humidity
controlled air. This removes approximately half of the excess water and is
intended to remove sufficient water such that the capsules are firm enough to
withstand tray drying without undergoing substantial deformation of the shape
owing to gravity. The balance of the excess water is removed during the
secondary drying stage, when the Softgels are spread in a single layer on
shallow trays. The trays are designed and stacked to allow air to pass through
the rack and around the Softgels (Fig. ). Secondary drying proceeds under
controlled conditions of temperature
Fig. Softgel
encapsulation process.
Fig. Close-up of die-wedge equipment.
and
humidity until the appropriate level of capsule hardness and/or fill moisture
is achieved.
Complete
drying can take from three days to three weeks depending on shell and fill
formulations and the size of the Softgel.
Once
the Softgels have reached the desired drying end point, they are placed into
bulk holding containers to prevent further drying.At this point, several
additional operations may be performed, including washing, off line printing,
inspecting, and packaging.
THERAPEUTIC PERFORMANCE
The
pharmacokinetic performance of drugs can be
enhanced by Softgel dosage form, the exact formulation
Fig. Tray drying of
Softgels in controlled drying tunnels.
of which depends
on the desired pharmacokinetic improvement. The two most common requirements
are faster and more complete absorption. In both cases, the ideal situation is
for the drug to be dosed in solution and formulated to remain in solution after
dispersion in gastrointestinal
media, possibly as a nanoemulsion. Formulation of nanoemulsion preconcentrates
for Softgel encapsulation requires the drug to be in solution in a mixture of
oils, surfactants, cosurfactants, and possibly cosolvents.
Rate
of Absorption
Noteworthy
advances recently have been made in the development
of Softgel formulations to address particular
performance issues in vivo. These include
presentation of the drug to the gastrointestinal tract in a solution from which the drug can be absorbed significantly faster than that from a
solid oral dosage form, which may be
rate limited by the need for disintegration
followed by drug dissolution. With the solution-Softgel
approach, the shell ruptures within minutes
to release the drug solution, usually in a
hydrophilic or highly dispersing vehicle that aids the rate of absorption. This can be a valuable attribute for treatments such as migraine or
acute pain, or where there is a
limited absorption window in the gastrointestinal tract. Fig. 10 compares the absorption rates between a solution Softgel formulation and a tablet of ibuprofen.[18] The data are based
on a pharmacokinetic comparison of
400 mg ibuprofen in 12 human volunteers.
Increased
Bioavailability
In addition to
increasing the rate of absorption, Softgels
may also improve the extent of absorption. This can be particularly effective for large hydrophobic drugs.
The protease
inhibitor saquinavir was relaunched in
a patented solution–Softgel formulation, providing approximately three times the bioavailability as the original hard-shell formulation.[19]
In some cases,
drugs may be solubilized in vehicles capable
of spontaneously producing a microemulsion
or nanoemulsion on contact with gastrointestinal fluids. This particular vehicle consists of oils and surfactants in appropriate proportions which, on
contact with aqueous fluids, produce
an emulsion preferably with an
average droplet size less than 100 nm. The
solubility of the drug should be maintained as long as possible, delivering solubilized drug directly to the enterocyte membrane. Fig. 11 depicts
the enhancement in plasma levels
achieved in 12 human volunteers when a
nanoemulsion Softgel was used to dose a hydrophobic drug as compared to a capsule containing a suspension of micronized drug particles.[19] It
may even be possible to utilize the
body’s own systems for oil digestion to produce
micelles containing solubilized drug.
Decreased
Plasma Variability
High variability
in drug plasma levels is a common characteristic
of drugs with limited bioavailability. By
dosing the drug optimally in solution, the variability of such drug plasma levels can often be reduced. Cyclosporin benefits from such an
approach.[20] Fig. 12 depicts the
administration of a 10 mg/kg dose of
Cyclosporin A (Sandimmune_) Softgel solution formulation in eight human volunteers.[21] Fig. 13 depicts the administration of a 10 mg/kg dose of Cyclosporin A (Neoral_) microemulsion
preconcentrate Softgel formulation
in eight fasting human volunteers.[21]
PRODUCT
QUALITY CONSIDERATIONS
Ingredient
Specifications
Numerous
specifications and control measures are employed
to determine final product quality, the first of which is ensuring adequate quality of excipients and active ingredients. Excipient testing
ensures compliance with compendial
specifications, as well as specifications
determined during development of the fill material and/ or shell formulation. Among these are limiting values for trace impurities, especially
peroxides, aldehydes, some metals,
and ionic salts.
Presence of
these impurities can result in gelatin cross-linking
and possible dissolution problems or in undesired
changes in the product appearance over time.
As gelatin is
the key ingredient for the shell and is
present in larger quantities than other excipients, it is important to ensure that the gelatin meets not only current United States Pharmacopeia
(USP) specifications, but the
additional controls of particle size, viscosity,
and bloom strength, all of which are significant for manufacturing process as well as final product stability. Other specifications, such
as the quantity of certain ionic
materials, are necessary to ensure stable
product appearance during storage. Furthermore, it is essential to specify or limit other gelatin properties, such as color or even the source of
the gelatin (bovine, porcine, bone,
hide), depending on the formulation and
intended market of the final product.
In-Process
Testing
Several tests
are conducted on a regular basis throughout the encapsulation portion of the
Softgel manufacturing process. These include weight determinations for both the
fill material and the shell, and measurements of the thickness of the seals of
the Softgels themselves. Fill moisture and/or hardness measurements are
performed during the drying process, the results of which are used to determine
the drying end point for each lot. Specifications for fill weight, shell
weight, seam thickness, and drying end points are based on the Softgel size,
amount and type of fill, and the results obtained during previous process
development studies.
Final
Product Testing
Once the
Softgels have completed all required processing steps, the lot is inspected and sampled for the final product-release test. Tests required
for final product release are
dependent on regulatory requirements for
the product and usually include microbiological testing, assay and identity of actives,
physical appearance, fill weight,
dissolution or disintegration, and dosage
uniformity.
RECENT
ADVANCES IN NEW TECHNOLOGY
Softgel as a
dosage form has been around for a long time
and remained largely unchanged. Recent advances in the development of Softgel formulations and manufacturing have been mainly on the shell
development. These include the
development of starch-based capsules that
can be made without gelatin[9,10] and enteric features of the dosage form from inside the shell.[22] Softgel technologies that provide
controlled release and modified
release profiles have also been reported
in the literature.[22–24]
There has been
great interest in the Softgel industry to
look for gelatin substitutes. As a matter of fact, several concepts based on synthetic polymers[11] and/or plant-derived hydrocolloids[9,10] have
been described in the literature.
However, only few have gained commercial
interest and commercial success. This is
because of the fact that capsule shell polymer needs to match certain mechanical properties to be able to form capsules on Softgel encapsulation
machine (a rotary die process). To
date, only couple of non-gelatin capsules
(e.g., VegiCap Soft_) with different process adjustments have reached the commercial stage. Vegi- Cap Soft, developed by Cardinal
Health, utilized the combination of iota
carrageenan and modified starch, as
a gelatin substitute. The combination of the two hydrocolloids leads to a synergistic interaction that produces a gel network, which is
suitable for Softgel production
using rotary die process. Certain modifications are required to the gel manufacturing operation, but the encapsulation and following
operations may proceed relatively
unchanged. These capsules do not show
cross-linking and exhibit greater mechanical stability when exposed to elevated humidity and temperature. They do not become sticky even under
hot and humid conditions. VegiSoft
Capsules have been used in the
nutritional market (with lipophilic formulation) for several years, showing that the process is robust. Recent research has shown that these capsules may be used to encapsulate hydrophilic
fill formulations and fill materials
that would not be possible using gelatin,
for example, fill formulations with high pH.[13]
Gelatin capsule
cross-linking is a well-known phenomenon
that results in reduced dissolution of capsule products with time. A few approaches have been reported in the literature to reduce or prevent the cross linking by incorporating certain
ingredients (e.g., citric acid, an
amine agent, or a sulfite agent) either in the fill formulation[25] or in the shell formulation.[26–29]
TRENDS
IN PATENT ACTIVITY
A review of the
World wide patent activities from 1985 to
2004 reveals some interesting trends within the Softgel technology arena. From 1985 to 1995, there were 22 issued patents containing
‘‘soft gelatin capsule’’ in title or
abstract. The number increased to 63 for
the next nine years from 1996 to 2004. While this number does not necessarily include all the patents citing soft gelatin capsule in the
specific claims or examples of
specific dosage forms, the significant increase
in the number of patents involving Softgels
may suggest a broader understanding of the benefits of this technology both in clinical performance and patient and consumer appeal.
Looking more
closely at U.S. patent activities, there
were 45 U.S. patents issued in 1990 where the soft gelatin capsule was a specific claim. In year
2000, there were approximately 300
patents with Softgels as a specific
claim. This sixfold increase in the number of patents specifically involving Softgel formulations may reflect greater and more
widespread expertise with regard to
Softgel formulation processes. It may also be an indication of the greater proportion of ‘‘difficult to formulate’’ drugs currently coming out
of basic research centers, that is,
low aqueous solubility and/ or poor
or variable gastrointestinal absorption. A listing of the more significant patents, sorted into groups relating to either
formulations,[30–39] manufacturing technology[24,40–49]
or Softgel design innovations,[50–62] has
been included in the reference section.
Examination of
the patent activity of the top 20 pharmaceutical
companies, or their predecessor companies,
in the year 2000 vs. 1990 suggests an industry sector shift in the use of soft gelatin capsules. In 1990, the top 20 pharmaceutical firms
obtained 85% of patents. This
decreased to 57% in year 2000. As overall
pharmaceutical application of Softgel technology has increased, a reasonable inference would be that the comparatively young and smaller biopharmaceutical industry sector is coming of age as
compounds begin to move from basic
research to development and
commercialization.
Over the 1990
and 2000 periods, 95% of patents granted
for pharmaceutical Softgel products relate
to drugs or fill formulations and not to specific claims or improvements regarding shell
formulations or manufacturing
processes. On the surface, this would appear
to indicate a mature technology, but as patents are public domain, and process patents are difficult to enforce, it is more likely that
industry leaders are reluctant to
pursue patents, except in unusual circumstances. In this process critical industry, it is more reasonable to expect that companies prefer to maintain technological advances as internal
in-house matters for competitive
reasons.
Despite the
specialized manufacturing process, Softgels
provide a versatile and efficient drug delivery system with distinct advantages over conventional
dosage forms, including improved
bioavailability, shorter development times,
superior patient preference, and enhanced dose uniformity. The inherent nature of the Softgel offers a wide variety of usage and fill
options. In any Softgel product
development effort, formulation of the fill
and gelatin shell should be considered concurrently to optimize product quality and performance.
Soft - Gelatin Capsules
Soft gelatin capsules are hermetically
sealed one - piece capsules containing a liquid or a semisolid fi ll. Like
liquid - fi lled hard capsules, although the drug is presented in a liquid
formulation, it is enclosed within a solid, thus combining the attributes of
both. Soft gelatin capsules (softgels) offer a number of advantages including
improved bioavailability, as the drug is presented in a solubilized form, and
enhanced drug stability. Consumer preference regarding ease of swallowing,
convenience, and taste can improve compliance, and they offer opportunities for
product differentiation via color, shape, and size and product line extension.
The softgels can be enteric coated for delayed release. They are popular for
pharmaceuticals, cosmetics, and nutritional products, but highly water -
soluble drugs and aldehydes are not suitable for encapsulation in softgels.
Formulations are tamper evident and can be used for highly potent or toxic
drugs. However, they do require specialist manufacture and incur high
production costs.
Manufacture of Soft
Gelatin Capsules
The shell is primarily composed of
gelatin, plasticizer, and water (30 – 40% wet gel), and the fi ll can be a
solution or suspension, liquid, or semisolid. The size of a softgel represents
its nominal capacity in minims, for example, a 30 oval softgel can accommodate
30 minims (or 1.848 cm 3 ). Glycerol is the major plasticizer used, although
sorbitol and propylene glycol can also be used. Other excipients are dyes,
pigments, preservatives, and fl avors. Up to 5% sugar can be added to give a
chewable quality. Most softgels are manufactured by the process developed by
Scherer [11] . The glycerol – gelatin solution is heated and pumped onto two
chilled drums to form two separate ribbons (usually 0.02 – 0.04 in. thick)
which form each half of the softgel. The ribbons are lubricated and fed into
the fi lling machine, forcing the gelatin to adopt the contours of the die. The
fi ll is manufactured in a separate process and pumped in, and the softgels are
sealed by the application of heat and pressure. Once cut from the ribbon, they
are tumble - dried and conditioned at 20% relative humidity.
Fill solvents are selected based on a
balance between adequate solubility of the drug and physical stability. Water -
miscible solvents such as low - molecular – weight PEGs, polysorbates, and
small amounts of propylene glycol, ethanol, and glycerin can be used. Water -
immiscible solvents include vegetable and aromatic oils, aliphatic, aromatic,
and chlorinated hydrocarbons, ethers, esters, and some alcohols. Emulsions,
liquids with extremes of pH ( 2.5 and 7.5), and
volatile components can cause problems with stability, and drugs that do not
have adequate stability in the solvents can be formulated as suspensions. In
these instances, the particle size needs to be carefully controlled and
surfactants can be added to promote wetting.
Vegicaps soft capsules from Cardinal
Health are an alternative to traditional softgels, containing carageenan and
hydroxyproyl starch. As with traditional soft gelatin capsules, the most
important packaging and storage criterion is for adequate protection against
extremes of relative humidity. The extent of protection required also depends
on the fi ll formulation and on the anticipated storage conditions.
Dissolution Testing of Capsules
In general, capsule dosage forms tend
to fl oat during dissolution testing with the paddle method. In
such cases, it is recommended that a few turns of a wire helix around the
capsule be used [12] . Inclusion of enzymes in the dissolution media must be
considered on case - by - case basis. A Gelatin Capsule Working Group
(including participants from the FDA, industry, and the USP) was formed to
assess the noncompliance of certain gelatin capsule products with the required
dissolution specifi cations and the potential implications on bioavailability
[13] . The working group recommended the addition of a second tier to the
standard USP and new drug and abbreviated new drug applications (NDA/ANDA)
dissolution tests: the incorporation of enzyme (pepsin with simulated gastric
fl uid and pancreatin with simulated intestinal fl uid) into the dissolution
medium. If the drug product fails the fi rst tier but passes the second tier,
the product ’ s performance is acceptable. The two – tier dissolution test is
appropriate for all gelatin capsule and gelatin - coated tablets and the
phenomenon may have little signifi cance in vivo.