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Dagadiye Ravindra B et al. / International Journal of Advances in Pharmaceutical Research
IJAPR
Available Online through
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Review Article
ISSN: 2230 – 7583
ADVANCEMENT IN MANUFACTURING OF NON-GELATIN
CAPSULE SHELL-A REVIEW
Dagadiye Ravindra B*, Kajale Archana D, Mahajan Vandana K, Joshi Manisha H.
Dr.V.P.P.College of Pharmacy, Paithan road, Aurangabad, Maharashtra, , 431006.
+919423467546. rickyravindra@gmail.com
Received on 10 – 05 - 2012 Revised on 17 – 06- 2012 Accepted on 20– 08 – 2012
ABSTRACT
The gelatin cap-sule shell may be soft or hard depending on their formulation. Capsules are intended to be
swallowed whole by the patient. In instances where patients (especially children) are unable to swallow capsules,
the contents of the capsule can be removed and added (e.g., sprinkled) on soft food immediately before ingestion.
In the manufacture of pharmaceuticals, encapsulation refers to a range of techniques used to enclose medicines in a
relatively stable shell known as a capsule, allowing them to, for example, be taken orally or be used as
suppositories. Hard-shelled capsules, which are normally used for dry, powdered ingredients or miniature pellets,
Both of these classes of capsules are made from aqueous solutions of gelling agents like:Animal protein mainly
gelatine And Non-gelatin such as Plant polysaccharides or their derivatives like carrageenans and modified forms
of starch and cellulose. Despite the great advantages, of gelatin capsules’, gelatin has several drawbacks that limit
its use for capsules. The animal source of gelatin can be a problem for certain consumers such as vegetarians or
vegans and religious or ethnic groups, Since unmodified gelatin is prone to cross linking when in contact with
aldehydes, solubility problems might be expected with certain fill formulations. The non-gelatin capsule shells are
made up of such as Starch, HPMC, PVA, and Alginate.
Key words: Gelatin/Non-Gelatin Material, capsule shell, Starch, HPMC, PVA, Alginate.
INTRODUCTION
Capsules are solid dosage forms in which the drug is
enclosed within either a hard or soft soluble
container or “shell.” The shells are usually formed
from gelatin; however, they also may be made from
starch or other suitable substances. [1]
The gelatin capsule shell may be soft or hard
depending on their formulation. Capsules are
intended to be swallowed whole by the patient. In
instances where patients (especially children) are
unable to swallow capsules, the contents of the
capsule can be removed and added (e.g., sprinkled)
on soft food immediately before ingestion. In this
case, capsules are used as a vehicle to deliver
premeasured medicinal powder. [2] In the manufacture
of pharmaceuticals, encapsulation refers to a range
of techniques used to enclose medicines in a
relatively stable shell known as a capsule, allowing
them to, for example, be taken orally or be used as
suppositories. The two main types of capsules are:
‣ Hard-shelled capsules, which are normally used for
dry, powdered ingredients or miniature pellets (also
‣ called beads that are made by the process of
Extrusion and Spheronization) - or mini tablets;
‣ Soft-shelled capsules, primarily used for oils and for
active ingredients that are dissolved or suspended in
oil.
Both of these classes of capsules are made from
aqueous solutions of gelling agents like:
‣ Animal protein mainly gelatin;
‣ Plant polysaccharides or their derivatives like
carrageenans and modified forms of starch and
cellulose.
Other ingredients can be added to the gelling agent
solution like plasticizers such as glycerine and/or
sorbitol to decrease the capsule's hardness, colouring
agents, preservatives, disintegrants, lubricants and
surface treatment.
TYPES OF CAPSULES
Gelatin capsules, informally called gel caps or
gelcaps, are composed of gelatin manufactured from
the collagen of animal skin or bone. (Gelatin is not
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derivable from ungulate hooves, which are
composed of a different protein, keratin.)
Vegetable capsules are composed of hypromellose,
a polymer formulated from cellulose. [3]
There are two types of capsules, “hard” and “soft”.
The hard capsule is also called “two pieces” as it
consists of two pieces in the form of small cylinders
closed at one end, the shorter piece is called the
“cap” which fits over the open end of the longer
piece, called the “body”. The soft gelatin capsule is
also called as “one piece”. Capsules are available in
many sizes to provide dosing flexibility. Unpleasant
drug tastes and odours can be masked by the
tasteless gelatin shell. The administration of liquid
and solid drugs enclosed in hard gelatin capsules is
one of the most frequently utilized dosage forms.
Advantages of Capsules
- Capsules mask the taste and odour of unpleasant
drugs and can be easily administered.
- They are attractive in appearance
- They are slippery when moist and, hence, easy to
swallow with a draught of water.
- As compared to tablets less adjuncts are required.
- The shells are physiologically inert and easily and
quickly digested in the gastrointestinal tract.
- They are economical
- They are easy to handle and carry.
- The shells can be opacified (with titanium dioxide)
or colored, to give protection from light.
Disadvantages of Capsules
- The drugs which are hygroscopic absorb water from
the capsule shell making it brittle and hence are not
suitable for filling into capsules.
- The concentrated solutions which require previous
dilution are unsuitable for capsules because if
administered as such lead to irritation of
stomach. [4][17]
Standard sizes of two-piece CAPSULES [3]
Size
Volume
(ml)
Locked
length (mm)
External
diameter (mm)
5 0.13 11.1 4.91
4 0.21 14.3 5.31
3 0.3 15.9 5.82
2 0.37 18 6.35
1 0.5 19.4 6.91
0 0.68 21.7 7.65
0E 0.7 23.1 7.65
00 0.95 23.3 8.53
000 1.37 26.14 9.91
13 3.2 30 15.3
12 5 40.5 15.3
12el 7.5 57 15.5
11 10 47.5 20.9
10 18 64 23.4
7 24 78 23.4
Su07 28 88.5 23.4
Raw materials used for capsule shell
manufacturing
GELATIN CAPSULE SHELL
Development of capsule shell by Gelatin
Gelatin is the major component of the capsules and
has been the material from which they have
traditionally been made. Gelatin has been the raw
material of choice because of the ability of a solution
to gel to form a solid at a temperature just above
ambient temperate conditions, which enables a
homogeneous film to be formed rapidly on a mould
pin.
The reason for this is that gelatin possesses the
following basic properties:
- It is non-toxic, widely used in foodstuffs and
acceptable for use worldwide.
- It is readily soluble in biological fluids at body
temperature.
- It is good film-forming material, producing a strong
flexible film
- The gelatin films are homogeneous in structure,
which gives them strength.
Some of the disadvantages with using gelatin for
hard capsules include: it has a high moisture content,
which is essential because this is the plasticizer for
the film and, under International Conference on
Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use
(ICH) conditions for accelerated storage testing,
gelatin undergoes a cross linking reaction that
reduces its solubility. Gelatin is a translucent brittle
solid substance, colourless or slightly yellow, nearly
tasteless and odourless, which is created by
prolonged boiling of animal skin connective tissue or
bones. Type A gelatin is derived from an acid-treated
precursor and exhibits an isoelectric point in the
region of pH 9, whereas type B gelatin is from an
alkali-treated precursor and has its isoelectric zone in
the region of pH 4.7. Capsules may be made from
either type of gelatin, but mostly a mixture of both
types is used considering availability and cost.
Difference in the physical properties of finished
capsules as a function of the type of gelatin used is
slight. Blends of bone and pork skin gelatins of
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relatively high strength are normally used for hard
capsule production. The bone gelatin produces a
tough, firm film, but tends to be hazy and brittle. The
pork skin gelatin contributes plasticity and clarity to
the blend, thereby reducing haze or cloudiness in the
finished capsule. [4][17]
I - HARD GELATIN CAPSULES
The majority of capsule products are made of hard
gelatin capsules. Hard gelatin capsules are made of
two shells: the capsule body and a shorter cap. The
cap fits snugly over the open end of the capsule
body. The basic hard gelatin capsule shells are made
from mixtures of gelatin, sugar, and water. They are
clear, colourless, and essentially tasteless.
Gelatin is a product obtained by partial hydrolysis of
collagen acquired from the skin, white connective
tissue, and bones of animals. Gelatin is a protein
which is soluble in warm (or hot) water, but
insoluble in cold water. At low temperatures, gelatin
dissolved in water becomes a gel (which is insoluble
in water). This property is used to prepare Jello and
other gelatin deserts. Gelatin capsules become
dissolved in warm gastric fluid and release the
contents. Normally, hard gelatin capsules contain
13–16% of moisture. If additional moisture is
absorbed when stored in a high relative
humidity environment, hard gelatin capsule
shell may lose their rigid shape and become
distorted. In an opposite environment of extreme
dryness, capsules may become too brittle and may
crumble during handling. Since moisture can be
absorbed or released by the gelatin capsules,
capsules containing moisture-sensitive drugs are
usually packaged in containers. Gelatin for making
hard shells is of bone origin and has 220–280 g
bloom strength (the weight required to depress a
standard plunger 4 mm into the gel). [5][15]
Manufacturing Of Hard Capsules
Some of the major suppliers of empty gelatin
capsules are: Eli Lilly and Company, Warner
Lambert’s Capsugel (formerly Park Davis) and R. P.
Scherer Corporation.
The metal moulds at room temperature are dipped
into a hot gelatin solution, which gels to form a film.
This is dried, cut to length, removed from the moulds
and the two parts are joined together, these processes
are carried out as a continuous process in large
machines.
The completely automatic machine most commonly
used for capsule production consists of mechanisms
for automatically dipping, spinning, drying,
stripping, trimming, and joining the capsules.
• Stainless steel pins are used on which the capsule is
formed and controls some of the final critical
dimensions of the capsule.
• One hundred and fifty pairs of these pins are dipped
in to gelatin sol of carefully controlled viscosity to
form caps and bodies simultaneously. The pins are
usually rotated to distribute the gelatin uniformly,
during which time the gelatin may be set or gelled by
a blast of cool air.
• The pins are moved through a series of controlled air
drying kilns for the gradual and precisely controlled
removal of water. The capsules are striped from the
pins by bronze jaws and trimmed to length by
stationary knives while the capsule halves are being
spun in chuks or collets. After being trimmed to
exact length, the cap and body sections are joined
and ejected from the machine. The entire cycle of the
machine lasts approximately 45 min.
• Thickness of the capsule wall is controlled by the
viscosity of the gelatin solution and the speed and
time of dipping. Mold pin dimensions, precise
drying, and machine control relating to cut lengths
are matters that are critical to the final dimensions.
Precise control of drying conditions is essential to
the ultimate quality of the cast film.
The in-process quality controls include periodic
monitoring, and adjustment when required, of film
thickness, cut lengths of cap and body, colour, and
moisture content.
Inspection processes to remove imperfect capsules
which were previously done visually, have recently
been automated following the development and
patenting of a practical electronic sorting mechanism
by Eli Lilly and Company. This equipment
mechanically orients the capsules and transports
them past a series of optical scanners, at which time
those having detectable visual imperfections are
automatically rejected. [5]
Excipients of Hard gelatin capsule
A) Gelatin
B) Colour & Opecifying agent
C) Preservatives (methyl paraben, propyl paraben,
butylated hy-droxyaniline, EDTA, sodium
benzoate)
D) Dyes, pigments,
E) pH-adjusting additive
F) Flavour and fragrance
II- SOFT GELATIN CAPSULES
Soft gelatin (also called softgel or soft
elastic) capsules consist of one-piece hermetically-
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sealed soft shells. Soft gelatin capsules are prepared
by adding a plasticizer, such as glycerine or
polyhydric alcohol (e.g., sorbitol), to gelatin. The
plasticizer makes gelatin elastic. Soft gelatin
capsules come in various shapes such as spherical,
elliptical, oblong, and special tube shapes with and
without twist off (see Figure 3.8). They can contain
non-aqueous liquids, suspensions, pasty materials, or
dry powders. They are especially important to
contain volatile drug substances or drug materials
susceptible to deterioration in the presence of air.
MANUFACTURING OF SOFT CAPSULES
There are several procedures to prepare soft gelatin
capsules, such as the plate process, the rotary die
process, and reciprocating die process. Most soft
gelatin capsules produced in industry are prepared by
the rotary-die process (see Figures 3.9 and 3.10). In
this process, two continuous gelatin ribbons are
brought together between twin rotating dies. At the
moment that the dies form pockets of the gelatin
ribbons, metered-fill material is injected between the
ribbons. Then the pockets of fill-containing gelatin
are sealed by pressure and heat. The capsules are
subsequently severed from the ribbon. As the
capsules are cut from the ribbons, they may be
collected in a refrigerated tank to prevent capsules
from adhering to one another and from getting dull.
Soft gelatin capsules contain more moisture than the
hard capsules. Since gelatin is subject to microbic
decomposition when it becomes moist, soft gelatin
capsules may be prepared with preservatives to
prevent the growth of fungi. Gelatin used for making
soft capsules is usually of bone and skin origin and
[5][6] [22]
has 150–175 g bloom strength.
Table:-Examples of commercial products prepared
in soft gelatin capsules
Ethchlorvynol (Placidyl ® ,
Abbott)
Demeclocycline HCl
(Declomycin ® , Lederle)
Chlortrianisene (TACE ® ,
Marion Merrell Dow)
Digoxin (Lanoxicaps ® ,
Burroughs Wellcome)
Docusate calcium
(Surfak ® , Upjohn)
Vitamin E (Aces ® ,
J.R. Carlson Lab.)
Neoral ® capsule
Zantac ®
Geldose
capsule
Procardia ®
capsule
(PEG based)
Advil ® liquicapsule
Figure, Schematic drawing of rotary-die soft gelatin
capsule filler (R.P. Scherer: Detroit, MI).
[6] [7]
Excipients of Softgels
- Gelatin
- Softener (plasticizer): sorbitol, xylose, maltitol,
glycerin, PEG, wa-ter)
- Preservatives (methyl paraben, propyl paraben,
butylated hy-droxyaniline, EDTA, sodium
benzoate)
- Dyes, pigments,
- Solvent
o Polar: glycerin, PEG, PEG 400, PEG 3350, ethanol,
PPG, water
o Nonpolar: beeswax, coconut oil, triglycerin, corn oil,
mineral oil, soybean oil, D,L-α-tocopherol
- pH-adjusting additive
- flavor and fragrance
- Pigment: titanium oxide, ferric oxide
- Anticaking agent: Silicone dioxide
- Humectant: polyol
Important Factors in Soft Gelatin Capsule [6][7]
- Solubility
- Permeability
- Organic solubility
o Common organic solvents: DMSO
o Acceptable softgel excipients: fatty liquids, PEGs,
propylene glycol, surfactants
- Drug-excipient compatibility
o Chemical stability
o Physical stability: Drug migration into shell, gelatin
disintegration, recrystallization of gelatin
o Polymorphism
Advantages of Soft Gelatin Capsules [6][7]
- Ease of swallowing
- Dosage accuracy/uniformity: Precise fill volume of
liquid fill unit delivers a greater degree of accuracy
and consistency from capsule-to-capsule and lot-tolot.
- Consistent manufacturing requirements: More
accurate compound-ing, blending, and dispensing of
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liquid fill facilitates manufacturing. Liquid blends
are more homogeneous.
- Increase in bioavailability: Absorption and
bioavailability can be enhanced by formulating
compounds in solution including solubilizers and
absorption enhancers, if necessary. Water-insoluble
drugs may be formulated in a softgel. Clinical
studies have shown enhanced absorption and
bioavailability with softgel forms. Examples are
temazepam (Salonen et al., 1986) and ibuprofen
(Saano et al., 1991).
- Enhanced stability and security: The tight hermetical
sealing protects fill from air and environmental
contamination. Gelatin shell can be formulated to
block out ultraviolet light. Streamlined, one-piece
design is tamper-evident.
- Pliable shell: soft gel shell allows for custom shapes
and sizes appropriate for oral, topical, chewable and
suppository delivery.
- Portability: Encapsulated liquid dosage formulations
become highly portable for consumers/patients. [17]
Raw materials used for capsule shell
manufacturing
NON-GELATIN CAPSULE SHELL
Development of Non-gelatin capsules
Traditionally, gelatin has been used almost
exclusively as shell-forming material of soft
capsules. This is due to its legal status and its unique
physicochemical properties, namely its oxygen
impermeability and the combination of film forming
capability and thermo reversible sol/gel formation
that favour its use for the industrial capsule
production especially in the rotary die process.
Despite these great advantages, which have been
described in detail in the section above on ‘Soft
gelatin capsules’, gelatin has several drawbacks that
limit its use for capsules:
- The animal source of gelatin can be a problem for
certain consumers such as vegetarians or vegans and
religious or ethnic groups (Jews, Muslims, Hindus,
etc.) who observe dietary laws that forbid the use of
certain animal products.
- Since unmodified gelatin is prone to cross linking
when in contact with aldehydes, solubility problems
might be expected with certain fill formulations.
- Transparent low-colour capsules are difficult to
produce owing to the effect of the intrinsic Maillard
reaction on gelatin colour.
- The temperature and moisture sensitivity of gelatinbased
soft capsules is an issue that complicates the
use of soft gelatin capsules in very hot and humid
regions and requires special packaging and storage
conditions to ensure product stability.
- For low-price health and nutrition products, pricing
of commercially available gelatin might be an
additional problem.
To address these concerns, there has been a great
interest in the soft capsule industry in looking for
gelatin substitutes. Indeed, several concepts based on
synthetic polymers and/or plant-derived
hydrocolloids have been described in the patent
literature. [6]
A) DEVELOPMENT OF STARCH CAPSULES
PROPERTIES OF STARCH
- Moisture content:-
Moisture content in starch capsule lies between 12%
to 14% w/w, with more than 50% being tightly
bound to starch. The presence of this bound moisture
indicates that starch capsules may provide better
stability properties and reduces susceptibilities to
change on storage.
- Dissolution
Similar to that of gelatine capsules.
Advantages
- Ready for filling immediately following
manufacturing.
- Offer greater resistance to humidity and heat than
gelatin and allow easy filling as they are non-static.
- Dissolution is independent of pH.
- Good surface finish.
- Coating of hard gelatine capsule with aqueous spray
formulations can lead to softening of gelatin shell or
gelatin shell may become brittle due to water
evaporation and drying.
Especially at the onset of coating. On the contrary,
the coating of starch capsules seems to be less
problematic because of smooth seal of the filled unit,
together with the higher bulk density of the capsules,
which provide a more uniform coating bed.
MANUFACTURING OF STARCH HARD
CAPSULES
- Hard gelatin capsules have been used most widely.
Recently, however, starch capsules have been used
in various controlled-release products as well as in
general use as demands for non-animal based
products increase. Starch capsules are more easily
coated than gelatin capsules. Gelatin shells may
soften and solubilise when sprayed with aqueous
dispersion of coatings and can become brittle during
the drying stage. The higher bulk density of the
starch capsule provides for a more uniform coating
bed.
- Starch capsules are manufactured by an injection
molding process that yields exact dimensions and
provides an excellent seal between “top” and
“bottom.” The filling and sealing process is
simultaneous, resulting in a finished product that is
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well-sealed, secure and relatively resistant to further
manipulation.
Starch and HPMC are good candidates for making
not only hard but also soft gelatin capsules. One of
the limitations of using them is the initial high
[7] [15] [23]
capital investment
B) DEVELOPMENT CAPSULES OF HYDROXY PROPYL
METHYL CELLULOSE (HPMC)
Hypromellose (INN), short for hydroxypropyl
methylcellulose (HPMC), is a semisynthetic, inert,
viscoelastic polymer used as an ophthalmic
lubricant, as well as an excipient and controlleddelivery
component in oral medicaments, found in a
variety of commercial products.
Product details:- [8]
Other names
Hydroxypropyl
methylcellulose;
hydroxypropyl methyl
cellulose; HPMC; E464
CAS number 9004-65-3
Chem Spider 21241863
UNII
Molecular formula
Molar mass
36SFW2JZ0W
Variable
Variable
Properties
- Appearance: HPMC is white or similar to white fiber
or granular powder; Odourless.
- Properties: Almost insoluble in ethanol, ether and
acetone; Quickly dispersed in 80-90 centigrade
water; Aqueous solution is very stable in room
temperature; Has good wetting / dispersing /
adhesive / thickening / emulsifying / water
preserving/film-forming properties; Can prevent the
infiltration of grease; Film formed has excellent
flexibility and transparency; Has good compatibility
with other emulsifier; Easy salting-out. Its solution is
stable with pH 2-12.
- Apparent density: 0.30-0.70g/cm3, density is
1.3G/cm3.
Dissolving process
HPMC will agglomerate when directly added to
water and then dissolve. In this way it dissolves very
slow and hard. Suggested methods as followers:
1. in hot water
HPMC does not dissolve in hot water. The primary
HPMC can be uniformly disperse in hot water. Then
cool down in two ways:
A) Add hot water in container and heated to over 70
centigrade. Add HPMC gradually while slowly, stir.
At the beginning, HPMC float on the top of water,
then turns into slurry state stir and cool down.
B) Add water in container to 1/3 or 2/3 of its content.
Heated to over 70 centigrade add HPMC by
sequence of a). Make it disperse to form slurry state.
Add cool water or ice to the residual content, stir and
cool down the mixture.
2. Powder combination.
Mix HPMC with identical volume of other powder,
disperses them sufficiently then add water to the. [9]
Despite the fact that most of pharmaceutical capsules
available in market are made of gelatin, several
HPMC capsules for powdered herbs and dietary
supplements have been available in recent years.
Many investigational new drugs with HPMC
encapsulation are in clinical trials. HPMC capsules
may offer attractive alternative to gelatine capsules
because of its vegetable source. The cross linking of
gelatin and drug incompatibilities and the strict
regulations regarding the use of animal derived
gelatin requiring the absence of bovine spongiform
encephalopathy (BSE)/ transmissible spongiform
encephalopathy (TSE) have encouraged the search
for gelatin replacement. Religious, cultural and
personal issues may affect patients’ preference
towards the medications presented in capsule dosage
forms. Vegetarians for example are becoming
increasingly aware of the capsule shell materials
which also encouraged the companies to search for
alternatives. As a result, the first vegetable capsules
with the trademark Vegicaps made of HPMC were
produced in 1989 by G S Technologies Inc. (now
R.P. Scherer Technologies ownership). [10]
MANUFACTURING OF (HPMC) CAPSULES
- The results from the search were filtered to use
information regarding the two-piece capsules (hard
capsules) only; since there are the soft capsules such
as Vegicaps Soft (Catalent Pharma Solutions),
HPMC based soft capsules, which are available as
alternative to soft gelatin capsules. Hard gelatin and
HPMC capsules are manufactured using similar
equipments developed by Eli Lilly (20).
- In hard gelatin capsule manufacturing, pins (molds
for making the capsules) at 22°C are dipped in a dip
pan or pot that holds a fixed quantity of gelatin at a
constant temperature, between 45° and 55°C. The
level of solution is maintained automatically by a
feed from the holding hopper. Once the molds are
dipped a film will be formed on them by gelling
since they are at lower temperature. The slowly
withdrawn pins from the dipping pan are rotated to
maintain uniform film thickness, where they are
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passed through a series of drying kilns at controlled
temperature and humidity. The dried films (shells)
are stripped of the pins, cut to the correct length and
the two pieces (cap and body) are joined together.
The pins are then cleaned and lubricated to start the
next cycle.
- The manufacture of HPMC based capsules
necessitates some modification to the molding
machine or to the formulation of the shell materials.
HPMC gelling from solution occurs when the
temperature is raised while it is converted to its
original solution as the temperature is lowered,
unlike gelatin solution. This means that the pins
immersed in the dip pan containing the HPMC
solution must be of higher temperature (70°C) in
order for the film to be formed. To avoid
liquefaction of the films formed on the pins, the
temperature of the pins must be further maintained
post-dip to facilitate gelation until the films dry out
in the kilns (21-24).
- Because HPMC shell walls are much weaker than
gelatin made shells, removal of the capsule from the
pins and subsequent handling and filling are in
jeopardy. To overcome these problems, three
approaches were adapted. These approaches were to
use a stripper jaw with depressions on the inner
surface, increase the formed HPMC film thickness
and the use of gelling agents. The following gelling
agents were experimented: tamarind seed
polysaccharide, carrageenan, pectin, curdlan, gellan
gum and furcellaran.
C) DEVELOPMENT OF PVA COPOLYMER CAPSULES
Hard capsules have been developed as an edible
container to mask the taste and odour of medicines.
Traditionally used for powder or granulated
formulations, capsules have also been adapted to
contain oily liquids, tablets and even powders for
inhalation. They are popular because of their relative
ease of manufacture (compared with other dosage
forms such as tablets) and their flexibility to
accommodate a range of fill weights. Additionally,
capsules readily demonstrate bioequivalence
between different strengths of the same formulation.
The solubility of many compounds used in potential
new drugs is very low because they are selected for
their affinity to receptors, which increases as the
lipophilicity of a compound increases. Although
these compounds are expected to have a high clinical
performance, they often fail to become new drug
entities because of their low absorption in the gastrointestinal
(GI) tract - a result of poor dissolution.
This suggests that pharmaceutical manufacturers
could develop dosage forms of insoluble drugs with
macrogol 400, improving the solubility of such
entities. Because the formulations and manufacturing
processes are simple, no scale-up studies would be
required - possibly reducing drug development
times. Because of the large potential of capsules that
can hold macrogol 400, the developed new capsules,
synthesizing materials that are suitable as capsule
shells. By copolymerizing acrylic acid (AA) and
methyl methacrylate (MMA) on PVA as a skeleton
and then using the obtained PVA copolymer as
capsule shells, the successfully developed capsules
that can be filled with macrogol 400.2,3 In this
paper, the physical properties of the PVA copolymer,
and the characteristics and pharmaceutical
applications of PVA copolymer capsules, are given.
[14]
Necessity of new materials:-
- Initially, examined why conventional capsule shells
do not tolerate macrogol 400. When gelatin capsules
were filled with macrogol 400, they became brittle
and broke easily because the moisture in the shell
was absorbed by the macrogol. When hydroxypropyl
methylcellulose (HPMC) capsules were filled with
macrogol 400, the agent oozed out through the
capsule shell.
- It is believed that new synthetic polymers would be
more suitable for capsule shell materials rather than
natural polymers or polysaccharides. Thus, different
polymers were synthesized, using styrene resin,
polyurethane, acrylic polymer and chitosan as a
skeleton.
Product Information [15]
Chemical Polyvinyl Alcohol
Name
Commodity PVA
Name
Category Linear polymer with hydroxyl
group
Molecular (CH3CHCOOCH3)x(CH2CHOH)y
formula
Molecular n/a
wt.
H.S.Code 3905300000
CAS No. 9002-89-5
Hazard
Class
UN No.
Packing
Group:
n/a
n/a
n/a
Technical Specification [15]
Appearance
White granular
Viscosity by mPa.s 27.0~ 32.0
Alcohol degree by
y/(x+y) x 100%
Sodium Acetate by wt %
98.0~ 99.0
2.5 max
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Dagadiye Ravindra B et al. / International Journal of Advances in Pharmaceutical Research
Volatile by wt %
Ash by wt %
5.0 max
0.7 max
pH value 5~ 7
Particle size by mesh about 15
MANUFACTURING OF (PVA) CAPSULES
Dissolution of PVA copolymer
- Capsules made only of PVA are available, although
they are easily softened by surrounding moisture. In
the PVA copolymer, MMA was used to increase the
hardness of the capsule shell; however, increasing
the amount of MMA decreases the polymer
solubility. Thus, AA was copolymerized to increase
the solubility at neutral pH. The composition ratios
of PVA, AA and MMA in the PVA copolymer can
be modified; the best copolymer is formed when the
levels of PVA, AA and MMA are 70–80%, 2.5–
5.0% and 15–25%, respectively.
- Drug capsules should dissolve in purified water, as
well as in simulated gastric fluid (pH 1.2) and
simulated intestinal fluid (pH 6.8) of the
disintegration test method listed in the Japanese
Pharmacopoeia (JP). The dissolution of PVA
copolymer cast film in the above media was
examined. The result showed that the film was
soluble in all three fluids, indicating that the
copolymer has suitable dissolution characteristics.
The film showed no erosion, swelling or dissolution
in macrogol 400.
-
Film strength
- PVA copolymer film was formed in 100 μm
thickness using the casting method. The breaking
strength and elongation rate of 40310 mm film
segments were examined, which showed the
breaking strength of the PVA copolymer film to be
32.2 N/mm2. The value was slightly lower than that
of gelatin film (55.8 N/mm2), but comparable to that
of HPMC film (30.8 N/mm2); therefore, the PVA
copolymer film was considered acceptable for
practical use.
- When the PVA copolymer film was moistened in a
chamber (25 °C/75% relative humidity [RH]), its
strength decreased by approximately 25%. Gelatin
and HPMC specimens showed larger reductions
(more than 50%) in strength when moistened at the
same condition.
Although the gelatin and HPMC films showed a low
elongation rate before and after moistening, the PVA
copolymer film showed a markedly higher rate
before and particularly after moistening (312% of the
original rate).
Gas permeability of the film:-
- The 100 μm thick film was also used to examine gas
permeability by the American Society for Testing
and Materials (ASTM) method. Water vapour
permeability through PVA copolymer film at 25
°C/90% RH was 323.2 g/m2/24 h, which was
between the values of the gelatin and HPMC films.
There was no marked difference in water vapour
permeability between the three films. In contrast,
oxygen permeability through PVA copolymer was
significantly less than through gelatin and HPMC
films, indicating that it should be impermeable to the
PVA copolymer film.
- Moisture absorption and desorption isotherm.
Generally, water-soluble polymers start to absorb
moisture when relative moisture increases by more
than 70% and the absorption rate dramatically
increases when relative moisture exceeds 80%. The
moisture absorption isotherm curve of PVA
copolymer is similar to that of gelatin. The moisture
desorption of PVA copolymer is similar to its
absorption isotherm curve, whereas, for gelatin film,
the desorption rate is slower than its absorption rate.
Physical properties
- PVA copolymer capsules were prepared by the
dipping and forming method. Carrageenan (0.05-
0.5%) was added as a gelling agent and potassium
chloride (0.05-0.5%) was added as a gelling
promoter. This method requires no additional
investment for capsule manufacturers because
conventional gelatin capsule manufacturing
machines can be used. Prototype PVA copolymer
capsules were coloured showed a good gloss and
were not different from conventional capsules.
-
Disintegration and dissolution
- Prototype PVA copolymer capsules (size #0) were
filled with macrogol 400 and the time taken for the
contents to begin to leak out was measured (Table
IV). The capsules were filled with the disintegrate
croscarmellose sodium and the paddle method (50
rpm) was used to measure the disintegration time as
an index of the start of dissolution. The capsules
opened in less than 10 min in all the media.
-
Capsule hardness
The relationships between the brittleness and
moisture content of PVA copolymer, gelatin and
HPMC capsules were compared using a hardness
tester (Shionogi Qualicaps, Japan). A 50 g weight
was dropped at a height of 10 cm onto a capsule and
the percentage of broken capsule was determined
(Figure 3). At a water content of 8%, the gelatin
capsules became brittle and the percentage of broken
capsules was 100%. The HPMC capsules did not
break, even at 1% water content. PVA copolymer
capsules became brittle when water content was less
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Dagadiye Ravindra B et al. / International Journal of Advances in Pharmaceutical Research
than 4%, but were less brittle compared with gelatin
capsules. PVA copolymer capsules did not become
brittle or break easily, even when filled with
macrogol 400 (which absorbs moisture from the
capsule shell) or silica gel grains (desiccant). The
authors concluded that these test conditions were too
severe to estimate capsule brittleness.
To evaluate capsule deformation, the load required
to deform each capsule by 50% was measured using
a load cell. The results illustrate that PVA copolymer
capsules can be deformed by moisture absorption,
but this can be prevented by controlling the water
content of the filling and the humidity of the
environment, or with moisture-proof packaging.
Filling dissolution
- When dissolution testing PVA copolymer capsules
(size #2) filled with macrogol 400, the bottom of the
capsules quickly dissolved (2 min) in purified water,
JP 1st fluid (pH 1.2) and JP 2nd fluid (pH 6.8), with
the macrogol 400 leaking out from the bottom.
- Two sets of capsules for the insoluble drugs
tolbutamide and indomethacin were prepared. One
capsule was filled with the drug as a solution of
macrogol 400 and the other was filled with a mixture
of the drug, lactose (as filler) and croscarmellose
sodium (as a disintegrant). The dissolution behaviour
of the capsules was compared using the JP paddle
method (50 rpm). The tolbutamide/macrogol 400
capsules almost dissolved completely in 10 min in
all the test solutions. However, for the capsules filled
with the drug, filler and disintegrant, only 80% of the
drug had dissolved after 60 min.
Absorption of indomethacin in rats. Indomethacin
PVA copolymer capsules were prepared using either
a solution of macrogol 400 or a mixed powder
formulated with lactose and croscarmellose sodium.
Both sets were filled into mini-capsules (size #9) and
administered to rats to compare the plasma profiles
of the drug .4 The results illustrate that between 180-
360 min, the capsule containing the drug as a
solution of macrogol 400 demonstrated a higher
plasma concentration (8 μg/mL) compared with the
capsules containing the mixed powder (1 μg/mL).
The data suggest that PVA copolymer capsules filled
with macrogol 400 improve the bioavailability of
insoluble drugs.
Tolerance of PVA copolymer capsules. The
solubilising agents macrogol 400, Tween 80 and
Labrasol were filled into PVA copolymer capsules
and stored in accelerating conditions (40 °C/75%
RH) in a sealed container to examine the tolerance of
the capsules to the agents. The capsules showed no
change in appearance after 6 months.
When a solubilising agent with high water content is
filled into a capsule, the moisture causes the capsule
shell to soften and/or deform. This can be prevented
by controlling the water content of the agent and the
humidity of the manufacturing environment, and by
using moisture-proof packaging, as done for
conventional capsules. [16][15][18]
D) DEVELOPMENT OF ALGINATE CAPSULES
Utilizing a novel patented process based on one of
FMC core Biopolymers (alginate) this technology
provides a unique seamless, enteric, vegetarian
alternative to gelatin soft capsules in one unit
process for pharmaceutical and nutraceutical
applications.
Alginate capsules advantages
Globally acceptable regulatory compliance with
Vegetarian (gelatin-free)
- Capsules easier to swallow:
- Smaller Capsule: Seamless thinner capsule shell,
allowing for capsules 30% smaller than traditional
gelatin for a given fill volume
- No Fish Burps: Naturally enteric providing superior
gastro resistant and enteric release properties to film
coated alternatives
- Superior elegance - high shell transparency
- Sugar and gluten free
Manufacture of capsules easier:
- Favourable unit cost - process does not produce
waste ribbon as seen in traditional rotary die
processes and eliminates need/cost of enteric film
coating maximizing production efficiency
- Process designed to provide oxidation protection
- QbD development philosophy
- Patented product and process enables product life
cycle enhancement. [19]
-
Alginate Capsules Basic Formulation
‣ Emulsion
…oil
…CaCl2•2H2O
…emulsifier
…water
‣ Gelling bath
…Alginate
‣ Washing
…Water
> Plasticizer
> Regulatory evaluation of shell components:
…All of the excipients used in the algicaps shell are
established excipients for use in oral dose forms at
levels used.
Alginate Capsules - Film thickness
‣ Thinner films than conventional soft capsules, in the
range of hard Capsules
…100-150 micron after drying
…Low film thickness variations
IJAPR / Oct. 2012/ Vol. 3 /Issue. 10 / 1178 – 1187 1186

Dagadiye Ravindra B et al. / International Journal of Advances in Pharmaceutical Research
…Conventional seam variations avoided
…Smaller capsules
…Easier to swallow
…More product per capsule
…Film thickness determined by
formulation and process conditions
…Amount of Ca2+ used
…Amount of alginate used
…Gelling temperature
…Gelling time
Manufacturing of alginate capsules [20]
Steps involved in alginate capsule shell formation:-
1. Extrude formation of Emulsion.
2. Introduce emulsion fragments into
alginate bath.
3. CaCl 2 diffuses through the
emulsion and react with sodium alginate at the
interface.
4. The capsule shell wall is formed
with the same thickness all around.
5. Washing and drying.
6. Dry capsule with transparent shell
and transparent core.
Fig. Alginate capsule shell manufacturing
process
Continuous capsule shell manufacturing process
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Pharmaceutics GS Banker & CT Rhodes, (1995) ,Eds., Marcel
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3) http://en.wikipedia.org/wiki/Capsule(pharmacy)
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26.
5) Ogura T, Furuya Y, Matuura S. “HPMC capsules: an alternative
to gelatin.” Pharm Tech Europe, 1998; 10(11): 32-42.
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“A comparison of the soft gelatin capsule and the tablet form of
temazepam(1986)” Acta Pharmacol Toxicol 58 ,page no:-49–54.
8) http://en.wikipedia.org/wiki/Hypromellose
9) http://kehongchem.en.made-in-
china.com/product/obrnIVtMCdkD/China-Hydroxypropyl-
Methyl-Cellulose-HPMC-MHPC-.html
10) M. Moawia . Al-Tabakha,” HPMC Capsules: Current Status and
Future Prospects”, College of Pharmacy, Al Ain University of
Science and Technology, Al-Ain, U.A.E.,J Pharm Pharmaceut Sci
(www.cspsCanada.org) 13(3) , 2010,428 – 442.
11) M. Sherry Kua,Weiyi Lia,,Wendy Dulina, Fran Donahuea,
Dominique Cadeb, Hassan Benameurb, Keith Hutchison,”
Performance Qualification of a New Hypromellose Capsule”,
Pharmaceutical Development, Wyeth Research, 401 N.
Middletown Road, Pearl River, NY 10965, USA.
12) Y. El-Malah; S.Nazzal;Carey B. Bottom”Hard Gelatin and
Hypromellose (HPMC) Capsules: Estimation of Rupture Time by
Real-time Dissolution Spectroscopy”.Published in:Drug
Development and Industrial Pharmacy, Volume 33, Issue 1
January 2007 , pages 27 - 34
13) https://data.epo.org/publicationserver/rest/v1.0/publicationdates/20081224/patents/EP1693056N
WB1/document.html
14) N.Hoshi, S.Uramatsu, T.Shimamoto, T.Ogura,” Development of
PVA Copolymer Capsules”, Pharmaceutical Technology Europe,
Apr 1, 2004.
15) http://www.lukem.cn/en/ProductShow.asp?ID=62
16) http://www.pharmtech.com/pharmtech/Raw+Materials/Developm
ent-of-PVA-Copolymer-
Capsules/ArticleLong/Article/detail/92479?contextCategoryId=25
92&ref=25
17) Leon Lachman.,"The Theory and Practice of Industrial
Pharmacy",varghese publication house,mumbay,page no:-374-
442.
18) http://www.capsugel.com
19) Magenta oral dosage formulation “Introduction to the Novel
Alginate Capsules Technology”, FMC.
20) http://www.fmcbiopolymer.com/Pharmaceutical/Products/Alginat
eCapsuleTechnology.aspx
21) http://www.trailab.net/Liam%20-%20Papers/23.pdf
22) www.liquidcapsules.com
23) http://www.google.com/patents/US5554385.pd
Fig. Continuous Alginate capsule shell
manufacturing process.
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