ADVANCEMENT IN MANUFACTURING OF NON-GELATIN
CAPSULE SHELL-A REVIEW
Author Name: - Dagadiye Ravindra B*, Kajale Archana D, Mahajan Vandana K, Joshi
Manisha H.
Affiliation:1) Dagadiye Ravindra B* – Author
2) Kajale Archana D – Guide
3) Mahajan, Vandana K – Co guide
4) Joshi Manisha H – Co guide
Dr.V.P.P.College of Pharmacy, Paithan road, Aurangabad, Maharashtra
Correspondence Details:-rickyravindra@gmail.com*
Address: - N-2, L-4-13/5, Ramnagar, CIDCO, Aurangabad, Maharashtra, 431006.
Contact no:-+919423467546.
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.
2
GELATIN/NON-GELATIN CAPSULE SHELL
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 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
3
“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]
4
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.
5
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 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]
6
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
7
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-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
8
preservatives to prevent the growth of fungi. Gelatin used for making soft capsules is usually
of bone and skin origin and has 150–175 g bloom strength.[5][6] [22]
Table:-Examples of commercial products prepared in soft gelatin capsules
®
®
Ethchlorvynol (Placidyl , Abbott)
Vitamin E (Aces , J.R. Carlson Lab.)
®
Demeclocycline HCl (Declomycin , Lederle)
®
®
Neoral capsule
®
Chlortrianisene (TACE , Marion Merrell Dow) Zantac Geldose capsule
®
Digoxin (Lanoxicaps , Burroughs Wellcome)
®
Docusate calcium (Surfak , Upjohn)
®
Procardia capsule (PEG based)
®
Advil liquicapsule
Figure, Schematic drawing of rotary-die soft gelatin capsule filler (R.P. Scherer: Detroit,
MI).
9

Excipients of Softgels [6] [7]
-
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-αtocopherol
-
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-to-lot.
10
-
Consistent manufacturing requirements: More accurate compound-ing, blending, and
dispensing of 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. Waterinsoluble 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 gelatin-based 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.
11
-
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.
12
-
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 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 capital investment [7] [15] [23]
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
controlled-delivery 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
36SFW2JZ0W
Molecular formula
Variable
Molar mass
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.
13
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).
14
-
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 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
15
often fail to become new drug entities because of their low absorption in the gastro-intestinal
(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 Name
Polyvinyl Alcohol
Commodity Name
PVA
Category
Linear polymer with hydroxyl group
Molecular formula
(CH3CHCOOCH3)x(CH2CHOH)y
Molecular wt.
n/a
H.S.Code
3905300000
CAS No.
9002-89-5
Hazard Class
n/a
UN No.
n/a
Packing Group:
n/a
16
Technical Specification:-[15]
Appearance
White granular
Viscosity by mPa.s
27.0~ 32.0
Alcohol degree by y/(x+y) x 100%
98.0~ 99.0
Sodium Acetate by wt %
2.5 max
Volatile by wt %
5.0 max
Ash by wt %
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
17
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
18
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 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
19
°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
20
 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
…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.
CaCl2 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.
21
Fig. Alginate capsule shell manufacturing process

Continuous capsule shell manufacturing process:-
Fig. Continuous Alginate capsule shell manufacturing process.
22
Reference:1) http://www.pharmacopeia.cnArtical%20capsule/General%20Chapters_%20_1151_%20PHA
RMACEUTICAL%20DOSAGE%20FORMS%20-%20CAPSULES.mht
2) LA Augsburger “Hard and soft gelatin capsules” in Modern Pharmaceutics GS Banker & CT
Rhodes, (1995) ,Eds., Marcel Dekker, Inc.: New York, NY, pp 395–440.
3) http://en.wikipedia.org/wiki/Capsule(pharmacy)
4) Dr. B.Bhatt,Prof. S.S. Agrawal "Pharmaceutical Technology Capsules(24-07-2007)" Delhi
Institute of Pharmaceutical Science and Research Sector – 3, ,Pushp Vihar ,New Delhi,page
no :-1 to 26.
5) Ogura T, Furuya Y, Matuura S. “HPMC capsules: an alternative to gelatin.” Pharm Tech
Europe, 1998; 10(11): 32-42.
6) MS Patel, FSS Morton, & H Seager “Advances in softgel formulation technology (1989)”
Manuf Chem, July 26–28.
7) M Salonen, E Aantaa, L Aaltonen, M Hovi-Viander, & J Kanto “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-HydroxypropylMethyl-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/EP1693056NWB1/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
23
16) http://www.pharmtech.com/pharmtech/Raw+Materials/Development-of-PVA-CopolymerCapsules/ArticleLong/Article/detail/92479?contextCategoryId=2592&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/AlginateCapsuleTechnology.aspx
21) http://www.trailab.net/Liam%20-%20Papers/23.pdf
22) www.liquidcapsules.com
23) http://www.google.com/patents/US5554385.pd
24