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CAPSULES: TYPES, MANUFACTURING, FORMULATION, QUALITY CONTROL TESTS AND, PACKAGING AND STORAGE - A COMPREHENSIVE REVIEW

Authors:

Abstract

Capsule types, packaging, storage, evaluation test.
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Aliyu et al. World Journal of Pharmaceutical and Life Science
CAPSULES: TYPES, MANUFACTURING, FORMULATION, QUALITY CONTROL
TESTS AND, PACKAGING AND STORAGE - A COMPREHENSIVE REVIEW
*1Aliyu R. S., 2Lawal A. M., 1Chasta P. and 1Sharma G. K.
1Department of Pharmacy, Mewar University, Gangrar, Chittorgarh, Rajasthan. 312901.
2Department of Chemistry, Mewar University, Gangrar, Chittorgarh, Rajasthan. 312901.
Article Received on 01/06/2020 Article Revised on 22/06/2020 Article Accepted on 12/07/2020
INTRODUCTION
Drugs
A drug is any substance that causes a change in an
organism's physiology or psychology when consumed.
Drugs are typically distinguished from food and
substances that provide nutritional support. Consumption
of drugs can be via inhalation, injection, smoking,
ingestion, absorption via a patch on the skin, or
dissolution under the tongue.[1]
In pharmacology, a drug is a chemical substance,
typically of known structure, which, when administered
to a living organism, produces a biological effect. A
pharmaceutical drug, also called a medication or
medicine, is a chemical substance used to treat, cure,
prevent, or diagnose a disease or to promote well-being.
Traditionally drugs were obtained through extraction
from medicinal plants, but more recently also by organic
synthesis. Pharmaceutical drugs may be used for a
limited duration, or on a regular basis for chronic
disorders.[2]
Dosage forms
Dosage forms are pharmaceutical drug products in the
form in which they are marketed for use, with a specific
mixture of active ingredients and inactive components
(excipients), in a particular configuration (such as a
capsule shell, for example), and apportioned into a
particular dose. The term dosage form can also
sometimes refer only to the pharmaceutical formulation
of a drug product's constituent drug substance(s) and any
blends involved, without considering matters beyond
(like how it is ultimately configured as a consumable
product such as a capsule, patch, etc.). Depending on the
method/route of administration, dosage forms come in
several types. These include many kinds of liquid, solid,
and semisolid dosage forms. Common dosage forms
include pill, tablet, or capsule, drink or syrup, and natural
or herbal form such as plant or food of sorts, among
many others. Notably, the route of administration (ROA)
for drug delivery is dependent on the dosage form of the
substance in question. A liquid dosage form is the liquid
form of a dose of a chemical compound used as a drug or
medication intended for administration or
consumption.[3]
Review Article
ISSN 2454-2229
wjpls, 2020, Vol. 6, Issue 8, 93-104
World Journal of Pharmaceutical and Life Sciences
WJPLS
www.wjpls.org
SJIF Impact Factor: 6.129
Corresponding Author: Aliyu R. S.
Department of Pharmacy, Mewar University, Gangrar, Chittorgarh, Rajasthan. 312901.
ABSTRACT
Capsules are solid preparations in which drug substance(s) and/or excipients are enclosed in either a soft or hard
soluble shell. The sell is normally made from gelatin or other suitable polymeric material and results in a simple,
tasteless, odourless, elegant, easy-to-swallow dosage form without the need for a secondary coating step.
Depending on the composition of the capsule shell, capsules may be classified as either hard or soft capsule, with
soft capsules possessing a flexible, plasticized gelatin film while the hard capsule is composed of two pieces in the
form of cylinders closed at one end; the shorter piece, called the „cap‟ and the longer piece, called the „body‟.
Capsules may be filled with a range of formulation types including dry powders, semisolids, nonaqueous liquids,
and other dosage forms such as beads, mini-tablets, and even mini capsules most of which are intended for oral
administration. There are also specialty applications such as capsules that can be loaded into dry-powdered
inhalers, add reagents as part of a diagnostic kit, and occasionally soft-shell capsules intended for rectal or vaginal
insertion as suppositories. Also, In the recent advancements, non-gelatin capsules have been discovered, which do
not contain gelatin as it‟s shell-forming agent. Under this category of capsules are the HPMC, PVA and starch
capsules. This review captures various categories of capsule types, formulation and filling of capsules, locking and
sealing of capsules, and, quality control tests. The various packaging and storage method were also highlighted.
KEYWORDS: Capsules, Manufacturing, Formulation, Quality control tests, Packaging and storage.
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Capsules
Capsules are defined as unit solid dosage form of
medicaments available as small containers (shells) made
up of gelatin enclosing accurately measured drug
substances. The term capsule is derived from the Latin
word capsula, meaning a small container. Capsule
occupy a significant position in the drug development.
They are often believed as the primary oral dosage form
because of their manufacturing process compared to
other dosage forms. Gelatin has the property of
disintegrating when it comes in contact with water,
thereby releasing the medicament completely. Instead, of
gelatin, denatured gelatin, methyl cellulose and polyvinyl
alcohol can also be used to make the capsule shells.[7]
There are mainly two types of capsules which are:
Hard-shelled capsules, which contain dry, powdered
ingredients or miniature pellets made by e.g. processes of
extrusion or spheronization. These are made in two
halves: a smaller-diameter “body” that is filled and then
sealed using a larger-diameter “cap”.
Both of these classes of capsules are made from aqueous
solutions of gelling agents, such as animal protein
(mainly gelatin) or plant polysaccharides or their
derivatives (such as carrageenans and modified forms of
starch and cellulose). Other ingredients can be added to
the gelling agent solution including plasticizers such as
glycerin or sorbitol to decrease the capsule's hardness.[4]
Capsule types
There exist various capsule types in scholarly articles,
they are; the soft gelatin and hard gelatin capsules,
Hydroxypropylmethyl cellulose (HPMC) capsules,
Polyvinyl alcohol (PVA) capsules, starch capsules.
These can be summarized as the gelatinous and non
gelatinous capsules.[11]
Gelatin capsules
This category of capsules is basically made from gelatin;
they can either be soft or hard gelatin capsules.
Soft gelatin capsules
General aspects
Originally developed in the 19th century to mask
unpleasant taste and odour of drug substances, soft
gelatin capsules are used in many applications, for
pharmaceutical, health and nutrition products, cosmetic
applications and even recreational products such as paint
balls.[12]
In the pharmaceutical field soft gelatin capsules are
increasingly being chosen for strategic reasons (line
extension), technological issues (high content uniformity
of low-dose drugs), safety aspects (reduced operator and
environmental contamination with highly potent or
cytotoxic compounds) and consumer preference (easy to
swallow). The most interesting advances have recently
been made in the area of developing liquid and semi-
solid formulations in a soft gelatin capsule to address
particular bio-performance issues, namely increased
bioavailability and decreased plasma variability by
improved solubility and absorption-enhancing
techniques.[13]
Basic components of soft gelatin capsule shell[15]
The various components of the soft gelatin capsule shell
are as follows:
a. Gelatin
Similar to hard gelatin capsule shells, the basic
component of soft gelatin capsule shell is gelatin. A large
number of different gelatin shell formulations are
available depending on the nature of the liquid fill
matrix. Most commonly, the gelatin is alkali- (or base-)
processed (type B) gelatin and it normally constitutes
40% of the wet molten gel mass. Type A acid-processed
gelatin can also be used. The properties of gelatin shells
are controlled by the choice of gelatin grade and by
adjusting the concentration of plasticizer in the shell.
b. Plasticising agents
Plasticizing agents are added in a soft gelatin capsule
formulation to ensure adequate flexibility. They interact
with gelatin chains to reduce the glass transition
temperature (Tg) of the gelatin shell and/or promotes the
retention of moisture (hygroscopicity). The most
common plasticizer used for soft gelatin capsules is
glycerol. Sorbitol, mannitol, and polypropylene glycol
can also be used in combination with glycerol.
c. Water
Water usually accounts for 30-40% of the wet gel
formulation and its presence is important both during the
manufacturing process (to facilitate manufacture) and in
the finished product to ensure that the capsule is flexible.
The desirable water content of the gelatin solution used
to produce a soft gelatin capsule shell depends on the
viscosity of the specific grade of gelatin used. It usually
ranges between 0.7 and 1.3 parts of water to each part of
dry gelatin.
d. Preservatives
Preservatives are often added to prevent the growth of
bacteria and mould in the gelatin solution during storage.
Examples of commonly used as preservatives include
potassium sorbate, and methyl, ethyl, and propyl
hydroxybenzoate.
e. Colorant and/or opacifier
A colourant (soluble dyes, or insoluble pigments or
lakes) and/or opacifier (e.g., titanium dioxide) may be
added to the shell for visual appeal and/or reducing the
penetration of light for the encapsulation of a
photosensitive drug. The colour of the capsule shell is
generally chosen to be darker than that of its contents.
f. Other excipients
Other, infrequently, used excipients can include
flavouring agents and sweeteners to improve palatability.
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Acid-resistant polymers are used to impart enteric release
characteristics. They can also be used to formulate
chewable soft gelatin capsules. A chelating agent, such
as ethylene diamine tetracetic acid (EDTA), can be
added to prevent chemical degradation of oxidation
sensitive drugs catalyzed by free metals in gelatin, such
as iron.
Hard gelatin capsules
General aspect
The majority of capsule products is made of hard gelatin
capsules. Hard gelatin capsules are made of two shells:
the capsule body and a shorter cap. The cap fits tightly
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, colorless, and
essentially tasteless.[17]
Hard gelatin capsule shells are fabricated and supplied
empty to the pharmaceutical industry by shell suppliers
and are then filled in a separate operation. During the
capsule filling unit operation, the body is filled with the
drug substances and the shell is closed by bringing the
body and the cap together.[18]
Two-piece capsules have been used for almost a century
in the pharmaceutical field, and the gelatin has been
adopted as the main material of these capsules due to its
excellent characteristic as a gelatinizer. However, gelatin
is one of the proteins derived from animals; therefore, it
is unstable from a chemical viewpoint and has a risk of
transmissible spongiform encephalopathy (TSE).
Basic component of hard gelatin capsules[19,20]
a. Gelatin
Gelatin is by far the most common and most well-known
material used to produce hard capsule shells. It is a
generic term for a mixture of purified protein fractions
obtained from irreversible hydrolytic extraction of
collagen obtained from the skin, white connective tissue,
and bones of animals.
b. Plasticizer
Plasticizers are added to gelatin to reduce the rigidity of
the polymer and make it more pliable. Common
examples of plasticizers are glycerine and polyhydric
alcohol. Water is also a good plasticizer and is naturally
present in the gelatin.
c. Colourants
Most frequently, hard gelatin capsules are coloured to
enhance the aesthetic properties and also to act as a
means of identifying the product. Colorants used must
meet the regulatory requirements of those countries
where the product will be sold. Examples of commonly
used capsule colourants include synthetic dyes such as
azo dyes and xanthene dyes. Iron oxide pigments are also
used.
d. Opacifying agents
Opacifiers (e.g., titanium dioxide) may be included to
make clear gelatin opaque. Opaquse capsules may be
employed to provide protection against light or to
conceal the contents.
e. Preservatives
Preservatives (often parabens esters) were formerly
added to hard capsules as an in-process aid in order to
prevent microbiological contamination during
manufacture. Manufacturers operating their plants to
Good Manufacturing Practice (GMP) guidelines no
longer use them. In the finished capsules, the moisture
levels, 1216% w/ v, are such that the water activity will
not support bacterial growth because the moisture is too
strongly bound to the gelatin molecule.
Special types of hard gelatin and soft gelatin capsules
Altered Release
The rate of release of capsule contents can be varied
according to the nature of the drug and the capsule
excipients. If the drug is water-soluble and a fast release
is desired, the excipients should be hydrophilic and
neutral. If a slow release of water-soluble drug is desired,
hydrophobic excipients will reduce the rate of drug
dissolution. If the drug is insoluble in water, hydrophilic
excipients will provide a faster release; hydrophobic and
neutral excipients will slow its release. A very rapid
release of the capsule contents can be obtained by
piercing holes in the capsule to allow faster penetration
by fluids in the gastrointestinal tract, or by adding a
small quantity of sodium bicarbonate and citric acid to
assist in opening the capsule by the evolution of carbon
dioxide.[21]
Coating capsules
Coatings have been applied extemporaneously to
enhance appearance and conceal taste, as well as to
prevent release of the medication in the stomach (enteric
coated products). Most coatings of capsules require
considerable formulation skill and quality control
equipment found in manufacturing facilities. The
capsules can be coated to delay the release of the active
drug until it reaches a selected portion of the
gastrointestinal tract.[22]
Sustained release capsules
The traditional method of taking a dose three or four
times a day leads to periods of excess and deficiency in
blood concentration of the medicament. One way of
correcting this and, at the same time, reducing the
number of doses per day, is to administer a capsule
containing numerous coated pellets that release the drug
successively over a long period.
The finely powdered drug is first converted into pellets,
usually by attaching it to sugar granules with an
adhesive. The pellets are then treated with protective
coatings that delay release of the drug, each batch
receiving a different thickness. The batches are mixed
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thoroughly and suitable doses are filled into capsules.
For example, a mixture might contain 30 percent of
uncoated pellets, for immediate release of drug, 30
percent each of coated pellets that release at 4 hours and
8 hours, and 10 percent of neutral pellets, used solely to
fill the capsule. Each batch may be colored differently to
simplify identification and facilitate control of mixing.[22]
Liquid filled hard gelatin capsules
It is generally accepted that many of today‟s NCE‟s
(New Chemical Entities) are poorly water soluble and
the classical methods, such as reduction in particle size
are no longer adequate to achieve satisfactory drug
adsorption from a solid oral dosage form. One of the
most promising strategies to deliver these insoluble
compounds is using dissolved systems like using lipids,
liquids or semi-solids to formulate new products. Two-
piece hard-shell capsules are one of the most logical
approaches when choosing the best dosage form to
deliver these new liquid formulations.[22]
Non-Gelatin Capsules
Traditionally, gelatin has been used almost exclusively
as shell-forming material of capsules. In the recent
advancements, non-gelatin capsules have been
discovered, which do not contain gelatin as it‟s shell-
forming agent. Under this category of capsules are the
HPMC, PVA and starch capsules.
HPMC Capsules
The commercial and neutraceutical markets have driven
the development of alternative forming materials for
traditional capsule shell material gelatin according to
need. Formulator requires a non-cross-linking capsule
that is well characterized, compatible with current
excipients and assays, and has a gelatin-like dissolution.
Marketing prefers a capsule that meets the dietary and
cultural needs of patients. Manufacturing needs a capsule
with gelatin-like performance that can run on existing
filling equipment. Regulatory wants a capsule polymer
that has a proven safety record and wide regulatory
acceptance. Clinicians need to be certain that patient
compliance is assured.[25]
PVA Capsules
International Patent Application WO 9 755 3723
describes the preferable use of polyvinyl alcohol (PVA)
and optional use of some other materials, all being film-
forming polymers that lack the gelling properties that are
necessary for soft capsule production using the
conventional rotary die process. The invention therefore
provides the use of preformed rolls of nearly water-free
plasticized films that may be fed to a rotary die
encapsulation unit for soft capsule production. To render
the film material more flexible and to assist the seam
formation at temperatures depending on the film
composition, the films are partially spray solvated prior
to encapsulation. PVA films according to this invention
may be composed of 7075% w/w PVA, 1015% w/w
glycerol and 510% w/w starch, with a sealing
temperature of 140180°C, depending on the degree of
solvation. PVA as an optional gelatin substitute has the
advantage of being less hygroscopic, thus leading to soft
capsule shells that are less sensitive to moisture than soft
gelatin capsule shell.[26]
Starch Capsules
It can be formulated with conventional plasticizers such
as glycerol, sorbitol, etc. (1060% w/w of dry shell) and
water to form a molten mass that can be extruded to set
within less than 20 secs producing mechanically strong,
elastic films on temperature-controlled casting
drums. Sealing may be performed at temperatures
between 25 and 80°C, by a fusion process comparable to
the one observed with soft gelatin capsules. After drying,
mechanically strong and highly elastic products can be
achieved.[27]
Prototype capsules with lipophilic fill formulations are
shiny with high appearance stability on storage. The
capsule shells do not show crosslinking and exhibit a
greater mechanical stability than soft gelatin shells when
exposed to elevated humidity and temperature, i.e. even
under hot and humid storage conditions they may not
become sticky. Formulation approaches with hydrophilic
fills are expected to be as challenging as for soft gelatin
capsules. Oxygen permeability is comparable to gelatin-
based shells. The dissolution mechanism is completely
different to the one of a soft gelatin capsule. On contact
with an enzyme-free aqueous medium at 37°C, the
capsule shell only swells, at a rate and to an extent
depending on the type and concentration of electrolytes
present. The capsule content may be released when the
shell bursts at its point of lowest resistance, i.e. at the
seams. Under in vivo conditions, capsule shell
dissolution may be induced by enzymatic degradation.
International Patent Application WO 0 137 81730
describes the formation of soft capsules from a potato
starch (4580% w/w), with a specific molecular weight
distribution and amylopectin content, together with a
conventional plasticizer such as glycerol (12% w/w), a
glidant and a disintegrant.[28]
Capsule formulation
Hard gelatin capsule formulation
It is estimated that the utilization of hard gelatin capsules
to prepare solid dosage forms exceeds that of soft gelatin
capsules by about 10-fold. Hard gelatin capsules are
fabricated and supplied empty to the pharmaceutical
industry by shell suppliers and are then filled in a
separate operation. Manufacturing gelatin capsules
involves a step by step process that requires strict quality
control.
Manufacture of Hard Gelatin Capsules[10]
Hard gelatin capsules are manufactured using a dip-
coating method and the various stages involved are as
follows:
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Step 1: Preparation of the gelatin solution (dipping
solution)
A concentrated solution of gelatin is prepared by
dissolving the gelatin in demineralized water which has
been heated to 6070°C in jacketed pressure vessels.
This solution contains 30 40% w/w of gelatin and is
highly viscous, which causes bubbles as a result of air
entrapment. The presence of these bubbles in the final
solution would yield capsules of inconsistent weight and
would also become problematic during capsule filling
and upon storage. To remove the air bubbles, a vacuum
is applied to the solution; the duration of this process
varies with batch size.
Following the above steps, colourants and pigments are
added to attain the desired final capsule appearance. At
this stage, other processing aids may be added, such as
sodium lauryl sulfate, to reduce surface tension. The
solution viscosity is measured and adjusted as needed
with hot demineralized water to achieve the target
specification.
Step 2: Dip-coating the gelatin solution on to metal
pins (moulds)
Capsule shells are manufactured under strict climatic
conditions by dipping pairs (body and cap) of
standardized steel pins arranged in rows on metal bars
into an aqueous gelatin solution (25 30% w/w)
maintained at about 50 ° C in a jacketed heating pan.
Because the moulds are below the gelling temperature,
the gelatin begins to form a thin gelatin layer or film on
the moulds.
The rows of pins are arranged so that caps are formed on
one side of the machine while bodies are simultaneously
formed on the opposite side of the machine.
Step 3: Rotation of the dip-coated pins
Following adsorption of the gelatin solution on to the
surface of the pins, the bar containing the pins is
removed and rotated several times to evenly distribute
the solution around the pins, correct gelatin distribution
being critical to uniform and precise capsule wall
thickness and dome strength.
Step 4: Drying of the gelatin-coated pins
Once the gelatin is evenly distributed on the mould, a
blast of cool air is used to set the gelatin on the mould.
At this point, the gelatin is dried, and the pins are then
passed through several drying stages to achieve the target
moisture content.
Step 5: Stripping and trimming
After the gelatin is dried, the capsule is stripped off the
mould and trimmed to the proper length.
Step 6: Joining of the trimmed capsule shell
Once trimmed, the two halves (the cap and body) are
joined to the pre-closed position using a pre lock
mechanism. At this point, printing is done if needed
before packing in cartons for shipping.
Step 7: Printing
After formation, the capsule shells can be printed to
improve identification. Printing can be achieved using
one or two colours, containing information such as
product name or code number, manufacturer‟s name or
logo and dosage details.
Printing reduces the risk of product confusion by the
numerous handlers and users of the product including
manufacturers, pharmacists, nurses, doctors, caregivers,
and patients.
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The sequence of two-piece hard gelatin capsule shell
manufacture.
Filling of hard gelatin capsules
The filling of hard gelatin capsules is an established
technology, with equipment available ranging from that
for very small-scale manual filling (e.g., Feton capsule
filling machine), through intermediate-scale semi-
automatic filling to large-scale fully automatic filling.
Hard gelatin capsules can also be hand-filled one at a
time, as done in a compounding pharmacy. The
difference between the many methods available is the
way in which the dose of material is measured into the
capsule body.[24]
The basic steps in filling hard gelatin capsules
include[23]
Rectification of capsules (placing empty gelatin
capsules on the removable plate with bodies facing
downward).
Separation of caps from bodies.
Dosing of fill material (The body is filled with the
formulation manually using a plastic spatula, and the
excess powder is removed).
Replacement of caps/ closing capsule shells and
Ejection of filled capsules
Filling of liquids/semisolid formulations into hard
gelatin capsules
As drug discovery continues to yield poorly water-
soluble molecules, there is an increasing need for
formulation techniques that can improve drug solubility.
One such approach is the use of liquid-based
formulations containing lipids, solvents, or surfactants,
usually in combination, to improve drug solubility and
bioavailability. The final formulation may be filled
through piston pump systems into hard gelatin capsules
as a room temperature liquid, or as a molten semisolid.
The filling of a liquid or semi-solid formulation is
dependent on the viscoelastic properties of the
formulation and the need to fulfil certain characteristics
at the filling temperature. As a general rule, the
formulation should have a viscosity of between 50 and
1000 Centipoise (cP) (although formulations of much
higher viscosity can be suitable for manufacturing) and
should not exceed 70 °C.[16]
Liquid Excipients Compatible with Hard Gelatin Capsule Shells[13]
Lipophilic
excipients
Vegetable oils e.g., Peanut oil, Castor oil, Olive oil, Fractionated coconut oil, Corn oil, Sesame
oil, Hydrogenated vegetable oil, Soybean oil
Esters e.g., Glycerol Stearate, Glycol Stearate, Isopropyl myristate, Ethyl oleate
Fatty Acids e.g., Stearic acid, Laurie acid, Palmitic acid, Oleic acid, Oleic acid
Fatty Alcohols e.g., Cetyl alcohol, Stearyl alcohol
Hydrophilic
excipients
PEG 30006000 MW
Amphiphilic
excipients
Poloxamers, Lecithin, PEG esters (e.g., Gelucir 44/14; 50/13; Labrafil)
Abbreviations: PEG, polyethylene glycol; MW, molecular weight.
Locking and sealing of hard gelatin capsules[14]
For the capsules filled by manual or hand filling
machines, locking and sealing is done to prevent the
detachment of caps from the bodies during packaging,
carrying or storing. Locking and sealing also prevents the
exudation of the capsule contents. Different
manufacturers adopt different methods for locking and
sealing the capsules.
Banding method
Moistening method
Spot welding method
Thermal welding method
By using coni-snap capsules
Soft gelatin capsule formulation
Soft gelatin capsules have gained popularity in the
pharmaceutical industry for human and veterinary use
due to the many advantages it possesses over other
commonly used solid dosage forms such as tablets, hard
gelatin capsules etc. The bioavailability of hydrophobic
drugs can be significantly increased when formulated
into soft gelatin capsules.[9]
Many problems associated with tableting, including poor
compaction and lack of content or weight uniformity, can
be eliminated when a drug is incorporated into a soft
gelatin capsule. Also, improved stability of drugs that are
highly susceptible to oxidation can be achieved with soft
gelatin capsule.[5]
Vehicles used in soft gelatin capsules[35]
Soft gelatin capsules are prepared to contain a variety of
liquid, paste, and dry fills. Liquids that may be
encapsulated into soft gelatin capsules include the
following:
Water-immiscible volatile and non-volatile liquids
such as vegetable and aromatic oils, aromatic and
aliphatic hydrocarbons, chlorinated hydrocarbons,
ethers, esters, alcohols, and organic acids.
Water-miscible non-volatile liquids, such as
polyethylene glycols, and nonionic surface-active
agents, such as polysorbate 80.
Water-miscible and relatively non-volatile
compounds such as propylene glycol and isopropyl
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alcohol, depending on factors such as concentration
used and packaging conditions.
Manufacture of Soft Gelatin Capsules[6]
Softgels are manufactured using the following methods
Plate process
This is the oldest commercial process used in the
manufacture of soft gelatin capsules. In this process, a
warmed sheet of plain or coloured plasticized gelatin is
placed over a die plate having a number of depression or
moulds or numerous die pockets. By applying vacuum,
the sheet is drawn into these depressions or pockets to
form capsule wells. The capsule wells are then filled
with medication-containing liquid. A second sheet of
gelatin is carefully placed on top of the filled wells
followed by the top plate of the mould. Pressure is then
applied to the combined plate to form, seal and cut the
capsules into individual units. This method is used for
small scale preparation of soft gelatin capsules and
capsules formed generally, had one flat side.
The major problems with this method of manufacturing
softgels were the lack of dosage uniformity, high
manufacturing losses, and its labour-/cost-intensiveness.
This equipment is no longer available.
Rotary Die Process
Most soft gelatin capsules are prepared by the rotary die
process, a method developed and perfected in 1933 by
Robert P. Scherer. This process almost eliminated all the
problems associated with the plate process and produced
soft gelatin capsules with improved uniformity and high
standards of accuracy.
In this process, two plasticized gelatin ribbons (prepared
in the rotary-die machine) are continuously and
simultaneously fed with the liquid, semiliquid or paste
fill between the rollers of the rotary die mechanism. The
forced injection of the feed material between the two
ribbons causes the gelatin to swell into the left- and
right-hand die pockets which govern the size and shape
of the softgels as they converge. As the die rolls rotate,
the convergence of the matching dies pockets
hermetically seals and cuts out the filled capsule.
Schematic drawing of a rotary-die soft gelatin capsule
filler.
Reciprocating Die Process (Norton Capsule Machine)
This continuous soft gelatin capsule processing
technology was developed by Norton Company in 1949.
This process is similar to rotary process in that ribbons of
gelatin are formed and used to encapsulate the fill, but it
differs in the actual encapsulating process. The gelatin
ribbons are fed between a set of vertical dies that
continually open and close to form rows of pockets in the
gelatin ribbons. These pockets are filled with the
medication and are sealed, shaped, and cut out of the
film as they progress through the machinery. As the
capsules are cut from the ribbons, they fall into a cooled
solvent bath that prevents the capsules from adhering to
one another.
Accogel Process
Although the rotary die process and reciprocating die
process were capable of producing soft gelatin capsules
containing oily liquids and pastes, Lederle Laboratories
in 1949 developed accogel process, a continuous process
that produces soft gelatin capsules containing powders
and granules.
The process involves a measuring roll that holds the fill
formulation in its cavities under the vacuum and rotates
directly above the elasticized sheet of the gelatin ribbon.
The ribbon is drawn into the capsule cavities of the
capsule die roll by vacuum. The measuring rolls empty
the fill material into the capsule-shaped gelatin cavities
on the die roll. The die roll then converges with the
rotating sealing roll covered with another sheet of
elasticized gelatin. The convergence of two rotary rolls
creates pressure to seal and cut the formed capsules.
Seamless process (Bubble Method)
The seamless technique produces one-piece soft gelatin
capsules without the use of dies. The process is often
referred to as a bubble method that creates seamless,
spherical soft gelatin capsules called pearl.
In this process, a molten gelatin stream flows though the
outer nozzle of a concentric tube at a constant rate, and
the medicated liquid formulation is dispensed through
the inner orifice by means of a precision metering pump.
The emerging stream is broken up into an intermittent
but steady flow of uniform-sized by a pulsating
mechanism, leading to the formation of droplets
enveloped in molten gelatin. The formed capsules are
quickly removed from the nozzle, slowly congealed, and
automatically ejected from the system.
Quality control tests for capsules
In capsule formulation development and during filling of
capsules, a number of quality control tests are performed
to ensure that capsules produced meet the requirements
as specified in official compendium and conventional
requirements established by the industries over the years.
These tests will be discussed in three stages: in-process
testing, finished product testing and shelf-life testing.[8]
In-process quality control tests for capsule drug
products[10]
In-process quality control tests for capsule drug products
are carried out at predefined intervals during the product
manufacturing, by the manufacturing personnel, and
their results recorded on the batch record. Adverse
findings in these tests can be used as a guide to altering
the manufacturing-process parameters.
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During the encapsulation of soft gelatin capsules, the
following parameters are usually closely monitored and
controlled:
Gel ribbon thickness and uniformity across the
ribbon
Softgels seal thickness at the time of encapsulation
Weight of the capsule fill and its variation from
capsule-to-capsule
Weight of the capsule shell and its variation from
capsule-to-capsule
Moisture level of the capsule shell before and after
drying
Visual inspection, fill weight, and fill-weight
uniformity are the key in-process tests used for hard
gelatin capsules.
Finished product quality control tests for capsule
drug products[12]
Finished capsules are subjected to a number of tests in
accordance with compendial standards and regulatory
requirements for unit dose capsule products. These
batteries of tests help identify whether the batch is
acceptable for marketing or its intended usage, the
finished capsules are evaluated by the following tests:
Permeability and sealing
Soft gelatin capsules are tested for physical integrity
(absence of leakage) by visual inspection. Similarly, hard
gelatin capsules are tested for any breach of physical
integrity (breakage or opened cap and body).
Potency and impurity content
All capsules are tested for drug content (potency, as a per
cent of label claim). In addition, most drug products are
tested for related substances or impurities. These must
meet predefined specifications for a batch to be
acceptable.
Weight variation test
The uniformity of dosage units may be demonstrated by
determining weight variation or content uniformity. The
weight variation method is as follows.
Weight variation test for hard gelatin capsules
Ten hard gelatin capsules are usually weighed
individually and the contents are removed. The emptied
shells are individually weighed and the net weight of the
contents is calculated by subtracting the weight of the
shell from the respective gross weight. The content of
active ingredient in each capsule may be determined by
calculation based on the per cent drug content in the
formulation.
Weight variation test for soft gelatin capsules
For soft gelatin capsules, the gross weight of 10 gelatin
capsules is determined individually. Then each capsule is
cut open with a suitable clean, dry cutting instrument
(e.g., scissors or a sharp open blade), and the contents are
removed by washing with a suitable solvent (that
dissolves the fill but not the shell). The solvent is
allowed to evaporate at room temperature over a period
of about 30 minutes, followed by weighing of the
individual washed shells. The net contents are calculated
by subtraction and the content of active ingredient in
each of the capsules can be determined by calculation
based on the per cent drug content in the formulation.
Fill-weight variation of capsules is often a function of
equipment setup and filling operation. An automated
capsule sizing machine and/or weight checker is
frequently used to discard over- or underfilled capsules.
Uniformity of content
This test is performed only when the content is specified
in the individual monographs and when capsules fail
weight variation test. If the weight of capsules is
completely filled no need of this test.
Unless otherwise stated in the monograph for an
individual capsule, the amount of drug substance,
determined by assay, is within the range of 85.0% to
115.0% of the label claim for nine (9) of ten (10) dosage
units assayed, with no unit outside the range of 75.0% to
125.0% of the labelled drug content. Additional tests are
prescribed when two or three dosage units are outside of
the desired range but within the stated extremes.
Disintegration time test for capsules
Disintegration of hard and soft gelatin capsules is
evaluated to ensure that the drug substance is fully
available for dissolution and absorption from the
gastrointestinal tract. The compendial disintegration test
for hard and soft gelatin capsules follows the same
procedure and uses the same apparatus described in the
article “Quality Control Tests for Tablets”.
The capsules are placed in the basket-rack assembly,
which is repeatedly lowered 30 times per minute into a
thermostatically controlled bath of fluid at 37 ± 2 ˚C and
observed over the time described in the individual
monograph.
Dissolution test for capsules
Drug absorption and physiological availability depend on
the drug substance being in the dissolved state at the site
of drug absorption. The rate and extent of dissolution of
the drug from the capsule dosage form is tested by a
dissolution test. This test provides means of quality
control in ensuring that, different batches of the drug
product have similar drug release characteristics and
also, a given batch has similar dissolution as the batch of
capsules that was shown initially to be clinically
effective.
Moisture content
Water content of the entire capsule or the capsule
contents are determined by Karl Fisher titrimetry to
enable the correlation of water content with the
degradation profile or drug-release characteristics of
capsules.
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Moisture permeation test
The USP requires determination of the moisture-
permeation characteristics of single-unit and unit dose
containers to assure their suitability for packaging
capsules. The degree and rate of moisture penetration is
determined by packaging the dosage unit together with a
colour-revealing desiccant pellet, exposing the packaged
unit to known relative humidity over a specified time,
observing the desiccant pellet for colour change
(indicating absorption of moisture) and comparing the
pre-test and post-test weight of the packaged unit.
Microbial content
The capsules are tested to ensure lack of growth of
bacteria and mould by microbiological tests. These tests
are usually carried out by incubation of the capsule
contents in a growth medium and counting the colonies
formed after a predefined period of time. Selection of the
growth medium and duration of the test, as well as
maintenance of aseptic conditions during the testing, are
critical to successful assessment of microbial
contamination by this method.
Shelf-life test[14]
These tests are frequently carried out after defined
periods of storage at predetermined conditions. They
help to assign and verify the shelf life and usability of the
drug product.
Stability testing of capsules
Stability testing of capsules is performed to determine
the physicochemical stability of the drug substance in the
finished drug product under specified package and
recommended storage conditions intrinsic stability of the
active drug molecule and the influence of environmental
factors (e.g., temperature, humidity, light), on
formulation components, and the container and closure
system. The battery of stress-testing, long-term stability
and accelerated stability tests help determine the
appropriate storage conditions and the product‟s
anticipated shelf life.
Packaging and storage of capsules
Packaging and storage of hard gelatin capsules[15]
Finished hard gelatin capsules normally contain an
equilibrium moisture content of 13 to 16%. This
moisture is critical to the physical properties of the shells
since at lower moisture contents (<12%), shells become
too brittle and may crack when exposed to the
appropriate stress. At higher moisture contents (>18%)
they become too soft and may lose shape. It is therefore
important to avoid extremes of temperature and to
maintain a relative humidity of 40 to 60% when handling
and storing capsules.
The bulk of the moisture in capsule shells is physically
bound, and it can readily transfer between the shell and
its contents, depending on their relative hygroscopicity.
The removal of moisture from the shell could be
sufficient to cause splitting or cracking, as has been
reported for the deliquescent materials potassium acetate
and sodium cromoglycate. Conditions that favour the
transfer of moisture to powder contents may lead to
caking and retarded disintegration or other stability
problems. It may be useful to first equilibrate the shell
and its contents to the same relative humidity within the
acceptable range before filling.
Another problem that has received substantial attention
in recent years is the loss of water solubility of shells,
apparently because of sufficient exposure to high
humidity and temperature or to exposure to trace
aldehydes. Such capsules develop a “skin” or pellicle,
during dissolution testing, exhibit retarded dissolution,
and may fail to meet the USP drug dissolution
specifications. This decrease in solubility of gelatin
capsules is presumed to be the result of gelatin cross-
linking caused by impurities such as formaldehyde.
Hard gelatin capsules can be individually protected by
enclosure in strip or blister packs. In the former, the units
are hermetically sealed in strips of aluminium foil or
plastic film. In the latter one of the films enclosing the
units is formed into blisters. An ideal foil or film for
these packs should be:
Heat stable
Impermeable to moisture, water vapour, air, and
odours
Strong enough for machine handling
Reasonably easy for patients to tear and open
Packaging and storage of soft gelatin capsules[14]
Soft gelatin capsules generally contain the medicament
dissolved or dispersed in oils or hydrophilic liquids (i.e.,
fill liquid). The inherent flexibility of the soft gelatin
capsule is due to the presence of plasticizers and residual
moisture in the capsule shell. Thus, the soft gelatin
capsule is a more dynamic system than conventional
tablets. The atmospheric moisture may permeate into the
capsule shell or into the fill liquid. The drug or fill liquid
may migrate into the capsule shell, while the plasticizer
or residual water in the gelatin shell can potentially
migrate into the fill. Volatile components in soft gelatin
capsules may escape into the atmosphere. It is these
characteristics that must be considered when designing a
shelf life stability program for soft gelatin capsules.
In most instances, the recommended storage conditions
are stated on the label in which case it is imperative to
maintain stability. Normally, the recommended storage
conditions for empty capsule shells are 15 to 25°C and a
relative humidity of between 35% and 65%. This
condition is designed to minimize moisture absorption or
loss, and the resultant changes in physical dimensions,
during the encapsulation operation. While there is no
strict guidance for stability testing of soft gelatin
capsules, there are a couple of guidelines available that
will help evaluate the storage conditions and length of
study required for specific formulations of soft gelatin
capsules.
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The guidelines indicate that testing of soft gelatin
capsules should be evaluated in terms of appearance
(including brittleness), color, and odor of content, assay,
degradation products, dissolution, microbial content, pH,
leakage, and pellicle formation. Also, fill medium should
be examined for precipitation and cloudiness. In general,
a drug product should be evaluated under storage
conditions (with appropriate tolerances) that test the
thermal stability, and if applicable, its sensitivity to
moisture or potential for solvent loss. If it is determined
that a particular product is heat sensitive, then these drug
products should be stored under an alternative lower
temperature condition which will eventually become the
designated long-term storage temperature. For example,
a 30°C storage condition versus a 40°C condition may be
justified.
Future perspective
In recent years, the interest in using hard gelatin capsules
in developing and manufacturing medicines has
increased considerably. This is most probably due to
rapid advances in capsule dosage form. The choice
available in terms of capsule type, the range of sizes, the
capsule's attractive appearance and printing directly onto
the capsule, ensure better patient compliance, product
recognition and product differentiation. The demand for
plant-based capsules will grow as customers look for
performance, quality and lifestyle fit. The unique
features of non-animal capsules offer distinct advantages
in manufacturing ease, marketing, global certification,
dissolution profiles, delivery of specific ingredients and
more. For multiple-units, hard and soft gelatin capsules
are the ideal solution. The latest developments in the
field of formulation in hard gelatin capsules (HGC) offer
new opportunities for filling liquid and semi-solid
formulations in them, as a rapid and easy sealing
technology is now available and the capital outlay is
reasonable. Formulation in liquid dosage form
incorporated in HGC enhances the bioavailability of
several slightly soluble drug actives. Also controlled
release characteristics can be developed using semisolid
formulation. The combination of liquid-filled
formulations with coatings that will reliably deliver the
capsule contents to the colon (for example, Encap‟s
ENCODE colonic coating technology) where there is
minimal water for dissolution of conventional powder
filled capsules or tablets could be a major advance for
the delivery of many drugs including proteins and
peptides a growing area of interest to the
pharmaceutical industry. With appropriate process
controls, careful machine set-up and trained operators,
leak-free liquid filled HGC products can be
manufactured. It is likely that there will be further
developments in the area of sealing technology. Mapping
of drugs is particularly valuable for modified release
development and for compounds in which local enteric
delivery is central to the product target profile. The
electronic and magnetic capsule drug delivery enables
the conventional capsule for novel therapies, diagnosis,
localized drug delivery, modified release and the next
move for monitoring drug absorption in developmental
stage (i.e. clinical evaluation).
Soft gelatin capsules are available in many sizes to
provide dosing flexibility. Unpleasant drug tastes and
odors can be masked by the tasteless gelatin shell. They
are suitable for encapsulation of lipid solutions, fish oil,
suspensions, or paste-like formulations, making them a
useful option when formulating poorly water-soluble
drugs. This will inherently lead to better absorption of
the active ingredient as compared with delivery in a
tablet or as a powder. Development of soft gelatin
capsule (soft gel) dosage form is of growing interest for
the oral delivery of poorly water soluble compounds
(BCS class II or class IV). There are establishments and
an on-going development of the manufacturing
technology for liquid fill capsules with focus on progress
and challenges of soft gelatin capsules formulation in
oral administration for improved solubility and as an
absorption-enhancing technique. These considerations
form a basis for new applications in oral drug delivery.
Capsule manufacturers will continue to improve the
materials, processes, and related technologies to this
versatile dosage form.
CONCLUSION
From the above premises, capsules are solid preparations
in which drug substance(s) and/or excipients are
enclosed in either a soft or hard soluble shell. The shell
is normally made from gelatin or other suitable
polymeric material and results in a simple, tasteless,
odourless, elegant, easy-to-swallow dosage form without
the need for a secondary coating step.
Depending on the composition of the capsule shell,
capsules may be classified as either hard or soft capsule,
with soft capsules possessing a flexible, plasticized
gelatin film. The shells may be composed of two pieces
in the form of cylinders closed at one end; the shorter
piece, called the „cap‟ and the longer piece, called the
„body‟, or they may be composed of a single piece. The
two-piece capsules and one-piece capsules are
commonly referred to as hard-shell capsules and soft-
shell capsules respectively.
Capsules may be filled with a range of formulation types
including dry powders, semisolids, nonaqueous liquids,
and other dosage forms such as beads, mini-tablets, and
even mini capsules most of which are intended for oral
administration. There are also specialty applications such
as capsules that can be loaded into dry-powdered
inhalers, add reagents as part of a diagnostic kit, and
occasionally soft-shell capsules intended for rectal or
vaginal insertion as suppositories.
Also, In the recent advancements, non-gelatin capsules
have been discovered, which do not contain gelatin as
it‟s shell-forming agent. Under this category of capsules
are the HPMC, PVA and starch capsules.
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Regardless of the type of capsule, the basic components
of these capsules include but not limited to; gelatin,
plasticizer, colourants, opacifying agents, preservatives,
water, thickening agents, flavouring agents, sweetening
agents, etc.
Hard gelatin capsules are manufactured using a dip-
coating method which involves the preparation of the
gelatin solution (dipping solution), dip-coating the
gelatin solution on to metal pins (moulds), rotation of the
dip-coated pins, drying of the gelatin-coated pins,
stripping and trimming, joining of the trimmed capsule
shell and printing. Also, the basic steps in filling hard
gelatin capsules include; rectification of capsules,
separation of caps from bodies, dosing of fill material
replacement of caps/ closing capsule shells and, ejection
of filled capsules, which is then followed by locking and
sealing, polishing and brushing among others. On the
other hand, softgels are manufactured using the
following methods; plate process, rotary die process,
reciprocating die process, accogel process and, seamless
process. The soft gelatin manufacturing and filling
occurs simultaneously.
The quality control process s involves the in-process
testing, finished product testing and shelf-life testing.
The in-process quality control tests for soft gelatin
capsule drug products are carried out at predefined
intervals during the product manufacturing which
involves; gel ribbon thickness and uniformity across the
ribbon, softgels seal thickness at the time of
encapsulation, weight of the capsule fill and its variation
from capsule-to-capsule, weight of the capsule shell and
its variation from capsule-to-capsule and, moisture level
of the capsule shell before and after drying. Visual
inspection, fill weight, and fill-weight uniformity are the
key in-process tests used for hard gelatin capsules. Also,
the finished product quality control tests for capsule drug
products include; permeability and sealing, potency and
impurity content, weight variation test, weight variation
test for hard gelatin capsules, weight variation test for
soft gelatin capsules, uniformity of content,
disintegration time test for capsules, dissolution test for
capsules, moisture content, moisture permeation test and,
microbial content. While the shelf-life test involves the
stability testing of capsules.
The main aim of packaging of filled capsules is to
prevent contamination and moisture gain or loss during
long term storage. They are plastic blister packed or
aluminium foil strip packed or packaged in glass or other
materials which are designed in such a way that they
prevent exposure of capsules to excessive humidity. On
the other hand, the storage which can be for a very long
time period requires proper maintenance of temperature
and humidity.
Recommendation
It is recommended that going by available research
articles, research should be focused on non-gelatinous
capsules, improvement of gelatinous capsules, and, also
presentation of capsule shells that will suit various
norms, cultures and, religions of various societies to
mention but few.
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... The prepared physical mixtures and solid dispersions were evaluated for percentage yield, drug content, solubility studies, Differential scanning calorimetry (DSC), X-ray diffraction (XRD), and in vitro drug release and dissolution efficiency [11]. ...
Article
Full-text available
Objective: Preparation of Rosuvastatin Calcium by Using Hydrophilic Polymers and Solid Dispersion Method, Rosuvastatin calcium is a Dyslipidaemic agent, which act as a selective competitive inhibitor of HMG CoA educates enzyme and is used in the treatment of hyperlipidemia. Methods: In the present work, Solid Dispersion was prepared by kneading method to increase the solubility of Rosuvastatin Calcium. Results: Solid dispersions were evaluated by determining percentage yield, drug content, solubility, Scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), DSC and in vitro dissolution profile. The prepared solid dispersion are formulated into capsule dosage form and characterized by various parameters i.e. weight variation, content uniformity, disintegration and dissolution. The evaluated parameters of capsule dosage form increase in solubility and dissolution rate of the pure drug. Conclusion: These are various techniques to enhance the solubility of the drug, such as particle size reduction, use of surfactants, solid dispersion etc. Carriers are the major players in these formulations, e. g. Hydroxypropylmethylcellulose, ethylcellulose, Carbopol, Acacia Gum etc. Carbopol and Acacia Gum is one of the most efficient polymers work as a carrier for these drugs to enhance solubility.
Book
This handbook features contributions from a team of expert authors representing the many disciplines within science, engineering, and technology that are involved in pharmaceutical manufacturing. They provide the information and tools you need to design, implement, operate, and troubleshoot a pharmaceutical manufacturing system. The editor, with more than thirty years' experience working with pharmaceutical and biotechnology companies, carefully reviewed all the chapters to ensure that each one is thorough, accurate, and clear.
Article
A new technique is reported for the study of migration of solutes from solution in oil to the glycerogelatin walls of soft capsules. The oily solution is applied to the top of a glycerogelatin column contained in a truncated disposable plastic syringe. The column is then extruded from the syringe, cut into slices, each slice analysed and diffusion coefficients calculated. The technique was validated by using bases of differing viscosity, and was used to study the effect of phenolic compounds and polysorbate on the permeability of glycerogelatin bases.
Article
The in vitro dissolution and the bioavailability of two pharmaceutical formulations of digoxin were compared, one being a common commercial tablet form and the other a solution of the glycoside in soft gelatin capsules. Digoxin capsules dissolved more readily in vitro and showed higher bioavailability than digoxin tablets in both dogs and humans. In dogs, the capsules and tablets were compared with an elixir of digoxin, which possesses complete bioavailability. The better bioavailability of digoxin capsules as compared with tablets may be explained by the fact that this formulation contains the cardiac glycoside in a solution.
Article
Analysis of the shells and contents of soft gelatin capsules containing acetomenaphthone, ephedrine, 4-hydroxyenzoic acid or phenobarbitone, dissolved in isopropyl myristate, revealed that the percentage of solute taken up by the shells increased with increasing aqueous solubility of the substrate. Thus no acetomenaphthone, which has a negligible aqueous solubility, was found in the shells, in comparison with 92% of the 4-hydroxybenzoic acid, which has a significant solubility in water. Uptake was not influenced by the solubility in isopropyl myristate. The effect of the oily solvent was studied using blends of 1-octanol and isopropyl myristate in which either 4-hydroxybenzoic acid or phenobarbitone were dissolved. Solute release shows that both release and migration can be predicted from a knowledge of the aqueous solubility of the solute and its partition coefficient between water and the non-polar solvent. Samples of capsules containing 4-hydroxybenzoic acid in isopropyl myristate were withdrawn at various stages of the manufacturing process, and the distributions between shell and contents noted. Most of the transfer took place while the capsules were being dried in rotating basket driers, and at this point 67% of the acid had migrated. This increased to 92% during tray drying, and remained so for at least 6 months after manufacture.
Article
Thermal analysis of soft gelatin capsule was used as a diagnostic tool to evaluate the effect of temperature and humidity stress conditions as well as formulation water, propylene glycol and ethanol on the softening of the gelatin shells. Results obtained using modulated and conventional DSC given as DeltaT(m) (change in gel-sol transition temperature) were compared with the results obtained using manual hardness tester given as % hardness loss. No difference between the two methods was observed in their ability to determine the extent of softening due to formulation water, propylene glycol and ethanol content. Thermal analysis and shifts in the reversible heat flow determined using MDSC provided additional insight into the structural changes and extent of deformation within the gelatin network upon exposure to formulation ingredients, temperature and humidity. Modulated thermal analysis is, therefore, a useful tool for screening the variables influencing the hardness of gelatin capsules.
Compliance Policy Guides -CPG Sec 430.100 Unit Dose Labeling for Solid and Liquid Oral Dosage Forms
  • Affairs
Affairs, Office of Regulatory. "Compliance Policy Guides -CPG Sec 430.100 Unit Dose Labeling for Solid and Liquid Oral Dosage Forms". www.fda.gov, 1984.