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PII: S0022-3549(17)30078-3
DOI: 10.1016/j.xphs.2017.02.006
Reference: XPHS 648
Please cite this article as: Gullapalli RP, Mazzitelli CL, Gelatin and Non-Gelatin Capsule Dosage Forms,
Journal of Pharmaceutical Sciences (2017), doi: 10.1016/j.xphs.2017.02.006.
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Corresponding author: RampurnaL@gmail.com; Phone 914-316-4935
ABSTRACT
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Capsules offer an alternate to tablets for oral delivery of therapeutic compounds. One
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advantage of capsules over tablets is their amenability to deliver not only solids but also
non-aqueous liquids and semisolids as a unit dose solid dosage form. Shell component is
an essential part of capsule dosage forms. Capsule shells, available as hard or soft shells,
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are formulated from gelatin or a non-gelatin polymeric material such as hypromellose and
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starch, water, and with or without a non-volatile plasticizer. The capsule shells may also
be formulated to modify the release of their fill contents in a site-specific manner in the
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gastrointestinal tract. The goal of the current review is to provide an in-depth discussion
on polymeric film forming materials and manufacturing technologies used in the
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Keywords
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1. INTRODUCTION
Capsule dosage forms are widely used to encapsulate powders, granules, pellets, liquids,
and semisolids (Figure 1). Capsules can be soft shell capsules (softgels), which are
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typically used to encapsulate non-aqueous liquid and semisolid formulations1 or hard
shell capsules, which are used to encapsulate both solid and non-aqueous formulations.2,3
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The soft capsule shells are commonly manufactured from gelatin or a non-gelatin
polymeric material, water, non-volatile plasticizer(s), and other minor additives such as
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opacifiers and colorants. Hard capsule shells, unlike those of soft capsules, do not contain
a non-volatile plasticizer. The shells of soft and hard capsules can also be formulated
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either to delay the release of their fill contents until the capsules pass through the stomach
region of the gastrointestinal tract (GIT) (enteric release) or to target the release at a
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specific region of the GIT (site-specific release). Alternately, the capsule shells can also
be used to contain fill materials to provide immediate release or modified release
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characteristics.
Gelatin has been used predominantly as the film former for both hard shell and soft shell
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capsules. In recent years, several non-gelatin polymers have been advanced either to
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replace gelatin partially or all together in the manufacture of capsule shells or to modify
the properties of capsule shells. In this paper, we review chemistry and properties of
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2.1.1. Gelatin
Gelatin is a purified protein obtained from collagen of animals (including fish and
poultry) by partial alkaline and/or acid hydrolysis, by enzymatic hydrolysis, or by thermal
hydrolysis (USP-NF). Gelatin is a mixture of water-soluble proteins and water (8-15%).
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The protein fraction contains almost entirely of amino acids in L-configuration with
traces in D-configuration linked by amide (peptide) bonds forming a linear polymer with
a molecular weight ranging from 15,000 to 250,000 Daltons.4,5 The gelatin polymer
chains are composed of repeating units of about twenty different amino acids with the
dicarboxylic amino acids (i.e., aspartic acid and glutamic acid) providing free carboxyl
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groups, di-amine amino acids (i.e., lysine and arginine) providing free amino groups, and
hydroxyl amino acid (i.e., hydroxyproline) providing free hydroxyl groups. These
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functional groups actively participate in several chemical reactions6, some of which will
be discussed in later sections. The frequency of occurrence of the most abundant amino
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acids are glycine (~33%), alanine (~11%), and imino acids (i.e., proline and
hydroxyproline; ~22%).7 Gelatin contains all the amino acids commonly found in
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proteins with the probable exception of tryptophan and cysteine.
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Gelatin is amphoteric in nature with its isoelectric point (i.e., pH at which the gelatin
molecule is electrically neutral) ranging from 7.0 to 9.0 for type A gelatin (i.e., acidic
treatment) and from 4.7 to 5.3 for type B gelatin (i.e., alkaline treatment), respectively.5
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reorganization of the collagen structure with minimal hydrolytic changes. By contrast, the
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collagen can undergo deguanidination to form ornithine and urea and potentially trace
amounts of citrulline and ammonia (Figure 2).8-11 The extent of ammonia evolved
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increases rapidly upon increasing concentrations of alkali, but remains low and
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practically negligible at pH values less than 5.4 (Figure 3).12 The presence of even
smaller quantities of ammonia in the gelatin capsule shell may induce degradation of
some encapsulated compounds.13 Collagens from marine sources are more susceptible to
degradation during chemical treatment due to the lower content of cross-links14, in
contrast to the more stable collagens from mammals (e.g., collagen from cattle bones,
hides, and pigskins).
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Gelatin undergoes hydrolytic degradation in aqueous media, the rate and extent of which
depend up on the pH, temperature, and time the reaction is allowed to proceed.15-18 The
degradation of gelatin was shown to be minimum between pH values 4 and 7, with the
rate accelerating on either side of this pH region. The hydrolytic degradation of gelatin
results in the reduction of the viscosity and gel-forming ability (gel strength) of a gelatin
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solution.
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2.1.1.1 Chemical Structure of Gelatin
Collagen, the parent protein of gelatin, consists of three polypeptide chains, each one
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twisted in a left-handed helix and super coiled together to form a right-handed triple
helix.19,20 In collagen, the single chains (α-chains) cross-link forming the β-chains (two
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covalently cross-linked single chains) and γ-chains (three covalently cross-linked single
chains). The triple helix of collagen is stabilized by firmly bound water molecules.
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During the denaturation process of collagen, the triple helix structure is broken down to
form a random-coil gelatin. In aqueous solutions, the gelatin chains coil around each
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other to form a collagen-like triple helix, when the solution is cooled below its coil to
helix (sol to gel) transition temperature, thereby recreating the three dimensional
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network.20-22 As the complete reversibility of gelatin transition into collagen requires the
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proper juxtaposition and recoiling of the three peptide chains and as the chances for such
a scenario are less than possible, it is assumed that gelatin could never be returned to the
complete native collagen structure, but could only to be returned to a partial recovery of
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High rigidity and elongation at fracture in a gelatin gel is generally attributed to the
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the formation gelatin films and integrity of capsules. When the gel mass is kept at 57-
60°C, the gelatin in the gel mass exists as single protein molecules in a random coil
configuration, sheathed by water molecules. As the temperature of the gel decreases
below 40°C, the gelatin molecules begin to re-form into the structural characteristics that
are typical to the parent collagen fibers. This conformational state assumed by gelatin is
determined by the molecular weight, type, and concentration of gelatin in the solution,
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process conditions, such as temperature, rate of drying, as well as by the nature of the
solvent and the content of various salts, denaturating and structuralizing substances.21-28
The various factors affecting the formation of helical structures in gelatin solutions can
be summarized as below:
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1. Related to gelatin:
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a. Gelatin requires at a minimum chain length of 40-80 amino acid residues to form
helical structures with their content and stability increasing with increasing polymer
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chain length. Lower temperatures promote the formation of larger helix contents with
longer cooling times providing additional amounts of helices.21,22,26,29
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b. Type A gelatin, a less modified form of collagen than type B gelatin, usually
generates more helical structures than type B gelatin.21,22,24
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c. Imino acid (proline and hydroxyproline) content contributes to the mechanism of
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and pigskins) usually form stronger gels with superior rheological and thermally
stable properties than those containing lesser imino acid content, such as fish
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gelatins.32 Calfskin gelatin, for example, contains approximately 138 proline and 94
hydroxyproline residues per 1000 total amino acid residues compared to 102 proline
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and 53 hydroxyproline residues in cod (cold water fish) skin gelatin.33 Gelatins from
warm water fish species (e.g., tilapia) contain approximately 119 and 70 residues of
proline and hydroxyproline, respectively, per 1000 total residues, and have physical
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and large variations in the quality of different fish gelatins make these gelatins
unsuited as mammalian gelatin replacements.
a. Gelatin generates the highest helical structures when the pH of the medium is at the
isoelectric point of the gelatin and the rate of formation of helical structures slows
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down considerably when the pH of the medium moves away from the isoelectric
point.21,22,24,26 The influence of the pH of the medium on the formation of helical
structures is diminished as the temperature is lowered.
b. Nonionic polyhydroxyl solvents and solutes, such as glycerol, sorbitol, glucose, and
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sucrose, enhance the formation of helices and the effect increases with increase in
their concentration and hydroxyl content (e.g., sorbitol > glycerol, sucrose >
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glucose).35,36
c. Citrate solutions may induce reorientation of gelatin molecules into helical structures
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as suggested by an increase in the viscosity, with a maximum observable effect at pH
near 7.0.37
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d. Alcohols inhibit generation of the helical structures with the longer carbon chain
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length alcohol imparting greater inhibition of the helices formation (e.g., n-propyl
alcohol > ethanol > methanol).24,36
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e. Salts, such as sodium chloride and calcium chloride, reduce the rate of generation
helical structures in gelatin.24
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The polar groups present in the side chains of gelatin are reactive and prone to chemical
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modifications. The chemical modification of the side chains can potentially influence the
viscosity and gel forming properties of gelatin. The carboxylic acid groups produce
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of the gel resulting from such a solution decrease with an increase in the ester content of
gelatin.6 The esters of gelatin are liable to hydrolysis in presence of an alkali.
The chemical modification of the free amino groups in gelatin (i.e., lysine) can be
achieved by selective treatment of gelatin with an acid anhydride under alkaline
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conditions.6,40,41 Under alkaline conditions, such as an aqueous sodium acetate solution,
the free amino groups are prevented from ionizing, which promotes selective acetylation
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of only the amino groups.42 Treatment of gelatin with a monocarboxylic acid anhydride,
such as acetic anhydride, under alkaline conditions results in the formation of acetylated
gelatin (a neutral amide) with a reduced isoelectric point.6 The chemical masking of the
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side chain free amino groups with a dicarboxylic acid anhydride, such as succinic
anhydride, under alkaline conditions results in the formation of succinylated gelatin (an
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acidic amide due to the presence the second free carboxylic group), which reduces the
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isoelectric point of gelatin further, compared to the acetylated gelatin.40 The viscosity of
an acetylated gelatin solution and rigidity of the gel resulting from such a solution are not
influenced by the N-acetyl content of gelatin and are similar to those of the un-acetylated
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In contrast, the acetylation of the hydroxyl groups in gelatin can be achieved selectively
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by treatment either in acetic acid, acetic anhydride, and perchloric acid medium or in
acetic anhydride and trifluoroacetic acid medium.41 Under acidic conditions, the amino
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groups exist in ionized form, which prevents acetylation of those groups and promotes
selective acetylation of the hydroxyl groups in gelatin. Unlike as in case of amidation of
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the amino groups with an acid anhydride, esterification of the hydroxyl groups is known
to have less significant influence on the isoelectric point of gelatin.
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The guanidino groups of the arginine residues in gelatin are responsible for the existence
of positive charges on the molecule at all measurable pH values, since these groups are
assumed to have a pKa value in the region of 14.6 The only reactions specific to the
guanidino groups occur in a strong alkali, which might result in deguanidination (Figure
2).
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Gelatin undergoes cross-linking (also known as pellicle formation) upon aging and when
exposed to (a) physical stress conditions, such as heat43, high temperature and humidity44,
UV radiation45, γ-radiation46-48, and rapid drying49, (b) chemical substances, such as
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aldehydes, ketones, imines, and carbodiimides50-57, or (c) enzymatic substances, such as
transglutaminase54. Aldehydes are thought to form methylene bonds between two amino
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groups on adjacent gelatin chains or within the same chain. The aldehyde induced cross-
linking of gelatin is thought to involve the ε–amino functional groups present in the
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lysine moieties and the guanidino functional groups present in the arginine moieties of
the gelatin chain.53,55,56,58 On the other hand, elevated temperatures are thought to deplete
water molecules between the side-chain carboxylic acid groups on a gelatin chain and
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hydroxyl or amino groups on an adjacent gelatin chain (or within the same chain) and
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promote formation of esters or amides, respectively.43
than the original molecules, leading to the reduced solubility of gelatin. The loss of
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ionizable groups in gelatin and the resulting decrease in its solubility may also arise from
the ionic, hydrogen, and van der Waals interactions of these groups with other
compounds used concurrently in the capsule shell formulations, e.g., FD&C Red # 3 and
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The cross-linking of gelatin can be reduced by masking the amino groups available along
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the molecular chain of gelatin through covalent bonds with a suitable masking agent,
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such as succinic acid.61-63 The dicarboxylic acid nature enables succinic acid to both the
reaction of one carboxylic group with an accessible amino group in the molecular chain
of the gelatin while the second carboxylic group concurrently providing steric prevention
of access of the cross-linking agent. Acetylation of the amino groups on gelatin is another
example that was shown to minimize cross-linking of gelatin in presence of aldehydes.52
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Other solutions to minimize the cross-linking of gelatin include: (a) use of excipients
with no or low aldehyde content, (b) minimize the formation of aldehydes in the
excipients by using appropriate antioxidants, and (c) use of excipients containing
abundant free amino groups (e.g., glycine) in the gel formulation that can compete with
the amino groups present in the gelatin chain for the available aldehyde impurities.
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Incorporation of a low molecular weight gelatin hydrolysate containing smaller peptides
of molecular weight of 100 to 1500 Daltons, free glycine, and other amino acids into the
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gel mass was also reported to reduce the tendency of gelatin cross-linking.64,65
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2.1.1.4 Microbial Growth in Gelatin
Microbial growth in gelatin may not be possible due to the lack of the essential amino
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acid, tryptophan, in gelatin and the very hypertonic nature (low water activity) of gelatin,
especially in the dried state. Any degree of microbial growth that could occur in gelatin
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might probably be due to the presence of excessive moisture. Microorganisms classified
as fungi (e.g., Aspergillus niger) have the best opportunity of growth in gelatin when
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excessive moisture is present. In contrast, bacteria, yeast, and fungi are not expected to
grow in dried gelatin. In the wet gel masses inoculated with different types of
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days for Candida albicans (yeast). In contrast, no observable reduction in the number of
surviving Aspergillus niger was observed within the study period of 40 days under
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similar conditions. The addition of methyl and propyl parabens, as the preservatives,
produce acceleration in the inactivation of all study microorganisms in the wet gel
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masses. The Candida albicans was shown to be more vulnerable to the parabens than
other bacteria tested. On the other extreme, it required more than 20 days for parabens to
produce a 5-log unit reduction in the number of surviving Aspergillus niger in wet gel
masses.
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The reported minimum levels of water activity necessary for the growth of Escherichia
coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Aspergillus niger are 0.9367,
0.9468, 0.8669, and 0.8470, respectively. In wet gel masses, water activity levels were
much higher than those required for the survival of microorganisms. In the case of dried
gel masses, the water activity levels fall to much lower than those required for
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microorganisms to survive. Thus, gelatin products, when dried properly and handled with
considerable care, provide sufficient microbial inhibition.66
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2.1.2. Plasticizers
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Hard gelatin capsule shells do not contain a non-volatile plasticizer and the presence of
moisture (12 - 16%) is essential to maintain their flexibility and integrity.71,72 At a lower
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moisture content, the shells become brittle and are prone to breakage, while at a higher
content, the shells may deform and become sticky. Thus, any alteration to this moisture
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range, due to its migration between the shell and encapsulated fill or between the shell
and external environment, could be detrimental to the integrity of the hard gelatin capsule
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shells.
interactions with a consequent increase in the mobility of protein chains and a decrease in
the glass transition temperature (Tg) of gelatin.73 The reduction in the protein-protein
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interactions results in improved flexibility and handling of the shell material during its
manufacturing and shelf life. In addition, a plasticizer, due to its hygroscopic nature,
promotes absorption and retention of moisture by gelatin that also contributes to the
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Typical hydrophilic plasticizers used in the soft gelatin capsule shells include glycerol,
sorbitol, partially dehydrated sorbitol (blend of sorbitol and 1,4-sorbitan), maltitol
(hydrogenated corn syrup), mannitol, propylene glycol, and low molecular weight
polyethylene glycols. Plasticizers are used typically at about 15-30% w/w of the total wet
mass of a shell formulation at the time of soft gelatin capsules encapsulation.77-80
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Glycerol is the most effective plasticizer and the higher plasticizing efficacy of glycerol
is attributed to its lower molecular weight and higher hygroscopicity than other higher
polyols.73,76,81 The moisture content of gelatin films plasticized with glycerol tends to
increase with increased glycerol concentration in the films. Sorbitol is prone to
crystallization from gelatin films (blooming) stored at lower humidity conditions due to
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the insufficient availability of water to keep the plasticizer in solution.82,83 As the
crystallization of sorbitol decreases the effective amount of ‘plasticizing’ sorbitol, it is
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expected to increase the molecular interactions within the gelatin network and change the
mechanical properties of the films.82 Glycerol is blended with sorbitol to yield a better
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control of the overall moisture content in gelatin films. Alternately, use of partially
dehydrated sorbitol as a plasticizer in gelatin films tends to pick up less moisture than
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glycerol and not to prone to crystallization as regular sorbitol.
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Lower molecular weight polyethylene glycols (e.g., PEG 200 and PEG 300) have a larger
number of hydroxyl groups per a mole and a higher hygroscopicity compared to those of
higher molecular weight polyethylene glycols and thus the former exhibit a more
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pronounced plasticizing effect than that by the latter. A more efficient plasticizing effect
of a lower molecular weight polyethylene glycol is also due to its smaller molecular size
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that facilitates its insertion into the polymer chains of gelatin more readily. Gelatin films
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plasticized with polyethylene glycols are known to exhibit a tendency for the plasticizer
to migrate to the surface of the films.84 This phenomenon is thought to take place when
the plasticizer concentration exceeds its compatibility limit in the polymer, thus causing
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phase separation and physical exclusion of the plasticizer from the polymer.85 This
phenomenon is referred to as blooming or blushing. The physical exclusion of the
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plasticizer from the polymer also results in films becoming opaque with time, with the
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opacity increasing with increase in the molecular weight and corresponding increase in
the melting point of the polyethylene glycols.84
The permeability of oxygen and volatile fill components, such as ethyl alcohol through a
gelatin film increases exponentially with an increase in glycerol concentration and
corresponding increase in the humidity in the film (Figure 4).86-88 The oxygen
permeability and loss of volatile fill components due to diffusion can be minimized by
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plasticizers such as oleic acid, triethyl citrate (TEC), acetyltriethyl citrate (ATEC),
tributyl citrate (TBC), and acetyltributyl citrate (ATBC) in gelatin films has also been
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investigated.84,89 Akin to hydrophilic plasticizers, the hydrophobic plasticizers provide
flexibility to gelatin films. However, the extent of this effect with hydrophobic
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plasticizers on gelatin films is far less than that produced with hydrophilic plasticizers.
The hydrophobic plasticizers are also less compatible with gelatin, resulting in phase
separation during the drying process. Though, the addition of an emulsifier such as
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lecithin may minimize the phase separation to some extent, films produced with
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hydrophobic plasticizers are generally opaque and the opacity of the gelatin films
increases with increased concentration of a hydrophobic plasticizer in the films.
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The manufacturing process for the production of soft gelatin capsules is the rotary die
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process90, in which a molten mass of a gelatin sheath formulation at 57-60°C is fed from
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a reservoir onto two separate rotating cooling drums to form two spaced flat ribbons of
gelatin in a semi-molten state. These flat ribbons are extracted from the cooling drums
and are fed around rollers that lubricate them, usually with fractionated coconut oil, and
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then brought together at a convergent angle into the nip of a pair of roller dies that
include opposing die cavities. A fill formulation, to be encapsulated, flowing from its
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own reservoir through a tube under gravity, is fed into a positive displacement pump.
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Accurately metered volumes of the fill formulation are injected from a heated wedge (~
35°C - <40°C) into the space between gelatin ribbons as they pass between the cavities
on the die rolls. As the ribbons meet on the rim of the opposing die cavities, the bottom
lips of the cavities initially seal, forming what is referred to as ‘lower seam’. The fill
formulation is then injected precisely into the semi formed soft gelatin capsules. The soft
gelatin capsule halves are then sealed together (forming the ‘upper seam’) by the
application of heat (provided by the heated wedge) and pressure (provided by the dies).
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The soft gelatin capsules, severed around each of the die cavities, are ejected by the
continuous rotation of the dies and are carried on a conveyer into a tumble dryer. After
the soft gelatin capsules exit the tumble dryer, they are spread on to shallow trays and
dried further in a drying tunnel maintained at 21-24°C and 20-30% RH.
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Empty hard capsule shells of various fill volumes are manufactured separately and
supplied ready for the encapsulation of fill formulations. The manufacturing process for
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the hard capsule shells is the dip molding process, in which a set of molding pins are
immersed in an aqueous solution of the film forming polymer (gelatin or hypromellose
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[HPMC]) with other additives, such as a gelling agent and a gelling promoter (in case of
HPMC capsules), an opacifier, and colorants, maintained 48-55°C. The molding pins
with the adhering solution are withdrawn and dried at 25-35°C to form capsule shells
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(body or cap). The dried body and cap parts of the capsule shells are cut to a suitable size
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and paired to form empty hard capsule shells.
The bodies of hard capsule shells are filled, capped, and sealed sequentially. Unlike soft
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capsules, which are one-piece, completely filled, and hermetically sealed, filled two-piece
hard capsules have substantial headspace within. The presence of the headspace within a
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hard capsule may compromise the elegance of a product designed with a transparent shell
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formulation and the oxidative stability of an encapsulated compound. The loss of fillable
volume in a hard capsule due to the headspace may also result in a relatively larger
capsule size compared to that of a soft capsule containing a similar fill volume.
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An essential part of producing liquid filled hard capsules is the ability to seal the capsules
effectively after encapsulation. The two most widely used methods are banding using a
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polymer solution (e.g., gelatin solution for banding hard gelatin capsules) and sealing
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In the capsule sealing process, every capsule is individually sprayed with a micro amount
of a hydroalcoholic sealing fluid at the junction of the cap and body of the capsules
followed by drying by gently tumbling the capsules in a rotating drum. For an efficient
sealing process, it is important that the fill material does not penetrate into the zone
between the body and cap before the sealing operation.
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The challenges arising from the leakage of the hard capsules may be able to overcome by
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maintaining the fill formulation in liquid form during the filling step that solidifies
subsequently. This can be achieved using a thixotropic formulation that remains a liquid
under shear (shear thinning)92,93 or a semisolid formulation that remains a liquid when
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heated (hot melt or thermo-softening)93,94 during capsule filling process. In the case of hot
melt fills, the effect of melting temperature and time held at this temperature on the
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potential for the formation of aldehyde impurities and thermal stability of compounds
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needs to be investigated. The rate of cooling can also have an influence on the structure
of certain excipients, which in turn may modify the drug release characteristics from the
matrix itself.95
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The readers are directed to the literature published by Cole et al.2, Cade et al.3, and
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Rowley96 to obtain any further understanding of the manufacturing process for the liquid
and semisolid filled hard capsules and their characteristics.
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4. FILL FORMULATIONS
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Until early 1980s, soft gelatin capsules were traditionally used to encapsulate non-
aqueous liquid and semisolid formulations, whereas, hard gelatin capsules were used to
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encapsulate powders and pellets. Later on, hard capsules were evolved as an alternate to
soft gelatin capsules for encapsulating non-aqueous liquids and semisolids.2,3,93,97 The
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hard capsule shells for liquid and semisolid filling are identical in composition to those
used for filling powders and pellets.
Lipophilic vehicles, such as long-chain free fatty acids and their esters, are compatible
with both soft and hard capsules. Hydrophilic vehicles for soft gelatin capsules fill
formulations include polyethylene glycols of 400-600 molecular weight and smaller
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amounts of propylene glycol, glycerol, and water. The use of propylene glycol, glycerol,
water, and lower molecular weight polyethylene glycols (molecular weight ≤ 300) in the
fill formulations is limited due to their ability to diffuse into the shell and thereby act as
gelatin plasticizers.84,98 Hydrophilic fill formulations have an affinity for water and
glycerol used in the shell formulation as plasticizers, leading to the migration of these
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shell components into the fill. Migration of a plasticizer from the shell into the fill in a
soft gelatin capsule could result in the reduced elasticity and increased brittleness of the
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shell shortly after production or on storage, especially when exposed to cold
temperatures.78,99,100 Migration of water could lead to physical and chemical instability of
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soft gelatin capsule products containing solubilized compounds, which are prone to water
induced precipitation and hydrolytic degradation.101-105 Polyethylene glycol and lipid
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excipients are inherently susceptible to autooxidation in the presence of air, moisture,
heat, and light and produce reactive peroxides, aldehydes (i.e., formaldehyde and
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acetaldehyde), and carboxylic acids (i.e., formic acid and acetic acid). These reactive
impurities are known to induce physical and chemical instability in capsule products.106-
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113
Hard gelatin capsule shells are compatible with polyethylene glycols of molecular weight
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higher than 4000.2,97 Polyethylene glycols of molecular weight ≤ 4000, due to their
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hydrophilicity, can extract water from the shell material, resulting in increased brittleness
of the shell shortly after production or on storage. Use of water, glycerol, sorbitol, and
propylene glycol in the fill formulations is known to be incompatible with the hard
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It is essential to keep the apparent pH of the fill formulation between 2.5 and 7.5 to
maintain the structural integrity of gelatin capsule shell during its shelf life. At pH values
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outside this range, gelatin is hydrolyzed causing leakage of capsule fill contents and
sticking of the capsules.16,114 Gelatin shells containing encapsulated acid salts, mineral
acids, and organic acids may also be at the potential risk of hydrolysis of gelatin due to
the migration of these compounds into the shell.115,116
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5. NON-GELATIN CAPSULE DOSAGE FORMS
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5.1. Non-Gelatin Hard Shell Capsules
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Alternate to hard gelatin capsules, hard capsule shells are also manufactured using non-
gelatinous polymers, such as hypromellose (hydroxypropyl methylcellulose [HPMC])
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and starch. The originally invented HPMC capsule shells contain a secondary gelling
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agent such as kappa-carrageenan (Quali-V® from Qualicaps) or gellan (Vcaps® from
Capsugel). HPMC alone does not gel at low temperatures. The use of a gelling agent is
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essential to be able to manufacture HPMC capsule shells using the conventional dip
molding process employed in the manufacture of hard gelatin capsule shells.
Carrageenans are algal (seaweed) polysaccharides consisting of high-molecular-weight
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linear sulfated galactan chains. Gellan gum is a microbial polysaccharide with a linear
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tetra-saccharide repeating sequence with one carboxyl group per repeat unit. In solution,
at the dipping stage of capsule shell manufacturing, both gelling agents exist as
disordered coils.121 On cooling, the chains associate by the formation of double helices.
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electrostatic repulsion between the helices and allow aggregation to occur. Divalent metal
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ions, such as calcium, are particularly effective in inducing gelation of gellan and
carrageenan.122,123 Monovalent cations, such as potassium, also produce strong gels at
moderate salt concentrations.123,124 Newer version of HPMC capsule shells without a
secondary gelling agent and a gelling promotor have also been manufactured and are
available under the trade name Vcaps® Plus (Capsugel).
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The use of a gelling agent is known to delay the HPMC shell dissolution in vitro and in
vivo in some circumstances.121,125 The dissolution of the HPMC capsule shells containing
a gelling agent is dependent on both pH and composition of the dissolution medium and
is usually longer than that of hard gelatin capsules. The delay in the dissolution of these
HPMC capsule shells is attributed to the interactions between the gelling agent and
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cations such as potassium and calcium present in the dissolution medium. The newer
HPMC capsule shells (Vcaps® Plus) without a secondary gelling agent exhibit dissolution
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independent of both pH and ionic nature of the dissolution medium.126-129
Cole et al.121 discussed the influence of pH and composition of the dissolution medium
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on the dissolution of the HPMC capsule shells containing a gelling agent in some detail.
If water is used as the dissolution medium, both gellan and carrageenan gels dissociate
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because of diffusion of cations out of the gel network, resulting in rapid film disruption of
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capsule shells and fast drug release.124,129,130 However, in acid conditions, the two gelling
agents behave differently. Carrageenan at pH 1.2 behaves in the same way as in water,
because the sulfate groups, having very low pKa, retain their negative charge, which
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other hand, have a much higher pKa (∼3.4), and therefore convert into the uncharged (-
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COOH) form at low pH, with consequent elimination of electrostatic repulsion between
the helices.123 Gellan gels, therefore, are less soluble at pH 1.2.
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When the dissolution medium contains sufficient gel forming potassium cations,
dissociation of the helix-helix aggregates is hindered with the result that the gel from
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gellan and carrageenan retains its structure and the solubility is reduced. When the
dissolution medium contains sodium cations, disruption of the film is faster than if
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potassium cations are present. The reason for this difference is thought to be due to the
binding efficiency with which ions of different sizes can fit into potential sites on the
helices. Dissolution behavior of HPMC capsule shells containing the gelling agents in
TRIS buffer, which contains no metal cations, is similar to that in water.
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HPMC capsule shells have three-fold lower average moisture content (2-6%) and are less
hygroscopic than hard gelatin capsule shells.126,131 The presence of 12 to 16% water in
the hard gelatin capsule shells, as a plasticizer, is essential to maintain their integrity and
flexibility.71,72 Any alteration to this moisture range could be detrimental to the integrity
of the hard gelatin capsule shells. As HPMC capsule shells are less dependent on water as
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a plasticizer, these shells are less likely to break even in dry conditions, thus helping to
maintain physical stability of products against breakage.132 As a consequence of being
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less hygroscopic and having a lower moisture content, moisture transfer from the HPMC
capsule shells into the encapsulated fill material could potentially be reduced, thus
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maintaining physical and chemical stability of products containing compounds prone to
water induced precipitation and hydrolysis. An additional advantage of HPMC capsules
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is any polar and hygroscopic solvents present in the fill formulations are less likely to
migrate into the capsule shell or to interact with the shell material. Unlike gelatin, HPMC
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is a non-ionic polymer and has less compatibility challenges with most encapsulated
materials and aldehyde impurities present therein.131
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Scanning electron microscopy studies suggest that HPMC films may have looser
structure compared to gelatin films, resulting in their relatively higher oxygen
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higher than through HPMC films. Higher oxygen permeability through HPMC films is
attributed to the looseness in the structure of these films, whereas, higher water
permeability of gelatin films is attributed to the hygroscopicity of these films.131 When
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In vivo gamma scintigraphic studies in human subjects by Tuleu et al.133 and Jones et
al.134 comparing HPMC capsules containing kappa-carrageenan as a gelling agent with
hard gelatin capsules suggested no significant differences in the disintegration times in
either fasting or fed state (mean ± SD): 8 ± 2 min and 7 ± 3 min for HPMC and gelatin
capsules, respectively, under fasting condition and 16 ± 5 min and 12 ± 4 min for HPMC
and gelatin capsules, respectively, under fed condition. In contrast, in vivo disintegration
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condition, the initial disintegration times were 1.00 ± 0.37 h and 0.39 ± 0.36 h and the
complete disintegration times were 1.61 ± 0.65 h and 1.22 ± 0.80 h for HPMC and gelatin
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capsules, respectively. However, these differences in the disintegration times between
HPMC and gelatin capsules were found to have no significant effect on the AUC(0−∞) and
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Cmax of the encapsulated compound in the study subjects. Orally administered
formulations in HPMC and gelatin hard capsules were also shown to be interchangeable
by several other investigators.131,135
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5.1.2. Starch based Hard Shell Capsules
Hard capsule shells using potato starch as the film forming material have been
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manufactured using the injection molding process and are available under the trade name
Capill®.136-138 These capsule shells are made of two pieces, a cap and a body, which can
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be sealed together at the time of filling to prevent their separation. Sealing is achieved by
applying a hydroalcoholic solution to the inner section of the cap, immediately prior to it
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is being placed onto the body. The moisture content of starch capsule shells ranges
between 12-14% w/w, with more than one-half of it being tightly bound to the starch.
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The dissolution of starch capsule shells is independent of pH. Studies, using amoxicillin
as a model drug, demonstrated that the GIT transit times and plasma amoxicillin
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concentrations were similar between the starch and gelatin capsules in normal human
volunteers under fasting condition.139
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The caps and bodies of the Capill® starch capsules are manufactured separately in
different sizes (sizes 0, 1, 2, 3, and 4). The same sized cap is designed to fit different
body lengths as the diameter of the junction of the cap and body is always the same for
all sizes of starch capsules. Unlike the ‘lipped’ seal on hard gelatin and hypromellose
capsules, the starch capsule cap fits evenly in place over the body, leading to a smooth
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surface finish. The area of closure between the cap and body of starch capsules is much
smaller compared to that of hard gelatin capsules. It is because the dimensions are more
tightly controlled in injection molding process used for the production of starch capsules
than in dip molding process used for the hard gelatin capsules (Figure 5).136-138 The
superior film adhesion properties of starch capsules compared to hard gelatin capsules
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make them amenable to coating process in the preparation of modified release dosage
forms.94 Coating of starch capsules can also be considerably easier due to their smooth
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seal, coupled with their higher bulk density. However, the starch hard capsules have not
gained wide acceptance due to the need for different design capsule filling equipment.
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5.2. Non-Gelatin Soft Shell Capsules
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The necessary properties required of polymer films for the manufacture of soft capsules
using the rotary die process include (a) the ability of the film forming composition to be
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cast to form a continuous film that is mechanically strong and exhibits elasticity
sufficient to allow the film to stretch during filling and (b) the ability of the film forming
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the two halves of the soft capsule to fuse together during the sealing process under
sufficient pressure and temperature.140,141 The temperature at which the fusion of the two
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opposing films occurs during encapsulation should be below the melting point of the
film. This property of fusion temperature being lower than melting temperature is crucial
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to the manufacturing of capsules using the continuous rotary die process. If the fusion
and melting temperatures are about the same, the film will nearly completely melt during
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sealing of capsules. It has proven difficult to find this combination of properties in non-
gelatin polymer systems, which are typical to the gelatin polymer.
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Starch and its derivatives in combination with other polymers have been investigated as
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the viscosities of non-gelatin shell compositions are much higher (10,000 to above 30,000
cps.) compared to those of gelatin shell compositions, it is difficult to utilize the
conventional spreader box metering device in the manufacturing of non-gelatin soft
capsules. Thus, melt-extrusion devices are employed as alternative to the spreader
boxes.143 The non-gelatin polymer blends are melt-extruded to produce films that are fed
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directly onto the surface of the casting drum to produce soft capsules. In contrast to soft
gelatin capsules which require the apparent pH of fill formulations be controlled between
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2.5 and 7.5 to maintain their stability16, the starch-carrageenan based soft capsules were
found to display high resistance to concentrated fills, alkaline fills, and those containing
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salts of weak acids and strong bases.144
Brown144 proposed using polyvinyl alcohol (PVA) films for the encapsulation process.
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Such films are available commercially (Hi-Selon™, Nippon Gohsei) or may be melt-
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extruded at the time of encapsulation process. These films are partially hydrated just
before encapsulation to improve their flexibility, adhesivity, and ability to glue the two
halves of soft capsules within the die cavity during encapsulation process. Misic et al.145
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introduced starch-PVA based soft capsules comprised a blend of starch, PVA, and
plasticizers (sorbitol solution and glycerol), produced by extrusion and subsequent rotary
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die encapsulation processes. These films were produced by initially extruding a mixture
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of potato starch and PVA with plasticizers through a double-screw extruder to form
granules. These granules were again extruded using a single-screw extruder and the
extrudate was pressed through a slit die to form a film for encapsulation. In contrast to
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soft gelatin capsules where considerable water migration from the soft gelatin shell into a
hydrophilic fill formulation and resulting drug crystallization may potentially occur, the
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risk of any substantial water migration or drug crystallization in starch-PVA based soft
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capsules was found to be minimal or absent.145 The starch-PVA based soft capsules were
also found to exhibit more surface roughness and higher resistance to mechanical
deformation compared with soft gelatin capsules. The surface roughness and higher
mechanical strength of the starch-PVA based soft capsules would make these capsules
more amenable to successful coating process.
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Coating of a solid dosage form such as tablets and pellets is routinely applied to protect
the dosage form and its contents against moisture and oxygen, to mask unpleasant taste
and odor, to improve elegance, and to control the site or rate of release of a drug. Enteric
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coating is desirable for the administration of medications, which cause gastric distress or
are unstable in the stomach acid environment. In addition to enteric coating, which delays
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the release of a drug from the dosage form until it reaches small intestine, other types of
coatings are also applied to deliver a drug at an intended site of the GIT (site specific
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release) or to release a drug over an extended period (extended release).
The enteric coating materials are carboxylic group containing polymers, such as cellulose
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acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP),
hydroxypropyl methylcellulose acetate succinate (HPMC-AS), polyvinyl acetate
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phthalate (PVAP), acrylic acid copolymers, and shellac. These enteric polymer
compositions can be applied onto dosage forms as aqueous dispersions or organic
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solutions. Coating of tablets and pellets can be achieved relatively easily by known
coating processes (e.g., pan coating or fluidized bed coating) owing to their porous
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surfaces, which readily adhere to the coating substances. In contrast, difficulties arise
when coating gelatin capsules because of their smooth, non-adsorptive surfaces and
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flexibility. The gelatin capsule shells may soften and become sticky during the coating
process due to solubilization of gelatin.146 In addition, the gelatin shells may become
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brittle during the drying process and prone to breakage under only slight pressure. The
acidic enteric polymers are also thought to possibly penetrate the gelatin shells and cause
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The surface of the gelatin capsules with an improved capacity for adhering to coating
compositions may be achieved by applying to the outer surface of the capsules a layer of
a sub-coating of HPMC146,147, hydroxypropyl cellulose148,149, polyvinylpyrrolidone148, or
cationic methacrylate/neutral methacrylate polymers150,151. This sub-coating is thought to
provide the gelatin capsules with better mechanical strength and improved capacity for
adhering to the coating compositions. The sub-coating layer can also prevent the
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penetration of the highly acidic enteric polymers into the gelatin shells and thereby
prevent their embrittlement.151 The addition of PEG 400 and PEG 6000 to the coating
formulation was also reported to provide improved adhesion of the polymer to the gelatin
shell.146 Scanning electron microscopy (SEM) studies suggest that, in contrast to gelatin
capsules, HPMC capsules have rough surfaces, which provide for good adhesion to the
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coating.148,152
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Studies by Dvorácková et al.148 suggest that hard gelatin capsules can be coated directly
with organic enteric polymer solutions at lower coating levels without any challenges.
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These lower coating levels may not be sufficient to cover the junction zone between the
capsule body and cap and to provide sufficient enteric protection to the capsules.148,149
However, these gelatin capsules were shown to display ‘orange peel effect’ at higher
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coating levels, which was eliminated by sub-coating the capsules with a hydroxypropyl
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cellulose (HPC) intermediate layer.148 The HPMC capsules, on the other hand, were
successfully coated at all coating levels with organic enteric polymer solutions without an
HPC intermediate layer. It appears that the application of an HPC intermediate layer is
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necessary for practical utilization of enteric coatings onto gelatin capsules. Dvorácková et
al.148 speculated that the intermediate sub-coat changed the smooth surface of gelatin
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The enteric-coated capsules may also require an overcoat typically composed of HPC or
HPMC to improve the physical stability by preventing adhesion of capsules together and
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chemical stability on storage and during stability studies, especially under accelerated
stability conditions (40 °C/75% RH).146,149 The enteric polymers are known to undergo
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hydrolysis thereby reduce their enteric effectiveness with time.149 The overcoat can
minimize the moisture transfer through the film and thereby reduce the hydrolysis of the
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Alternate to the surface coating of capsules with enteric polymers, enteric capsules can
also be manufactured by incorporating the enteric polymers within the capsule shell
itself153-156 These enteric capsules were shown to be soluble in or disintegrated by the
intestinal secretions but insoluble or resistant to the acid secretions of the stomach. As an
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approach, patented by Okajima153, the body and cap portions of hard shell capsules can
be formed by dip molding using a homogeneous film-forming mixture comprising a film
former such as HPMC or gelatin, an ammonium salt of cellulose acetate phthalate
polymer or of a copolymer of methacrylic acid and methacrylic acid alkyl ester, and with
an optional plasticizer. The body and cap portions of such acid resistant two-piece hard
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capsules can be sealed with an acid resistant banding solution to achieve increased acid
resistance.157,158
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Ready-to-use enteric hard capsule shells in which the enteric polymer is already
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incorporated within are commercially available (DRcaps™, Vcaps™ Enteric, and
enTRinsic™ from Capsugel) which can be filled with formulations.156 Capsugel Vcaps®
HPMC hard capsule shells contain a small amount of gellan as the gelling agent
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(typically below 1 part by weight per about 100 parts by weight of HPMC) and either
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ethylenediamine tetra acetic acid (EDTA) or sodium citrate as a gelling promoter.126 The
use of a gelling agent is essential to be able to manufacture HPMC hard capsule shells
using the conventional dip molding process. The carboxyl groups of gellan have a pKa
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around 3.4 and convert into the unionized form (-COOH) with a lower aqueous solubility
at pH 1.2, thus providing some level of enteric protection. The lower amounts of gellan
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used in the Vcaps® HPMC capsules, however, do not provide sufficient acid resistance to
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qualify for the enteric dosage form (i.e., to meet compendial dissolution test requirements
for enteric products). Use of higher amounts of gellan may cause excessive increase in
viscosity of the aqueous composition thus making it difficult to manufacture the capsule
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shells at the commercially desirable high speeds and quality using the conventional dip
molding process. Cade and He156 identified that when the hard capsule shells (DRcaps™
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from Capsugel) were produced at 4 to 15 parts by weight of gellan per 100 parts by
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weight of HPMC, such capsule shells can exhibit acid resistance for at least one hour at
pH 1.2 and also can be produced without compromising processability during the
conventional dip molding process. These compositions also provide an advantage of not
requiring any additional gelling promoter. Ready-to-use Capsugel Vcaps® Enteric HPMC
capsule shells contain hydroxypropyl methylcellulose acetate succinate (HPMC-AS) to
provide enteric protection.
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In another approach, Hassan et al.154 and Rao and Khadgapathi155 presented compositions
comprising of gelatin, an enteric polymer, an aqueous alkaline solvent, and a plasticizer
to manufacture enteric soft gelatin capsules using rotary die process. This approach
provides a method for manufacturing enteric soft capsules without the need for coating.
In this approach, the enteric gel mass is prepared by initially dissolving the enteric
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polymer in an aqueous solution of an alkali to get a clear enteric polymer solution.
Gelatin is wetted with water and a plasticizer separately in a heated vessel, which is then
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mixed with the enteric polymer solution to make a final clear homogeneous gel mass.
The gel mass is degassed under vacuum to remove any entrapped air and excess of the
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alkali. The step to neutralize (ionize) the enteric polymer with an alkali before addition to
the gel mass is essential in producing clear gel films for encapsulation. Gel films
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produced without the neutralization step are usually cloudy. A volatile alkali such as
ammonium hydroxide is preferred as it is easier to remove any excess amount during
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degassing the gel mass. Neutralization of the enteric polymer can also be achieved using
a basic amino acid such as arginine.159 However, gel films produced using the basic
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amino acids are usually cloudy due to the weak neutralizing capacity of these basic amino
acids. The cloudy appearance these enteric gelatin films can be improved by the use of
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Valproic acid delayed release soft gelatin capsules (Stavzor®, Banner Pharmacaps, Inc.)
were commercially available in 125 mg, 250 mg, and 500 mg strengths for the treatment
of seizure disorders, manic episodes, and migraine prophylaxis. The immediate release
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valproic acid dosage forms are associated with gastric side effects such as nausea and
vomiting. The delayed release property is purported to help alleviate these side effects.
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The Stavzor® delayed release soft gelatin capsules contain neat valproic acid fill
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The choice of the salt form used to prepare the enteric coating solution can influence the
disintegration properties of the enteric-coated capsules. Al-Gousous et al.161
demonstrated that the shellac-based enteric coatings obtained using alkali metal salts
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explanation for the loss of disintegration properties of the enteric-coated capsules with
ammonium salts compared to those with alkali metal salts.
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Prior to the application of polymers to effect enteric properties to gelatin capsules, gelatin
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capsules were rendered resistant to gastric juices by treating them with formaldehyde
either in gaseous state or in solution state.162,163 However, it is very difficult to control the
exposure of the gelatin capsules to formaldehyde to yield consistent gastric juice resistant
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and intestinal solubility properties of the capsules. In addition, these properties of
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formaldehyde treated gelatin capsules tend to change with time.149 The stomach and
intestinal solubilities of the gelatin capsules treated with formaldehyde also depend on the
levels of digestive enzymes (e.g., pepsin and pancreatin), which are known to show
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significant inter and intra subject variability. In contrast, the dissolution of capsule shells
containing enteric polymers is exclusively dependent on the pH of the digestive juices
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Any alteration to the moisture range outside 12 - 16% in the hard gelatin capsule
shells due to its migration could be detrimental to the integrity the shells. Hard gelatin
capsule shells filled with PEG 400 and PEG 600 are prone to become fragile and
breakage due to the migration of moisture from the capsule shell into the PEG fill.
These lower molecular weight PEGs are also expected to migrate into the hard gelatin
capsule shells and soften them due to their plasticizing effect. Hard gelatin shells, on
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the other hand, have been reported to be compatible with PEGs of molecular weights
higher than 4000. In contrast, the presence of a plasticizer in the soft gelatin capsule
shells imparts elasticity that allows the shells to accommodate a wide range of
hydrophilic excipients such as PEG 400 and PEG 600. Lipophilic vehicles are
compatible with both soft and hard capsule shells.
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b. Tolerance of the fill formulation towards the shell water content:
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Soft gelatin capsule shells typically contain water from 30 to 40% w/w at the time of
encapsulation process and about 8 to 10% during the shelf life.164 Depending on the
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nature of the fill formulation, it may pick up and retain water anywhere from near
zero percent (e.g., soybean oil, olive oil) to 10% (e.g., PEG 400).164 In contrast,
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though, hard gelatin capsule shells may contain water from 12 to 16%71,72, the
absolute water amount is relatively much lower compared to soft gelatin capsule
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shells (as hard capsule shells are much thinner and lighter) and also is in the bound
state, the extent of its migration into the fill and thus any adverse influence on the
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6%)126,131 compared to those of hard gelatin capsules, the extent of water migration
and its adverse influence on the stability of encapsulated compounds are even much
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lower in HPMC capsules. Thus, the relative stability against crystallization and/or to
hydrolytic degradation of encapsulated compounds in capsules follows the order:
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HPMC capsules > hard gelatin capsules > soft gelatin capsules.
capsules due to its potential hydrolysis to salicylic acid. USP-NF limits the presence
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of salicylic acid content in aspirin dosage forms at not more than 3%. Aspirin is
stabilized in the capsule product by formulating as a lipid suspension and
encapsulating into HPMC hard capsules (NDA 203697; PLx Pharma Inc.).165
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capsules may compromise oxidative stability of encapsulated compounds and may
risk leakage of low viscous fill materials.
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Fill formulations requiring encapsulation at temperatures much higher (e.g., hot
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melts, high viscosity fills) than what soft gelatin capsule encapsulation process can
tolerate (~ 35°C - <40°C) can be readily encapsulated into hard capsules. The
commercially available vancomycin capsules are produced by filling a dispersion of
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vancomycin hydrochloride in PEG 6000 into hard gelatin capsules at temperatures
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higher than the melting point of PEG 6000 (55-63°C).166 Vancomycin hydrochloride
is highly hygroscopic and picks up moisture rapidly and extensively during routine
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protection to vancomycin against high relative humidity conditions and thus improves
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that may potentially cross-link gelatin and reduce the dissolution of gelatin capsule
shells. Use of HPMC capsule shells may be sensible in those cases.
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desired features (i.e., size, color, and logo) and equipment for filling and sealing the
capsule shells are readily available, it is easier for an organization to set up
capabilities and manufacture hard capsule products in-house.
8. CONCLUSION
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Polymeric film forming materials and manufacturing technologies used in the production
of capsule shells have been developed to offer additional consumer acceptability, to
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improve the dosage form physical and chemical stability, and to modify release of the
encapsulated contents from the dosage form. These developments resulted in the use of
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hypromellose and starch based polymeric materials as alternate to the animal source
gelatin in the manufacture of capsule shells. Hypromellose capsule shells have lower
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moisture content and hygroscopicity than gelatin capsule shells. As a result, moisture
transfer from the hypromellose capsule shells into the encapsulated fill material is lower
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and thus the physical and chemical stability of hypromellose shell based products
containing compounds prone to water induced precipitation and hydrolysis is improved.
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Gelatin and non-gelatin capsule shells can also be formulated to modify the release of
their fill contents in a site-specific manner in the GIT either by coating the filled capsules
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with a modified release polymer or by incorporating the polymer within the capsule shell
before filling. These modified release capsule shells are soluble in or disintegrated by the
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Soft Shell Hard Shell
Fills Fills
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• Non-aqueous solutions, • Powders, pellets, granules
suspensions, semi-solids • Non-aqueous solutions,
suspensions, semi-solids
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Gelatin Shell Non-gelatin shell Non-gelatin Shell Gelatin Shell
Gelatin, plasticizer, Starch/Carrageenan, HPMC, Starch, Gelatin, water
water PVA, or Starch/PVA, HPMC/Carrageenan or
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plasticizer, water AN HPMC/Gellan, water
Figure 1. Designs of capsule dosage forms used to encapsulate solids, liquids, and semi-solids.
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Figure 2. Possible pathways of deguanidination of arginine moieties in collagen and
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Figure 4. Influence of (A) glycerol content and (B) relative humidity on oxygen
permeability, and of (C) glycerol content on equilibrium water content of gelatin films at
21±1°C.1,87. (Reprinted with permission from Hom et al.87. Copyright Elsevier)
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Figure 5. (A) Starch hard capsules produced by injection molding process and (B) Cap
and body design differences between starch and gelatin hard capsules. (Figure A is
reprinted with permission from Vilivalam et al.137. Copyright Elsevier Science and Figure
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