11
`
`Formulation and physical properties of soft capsules
`
`Gabriele Reich
`
`Introduction
`
`Soft capsules are a single-unit solid dosage form,
`consisting of a liquid or semi-solid fill enveloped
`by a one-piece hermetically sealed elastic outer
`shell. They are formed, filled and sealed in one
`continuous operation, preferably by the rotary
`die process. Depending on the polymer forming
`the shell, they can be subdivided into two
`categories, namely soft gelatin capsules or ‘soft-
`gels’ and non-gelatin soft capsules. The majority
`of soft capsules are made from gelatin owing to
`its unique physical properties that make it an
`ideal excipient for the rotary die process. Soft
`capsules based on plant-derived and/or synthetic
`non-gelatin alternatives have, however, been
`patented and a few prototype products have
`recently entered the market. Formulation and
`physical properties of both soft capsule categories
`will be discussed.
`
`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 appli-
`cations, for pharmaceutical and health and nutri-
`tion products, cosmetic applications and even
`recreational products such as paint balls.
`In the pharmaceutical field soft gelatin cap-
`sules 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 bioperfor-
`mance issues, namely increased bioavailability
`and decreased plasma variability by improved
`solubility and absorption-enhancing techniques.
`The proper design for a specific soft gelatin
`capsule formulation requires the appropriate
`selection of shell and fill composition and the
`optimisation of the two to allow for the efficient
`production of a chemically and physically stable
`product with the desired biopharmaceutical
`properties.
`
`Composition of the capsule shell
`
`The shell of a soft gelatin capsule is composed of
`gelatin, a plasticizer or a combination of plasti-
`cizers and water. In addition, it may contain
`preservatives, colouring and opacifying agents,
`flavourings and sweeteners, possibly sugars to
`impart chewable characteristics to the shell,
`gastroresistant substances and in special cases
`even active compounds.
`The water serves as a solvent to make a molten
`gelatin mass with a pourable viscosity at 60–70°C.
`The ratio by weight of water to dry gelatin (W/G)
`can vary from 0.7 to 1.3, depending on the vis-
`cosity of the gelatin being used. After capsule for-
`mation, most of the water is removed by drying,
`leading to finished capsules with a moisture
`content of 4–10%.
`
`201
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`
`

`
`202
`
`Chapter 11 • Formulation and physical properties of soft capsules
`
`Gelatin
`
`The gelatins used for pharmaceutical or health
`and nutrition soft capsule products are described
`by the official pharmacopoeias such as USP
`(United States Pharmacopoeia), PhEur (European
`Pharmacopoeia) etc., or approved by local author-
`ities, with additional physicochemical specifi-
`cations (Babel, 2000). The specifications and
`controls for gelatins are discussed in Chapter 2.
`For soft capsule production, the pharma-
`copoeial specifications generally represent the
`minimum
`requirements. Capsule manu-
`facturers’ specifications are more detailed and
`stringent with respect to the performance-
`related physicochemical properties of
`the
`gelatins (Reich and Babel, 2001). This is due to
`the fact that these parameters are critical for
`economic soft capsule production by the rotary
`die process and for the quality of the final
`product. Gelatin types and grades that are ade-
`quate for continuous commercial soft capsule
`production require the ability to set at a fast rate
`to ribbons of defined thickness and reproducible
`microstructure and to produce films with a
`mechanical strength and elasticity sufficient to
`survive all the manipulations on the encapsula-
`tion machine, i.e. to allow the wet films to be
`easily removed from the drums, to stretch during
`filling, to be sealed at temperatures below the
`melting point of the film and to be dried quickly
`under ambient conditions to a specified capsule
`strength. Moreover, the dissolution character-
`istics of the resulting capsules have to fulfil the
`pharmacopoeial requirements.
`
`Considering these aspects, the technologically
`relevant gelatin parameters are gel strength, vis-
`cosity at 60°C and 6–2
`3% w/w concentration in
`water, viscosity breakdown (the impact of tem-
`perature and time on the degradation of gelatin),
`melting point, setting point, setting time, parti-
`cle size and molecular weight distribution. A
`perfect soft capsule gelatin should have the
`following specifications:
`
`• Gel strength: 150–200 Bloom, depending on
`the gelatin type;
`• Viscosity (60°C/6–2
`3% w/w in water): 2.8–4.5
`mPa s, depending on the gelatin type;
`• Well-controlled degree of viscosity breakdown;
`• Well-defined particle size to allow fast dissolu-
`tion and deaeration of the molten mass, even
`at high gelatin concentrations;
`• A broad molecular weight distribution to
`provide a fast setting and the fusion tempera-
`ture being well below the melting temperature
`of the plasticized wet film.
`
`The main gelatin types and grades used for the
`manufacture of soft capsules are listed in Table
`11.1 together with their physicochemical specifi-
`cations.
`The proper choice of the gelatin type and
`grade is related to technological issues, consumer
`preference and pricing. For pharmaceutical or
`health and nutrition products, medium bloom
`limed bone (LB) gelatins, or blends of limed bone
`and pigskin (LB/PS) or limed bone, pigskin and
`limed hide gelatin (LB/LH/PS) are commonly
`used, with a certain preference for LB gelatin in
`the United States and for blended gelatins in
`
`Table 11.1
`
`Physicochemical properties of pharmacopoeial-grade soft capsule gelatins
`
`Gelatin
`
`Raw material
`
`160 LB (= limed bone)
`160 LH (= limed hide)
`160 LB/LH
`
`200 AB (= acid bone)
`200 PS (= pigskin)
`160 PS/LB/LH
`
`Bovine/porcine bone
`Bovine hide
`Blend of bovine/porcine
`bone and bovine hide
`Bovine bone
`Pigskin
`Blend of pigskin, bovine/
`porcine bone and bovine hide
`
`Type
`
`B
`B
`B
`
`A
`A
`A/B
`
`Bloom (g)
`(10°C; 6–2
`3% w/w)
`155–185
`150–170
`150–170
`
`180–210
`190–210
`145–175
`
`Viscosity (mPa s)
`(60°C; 6–2
`3% w/w)
`
`3.4–4.2
`3.5–4.2
`3.5–4.2
`
`2.7–3.2
`2.5–3.1
`2.7–3.3
`
`

`
`Europe. Low-viscosity, high-bloom gelatins such
`as a 200 Bloom pigskin (PS) or acid bone (AB)
`gelatin are often used for the encapsulation of
`hygroscopic formulations and/or water-sensitive
`drugs, where standard gelatin formulations have
`to be modified to contain less water and dry
`faster, thus improving the product stability
`during capsule manufacturing. Mixtures of low
`(⬍100 Bloom) and medium Bloom (⬎150 Bloom)
`gelatins have been proposed for the formulation
`of chewable soft capsules (Overholt, 2001) to
`achieve the desired mouthfeel and solubility of
`the shells, a low stickiness for improved machin-
`ability and sufficient integrity for stable fill
`encapsulation.
`In addition to the pharmacopoeial grade
`gelatin types listed in Table 11.1, succinylated
`pigskin gelatin (Bloom: 190–210 g; viscosity:
`3.3–4.1 mPa s) is often used for products with
`reactive fill ingredients, such as aldehydes, to
`prevent cross-linking of the shell. Gelatins
`derived from poultry, fish or other sources have
`recently been proposed in the patent literature as
`alternatives to gelatin of bovine and porcine
`origin. Poultry and fish gelatins have recently
`been approved by PhEur.
`From a technological point of view, poultry
`gelatin is a potential alternative to the con-
`ventional soft capsule gelatins derived from
`bovine and porcine origin, since its physico-
`chemical properties are comparable to those of
`pigskin gelatins. In practice, it has not gained
`high commercial interest yet because its avail-
`ability is limited.
`The use of cold- or warm-water fish gelatins for
`soft capsule production is limited by the fact that
`their gelling, setting and drying properties are
`more or less different to those of mammalian
`gelatins. Owing to their low degree of proline
`hydroxylation, cold-water fish gelatins lack the
`gelling and setting attributes that are required to
`allow their use in the conventional rotary die
`process. Although addition of a setting system,
`such as carrageenan, has been described to enable
`the adaptation of specific and desired gelling
`properties (Scott et al., 1997), this approach has
`not yet reached commercial status. Only warm-
`water fish gelatins with a somewhat higher
`degree of proline hydroxylation, and thus an
`intrinsic gelling and setting ability sufficient for
`
`Soft gelatin capsules
`
`203
`
`conventional soft capsule production, have been
`used for a small number of products. Acceptable
`soft capsules can be produced by adjusting the
`formulation and process parameters, such as the
`production speed in accordance to the reduced
`setting rates, the mechanical properties and the
`drying characteristics of this gelatin type.
`The use of plant-derived genetically engineered
`gelatins for soft capsule production is not practi-
`cable. This is mainly due to technological issues,
`supply problems, high costs and, for pharma-
`ceutical products, the regulatory issues. Only
`small amounts of gelatins, with gelling and
`setting properties and mechanical characteristics
`different to mammalian gelatins, are available at
`a multiple of the price of conventional gelatins.
`
`Plasticizers
`
`The formation of a soft capsule requires the use of
`a non-volatile plasticizer in addition to water to
`guarantee the mechanical stability, i.e. the elas-
`ticity of the capsule shells during and after the
`drying process. The additional plasticizer has to
`counterbalance the stresses that are induced in
`the shrinking capsule shells, as the plasticizing
`effect of water in the shells decreases upon drying.
`Practically, only a few plasticizers are in use,
`namely polyalcohols, which are approved by the
`official pharmacopoeias or by local regulatory
`authorities. Glycerol (85% and 98% w/w), special
`grades of non-crystallising aqueous sorbitol and
`sorbitol/sorbitan solutions and combinations of
`these are the most used. In addition, propylene
`glycol and low molecular weight polyethylene
`glycol (PEG 200) have been used.
`The type and concentration of plasticizer(s) in
`the shell is related to the composition of the fill,
`i.e. the possible interactions with the fill, the
`capsule size and shape, the end use of the product
`and the anticipated storage conditions. The ratio
`by weight of dry plasticizer to dry gelatin (P/G)
`determines the strength of the shell and usually
`varies between 0.3 and 1.0. The choice of the
`proper shell formula with respect to the gelatin/
`plasticizer combination is crucial to the physical
`stability of the capsules, during manufacture
`and on storage. A rational shell design therefore
`requires analytical tools that allow the perform-
`ance-related test parameters to be assessed.
`
`

`
`204
`
`Chapter 11 • Formulation and physical properties of soft capsules
`
`Differential scanning calorimetry (DSC) and
`dynamic mechanical thermal analysis (DMTA)
`have been reported as suitable methods to
`monitor phase transitions and elastic moduli
`indicating molecular gelatin/plasticizer interac-
`tions and their effect on shell elasticity, i.e. to
`evaluate plasticizer effectivity and compatibility
`(Reich, 1983, 1994).
`An ideal plasticizer should interact with the
`gelatin molecules in such a way as to reduce
`effectively the glass transition temperature (Tg)
`of the gelatin shell without inhibiting the for-
`mation of crystallites that stabilise the three-
`dimensional gel network structure. In addition,
`if present in concentrations higher than satura-
`tion, it should be physically embedded in the sol
`phase of the gel network to avoid bleeding out
`(Reich, 1994).
`Glycerol, the most frequently used soft gelatin
`capsule plasticizer, combines these advantages of
`a high plasticizer effectivity, a sufficient compat-
`ibility and a low volatility with the ability to
`interact specifically with the gelatin allowing for
`the formation of a stable thermoreversible gel
`network. Its plasticizing capability is mainly
`resulting from direct interactions with the gelatin
`and only slightly from its hygroscopicity allow-
`ing for an additional indirect moisturising effect
`(Reich, 1994).
`Sorbitol, on the other hand, is an indirect plas-
`ticizer, mainly acting as a moisturising agent with
`water being the effective plasticizer. Compared to
`glycerol, its direct plasticizing capability is very
`much reduced, as indicated by a minor reduction
`of the gelatin glass transition temperature.
`Gradual differences of various grades of non-
`crystallising sorbitol solutions in their plasticizing
`capability and their compatibility with gelatin
`are the result of differences in the amount of by-
`products, namely hydrogenated oligosaccharides
`and sorbitol anhydrides, i.e. sorbitans (Reich,
`1996). Only sorbitol grades with a high amount
`of sorbitans, such as Anidrisorb, can effectively
`replace glycerol owing to a certain direct plasti-
`cizing effect. On the other hand, hydrogenated
`oligosaccharides such as maltitol in combination
`with glycerol are very effective additives for the
`formulation of chewable soft gelatin capsules,
`since they augment the taste and chewability and
`assist in the rapid dissolution of the shell upon
`
`chewing, thus improving the mouthfeel (Berry
`et al., 1988; Montes and Steele, 1999).
`Regarding plasticizing capability, propylene
`glycol is superior to sorbitol/sorbitan blends and
`even to glycerol. However, owing to its high
`solvent power for gelatin, it has a slightly nega-
`tive effect on the formation of the gel structure
`that has to be compensated for by adjusting the
`manufacturing parameters at the encapsulation
`machine (Reich, 1994). Liquid polyethylene
`glycols can only be used in combination with
`glycerol or propylene glycol, since their com-
`patibility with gelatin is limited.
`
`Other additives
`
`In addition to gelatin, the plasticizer(s) and water,
`optional components in the capsule shell are
`limited in their use. For economic reasons, the
`addition of active ingredients in the shell is
`usually not recommended and limited to inex-
`pensive compounds in chewable capsules. The
`use of water-insoluble polymers to impart sus-
`tained-release characteristics to the capsules has
`failed owing to their limited compatibility with
`the gelatin mass (Reich, 1983). Formulations
`with gastroresistant enteric soluble polymers are
`under development.
`Colouring and opacifying agents are used fre-
`quently to give the shells the desired colour and
`a proper finish, i.e. to allow the shell to protect
`the fill from light and to mask the unpleasant
`look of the fill. As a general rule, the colour of the
`capsule shell is chosen to be darker than the
`colour of the fill. Before a colour is chosen, mix-
`tures should be checked to ascertain that fading
`or darkening of the capsule shells does not occur
`on storage, as a result of reactions between the
`colouring agent and other components of the
`shell or fill.
`
`Fill compositions
`
`Soft gelatin capsules can be used to dispense
`active compounds that are formulated as a liquid
`or semi-solid solution, suspension or micro-
`emulsion preconcentrate. The formulation of the
`fill is individually developed to fulfil the follow-
`ing requirements:
`
`

`
`• to optimise the chemical stability of the active
`compound
`• to improve bioavailability of the active com-
`pound
`• to allow for an efficient and safe filling process
`• to achieve a physically stable capsule product.
`
`Final product stability is related to shell compat-
`ibility and will be discussed later.
`For a soft gelatin capsule-filling operation, the
`technologically important factors to bear in mind
`are temperature, viscosity and surface activity of
`the fill material and, in the case of suspensions,
`the particle size of the suspended drug. Liquids or
`combinations of liquids for encapsulation must
`possess a viscosity sufficient to be precisely dosed
`by displacement pumps at a temperature of 35°C
`or below and may not show stringing to allow
`for a clean break from the dosing nozzle. The
`temperature specification is necessary owing to
`the sealing conditions, which are usually in the
`range of 37 to 40°C. Owing to certain tolerances
`of the encapsulation equipment, suspended solids
`should have a particle size below 200 μm to
`ensure maximum homogeneity of the suspen-
`sion. Moreover, the surface-active properties of
`the fill, whether a solution or a suspension, may
`not interfere with the formation of the seals.
`Interestingly, soft gelatin capsule fill formu-
`lations have changed over time from basic
`lipophilic to hydrophilic solutions or suspensions
`and recently to more complex self-emulsifying
`systems. The reason for these developments is
`that new chemical entities (NCEs) present increas-
`ing biopharmaceutical formulation demands.
`Basic lipophilic solutions or suspensions have
`been the traditional and most frequently used soft
`gelatin capsule fill formulations in the past. They
`have been applied successfully to formulate oily
`and lipophilic low melting point drugs such as the
`vitamins A, D and E, drugs with unpleasant taste
`and/or odour such as the vitamins of the B group
`or herbal extracts, drugs with critical stability, i.e.
`oxygen- and light-sensitive drugs and low-dose or
`highly potent drugs. The vehicles used for this
`purpose are lipophilic liquids and semi-solids, and
`the optional use of surfactants. The lipophilic
`liquids are refined speciality oils such as soya bean
`oil, castor oil etc. and/or medium chain triglyc-
`erides (MCT). The semi-solids, acting as viscosity
`
`Soft gelatin capsules
`
`205
`
`modifier for the liquid oils, are hydrogenated
`speciality oils or waxes, such as hydrogenated
`castor oil or bees wax. Surfactants such as lecithin
`may be present to improve the dispersion of sus-
`pended drug particles, thus improving content
`uniformity. Antioxidants are usually added to sta-
`bilise oxygen-sensitive drugs. Moreover, impreg-
`nation of solid polymer particles with the drug or
`drug coating prior to suspension in the oil formu-
`lation has been reported as a successful means to
`improve the content uniformity of low-dose sus-
`pended drugs and further increase chemical
`stability of sensitive drugs. Examples are vitamin
`B12 (Sanc et al., 2000) and retinol (Rinaldi et al.,
`1999).
`Hydrophilic soft gelatin capsule fill formu-
`lations are based on polyethylene glycols (PEGs).
`Low molecular weight polyethylene glycols are
`usually used for liquid solutions, with PEG 400
`and PEG 600 being the most frequently used. For
`the formulation of semi-solid solutions and sus-
`pensions, the low molecular weight polyethylene
`glycols (PEG 300–600) are mixed with high mol-
`ecular weight solid polyethylene glycols, such as
`PEG 4000–10 000, to increase the viscosity.
`PEG-based formulations are often chosen to
`address bioavailability concerns, i.e. to improve
`the solubility of poorly soluble drugs, or to
`dispense low-dose and/or high-potency drugs.
`Digoxin (Gardella and Kesler, 1977; Ghirardi
`et al., 1977), nifedipin (Radivojevich et al., 1983),
`temazepam (Brox, 1983) and ibuprofen (Gulla-
`palli, 2001) are active compounds that have been
`successfully formulated as PEG solutions in soft
`gelatin capsules.
`Complex self-emulsifying lipophilic systems
`and microemulsion preconcentrates are additional
`approaches that have gained increasing interest
`as soft gelatin capsule fill formulations to increase
`the bioavailability and/or reduce the plasma vari-
`ability of poorly soluble and/or poorly absorbed
`drugs (Charman et al., 1992; Amemiya et al., 1998,
`1999). These systems are typically composed of a
`lipophilic solvent and surfactant(s), and optional
`use of co-solvent(s) and/or co-surfactant(s), and
`may exert solubilising and absorption-enhancing
`effects. On contact with aqueous gastrointestinal
`fluids, these formulations spontaneously produce
`an emulsion with an average droplet size of less
`than 100 nm, thus improving drug delivery.
`
`

`
`206
`
`Chapter 11 • Formulation and physical properties of soft capsules
`
`Active compounds that have been successfully
`formulated as a microemulsion preconcentrate
`in softgels are ciclosporin and the protease
`inhibitor ritonavir. A patent has also been filed
`for ibuprofen (Rouffer, 2001). Examples of micro-
`emulsion pre-concentrate soft gelatin capsule fill
`formulations are given in Table 11.2, indicating
`the use of hydrophilic co-solvents such as ethanol
`and propylene glycol.
`
`Formulation strategies
`
`Soft gelatin capsule formulation strategies have
`to consider the specific shell/fill interactions that
`may occur during manufacture, drying and on
`storage and control their rate and extent to
`achieve a stable product.
`Two major types of interactions have to be dis-
`tinguished:
`
`• Chemical reactions of fill components with
`the gelatin and the plasticizer
`• Physical interactions, i.e. migration of fill
`components in or through the shell and vice
`versa.
`
`Cross-linking of gelatin leading to solubility
`problems of the shell is a well-known problem
`associated with the encapsulation of drugs con-
`taining reactive groups such as the aldehyde
`group. It can be successfully reduced by the use of
`succinylated gelatin, an approach that is often
`
`used for health and nutrition products, and in
`some countries even for pharmaceutical products.
`Esterification and transesterification of drugs
`with polyols present another unwanted chemical
`reaction that may occur. Since glycerol is more
`reactive than other polyols, glycerol-free shell
`formulations and/or the addition of polyvinyl
`pyrrolidone to the fill (Gullapalli, 2001) are pre-
`ferred to reduce this problem.
`The rate and extent of physical shell/fill inter-
`actions depend strongly on the qualitative and
`quantitative composition of both, the shell and
`the fill. As a general rule, the water content of the
`fill should not exceed a critical value of about 5%.
`Fill formulations simply composed of a lipo-
`philic drug in a lipophilic oily vehicle do not
`interact with the hydrophilic gelatin capsule
`shell at any time, i.e. either during production or
`on storage. The proper choice of the shell com-
`position therefore only depends on the stability
`of the active ingredient, the capsule size, shape
`and end use and the anticipated storage con-
`ditions. For very soft capsules and those stored at
`ambient conditions, glycerol is the plasticizer of
`choice. For more rigid soft gelatin capsules and
`those intended to be used in hot and humid
`climates, glycerol/sorbitol blends are preferred.
`The latter is also valid for soft capsules contain-
`ing oxygen-sensitive compounds in the fill (Hom
`et al., 1975; Meinzer, 1988). In any case, the P/G
`ratio is adjusted to the size and intended use of
`the capsules. To obtain light protection, the shell
`
`Table 11.2
`
`Examples of microemulsion preconcentrate compositions for soft gelatin capsules
`
`Active ingredient
`
`Ciclosporin
`
`Ritonavir
`
`Fill excipients
`
`Ethanol
`Propylene glycol
`Mono-, di-, triglycerides from corn (maize) oil
`Polyoxyethylene (40) hydrogenated castor oil
`DL-alpha-tocopherol
`Ethanol
`Propylene glycol
`Polyoxyethylene (35) castor oil
`Polysorbate 80
`Polyoxyethylene/glyceryl mono-, di-, tri-alcanoate (C8–C18)
`Medium chain triglycerides
`Citric acid
`
`

`
`can be formulated with pigments such as tita-
`nium dioxide and/or iron oxides.
`Compared to lipophilic solutions, fill compo-
`sitions with hydrophilic components are more
`challenging to encapsulate, since they are prone
`to interact with the shell (Armstrong et al., 1984,
`1985, 1986). The most critical period for diffu-
`sional exchanges between shell and fill is the
`manufacturing process, since the moisture
`content of the initial shells before drying is
`around 40% and the equilibrium moisture level is
`only reached after several days. Thus, during
`manufacture and drying, hydrophilic com-
`ponents of the fill may migrate rapidly into the
`shell and vice versa, thereby changing the initial
`composition of both, the shell and the fill
`(Serajuddin et al., 1986). On storage, these pro-
`cesses may continue until equilibrium is reached.
`As a result, the capsule shells can become brittle
`or tacky and the fill formulation may be deterio-
`rated, either shortly after production or on
`storage. To guarantee the stability of the final
`product, the initial composition of shell and fill
`has to be designed in such a way as to minimise
`exchange processes. Several approaches
`to
`demonstrate the proof of this concept will be
`discussed as follows.
`Hydrophilic and/or hygroscopic drug particles
`suspended in an oily vehicle may attract and
`retain water from the shell and/or migrate them-
`selves into the shell. This can lead to stability
`problems such as hydrolysis or oxidation of the
`active ingredient, to assay failure and/or shell dis-
`coloration. To overcome these problems, the
`following solutions have been proposed:
`
`• Use of high-Bloom, low-viscosity pigskin or
`acid bone gelatin to reduce the initial water
`content in the capsule shell and accelerate the
`drying process;
`• Replacement of glycerol by glycerol/sorbitol
`or sorbitol/sorbitan blends
`to minimise
`diffusion of glycerol-soluble active ingredients
`into the shell;
`• Coating of drug particles to inhibit the brown-
`ing reaction between active ingredients, such
`as ascorbic acid and gelatin (Oppenheim and
`Truong, 2002).
`
`Considerable difficulties have been encoun-
`tered with the design of physically stable and
`
`Soft gelatin capsules
`
`207
`
`durable soft capsules containing liquid poly-
`ethylene glycols (PEG 300–600) as the fill vehicle.
`This is owing to the fact that polyethylene glycols
`have a high affinity for water, glycerol and even
`gelatin, i.e. they have a high tendency to attract
`water and glycerol from the shell and may
`migrate to a certain extent into the shell. As a
`result of these processes, capsules may become
`brittle shortly after production or on storage,
`especially when exposed to cold temperatures
`(Shah et al., 1992). Several approaches have been
`reported in the patent literature to provide PEG-
`containing soft capsules, in which the optimum
`shell strength and elasticity and the desired con-
`stitution of the fill, adjusted after production,
`remain unchanged on storage (Brox, 1983, 1988).
`EP 0 121 321 (Brox, 1983) describes the com-
`bined use of glycerol and a sorbitol/sorbitan
`blend, namely Anidrisorb 85/70, as shell plasticiz-
`ers. At the same time the addition of minor
`amounts of glycerol and/or propylene glycol to
`the liquid PEG fill is proposed. The combination
`of these two strategies prevents capsule shell
`embrittlement, since exchange processes between
`shell and fill are reduced to a minimum. The tend-
`ency of PEG to migrate into the shell is signifi-
`cantly reduced owing to the fact that PEG is less
`soluble in the sorbitol/sorbitan blend than in glyc-
`erol. On the other hand, the excess of plasticizer
`in the fill prevents the glycerol from migrating
`from the shell into the fill (Shah et al., 1992; Reich,
`1996). US 4 744 988 (Brox, 1988), an extended
`version of EP 0 121 321, recommends the selec-
`tion of PEG 600 with a higher molecular weight
`and a lower hygroscopicity compared to PEG 400
`as an additional means of reducing shell/fill inter-
`actions and improving capsule shell elasticity.
`Microemulsion preconcentrates, comprising
`hydrophilic co-solvents such as propylene glycol
`and/or ethanol, in addition to oil(s) and surfac-
`tant(s), are another type of fill composition with
`challenging demands on the soft gelatin formu-
`lation concept. The hydrophilic co-solvents are
`prone to migrate into the shell, with propylene
`glycol softening the shell and ethanol volatilising
`through the shell, thereby upsetting the fill
`formulation in such a way as to change its solu-
`bilising and/or emulsifying properties.
`The problems associated with propylene glycol
`may be solved by adjusting the shell formulation
`
`

`
`208
`
`Chapter 11 • Formulation and physical properties of soft capsules
`
`in such a way as to reduce the tendency of propy-
`lene glycol to migrate, during production and on
`storage, by using it as a plasticizer component in
`the shell and adjusting the manufacturing con-
`ditions at the drums to reduce tackiness of the
`ribbons (Brox et al., 1993; Woo, 1997). An
`additional benefit of this approach is, that the
`amount of water required for dissolving and
`melting the gelatin may be reduced owing to the
`lower viscosity of propylene glycol compared to
`glycerol and sorbitol solutions, thus reducing the
`overall water exchange between shell and fill.
`The problems associated with the use of a
`volatile solvent such as ethanol are more difficult
`to solve. To prevent volatilisation of ethanol, the
`finished capsules have to be enclosed in a solvent-
`tight packaging material such as an aluminium
`blister. Moreover, replacement of glycerol by
`higher polyols such as xylitol, sorbitol, sorbitol/
`sorbitan blends and/or hydrogenated starch
`hydrolysates has been reported as an effective
`means of reducing the rate and extent of ethanol
`diffusion into the shell (Reich, 1996; Moreton and
`Armstrong, 1998). In certain cases, however, both
`approaches may not be sufficient to prevent fill
`deterioration, since ethanol diffusion cannot be
`fully prevented. Thus, for a microemulsion pre-
`concentrate formulation that is very sensitive to
`the co-solvent concentration, the only way to
`overcome the problem at present, is the use of a
`co-solvent other than ethanol, that is not volatile
`and does not show any diffusion into the capsule
`shell. For ciclosporin microemulsion preconcen-
`trate soft capsules, such approaches have been
`filed in two patents, namely a European Patent
`Application (Woo, 1995) describing the use of
`dimethylisosorbide and a US Patent Application
`(Shin et al., 2000) that describes the use of a
`microemulsion preconcentrate containing a
`lipophilic instead of a hydrophilic co-solvent.
`
`Post-treatments and coatings
`
`Soft gelatin capsules may be post-treated after pro-
`duction or coated to improve product stability, to
`modify the dissolution rate and to enable enteric
`capsules to be produced. Several patents have
`been filed describing the use of protective coat-
`ings to overcome the stability problems of soft
`
`capsules arising from the hygroscopic nature and
`heat sensitivity of the soft capsule shell. However,
`most of these attempts have failed in practice,
`since coating of soft capsules is not an easy task.
`The low surface roughness of soft capsule shells
`and the intrinsic insolubility of the shell com-
`ponents in organic solvents means that coatings
`applied as an organic solution usually do not
`adhere properly to the capsules, resulting in
`onion-like coatings of layers peeling off immedi-
`ately after drying or on storage. Aqueous coatings,
`on the other hand, may result in capsule swelling,
`softening and/or sticking together, since water is
`acting as a plasticizer for the gelatin capsule shells.
`To balance the two extremes, emulsion-based
`formulations or solutions in a mixture of water
`and alcohol have been recommended (Osterwald
`et al., 1982). The technological approach of choice
`for soft capsules to be coated is using the fluidised-
`bed air-suspension technique.
`Capsules with modified dissolution character-
`istics, such as gastroresistant enteric soft gelatin
`capsules, have been described in the scientific
`and patent literature and can be achieved by
`adding gastroresistant, enteric-soluble polymers
`to the gelatin mass prior to capsule formation, or
`by aldehyde post-treatment or enteric coating of
`the dried capsules. All three attempts have their
`specific difficulties. For soft gelatin capsules pro-
`duced by the rotary die process, the last two
`approaches are in practical use.
`Aldehyde post-treatment of soft gelatin cap-
`sules has been known for many years as a popular
`means to reduce their dissolution rate, i.e. the
`capsules take a long time to dissolve and have left
`the stomach before this occurs. Formaldehyde
`has been described to cross-link effectively soft
`capsules to render them gastroresistant. Since
`safety questions have been raised about the
`presence of trace amounts of formaldehyde in
`foods and pharmaceuticals, the use of aldehydes
`without health concerns such as aldoses have
`been claimed in a patent (Fischer, 1986) and are
`actually used. The major disadvantage of any
`aldehyde treatment of soft gelatin capsules is that