. '
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`PROT~IN·BA~~D
`filM~ an~ COATING~
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`CRC PRESS
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`

`

`Soft Gelatin Capsules
`
`CHAPTER 16
`
`ARISTIPPOS GENNADIOS
`
`INTRODUCTION
`
`SOFT gelatin capsules are one-piece, hermetically sealed soft gelatin shells
`
`containing a liquid, a suspension, or a semi-solid (Figure 16. 1) (Hom and
`Jimerson, 1990; Wilkinson and Hom, 1990). In contrast to the rigid two-piece
`hard gelatin capsule shells, soft gelatin capsule shells contain large amounts of
`plasticizers, which make them flexible. Similar to hard gelatin capsules, they are
`solid dosage forms intended mainly for oral administration, although they may
`also be used as rectal or vaginal suppositories. In the late 1980s, a trade associa(cid:173)
`tion comprised of soft gelatin manufacturers in the U.S. introduced the name
`"softgels" to further distinguish this dosage form from hard gelatin capsules.
`Softgels are formed, fi lled, and sealed in a continuous operation, which has
`been most cost-effective for a few contract manufacturers (Hom and Jimerson,
`1990). The list of companies operating softgel manufacturing facilities in
`North America in 2000 includes Banner Pharmacaps (High Point, NC), R.P.
`Scherer (Basking Ridge, NJ), Accucaps Limited (Windsor, Ontario, Canada),
`Soft Gel Technologies (Los Angeles, CA), Pharmavite ( Mission Hills, CA),
`Nutricia Manufacturing USA (Greenville, SC), Goldcaps (Miami, FL),
`Capsule Works (Bayport, NY), Tishcon Corporation (Westbury, NY), IVC In(cid:173)
`dustries (Freehold, NJ), Swiss Caps (Miami, FL), Gelcell Capsules Limited
`(Tecumseh, Ontario, Canada), Captek Softgellnternational (Cerritos, CA), and
`National Vitamin Company (Po rterville, CA). At present, the number of in-
`
`393
`
`0003
`
`

`

`394
`
`SOFT GELATIN CAPSULES
`
`Figure 16.1 Softgeb manufactured u;,ing the rotary die encapsulation process.
`
`stalled soft gel e ncapsul ation lines/machines in North America is estimated at
`250. This chapte r discusses the advantages, limitatio ns, uses. and manufactur(cid:173)
`ing of softgels. Gelatin-enro bed and gelatin-coated table ts/caplets also are
`briefly discussed.
`
`NATURE AND USES
`
`HISTORICAL BACKGROUND
`
`The Fre nch pharmacists Mothes and DuBianc are credited with developing
`the softgel dosage form in the 1830s (Ho m and Jimerson, 1990). They patented
`a method of preparing capsules by dipping a mercury-fill ed leather sac into
`molte n gelatin . The gelatin coating was allowed to solidify, the sac was re(cid:173)
`moved , and medications were added to the capsu le with a pipette (Horn and
`Jimerson. 1990; Wilkinson and Hom, 1990). The capsule was then hand-sealed
`with molte n gelatin. Altho ugh iron molds were later introduced, this tedious
`soft gel pre paration method had high fi II variations and yield losses, and was not
`commercially viable.
`
`0004
`
`

`

`Nature and Uses
`
`395
`
`Later, a plate method was developed that made the commercialization of
`softgels viable. This batch process used two sets of metallic plates with match(cid:173)
`ing cavities. A gelatin sheet was cast on the surface of the lower die plate, vac(cid:173)
`uum was applied to pull the sheet into the die pockets, medication was filled
`into the formed pockets, a second gelatin sheet was laid on top, and the two
`plates were pressed together to form and separate the capsules (Hom and
`Jimerson, 1990). The plate method was used for many years by The Upjohn
`Company (Kalamazoo, Ml) until it was discontinued in 1989 (Wilkinson and
`Hom, 1990).
`In the early 1930s, Robert P. Scherer invented the continuous rotary die en(cid:173)
`capsulation process for large-scale manufacturing of softgels (Scherer, 1934).
`Over the years, this process has undergone various modifications and improve(cid:173)
`ments in automation and has become the industry standard worldwide (Ebert,
`1977). The concept of the Scherer process was the basis for two additional pro(cid:173)
`cesses suitable for fill ing softgels with powders and pelleted formulations.
`One, the Accogel process, was developed by Lederle Laboratories in 1948, and
`the other, the reciprocating die process, was developed by the Norton Company
`in 1949 (Hom and Jimerson, 1990; Wilkinson and Hom, 1990). Today, the vast
`majority of encapsulating machines operating around the world are cus(cid:173)
`tom-manufactured based on the Scherer concept and are self-maintained by the
`softgel manufacturers. However, "tum-key" softgel manufacturing systems
`have become available in recent years, thus lowering the technological barrier
`for entry into the soft gel business (at least for dietary supplements, such as oils
`and vitamin E, which require minimal fill formulation expertise).
`
`ADVANTAGES OF SOFTGELS
`
`The following are generally recognized as functional and commercial ad(cid:173)
`vantages of the soft gel as a dosage form for administering pharmaceutical and
`dietary formulations:
`
`(I) Softgels generally exhibit enhanced dissolution rates of encapsulated bio(cid:173)
`logically active compounds because they absorb water, open at the seams,
`disintegrate, and rapidly release their contents (Hom and Miske!, 1970,
`1971 ). The elevated body temperature accelerates the rapid in vivo release
`of the softgel contents because some degree of gel melting occurs.
`(2) Biologically active compounds with poor water solubility can be
`solubilized or dispersed in oils or aqueous-miscible liquids within the
`softgels. Upon ingestion, the capsule shell disintegrates, and the fill formu(cid:173)
`lation dissolves or emulsifies, yielding dispersions of high surface area and
`good bioavailability (Berry, 1983 ; Seager, 1985; Karunakar, 1998). The
`enhanced bioavailability of several pharmaceutical compounds adminis(cid:173)
`tered within softgels compared to hard gelatin capsules and/or tablets has
`
`0005
`
`

`

`396
`
`SOFT GELATIN CAPSULES
`
`been demonstrated (Mallis et al., 1975; Angelucci et al., 1976; Ghirardi et
`al., 1977; Lindenbaum, 1977; Lucchelli et al., 1978; Stella et al., 1978;
`Alvisi et al., 1979; Astorri et al., 1979; Nitsche and Mascher, 1982;
`Helqvist et al., 1991; Gumkowski et al., 1994). However, other studies re(cid:173)
`ported no significant differences in the bioavailability of various pharma(cid:173)
`ceutical compounds administered within softgels versus hard gelatin
`capsules and/or tablets (Albert et al., 1974; Fuccella et al., 1977; Steinbach
`et al., 1980a, b; Pierce et al., 1984 ).
`(3) The improved bioavailability of compounds delivered within softgels al(cid:173)
`lows for administering lower dosages, thus resulting in reduced raw mate(cid:173)
`rial costs (Seager, 1985).
`(4) Compounds sensitive to oxidation can be protected through solubilization
`or dispersion in oils or aqueous-miscible liquids within the softgels
`(Seager, 1985). In addition, the gelatin shell is a potent oxygen barrier
`(Hom et al., 1975; Anonymous, 1992), as is generally the case with pro(cid:173)
`tein-based films (at least at low relative humidity conditions) (Gennadios
`et al., 1993).
`(5) The softgel manufacturing process often allows for higher dosage accuracy
`and content uniformity than other oral dosage forms (Berry, 1982).
`(6) Highly potent (e.g., cytotoxic) compounds present health and safety con(cid:173)
`cerns with the resulting airborne particles during tableting. Such concerns
`can be alleviated by introducing the compounds into liquid formulations
`and encapsulating them into softgels.
`(7) Although not tamper-proof, softgels are both tamper-evident and tam(cid:173)
`per-resistant. Puncturing the softgel shell, introducing a contaminant, and
`resealing the shell without resultant leakage or signs of alteration is a
`highly difficult task (Berry, 1982; Hom and Jimerson, 1990).
`(8) Unpleasant tastes and odors of active compounds are masked by the cap(cid:173)
`sule shell (Ebert, 1977; O' Brien, 2000).
`(9) There is a high degree of flexibility in selecting soft gel sizes, shapes, and
`colors, which, combined with capsule printing capabilities, offers wide op(cid:173)
`portunities for product identification and differentiation (Stanley, 1986;
`Schofield, 1999).
`( I 0) As an oral dosage form, softgels typically rate high in consumer preference
`because of their elegance, ease of swallowing, and strong perceived effec(cid:173)
`tiveness due to their liquid fill formulations (Berry, 1983; Schofield, 1999).
`
`LIMITATIONS OF SOFTGELS
`
`The following are often identified as limitations of the softgel dosage form
`and technology:
`
`0006
`
`

`

`Nature and Uses
`
`397
`
`(I) The softgel manufacturing process is slower than tableting.
`(2) Softgels require intensive inspection due to several potential defects, such
`as capsules that leak, have shape imperfections, or are stuck together.
`(3) The lengthy drying process substantially extends the manufacturing cycle
`of softgels.
`(4) Operation of softgel encapsulation machines requires experienced person(cid:173)
`nel.
`(5) The encapsulation process is not fully automated in terms of monitoring
`in-process parameters, such as capsule seal strength and wet shell thickness
`or weight.
`(6) Although the softgel encapsulation process allows for accurate dosing and
`thus economical use of the fill material, it results in a notable waste of shell
`formulations (about 30% ).
`(7) Due to increased labor requirements, softgels are generally produced at a
`higher cost than directly compressed tablets.
`(8) Prior to drying, softgel shells have a high moisture content, which allows for
`increased interactions among shell and fill ingredients.
`
`ENCAPSULATED MATERIALS
`
`Pharmaceutical Compounds
`
`Both over-the-counter (OTC) and ethical (prescription; Rx) drugs are en(cid:173)
`capsulated and marketed in softgels. It is noted that few facilities worldwide
`have the necessary technical expertise and regulatory approvals for manufac(cid:173)
`turing softgels containing drugs, particularly ethical drugs. The categories of
`OTC drugs
`typically available
`in softgels
`include analgesics (e.g.,
`acetaminophen); anti-inflammatory agents (e.g., ibuprofen); antihistamines
`(e.g., chlorpheniramine maleate, brompheniramine maleate, doxylamine
`succinate, and diphenhydramine hydrochloride); stool softeners (e.g., docusate
`salts); decongestants (e.g., pseudoephedrine hydrochloride); antitussive agents
`(e.g., dextromethorphan hydrochloride); expectorants (e.g., guaifenesin); and
`antiflatulents (e.g., simethicone). Combinations of two or more active com(cid:173)
`pounds are quite common, particularly in formulating cough and cold medica(cid:173)
`tions.
`The ethical drugs that have been or are currently formulated within softgels
`cover a wide range of therapeutic indications and include nifedipine
`(antianginal), valproic acid (anticonvulsant), benzonatate (antitussive),
`isotretinoin (treatment of severe recalcitrant nodular acne), amantadine hydro(cid:173)
`chloride (antiviral and antiparkinsonian), calcitriol (hypocalcemia manage(cid:173)
`ment), ergocalciferol (treatment of refractory rickets and hypoparathyroidism),
`
`0007
`
`

`

`398
`
`SOFT GELATIN CAPSULES
`
`etoposide
`(antibacterial),
`amoxycillin
`(antibacterial),
`cephalexin
`(antineoplastic), cyclosporine (immunosuppressant), ritonavir (HIV protease
`inhibitor), ethosuximide
`(anticonvulsant), chloral hydrate
`(sedative),
`dronabinol (cannabinoid; complex effects on central nervous system),
`ethchlorvynol (hypnotic), and ranitidine hydrochloride (ulcer treatment).
`
`Dietary Supplements
`
`A wide array of traditional dietary supplements and compounds associated
`with supplement-style structure/function claims-regulated in the U.S. by the
`Food and Drug Administration (FDA) under the Dietary Supplement Health
`and Education Act of 1994 (DSHEA)-are currently available in softgels in(cid:173)
`cluding the following:
`
`( I) Vitamins (mainly oil-soluble such as vitamins A, D, and E), minerals (e.g.,
`calcium as calcium carbonate and chromium as chromium picolinate), and
`multi-vitamin and multi-mineral combinations
`(2) Antioxidants (e.g., grape skin extract, alpha-lipoic acid, rosemary extract,
`astaxanthin, and coenzyme QlO)
`(3) Phospholipids (e.g., lecithins)
`(4) Carotenoids (e.g., lycopene and lutein)
`(5) Oils that are rich in essential fatty acids (e.g., flaxseed oil, borage oil, eve(cid:173)
`ning primrose oil, and black currant seed oil) or omega-3 fatty acids (e.g.,
`marine oils)
`(6) Herbal supplements (e.g., saw palmetto, aloe vera, panax ginseng, Siberian
`ginseng, St. John's wort, valerian, kava, maca, echinacea, eat's claw, dong
`quai, elderberry, ginkgo biloba, goldenseal, black cohosh, horsechestnut,
`olive leaf, and milk thistle)
`(7) Enzymes (e.g., lactase)
`(8) Amino acids and protein hydrolyzates
`
`In addition to dietary supplements and herbals, which also are widely re(cid:173)
`ferred to as nutraceuticals, traditional food items and food processing ingredi(cid:173)
`ents (e.g., cooking oils, peanut butter, tallow, butter, sauces, and chocolate
`syrup) also have been encapsulated into softgels to form single-use, sin(cid:173)
`gle-dosage packages (Yamada and Makino, 1986; Anonymous, 1992). How(cid:173)
`ever, such a use of soft gels has remained a niche application with limited com(cid:173)
`mercialization.
`
`Personal Care Products
`
`Bath oils are the most common personal care products marketed in softgels.
`
`0008
`
`

`

`Nature and Uses
`
`399
`
`The functional properties of gelatin are well suited for suc h products (bath
`beads) because the plasticized gelatin shells quickly swell and then dissolve in
`contact with hot water, thus releasing the aromatic oils. In addition, softgels
`also are used as single-dose packages for higher value cosmetic formulations
`intended for topical use. Typically, such softgels have a "twist-off' or
`"break-off' feature at one end for dispensing the fill material (Spellman et at.,
`1991 ; Rinaldi et at., 1999). For example, Melnik et at. ( 1992) described the en(cid:173)
`capsulation of cosmetic compositions (e.g., sun screens, tanning agents, skin
`care, and anti-dandruff agents) using silicone polymers as carriers. Punto et al.
`( 1996) disclosed a skin-treating formulation incorporated into softgels in the
`form of an emulsion comprised of a water-soluble active ingredient (e.g .• ascor(cid:173)
`bic acid). polyethylene glycol, and an oil (e.g, silicone, paraffin, or vegetable
`oil). Lambrechts ( 1996) described a shampoo/conditioner formulation in a
`softgel that included a concentrated surfactant, a cationic conditioner, and a
`carrier (e.g .• polyethylene glycol). Morton et at. ( 1997) discussed fra(cid:173)
`grance-containing softgels intended primarily for dispensing as perfume test(cid:173)
`ers or samples. Lambrechts ( 1997) described skin conditioning compositions
`that were comprised of hydroxy and/or keto acids, a thixotropic agent, and an
`emulsifying agent (e.g., glyceryl monoesters of long-chain fatty acids) and
`were suitable for encapsulation into softgels. Skin lotion compositions contain(cid:173)
`ing vitamin E and/or vitamin A palmitate that were encapsulated into softgels
`were described by Fishman ( 1998). Softgel fill formulations intended for skin
`care that contained retinol-impregnated microparticles and, optionally, ascor(cid:173)
`bic acid-impregnated microparticles were described by Rinaldi et at. ( 1999).
`
`Recreational Products
`
`Over the past 25 years. paintballs have emerged as an important application
`for softgels. The paintballs are softgels containing dyes in an oil (Haman and
`Schmoke, 1987), polyoxyethylene sorbitol monolaureate (Skogg, 1987), or
`polyethylene glycol (Rouffer, 1995) vehicle. They are fired from compressed
`air guns, including rapid firing devices, during adult war games or training and
`target shooting. Upon impact, the paintballs readily crush, thus "splattering"
`the contained dyes and marking the hit target. The paintball sport or recre(cid:173)
`ational activity started in the U.S. in the 1970s and has been growing in popular(cid:173)
`ity, both in the U.S. and overseas, ever since. In addition to recreational prod(cid:173)
`ucts, other niche industrial applications of softgels have been commercialized
`over the years. Examples include tube-shaped softgels filled with glue or tech(cid:173)
`nical grade grease, and round-shaped softgels filled with starter fluid for trucks.
`
`SHAPES AND SIZES
`
`Hard gelatin capsules are mainly produced in traditional oblong shapes and
`
`0009
`
`

`

`400
`
`SOFT GELATIN CAPSULES
`
`in eight different sizel.. In contral.t, softgels for oral administration a re manu(cid:173)
`factured in oval, oblong, and round shapes (Figure 16.2) and are able to accom(cid:173)
`modate a wide range of fill volumes. The nominal fill volume in minims is tra(cid:173)
`ditionally used to indicate the size of a softgel. A minim is I /60 of a fluid dram
`(I fluid dram = 1/8 fluid ounce). Thus, a I cm3 volume corresponds to approxi(cid:173)
`mately 16.2 minims. Ove rall. softgels can range in !>ize from I to 480 minims.
`Fo r oral consumption in particular. oval-, oblong-. and round-shaped softgels
`typically range in size from 2 to 16, 3 to 24, and 2 to 9 minims, respecti vely.
`Sample calculations used for determining the minimum fill volume of a
`softgel product based on the desired active dose and the necessary excipients
`were presented by Stanley ( 1986). Fill formu lations sho uld result in a softgel of
`the smallest possible size so that raw material usage. ma nufacturing output, and
`patient compliance are optimized. To some extent, the capsule shell can shrink
`to the volume of its conte nts w ithout negati vely affecting product appearance.
`This o ffers sufficient leeway for filling a capsule with a lesser than the no minal
`volume. According to Stanley ( 1970). this leeway for smalle r volume filling is
`I 0, 20. or 30% o f the nominal capacity for oblo ng, oval, or round capsules, re(cid:173)
`specti vely. In contrast, overfilling is not recomme nded because it can affect
`product appearance and stress the capsule seams leading to leakage and possi(cid:173)
`bly rupture. Also, overfilled products can cause problems in post-processing
`operations such as blister packaging.
`In addition to the traditional oval, oblong, and ro und shapes used for human
`consumption, softgels also are manufactured in a wide variety of shapes for
`personal care products. For example, bath oil softgels o ften are marketed in the
`shapes of a nimals, seashells, stars, hearts. teardrops. a nd triangles. Bath oil
`soflgels with a partially or fu lly textured o ute r surface also are manufactured.
`This surface texture can be applied on the ca t. mo lda ble gelatin ribbons
`
`Figure 16.2 Examples of differently s haped softgels. From left to right: oval. oblong. round. and a
`tube with the "twi>t-off" feature .
`
`0010
`
`

`

`Nature and Uses
`
`401
`
`through contact with a roller having a textured surface (Ratko eta!., 1993). An(cid:173)
`other method for enhancing softgel appearance and differentiation was de(cid:173)
`scribed by Schurig et a!. ( 1997). They produced color-striped or marblelized
`softgels by using patterned gelatin ribbons. Stone (1998) described the manu(cid:173)
`facture of softgels having a filled and a non-filled portion with one or both por(cid:173)
`tions carrying impressed graphical representations (Stone, 1998). Single-use
`softgels containing cosmetic formulations for topical application are marketed
`in the form of tubes (regular, oval, or round) with a "break-off' or "twist-off'
`feature (Figure 16.2). Finally, softgel suppositories are typically manufactured
`in bullet-like shapes.
`
`FILL FORMULATION ASPECTS
`
`Details on softgel fill formulations are beyond the scope of this chapter, and
`only a few general considerations are discussed here. A comprehensive discus(cid:173)
`sion on the nature of soft gel contents was presented by Stanley ( 1986). Further(cid:173)
`more, substantial information on softgel fill formulation approaches, often tar(cid:173)
`geted to a specific active compound, is available in the patent literature
`(Grainger, 1980; Stoopak et a!., 1982; Shah et a!., 1984; Henmi eta!., 1987;
`Brox, 1988a, b; Yu et al., 1991 ; Torosian, 1992; Makino eta!., 1993; Shelley et
`a!., 1996; Tanner and Shelley, 1996; Vasquez, 1997; Cimi1uca, 1997; Woo,
`1997; Becourt et al., 1998; Cody et al., 1999; Devlin and Hoy, 1999; Goldman,
`2000; Hong eta!., 2000; Hoy, 2000; Lacy et al. , 2000; Rouffer, 2000). Fill for(cid:173)
`mulations intended specifically for chewable softgels also have been discussed
`in the patent literature (Steele and Montes, 1999; Lech, 2000).
`
`Fill Materials
`
`With the rotary die encapsulation process, the capsule contents are typically
`a liquid or a combination of miscible liquids; a solution of a solid(s) dissolved
`in a liquid(s); or a suspension of a solid(s) in a liquid(s) (Stanley, 1986). Rotary
`die apparatuses for encapsulating solids into softgels have been developed
`(Rowe, 1998) but have found limited application thus far. A large number of
`liquids that are either actives themselves or function as solubilization excipi(cid:173)
`ents for solid actives can be encapsulated. Such liquids that can be encapsulated
`without any limitations include water-immiscible liquids (e.g., vegetable oils,
`aromatic oils, aromatic and aliphatic hydrocarbons, chlorinated hydrocarbons,
`ethers, esters, alcohols, and organic acids) and water-miscible, non-volatile liq(cid:173)
`uids (mainly limited to polyethylene glycols and non-ionic surfactants such as
`polysorbate 80) (Ebert, 1977; Stanley, 1986).
`A few other water-miscible and relatively non-volatile liquids, such as glyc(cid:173)
`erin and propylene glycol, can be included in fill formulations but only in small
`
`0011
`
`

`

`402
`
`SOFT GELATIN CAPSULES
`
`amounts (not more than 5-10% of the total liquid in the fill) (Stanley, 1986).
`Typically, water itself cannot be present in the fill at more than 8%
`(Sundararajan et al., 1996). However, a method to encapsulate fills with up to a
`20% water content was described by Miske) et al. (1974). They prepared fill
`formulations by incorporating active compounds into aqueous solutions of gel(cid:173)
`ling proteins (e.g., collagen, gelatin, soy protein, egg albumin, and casein). The
`gelling proteins formed fluid macromolecular gel matrices, and, upon drying of
`the softgels, these matrices set into rigid gels that retained as much as 20% wa(cid:173)
`ter (Miske) et al., 1974). Addition of colloidal silica into fill formulations (0 .5
`to 10% by weight) to immobilize water also was suggested for encapsulating
`fills having a high water content (Altmann, 1995).
`Solid compounds that are poorly soluble in the abovementioned liquids can
`be encapsulated by being formulated into stable, homogeneous suspensions.
`To achieve good content uniformity and stability. the particle size of suspended
`solids typically should not exceed 80 mesh ( 180 Jlm) (Hom and Jimerson,
`1990). The suspending medium (referred to as the base, carrier, or vehicle) is
`typically a vegetable oil (e.g., soybean oil}, a combination of a vegetable oil and
`a surfactant, a non-ionic surfactant (e.g., polysorbate 80), or polyethylene gly(cid:173)
`col (PEG, 400 or 600 molecular weight} (Stanley, 1986). PEG having a lower
`molecular weight (e.g., 200) is avoided because it can easily migrate into the
`gelatin shell over time causing overplasticization (softening). To facilitate the
`complete wetting of solids by oil bases, a wetting agent (often lecithin) is added
`at 2- 3% by weight of the oil (Stanley, 1986). Suspensions also require a sus(cid:173)
`pending agent to ensure homogeneity (content uniformity) and good flow char(cid:173)
`acteristics (Ebert, 1977). Typical suspending agents for oil suspensions are
`waxes (e.g., beeswax and paraffin wax), stearates, and cellulose ethers (Ebert,
`1977; Stanley, 1986). For non-oil suspending mediums, PEGs of high molecu(cid:173)
`lar weight (e.g., 4000 and 6000), glycol esters, and acetylated monoglycerides
`are generally used as suspending agents (Ebert, 1977; Stanley, 1986).
`
`Umitations
`
`There are several limitations in the types of compounds that are suitable for
`encapsulation into softgels. Aldehydes (e.g., formaldehyde, acetaldehyde, and
`glutaraldehyde) can cross-link gelatin, thus slowing capsule disintegration and
`dissolution (Digenis et al., 1994; Hakata et al., 1994; Bottom et al., 1997). In
`general, the cross-linking of proteins by aldehydes is well documented (Feeney
`et al., 1975). Formaldehyde-induced cross-linking of gelatin mainly involves
`the lysine and arginine amino acids (Taylor et al., 1978; Albert et al., 1986,
`1991; Gold et al., 1996). Aldehydes may be directly present as impurities in fill
`or shell ingredients, or they may be generated by autoxidation of lipid excipi(cid:173)
`ents, such as polysorbate 80 (Chafetz et al., 1984; Doelker and
`
`0012
`
`

`

`Nature and Uses
`
`403
`
`Vial-Bemasconi, 1988; Singh et al., 2000). PEG can be particularly problem(cid:173)
`atic because it tends to react with atmospheric oxygen to form aldehydes (Tan(cid:173)
`ner and Shelley, 1996). To alleviate this problem, PEG is typically handled in
`an inert atmosphere, for example, under a nitrogen blanket (Tanner and Shel(cid:173)
`ley, 1996). Even capsule packaging materials can function as a source of
`cross-linking aldehydes as was shown for furfural from the rayon fiber inserted
`into high-density polyethylene bottles (Schwier et al., 1993). Recently, the use
`of near-infrared spectrophotometry as a non-invasive and non-destructive
`method for assessing aldehyde-induced cross-linking in softgels was proposed
`(Gold et al., 1998).
`Reducing carbohydrates (e.g., glucose, fructose, lactose, maltodextrin, and
`corn syrup solids), which often are used as drug or dietary supplement excipi(cid:173)
`ents, also cross-link proteins through the Maillard reaction (non-enzymatic
`browning) (Cheftel et al., 1985; Ames, 1998) and can affect the gelatin shell
`(Tanner and Shelley, 1996). However, satisfactory in vitro dissolution of
`cross-linked softgels or hard gelatin capsules may be obtained by adding
`proteolytic enzymes to the dissolution medium (Hom et al., 1973; Doelker and
`Vial-Bemasconi, 1988; Murthy et al., 1989b; Digenis et al., 1994; Gelatin Cap(cid:173)
`sule Working Group, 1998).
`Succinylated gelatin, which is not susceptible to aldehyde-induced
`cross-linking, can be used in capsule manufacturing (Kobayashi et al., 1986;
`Sato et al., 1986; Yamamoto et al., 1995). Acylation of proteins with succinic
`anhydride reduces thee-amino groups, which are the prime reactive sites for al(cid:173)
`dehydes (Cheftel et al., 1985). However, succinylated gelatin is not approved
`for use with ingestible softgels in the U.S. Nonetheless, personal care formula(cid:173)
`tions containing high amounts of aldehydes have occasionally been encapsu(cid:173)
`lated into softgels manufactured with succinylated gelatin.
`Organic compounds of low molecular weight that are volatile (e.g., alco(cid:173)
`hols. ketones, acids, amines, and esters) tend to readily migrate through the cap(cid:173)
`sule shell (Hom and Jimerson, 1990). Emulsions (oil-in-water or water-in-oil),
`although occasionally investigated as softgel fills (Bauer and Dortunc, 1984),
`are typically unsuitable for encapsulation because they eventually become
`destabilized, thus releasing water that migrates into the gelatin shell (Ebert,
`1977). In general, strong acids or bases break non-covalent and covalent
`cross-links within the gelatin structure. Therefore, acidic liquids (pH< 2.5) en(cid:173)
`capsulated into soft gels can hydrolyze gelatin and cause capsule leakage (Stan(cid:173)
`ley, 1970). Highly alkaline liquids also can disrupt the shell structure, causing
`leakage. Salts of strong acids and bases (e.g., potassium, sodium, and choline
`chlorides) and ammonium salts (e.g., ammonium chloride) can also be destruc(cid:173)
`tive to the shell (Stanley, 1970; Ebert, 1977). Finally, compounds that are un(cid:173)
`stable in the presence of moisture, such as aspirin, are not suitable for encapsu(cid:173)
`lation into softgels (Hom and Jimerson, 1990).
`
`0013
`
`

`

`404
`
`SOFT GELATIN CAPSULES
`
`MANUFACTURING
`
`SHELL INGREDIENTS
`
`Gelatin
`
`Sources
`
`Gelatin, the product of partial hydrolysis of collagen, is the main component
`of the softgel shell. Its manufacture and characteristics are discussed in detail
`elsewhere in this book. It is estimated that about 7.6% of the total gelatin pro(cid:173)
`duced worldwide ( 19,000 out of 250,000 metric tons) in 1998 was used in
`softgel manufacturing (Pluvinet, 2000). In fact, the softgel business has been
`growing in recent years so that about I 0% of the worldwide gelatin production
`is now allocated to softgels (Pluvinet, 2000). Both Type A and Type B gelatins
`(derived from acid and alkali hydrolysis of collagen, respectively), occasion(cid:173)
`ally blended together by either the gelatin manufacturers or the softgel manu(cid:173)
`facturers, are used for preparing softgels. Gelatin type selection is influenced
`by both technical and economic considerations. Traditionally, bovine bones
`and skins (trimmings from the leather industry prior to tanning) have been used
`as collagenous raw materials for manufacturing Type A or Type B gelatin,
`while porcine skins have been used extensively for manufacturing Type A gela(cid:173)
`tin (AIIeavitch et al., 1989; Johnston-Banks, 1990; GMIA, 1993). In recent
`years, porcine bones also have entered the stream of gelatin raw materials in
`Europe where they are either processed separately or co-processed with bovine
`bones to produce Type A or Type B gelatins.
`In the mid 1980s, fish gelatin became commercially available and has been
`marketed as an alternative to mammalian gelatins that present concerns for
`such religions as Judaism, Islam, and Hinduism. All fi sh are acceptable to most
`Islamic groups, while fish with removable scales are acceptable in Judaism
`with minimal restrictions (Choi and· Regenstein, 2000). The skins of cod (a
`cold-water fish) were initially used for the commercial production of fish gela(cid:173)
`tin (Norland, 1987). However, due to its low content of hydr