(cid:61)(cid:86)(cid:99)(cid:89)(cid:87)(cid:100)(cid:100)(cid:96)(cid:21)(cid:100)(cid:91)(cid:21)
`(cid:69)(cid:93)(cid:86)(cid:103)(cid:98)(cid:86)(cid:88)(cid:90)(cid:106)(cid:105)(cid:94)(cid:88)(cid:86)(cid:97)(cid:21)(cid:58)(cid:109)(cid:88)(cid:94)(cid:101)(cid:94)(cid:90)(cid:99)(cid:105)(cid:104)
`
`(cid:72)(cid:94)(cid:109)(cid:105)(cid:93)(cid:21)(cid:90)(cid:89)(cid:94)(cid:105)(cid:94)(cid:100)(cid:99)
`
`(cid:58)(cid:89)(cid:94)(cid:105)(cid:90)(cid:89)(cid:21)(cid:87)(cid:110)(cid:21)
`(cid:71)(cid:86)(cid:110)(cid:98)(cid:100)(cid:99)(cid:89)(cid:21)(cid:56)(cid:21)(cid:71)(cid:100)(cid:108)(cid:90)(cid:33)(cid:21)(cid:69)(cid:86)(cid:106)(cid:97)(cid:21)(cid:63)(cid:21)(cid:72)(cid:93)(cid:90)(cid:104)(cid:96)(cid:90)(cid:110)(cid:21)(cid:86)(cid:99)(cid:89)(cid:21)(cid:66)(cid:86)(cid:103)(cid:94)(cid:86)(cid:99)(cid:21)(cid:58)(cid:21)(cid:70)(cid:106)(cid:94)(cid:99)(cid:99)
`
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`

`Handbook of Pharmaceutical Excipients
`
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`

`Handbook of
`Pharmaceutical Excipients
`
`S I X T H E D I T I O N
`
`Edited by
`Raymond C Rowe BPharm, PhD, DSC, FRPharmS, FRSC, CPhys, MInstP
`Chief Scientist
`Intelligensys Ltd, Stokesley, North Yorkshire, UK
`Paul J Sheskey BSc, RPh
`Application Development Leader
`The Dow Chemical Company, Midland, MI, USA
`Marian E Quinn BSc, MSc
`Development Editor
`Royal Pharmaceutical Society of Great Britain, London, UK
`
`London . Chicago
`
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`

`Published by the Pharmaceutical Press
`An imprint of RPS Publishing
`
`1 Lambeth High Street, London SE1 7JN, UK
`100 South Atkinson Road, Suite 200, Grayslake, IL 60030-7820, USA
`
`and the American Pharmacists Association
`2215 Constitution Avenue, NW, Washington, DC 20037-2985, USA
`
`# Pharmaceutical Press and American Pharmacists Association 2009
`
`is a trade mark of RPS Publishing
`
`RPS Publishing is the publishing organisation of the Royal Pharmaceutical Society of Great Britain
`
`First published 1986
`Second edition published 1994
`Third edition published 2000
`Fourth edition published 2003
`Fifth edition published 2006
`Sixth edition published 2009
`
`Typeset by Data Standards Ltd, Frome, Somerset
`Printed in Italy by L.E.G.O. S.p.A.
`
`ISBN 978 0 85369 792 3 (UK)
`ISBN 978 1 58212 135 2 (USA)
`
`All rights reserved. No part of this publication may be
`reproduced, stored in a retrieval system, or transmitted in any
`form or by any means, without the prior written permission
`of the copyright holder.
`The publisher makes no representation, express or implied,
`with regard to the accuracy of the information contained in
`this book and cannot accept any legal responsibility or
`liability for any errors or omissions that may be made.
`
`A catalogue record for this book is available from the British Library
`
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`

`

`A
`
`Agar
`
`Nonproprietary Names
`1
`JP: Agar
`PhEur: Agar
`USP-NF: Agar
`
`Synonyms
`2
`Agar-agar; agar-agar flake; agar-agar gum; Bengal gelatin; Bengal
`gum; Bengal isinglass; Ceylon isinglass; Chinese isinglass; E406;
`gelosa; gelose; Japan agar; Japan isinglass; layor carang.
`
`Chemical Name and CAS Registry Number
`3
`Agar [9002-18-0]
`
`Empirical Formula and Molecular Weight
`4
`See Section 5.
`
`Structural Formula
`5
`Agar is a dried, hydrophilic, colloidal polysaccharide complex
`extracted from the agarocytes of algae of the Rhodophyceae. The
`structure is believed to be a complex range of polysaccharide chains
`having alternating a-(1!3) and b-(1!4) linkages. There are three
`extremes of structure noted: namely neutral agarose; pyruvated
`agarose having little sulfation; and a sulfated galactan. Agar can be
`separated into a natural gelling fraction, agarose, and a sulfated
`nongelling fraction, agaropectin.
`
`Table I: Pharmacopeial specifications for agar.
`
`Test
`JP XV
`þ
`Identification
`þ
`Characters
`Swelling index
`—
`Arsenic
`—
`Lead
`—
`þ
`Sulfuric acid
`Sulfurous acid and starch þ
`Gelatin
`—
`Heavy metals
`—
`415.0 mg
`Insoluble matter
`475 mL
`Water absorption
`422.0%
`Loss on drying
`Microbial contamination —
`44.5%
`Total ash
`40.5%
`Acid-insoluble ash
`Foreign organic matter —
`Limit of foreign starch
`—
`
`PhEur 6.3
`þ
`þ
`þ
`—
`—
`—
`—
`þ
`—
`41.0%
`—
`420.0%
`4103 cfu/g(a)
`45.0%
`—
`—
`—
`
`USP32–NF27
`þ
`—
`—
`43 ppm
`40.001%
`—
`—
`þ
`40.004%
`415.0 mg
`475 mL
`420.0%
`þ
`46.5%
`40.5%
`41.0%
`þ
`
`(a) Total viable aerobic count, determined by plate-count.
`
`10 Typical Properties
`NIR spectra see Figure 1.
`Solubility Soluble in boiling water to form a viscous solution;
`practically insoluble in ethanol (95%), and cold water. A 1% w/v
`aqueous solution forms a stiff jelly on cooling.
`
`Functional Category
`6
`Emulsifying agent; stabilizing agent; suppository base; suspending
`agent; sustained-release agent; tablet binder; thickening agent;
`viscosity-increasing agent.
`
`11 Stability and Storage Conditions
`Agar solutions are most stable at pH 4–10.
`Agar should be stored in a cool, dry, place. Containers of this
`material may be hazardous when empty since they retain product
`residues (dust, solids).
`
`12 Incompatibilities
`Agar is incompatible with strong oxidizing agents. Agar is
`dehydrated and precipitated from solution by ethanol (95%).
`Tannic acid causes precipitation; electrolytes cause partial dehydra-
`tion and decrease in viscosity of sols.(9)
`
`0.6
`
`log(1/R)
`
`1887
`
`1386
`
`1667
`
`2236
`
`2011
`
`2370
`
`1702
`
`2450
`
`1432
`
`6.0
`
`0.0
`
`1162
`
`10000 × [2nd deriv. log(1/R)]
`
`1920
`−7.0
`−0.2
`1100 1300 1500 1700 1900 2100 2300 2500
`Wavelength/nm
`
`2261
`
`Figure 1: Near-infrared spectrum of agar measured by reflectance.
`
`13
`
`7
`
`Applications in Pharmaceutical Formulation or
`Technology
`Agar is widely used in food applications as a stabilizing agent. In
`pharmaceutical applications, agar is used in a handful of oral tablet
`and topical formulations. It has also been investigated in a number
`of experimental pharmaceutical applications
`including as a
`sustained-release agent in gels, beads, microspheres, and tablets.(1-
`4) It has also been reported to work as a disintegrant in tablets.(5)
`Agar has been used in a floating controlled-release tablet; the
`buoyancy in part being attributed to air entrapped in the agar gel
`network.(6) It can be used as a viscosity-increasing agent in aqueous
`systems. Agar can also be used as a base for nonmelting, and
`nondisintegrating suppositories.(7) Agar has an application as a
`suspending agent in pharmaceutical suspensions.(8)
`
`Description
`8
`Agar occurs as transparent, odorless, tasteless strips or as a coarse
`or fine powder. It may be weak yellowish-orange, yellowish-gray to
`pale-yellow colored, or colorless. Agar is tough when damp, brittle
`when dry.
`
`Pharmacopeial Specifications
`9
`See Table I.
`
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`

`19 Specific References
`1 Bhardwaj TJ et al. Natural gums and modified natural gums as
`sustained release carriers. Drug Dev Ind Pharm 2000; 26(10): 1025–
`1038.
`2 Sakr FM et al. Design and evaluation of a dry solidification technique
`for preparing pharmaceutical beads. STP Pharma Sci 1995; 5(4): 291–
`295.
`theophylline and
`3 Boraie NA, Naggar VF. Sustained release of
`aminophylline from agar tablets. Acta Pharm Jugosl 1984; 34(Oct–
`Dec): 247–256.
`4 Nakano M et al. Sustained release of sulfamethizole from agar beads. J
`Pharm Pharmacol 1979; 31: 869–872.
`5 Fassihi AR. Characteristics of hydrogel as disintegrant in solid dose
`technology. J Pharm Pharmacol 1989; 41(12): 853–855.
`6 Desai S, Boston S. A floating controlled-release drug delivery system: in
`vitro–in vivo evaluation. Pharm Res 1993; 10: 1321–1325.
`7 Singh KK et al. Studies on suppository bases: design and evaluation of
`sodium CMC and agar bases. Indian Drugs 1994; 31(April): 149–154.
`8 Kahela P et al. Effect of suspending agents on the bioavailability of
`erythromycin ethylsuccinate mixtures. Drug Dev Ind Pharm 1978;
`4(3): 261–274.
`9 Gennaro AR, ed. Remington: The Science and Practice of Pharmacy,
`20th edn. Baltimore: Lippincott Williams & Wilkins, 2000; 1030.
`10 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th
`edn. New York: Wiley, 2004; 90–91.
`11 Patil AK et al. Preparation and evaluation of agar spherules of
`felodipine. J Pure Appl Microbiol 2007; 1(2): 317–322.
`12 Bertram U, Bodmeier R. In situ gelling, bioadhesive nasal inserts for
`extended drug delivery: in vitro characterization of a new nasal dosage
`form. Eur J Pharm 2006; 27(1): 62–71.
`
`20 General References
`
`— 2
`
`1 Author
`VK Gupta.
`
`22 Date of Revision
`10 February 2009.
`
`14
`
`Albumin
`
`A
`
`13 Method of Manufacture
`Agar is obtained by freeze-drying a mucilage derived from Gelidium
`amansii Lamouroux, other species of the same family (Gelidiaceae),
`or other red algae (Rhodophyta).
`
`14 Safety
`Agar is widely used in food applications and has been used in oral
`and topical pharmaceutical applications. It is generally regarded as
`relatively nontoxic and nonirritant when used as an excipient.
`LD50 (hamster, oral): 6.1 g/kg(10)
`LD50 (mouse, oral): 16.0 g/kg
`LD50 (rabbit, oral): 5.8 g/kg
`LD50 (rat, oral): 11.0 g/kg
`
`15 Handling Precautions
`Observe normal precautions appropriate to the circumstances and
`quantity of the material handled. When heated to decomposition,
`agar emits acrid smoke and fumes.
`
`16 Regulatory Status
`GRAS listed. Accepted for use as a food additive in Europe.
`Included in the FDA Inactive Ingredients Database (oral tablets).
`Included in the Canadian List of Acceptable Non-medicinal
`Ingredients. Included in nonparenteral medicines licensed in the UK.
`
`17 Related Substances
`
`— 1
`
`8 Comments
`The drug release mechanism of agar spherules of felodipine has been
`studied and found to follow Higuchi kinetics.(11) Agar has also been
`used to test the bioadhesion potential of various polymers.(12)
`The EINECS number for agar is 232-658-1.
`
`Albumin
`
`Nonproprietary Names
`1
`BP: Albumin Solution
`PhEur: Human Albumin Solution
`USP: Albumin Human
`
`Synonyms
`2
`Alba; Albuconn; Albuminar; albumin human solution; albumini
`humani solutio; Albumisol; Albuspan; Albutein; Buminate; human
`serum albumin; normal human serum albumin; Octalbin; Plasbu-
`min; plasma albumin; Pro-Bumin; Proserum; Zenalb.
`
`Chemical Name and CAS Registry Number
`3
`Serum albumin [9048-49-1]
`
`Characteristic features are a single tryptophan residue, a relatively
`low content of methionine (6 residues), and a large number of
`cysteine (17) and of charged amino acid residues of aspartic acid
`(36), glutamic acid (61), lysine (59), and arginine (23).
`
`Structural Formula
`5
`Primary structure Human albumin is a single polypeptide chain of
`585 amino acids and contains seven disulfide bridges.
`Secondary structure Human albumin is known to have a
`secondary structure that is about 55% a-helix. The remaining
`45% is believed to be divided among turns, disordered, and b
`structures.(1)
`Albumin is the only major plasma protein that does not contain
`carbohydrate constituents. Assays of crystalline albumin show less
`than one sugar residue per molecule.
`
`Empirical Formula and Molecular Weight
`4
`Human serum albumin has a molecular weight of about 66 500 and
`is a single polypeptide chain consisting of 585 amino acids.
`
`Functional Category
`6
`Stabilizing agent; therapeutic agent.
`
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`

`G
`
`Gelatin
`
`Nonproprietary Names
`1
`BP: Gelatin
`JP: Gelatin
`PhEur: Gelatin
`USP-NF: Gelatin
`
`G
`
`Synonyms
`2
`Byco; Cryogel; E441; gelatina; gelatine; Instagel; Kolatin; Solugel;
`Vitagel.
`
`Chemical Name and CAS Registry Number
`3
`Gelatin [9000-70-8]
`
`Empirical Formula and Molecular Weight
`4
`Gelatin is a generic term for a mixture of purified protein fractions
`obtained either by partial acid hydrolysis (type A gelatin) or by
`partial alkaline hydrolysis (type B gelatin) of animal collagen
`obtained from cattle and pig bone, cattle skin (hide), pigskin, and
`fish skin. Gelatin may also be a mixture of both types.
`The protein fractions consist almost entirely of amino acids
`joined together by amide linkages to form linear polymers, varying
`in molecular weight from 20 000–200 000.
`The JP XV also includes a monograph for purified gelatin.
`
`Structural Formula
`5
`See Section 4.
`
`Functional Category
`6
`Coating agent; film-forming agent; gelling agent; suspending agent;
`tablet binder; viscosity-increasing agent.
`
`7
`
`Applications in Pharmaceutical Formulation or
`Technology
`Gelatin is widely used in a variety of pharmaceutical formulations,
`including its use as a biodegradable matrix material
`in an
`implantable delivery system,(1) although it is most frequently used
`to form either hard or soft gelatin capsules.(2–4)
`Gelatin capsules are unit-dosage forms designed mainly for oral
`administration. Soft capsules on the market also include those for
`rectal and vaginal administration. Hard capsules can be filled with
`solid (powders, granules, pellets, tablets, and mixtures thereof),
`semisolid and liquid fillings, whereas soft capsules are mainly filled
`with semisolid or liquid fillings. In hard capsules, the active drug is
`always incorporated into the filling, while in soft capsules the drug
`substance can also be incorporated into the thick soft capsule shell.
`Gelatin is soluble in warm water (>308C), and a gelatin capsule will
`initially swell and finally dissolve in gastric fluid to release its
`contents rapidly.(5)
`Hard capsules are manufactured in two pieces by dipping
`lubricated stainless steel mold pins into a 45–558C gelatin solution
`of defined viscosity, which depends on the size of the capsules and
`whether cap or body are to be formed. The gelatin is taken up by the
`pins as a result of gelation, and the resulting film thickness is
`governed by the viscosity of the solution. The capsule shells are
`passed through a stream of cool air to aid setting of the gelatin, and
`afterwards they are slowly dried with large volumes of humidity
`controlled air heated to a few degrees above ambient temperature
`and blown directly over the pins. The capsule halves are removed
`from their pins, trimmed and fitted together. Gelatin that is used to
`
`278
`
`produce hard capsules may contain various coloring agents and
`antimicrobial preservatives. Surfactants may be present in small
`quantities in the shells being a residue of the pin lubricant. However,
`the use of preservatives is no longer encouraged in line with current
`GMP principles. Capsule shells may be treated with formaldehyde
`to make them insoluble in gastric fluid. Standard capsules vary in
`volume from 0.13 to 1.37 mL. For veterinary use, capsules with a
`volume between 3 and 28 mL are available, and capsules with a
`capacity of 0.025 mL are available for toxicity studies in rats.
`In contrast to two-piece hard capsules, soft gelatin capsules are
`manufactured, filled and sealed in one process. The gelatin used to
`form the soft shells has a lower gel strength than that used for hard
`capsules, and the viscosity of the solutions is also lower, which
`results in more flexible shells. Additives to soft shell formulations
`are plasticizers such as polyalcohols (glycerin, propylene glycol,
`polyethylene glycol). Sorbitol can be added as moisturizing agent,
`whereby the larger amount of water will act as plasticizer. Coloring
`and opacifying agents are also added. The filling can interact with
`the gelatin and the plasticizer chemically. There may be migration of
`filling components into the shell and plasticizer from the shell into
`the filler. These interactions have to be taken into account during the
`formulation of the gelatin shell and the filling. The main method to
`produce soft gelatin capsules is the rotary die method (RP Scherer),
`and an alternative method for small volumes of round capsules is
`the Globex system (Industrial Techno-logic Solutions Ltd).(4) Soflet
`Gelcaps (Banner Pharmacaps) are tablets that have been coated
`with a gelatin film.
`Gelatin is also used for the microencapsulation of drugs, where
`the active drug is sealed inside a microsized capsule or beadlet,
`which may then be handled as a powder. The first microencapsu-
`lated drugs (beadlets) were fish oils and oily vitamins in gelatin
`beadlets prepared by coacervation.
`Low-molecular-weight gelatin has been investigated for its
`ability to enhance the dissolution of orally ingested drugs.(6)
`Ibuprofen–gelatin micropellets have been prepared for the con-
`trolled release of the drug.(7) Other uses of gelatin include the
`preparation of pastes, pastilles, pessaries, and suppositories. In
`addition, it is used as a tablet binder and coating agent, and as a
`viscosity-increasing agent for solutions and semisolids.
`Therapeutically, gelatin has been used in the preparation of
`wound dressings(8) and has been used as a plasma substitute,
`although anaphylactoid reactions have been reported in the latter
`application.(9) Absorbable gelatin is available as sterile film,
`ophthalmic film, sterile sponge, sterile compressed sponge, and
`sterile powder from sponge. Gelatin sponge has hemostatic
`properties.
`Gelatin is also widely used in food products and photographic
`emulsions.
`
`Description
`8
`Gelatin occurs as a light-amber to faintly yellow-colored, vitreous,
`brittle solid. It is practically odorless and tasteless, and is available
`as translucent sheets, flakes, and granules, or as a coarse powder.
`
`Pharmacopeial Specifications
`9
`See Table I. See also Section 18.
`
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`

`Gelatin
`
`279
`
`G
`
`50
`
`40
`
`30
`
`20
`
`10
`
`Equilibrium moisture at 20°C (%)
`
`0
`
`0
`
`10
`
`20
`
`30
`40
`50
`60
`70
`Relative humidity (%)
`
`80
`
`90
`
`100
`
`Figure 1: Equilibrium moisture content of gelatin (Pharmagel A).
`50
`
`40
`
`30
`
`20
`
`10
`
`Equilibrium moisture at 25°C (%)
`
`0
`
`0
`
`10
`
`20
`
`30
`40
`50
`60
`70
`Relative humidity (%)
`
`80
`
`90
`
`100
`
`Figure 2: Sorption–desorption isotherm of gelatin.
`7.0
`
`1882
`
`1665
`
`1710
`
`1382
`
`2236
`
`2018
`
`0.80.8
`
`log(1/R)
`log(1/R)
`
`10000 × [2nd deriv. log(1/R)]
`
`−6.0
`1100
`
`0.0
`
`1175
`
`1423 1498
`
`1686
`
`1727
`1913
`
`1300
`
`2100
`1500
`1700
`1900
`Wavelength/nm
`
`2170
`
`2045
`
`2260
`
`−0.2−0.2
`2500
`
`2300
`
`Figure 3: Near-infrared spectrum of gelatin measured by reflectance.
`
`Table I: Pharmacopeial specifications for gelatin.
`
`JP XV
`þ
`—
`—
`
`Test
`Identification
`Characters
`Microbial
`contamination
`Aerobic bacteria —
`þ
`Fungi
`42.0%
`Residue on ignition
`415.0%
`Loss on drying
`þ
`Odor and water-
`insoluble
`substances
`Isoelectric point
`Type A
`Type B
`Conductivity
`Sulfur dioxide
`Sulfite
`Arsenic
`Iron
`Chromium
`Zinc
`Heavy metals
`pH
`Mercury
`Peroxides
`Gel strength
`
`þ
`7.0–9.0
`4.5–5.0
`—
`—
`þ
`41 ppm
`—
`—
`—
`450 ppm
`—
`40.1 ppm
`—
`—
`
`PhEur 6.3
`þ
`þ
`þ
`
`4103 cfu/g
`4102 cfu/g
`—
`415.0%
`—
`
`þ
`6.0–9.5
`4.7–5.6
`41 mS/cm
`450 ppm
`—
`—
`430 ppm
`410 ppm
`430 ppm
`—
`3.8–7.6
`—
`410 ppm
`þ
`
`USP32–NF27
`þ
`—
`þ
`
`4103 cfu/g
`—
`42.0%
`—
`þ
`
`þ
`—
`—
`—
`40.15%
`—
`40.8 ppm
`—
`—
`—
`40.005%
`—
`—
`—
`—
`
`10 Typical Properties
`Acidity/alkalinity
`For a 1% w/v aqueous solution at 258C (depending on source
`and grade):
`pH = 3.8–5.5 (type A);
`pH = 5.0–7.5 (type B).
`Density
`1.32 g/cm3 for type A;
`1.28 g/cm3 for type B.
`Isoelectric point
`7.0–9.0 for type A;
`4.7–5.4 for type B.
`Moisture content 9–11%.(10) See also Figures 1 and 2.
`NIR spectra see Figure 3.
`Solubility Practically insoluble in acetone, chloroform, ethanol
`(95%), ether, and methanol. Soluble in glycerin, acids, and
`alkalis, although strong acids or alkalis cause precipitation. In
`water, gelatin swells and softens, gradually absorbing between
`five and 10 times its own weight of water. Gelatin is soluble in
`water above 408C, forming a colloidal solution, which gels on
`cooling to 35–408C. This gel–sol system is thixotropic and heat-
`reversible, the melting temperature being slightly higher than the
`setting point; the melting point can be varied by the addition of
`glycerin.
`Viscosity (dynamic)
`
`see Table II.(4)
`
`Table II: Dynamic viscosity of gelatin solutions at 608C.
`
`Grade
`
`Viscosity (dynamic)/mPa s
`
`Acid ossein
`Acid pigskin
`Fish skin
`Limed ossein/hide
`
`6.67% w/v aqueous
`solution
`2.7–3.7
`4.2–4.8
`3.0–4.5
`3.6–4.8
`
`12.5% w/c aqueous
`solution
`12.5–14.5
`19.0–20.5
`13.0–20.0
`19.0–20.5
`
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`manner to that in the acid process, except that the pH is kept at
`values between 5.0–6.5 (neutral extraction).
`During the preparation of
`the bovine bones used in the
`production of gelatin, specified risk materials that could contain
`transmissible spongiform encephalopathies (TSEs) vectors are
`removed. TSE infectivity is not present in pharmaceutical grade
`gelatin.
`
`14 Safety
`Gelatin is widely used in a variety of pharmaceutical formulations,
`including oral and parenteral products.
`In general, when used in oral formulations gelatin may be
`regarded as a nontoxic and nonirritant material. However, there
`have been rare reports of gelatin capsules adhering to the
`esophageal lining, which may cause local irritation.(12) Hypersensi-
`tivity reactions, including serious anaphylactoid reactions, have
`been reported following the use of gelatin in parenteral pro-
`ducts.(9,13)
`There have been concerns over the potential spread of BSE/TSE
`infections through bovine derived products. However, the risk of
`such contamination of medicines is extremely low.
`LD50 (rat, oral): 5 g/kg(14)
`TDLo (mouse, IP): 700 mg/kg(15)
`
`15 Handling Precautions
`Observe normal precautions appropriate to the circumstances and
`quantity of material handled. Eye protection and gloves are
`recommended. Gelatin should be handled in a well-ventilated
`environment and kept away from sources of ignition and heat.
`Empty containers pose a fire risk, and the gelatin residues should be
`evaporated under a fume hood.
`
`16 Regulatory Status
`GRAS listed. Included in the FDA Inactive Ingredients Database
`(dental preparations; inhalations; injections; oral capsules, pastilles,
`solutions, syrups and tablets; topical and vaginal preparations).
`Included in medicines licensed in the UK, Europe, and Japan.
`Included in the Canadian List of Acceptable Non-medicinal
`Ingredients.
`
`17 Related Substances
`
`— 1
`
`8 Comments
`the materials that have been selected for
`Gelatin is one of
`harmonization by the Pharmacopeial Discussion Group. For further
`information see the General Information Chapter <1196> in the
`USP32–NF27, the General Chapter 5.8 in PhEur 6.0, along with the
`‘State of Work’ document on the PhEur EDQM website, and also
`the General Information Chapter 8 in the JP XV.
`In the past there has been a significant amount of regulatory
`activity and legislation due to the attention given to bovine sourced
`gelatin manufacturing processes and the potential transmission of
`TSE vectors from raw bovine materials into gelatin.(4) In Europe,
`the criteria by which the safety is assured involves controlling the
`geographical sourcing of animals used; the nature of the tissue used
`(based on scientific data showing where animal BSE infectivity is
`located); and the method of production.
`is
`the starting material
`Gelatin produced with hides as
`considered much safer than using bones, although it is recom-
`mended that measures are undertaken to prevent cross-contamina-
`tion with potentially contaminated materials. When gelatin is
`produced from bones, the bones should ideally not be sourced from
`countries classified as Geographical BSE Risk (GBR) I and II,
`
`280
`
`Gelatin
`
`11 Stability and Storage Conditions
`Dry gelatin is stable in air. Aqueous gelatin solutions are also stable
`for long periods if stored under cool conditions but they are subject
`to bacterial degradation.(4) At temperatures above about 508C,
`aqueous gelatin solutions may undergo slow depolymerization and
`a reduction in gel strength may occur on resetting. Depolymeriza-
`tion becomes more rapid at temperatures above 658C, and gel
`strength may be reduced by half when a solution is heated at 808C
`for 1 hour. The rate and extent of depolymerization depends on the
`molecular weight of the gelatin, with a lower-molecular-weight
`material decomposing more rapidly.(11)
`Gelatin may be sterilized by dry heat.
`The bulk material should be stored in an airtight container in a
`cool, well-ventilated and dry place.
`
`12 Incompatibilities
`Gelatin is an amphoteric material and will react with both acids and
`bases. It is also a protein and thus exhibits chemical properties
`characteristic of such materials;
`for example, gelatin may be
`hydrolyzed by most proteolytic systems to yield its amino acid
`components.
`Gelatin will also react with aldehydes and aldehydic sugars,
`anionic and cationic polymers, electrolytes, metal ions, plasticizers,
`preservatives, strong oxidizers, and surfactants. It is precipitated by
`alcohols, chloroform, ether, mercury salts, and tannic acid. Gels can
`be liquefied by bacteria unless preserved.
`Some of these interactions are exploited to favorably alter the
`physical properties of gelatin: for example, gelatin is mixed with a
`plasticizer, such as glycerin, to produce soft gelatin capsules and
`suppositories; gelatin is treated with formaldehyde to produce
`gastroresistance; see Section 7.
`
`13 Method of Manufacture
`Gelatin is extracted from animal tissues rich in collagen such as skin,
`sinews, and bone. Although it is possible to extract gelatin from
`these materials using boiling water, it is more practical to first
`pretreat the animal tissues with either acid or alkali. Gelatin
`obtained from the acid process is called type A, whereas gelatin
`obtained from the alkali process is called type B.
`The acid-conditioning process (manufacture of type A gelatin) is
`restricted to soft bone ossein (demineralized bones), sinew, pigskin,
`calfskin and fish skins for reasons of gaining sufficient yield. The
`material is cut in pieces and washed in cold water for a few hours to
`remove superficial fat. It is then treated with mineral acid solutions,
`mainly HCl or H2SO4, at pH 1–3 and 15–208C until maximum
`swelling has occurred. This process takes approximately 24 hours.
`The swollen stock is then washed with water to remove excess acid,
`and the pH is adjusted to pH 3.5–4.0 (pigskin, fish skin) or 2.0–3.5
`(all other tissues) for the conversion to gelatin by hot-water
`extraction.
`The hydrolytic extraction is carried out in a batch-type operation
`using successive portions of hot water at progressively higher
`temperatures (50–758C) until the maximum yield of gelatin is
`obtained. The gelatin solution is then filtered through previously
`sterilized cellulose pads, deionized, concentrated to about 20–25%
`w/v and sterilized by flashing it to 1388C for 4 seconds. The dry
`gelatin is then formed by chilling the solution to form a gel, which is
`air-dried in temperature-controlled ovens. The dried gelatin is
`ground to the desired particle size.
`In the alkali process (liming), demineralized bones (ossein) or
`cattle skins are usually used. The animal tissue is held in a calcium
`hydroxide (2–5% lime) slurry for a period of 2–4 months at
`14–188C. At the end of the liming, the stock is washed with cold
`water for about 24 hours to remove as much of the lime as possible.
`The stock solution is then neutralized with acid (HCl, H2SO4,
`H3PO4) and the gelatin is extracted with water in an identical
`
`G
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`G
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`although bones from GBR III countries can be used if the removal of
`vertebrae from the raw materials is assured (see Table III).(16)
`Various grades of gelatin are commercially available that differ
`in particle size, molecular weight, and other properties. Grading is
`usually by gel strength, expressed as ‘Bloom strength’, which is the
`weight in grams that, when applied under controlled conditions to a
`plunger 12.7 mm in diameter, will produce a depression exactly 4
`mm deep in a matured gel containing 6.66% w/w of gelatin in
`water.
`Gelatin–acacia complex coacervation has been used in the
`preparation of microcapsules of vitamin A.(17) Pindolol-loaded
`alginate–gelatin beads have been developed for the sustained release
`of pindolol.(18)
`A specification for gelatin is contained in the Food Chemicals
`Codex (FCC).(19)
`The EINECS number for gelatin is 232-554-6.
`
`Table III: The European Scientific Steering Committee classification of
`geographical BSE risk (GBR).
`
`GBR level Presence of one or more cattle clinically or pre-clinically infected
`with BSE in a geographical region/country
`Highly unlikely
`Unlikely but not excluded
`Likely but not confirmed or confirmed at a lower level
`Confirmed at a higher level
`
`I
`II
`III
`IV
`
`19 Specific References
`1 Fan H, Dash AK. Effect of cross-linking on the in vitro release kinetics
`of doxorubicin from gelatin implants. Int J Pharm 2001; 213: 103–116.
`2 Armstrong NA et al. Drug migration in soft gelatin capsules. J Pharm
`Pharmacol 1982; 34(Suppl.): 5P.
`3 Tu J et al. Formulation and pharmacokinetics studies of acyclovir
`controlled-release capsules. Drug Dev Ind Pharm 2001; 27: 687–692.
`4 Podczeck F, Jones BE, eds. Pharmaceutical Capsules, 2nd edn. London:
`Pharmaceutical Press, 2004.
`5 Chiwele I et al. The shell dissolution of various empty hard capsules.
`Chem Pharm Bull 2000; 48: 951–956.
`6 Kimura S et al. Evaluation of low-molecular gelatin as a pharmaceutical
`additive for rapidly absorbed oral dosage formulations. Chem Pharm
`Bull 1991; 39: 1328–1329.
`7 Tayade PT, Kale RD. Encapsulation of water insoluble drug by a cross-
`linking technique: effect of process and formulation variables on
`encapsulation efficiency, particle size, and in vitro dissolution rate.
`AAPS Pharm Sci 2004; 6(1): E12.
`8 Thomas S. Wound Management and Dressings. London: Pharmaceu-
`tical Press, 1990.
`9 Blanloeil Y et al. [Severe anaphylactoid reactions after infusion of
`modified gelatin solution.] Therapie 1983; 38: 539–546[in French].
`10 Callahan JC et al. Equilibrium moisture content of pharmaceutical
`excipients. Drug Dev Ind Pharm 1982; 8: 355–369.
`11 Ling WC. Thermal degradation of gelatin as applied to processing of gel
`mass. J Pharm Sci 1