(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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`6 Nater JP. Allergic contact dermatitis caused by potassium metabisulfite.
`Dermatologica 1968; 136(6): 477–478.
`7 Vena GA et al. Sulfite contact allergy. Contact Dermatitis 1994; 31(3):
`172–175.
`8 Twarog FJ. Metabisulfite sensitivity in asthma: a review. N Engl Reg
`Allergy Proc 1983; 4(2): 100–103.
`9 Mathison DA et al. Precipitating factors in asthma: aspirin, sulfites, and
`other drugs and chemicals. Chest 1985; 87(Suppl.): 50S–54S.
`10 Anonymous. Sulfites in drugs and food. Med Lett Drugs Ther 1986; 28:
`74–75.
`11 Belchi-Hernandez J et al. Sulfite-induced urticaria. Ann Allergy 1993;
`71(3): 230–232.
`12 Sweetman SC, ed. Martindale: The Complete Drug Reference, 36th
`edn. London: Pharmaceutical Press, 2009; 1662–1663.
`13 Anonymous. Warning for prescription drugs containing sulfites. FDA
`Drug Bull 1987; 17: 2–3.
`14 FAO/WHO. Evaluation of the toxicity of a number of antimicrobials
`and antioxidants. Sixth report of the joint FAO/WHO expert committee
`on food additives. World Health Organ Tech Rep Ser 1962; No. 228.
`
`Potassium Sorbate
`
`579
`
`15 Food Chemicals Codex, 6th edn.
`Pharmacopeia, 2008; 812.
`
`Bethesda, MD: United States
`
`20 General References
`Smolinske SC. Handbook of Food, Drug and Cosmetic Excipients. Boca
`Raton, FL: CRC Press, 1992; 393–406.
`Valade J-P, Le Bras G. Sulfur dioxide release from effervescent tablets. Rev Fr
`Oenol 1998; 171: 22–25.
`
`21 Author
`PJ Sheskey.
`
`22 Date of Revision
`10 March 2009.
`
`Potassium Sorbate
`
`Nonproprietary Names
`1
`BP: Potassium Sorbate
`PhEur: Potassium Sorbate
`USP-NF: Potassium Sorbate
`
`Synonyms
`2
`E202; 2,4-hexadienoic acid (E,E)-potassium salt; kalii sorbas;
`potassium (E,E)-hexa-2,4-dienoate; potassium (E,E)-sorbate; sor-
`bic acid potassium salt.
`
`Chemical Name and CAS Registry Number
`3
`2,4-Hexadienoic acid potassium salt [24634-61-5]
`
`Empirical Formula and Molecular Weight
`4
`C6H7O2K
`150.22
`
`5
`
`Structural Formula
`
`solubility and stability in water. Like sorbic acid, potassium sorbate
`has minimal antibacterial properties in formulations above pH 6.
`
`Description
`8
`Potassium sorbate occurs as a white crystalline powder with a faint,
`characteristic odor.
`
`Pharmacopeial Specifications
`9
`See Table I.
`
`Table I: Pharmacopeial specifications for potassium sorbate.
`
`Test
`
`Identification
`Characters
`Appearance of solution
`Acidity or alkalinity
`Loss on drying
`Heavy metals
`Aldehydes (as C2H4O)
`Assay (dried basis)
`
`PhEur 6.0
`þ
`þ
`þ
`þ
`41.0%
`410 ppm
`40.15%
`99.0–101.0%
`
`USP32–NF27
`þ
`—
`—
`þ
`41.0%
`40.001%
`—
`98.0–101.0%
`
`P
`
`Functional Category
`6
`Antimicrobial preservative.
`
`7
`
`Applications in Pharmaceutical Formulation or
`Technology
`Potassium sorbate is an antimicrobial preservative, with antibacter-
`ial and antifungal properties used in pharmaceuticals, foods, enteral
`preparations, and cosmetics. Generally, it is used at concentrations
`of 0.1–0.2% in oral and topical formulations, especially those
`containing nonionic surfactants. Potassium sorbate has been used to
`enhance the ocular bioavailability of timolol.(1)
`Potassium sorbate is used in approximately twice as many
`pharmaceutical formulations as is sorbic acid owing to its greater
`
`10 Typical Properties
`Antimicrobial activity Potassium sorbate is predominantly used
`as an antifungal preservative, although it also has antibacterial
`properties. Similarly to sorbic acid, the antimicrobial activity is
`dependent on the degree of dissociation; there is practically no
`antibacterial activity above pH 6. Preservative efficacy is
`increased with increasing temperature,(2) and increasing con-
`centration of potassium sorbate.(2) The efficacy of potassium
`sorbate is also increased when used in combination with other
`antimicrobial preservatives or glycols since synergistic effects
`occur.(3) Reported minimum inhibitory concentrations (MICs) at
`the pH values indicated are shown in Table II.(3)
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`14 Safety
`Potassium sorbate is used as an antimicrobial preservative in oral
`and topical pharmaceutical formulations and is generally regarded
`as a relatively nontoxic material. However, some adverse reactions
`to potassium sorbate have been reported, including irritant skin
`reactions which may be of the allergic, hypersensitive type. There
`have been no reports of adverse systemic reactions following oral
`consumption of potassium sorbate.
`The WHO has set an estimated total acceptable daily intake for
`sorbic acid, calcium sorbate, potassium sorbate, and sodium
`sorbate expressed as sorbic acid at up to 25 mg/kg body-weight.(4,5)
`LD50 (mouse, IP): 1.3 g/kg(6)
`LD50 (rat, oral): 4.92 g/kg
`See also Sorbic Acid.
`
`15 Handling Precautions
`Observe normal precautions appropriate to the circumstances and
`quantity of material handled. Potassium sorbate is irritant to the
`skin, eyes, and mucous membranes; eye protection and gloves are
`recommended. In areas of limited ventilation, a respirator is also
`recommended.
`
`16 Regulatory Status
`GRAS listed. Accepted for use as a food additive in Europe.
`Included in the FDA Inactive Ingredients Database (nasal sprays;
`oral capsules, solutions, suspensions, syrups, tablets; topical creams
`and lotions). Included in nonparenteral medicines licensed in the
`UK. Included in the Canadian List of Acceptable Non-medicinal
`Ingredients.
`
`17 Related Substances
`Sorbic acid.
`
`18 Comments
`Much of the information contained in the sorbic acid monograph
`on safety, incompatibilities, and references also applies to potas-
`sium, calcium, and sodium sorbates. See Sorbic Acid for further
`information.
`Potassium sorbate has less antimicrobial activity than sorbic
`acid, but
`is more water
`soluble. Most potassium sorbate
`compounds will contain sorbic acid.
`A specification for potassium sorbate is contained in the Food
`Chemicals Codex (FCC).(7)
`The EINECS number for potassium sorbate is 246-376-1. The
`PubChem Compound ID (CID) for potassium sorbate includes
`23676745 and 24184641.
`
`19 Specific References
`1 Mandorf TK et al. A 12 month, multicentre, randomized, double-
`masked, parallel group comparison of timolol-LA once daily and
`timolol maleate ophthalmic solution twice daily in the treatment of
`adults with glaucoma or ocular hypertension. Clin Ther 2004; 26(4):
`541–551.
`2 Lusher P et al. A note on the effect of dilution and temperature on the
`bactericidal activity of potassium sorbate. J Appl Bacteriol 1984; 57:
`179–181.
`3 Woodford R, Adams E. Sorbic acid. Am Perfum Cosmet 1970; 85(3):
`25–30.
`4 FAO/WHO. Toxicological evaluation of certain food additives with a
`review of general principles and of specifications. Seventeenth report of
`the joint FAO/WHO expert committee on food additives. World Health
`Organ Tech Rep Ser 1974; No. 539.
`5 FAO/WHO. Evaluation of certain food additives and contaminants.
`Twenty-ninth report of the joint FAO/WHO expert committee on food
`additives. World Health Organ Tech Rep Ser 1986; No. 733.
`6 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th
`edn. New York: Wiley, 2004; 3043.
`
`0.6
`
`2348
`
`2388
`
`log(1/R)
`
`580
`
`Potassium Sorbate
`
`4.0
`
`0.0
`
`1766
`
`2126
`
`1000 × [2nd deriv. log(1/R)]
`
`1160
`
`1199
`
`1710
`
`1779
`1750
`
`2139
`
`2371
`2462
`
`−5.0
`1100 1300 1500 1700 1900 2100 2300
`Wavelength/nm
`
`2331
`
`–0.2
`2500
`
`Figure 1: Near-infrared spectrum of potassium sorbate measured by
`reflectance.
`
`Table II: Minimum inhibitory concentrations (MIC) of potassium
`sorbate.
`
`Microorganism
`
`MIC (mg/mL) at the stated pH
`
`5.5
`
`6.0
`
`7.0
`
`Escherichia coli
`Pseudomonas aeruginosa
`Staphylococcus aureus
`
`1400
`1600–2300
`1200
`
`1500
`1900–2500
`1000
`
`3800
`5600–9000
`3800
`
`Density 1.363 g/cm3
`Melting point 2708C with decomposition.
`NIR spectra see Figure 1.
`Solubility see Table III.
`
`Table III: Solubility of potassium sorbate.
`
`P
`
`Solvent
`
`Acetone
`Benzene
`Chloroform
`Corn oil
`Ethanol
`Ethanol (95%)
`Ethanol (5%)
`Ether
`Propylene glycol
`
`Water
`
`Solubility at 208C unless otherwise stated
`
`1 in 1000
`Practically insoluble
`Very slightly soluble
`Very slightly soluble
`1 in 50
`1 in 35
`1 in 1.7
`Very slightly soluble
`1 in 1.8
`1 in 2.1 at 508C
`1 in 5 at 1008C
`1 in 1.72
`1 in 1.64 at 508C
`1 in 1.56 at 1008C
`
`11 Stability and Storage Conditions
`Potassium sorbate is more stable in aqueous solution than sorbic
`acid; aqueous solutions may be sterilized by autoclaving.
`The bulk material should be stored in a well-closed container,
`protected from light, at a temperature not exceeding 408C.
`
`12 Incompatibilities
`Some loss of antimicrobial activity occurs in the presence of
`nonionic surfactants and some plastics. See also Sorbic Acid.
`
`13 Method of Manufacture
`Potassium sorbate is prepared from sorbic acid and potassium
`hydroxide.
`
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`7 Food Chemicals Codex, 6th edn.
`Pharmacopeia, 2008; 818.
`
`Bethesda, MD: United States
`
`21 Authors
`ME Quinn, PJ Sheskey.
`
`20 General References
`Smolinske SC, ed. Handbook of Food, Drug, and Cosmetic Excipients. Boca
`Raton, FL: CRC Press, 1992; 363–367.
`Sofos JN, Busta FF. Sorbates. Branen AL, Davidson PM, eds. Antimicrobials
`in Foods. New York: Marcel Dekker, 1983; 141–175.
`Walker R. Toxicology of sorbic acid and sorbates. Food Add Contam 1990;
`7(5): 671–676.
`
`22 Date of Revision
`17 February 2009.
`
`Povidone
`
`581
`
`Povidone
`
`Nonproprietary Names
`1
`BP: Povidone
`JP: Povidone
`PhEur: Povidone
`USP: Povidone
`
`Synonyms
`2
`E1201; Kollidon; Plasdone; poly[1-(2-oxo-1-pyrrolidinyl)ethylene];
`polyvidone; polyvinylpyrrolidone; povidonum; Povipharm; PVP; 1-
`vinyl-2-pyrrolidinone polymer.
`
`Chemical Name and CAS Registry Number
`3
`1-Ethenyl-2-pyrrolidinone homopolymer [9003-39-8]
`
`Empirical Formula and Molecular Weight
`4
`(C6H9NO)n
`2500–3 000 000
`The USP 32 describes povidone as a synthetic polymer consisting
`essentially of linear 1-vinyl-2-pyrrolidinone groups, the differing
`degree of polymerization of which results in polymers of various
`molecular weights. It is characterized by its viscosity in aqueous
`solution, relative to that of water, expressed as a K-value, in the
`range 10–120. The K-value is calculated using Fikentscher’s
`equation:(1)
`
`where z is the relative viscosity of the solution of concentration c
`(in % w/v), and k is the K-value  10–3. Alternatively, the K-value
`may be determined from the following equation:
`
`where z is the relative viscosity of the solution of concentration c
`(in % w/v). Approximate molecular weights
`for different
`povidone grades are shown in Table I.
`
`Approximate molecular weight
`
`Table I: Approximate molecular weights for different grades of
`povidone.
`K-value
`12
`15
`17
`25
`30
`60
`90
`120
`
`2 500
`8 000
`10 000
`30 000
`50 000
`400 000
`1 000 000
`3 000 000
`
`See also Section 8.
`
`5
`
`Structural Formula
`
`P
`
`Functional Category
`6
`Disintegrant; dissolution enhancer; suspending agent; tablet binder.
`
`7
`
`Applications in Pharmaceutical Formulation or
`Technology
`Although povidone is used in a variety of pharmaceutical
`formulations, it is primarily used in solid-dosage forms. In tableting,
`povidone solutions are used as binders
`in wet-granulation
`processes.(2,3) Povidone is also added to powder blends in the dry
`form and granulated in situ by the addition of water, alcohol, or
`hydroalcoholic solutions. Povidone is used as a solubilizer in oral
`and parenteral formulations, and has been shown to enhance
`dissolution of poorly soluble drugs from solid-dosage forms.(4–6)
`Povidone solutions may also be used as coating agents or as binders
`when coating active pharmaceutical ingredients on a support such
`as sugar beads.
`Povidone is additionally used as a suspending, stabilizing, or
`viscosity-increasing agent
`in a number of
`topical and oral
`suspensions and solutions. The solubility of a number of poorly
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