! .
`
`HANDBOOK OF
`
`CIPIENTS
`
`THIRD EDITION
`
`EDITED BY
`
`ARTIRJR H. KIBBE
`
`·ouTDATED '
`...
`
`v.
`Helsinn Healthcare SA, et al.
`U.S. Patent No. 8,729,094
`Reddy Exhibit 1 036
`
`Exh. 1036
`
`

`
`AUG 0 7 2.tltl1
`
`LDLK&M
`LIBRARY
`800 SOUTH AVE. WEST
`WESTFIELD, NJ 07090
`
`Exh. 1036
`
`

`
`Published by the American Pharmaceutical Association
`2215 Constitution Avenue NW, Washington, DC 20037-2985, USA
`www.aphanet.org
`and the Pharmaceutical Press
`1 Lambeth High Street, London SE1 7JN, UK
`www. pharmpress.com
`
`© 1986, 1994, 2000 American Pharmaceutical Association and Pharmaceutical Press
`
`First edition 1986
`Second edition 1994
`Third edition 2000
`
`Printed in the United States of America
`
`ISBN: 0-85369-381-1 (UK)
`ISBN: 0-917330-96-X (USA)
`
`Library of Cong..-css Cataloging-in-Publication Data
`Handbook of pharmaceutical excipients I edited by Arthur H. Kibbe.--3rd ed.
`p.; em.
`Includes bibliographical references and index.
`ISBN 0-917330-96-X
`1. Excipients--Handbooks, manuals, etc.
`Pharmaceuti'cal Association.
`[DNLM: l. Excipients--Handbooks. QV 735 H236 2000]
`RS201.E87 H36 2000
`615'.19--dc21
`
`I. Kibbe, Arthur H. ll. American
`
`A catalogue record for this book is available from the British Library.
`
`99-044554
`
`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 infom1ation contained in this book and! cannot accept any legal responsibility or
`liability for any errors or omissions that may be made.
`
`Managing Editor:
`Copyeditor:
`Indexer:
`Compositor:
`Cover Designer:
`
`Melanie Segala
`Paul Gouehrer
`Lillian Rodberg
`Roy Barnhill
`Tim Kaage
`
`Exh. 1036
`
`

`
`Handbook of
`PHARMACEUTICAL
`EXCIPIENTS
`
`Third Edition
`
`Edited by
`Arthur H. Kibbe, Ph.D.
`Professor and Chair
`Department of Pharmaceutical Sciences
`Wilkes University School of Pharmacy
`Wilkes-Barre, Pennsylvania
`
`American Pharmaceutical Association
`Washington, D.C.
`
`(RP)
`
`Phcrrmac.,Hcal Press
`London, United Kingdom
`
`Exh. 1036
`
`

`
`140 Citric Acid Monohydrate
`
`Citric Acid
`Monohydrate
`
`1. Nonproprietary Names
`BP: Citric acid monohyd.-atc
`JP: Citric acid
`PhEur: Acidum citricum monohydricum
`USP: Citric acid
`
`2. Synonyms
`2-Hydroxypropane-1 ,2,3-tricarboxylic acid monohydrate.
`
`3. Chemical Name and CAS Registry Number
`2-Hydroxy-1,2,3-propanetricarboxylic acid monohydrate
`[5949-29-1]
`
`4. Empirical Formula
`C6H 80TH20
`
`Molecular Weight
`2 10.14
`
`5. Structural Formula
`
`6. Functional Category
`Acidifying agent; antioxidant; buffering agent; chelating agent;
`flavor enhancer.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`Citric acid, as either the monohydrate or anhydrous material,
`is widely used in pharmaceutical formulations and food prod-
`ucts primarily to adjust the pH of solutions. Citric acid mono-
`hydrate is used in the preparation of effer vescent granules
`while a.nhydrous citric aci d is widely used in the preparation
`of effervescent tablets. OJ
`In food products, citric acid is used as a flavor enhancer, for
`its tart, acid taste. Citric acid monohydrate is also used as a
`sequestering agent and antioxidant synergist. It is a compo-
`nent of anticoagulant citrate solutions. Therapeutically. prep-
`arations containing citric acid have been used to dissolve renal
`calculi.
`
`Use
`Buffer solutions
`Flavor enhancer for liquid formulations
`Sequestering agent
`
`Concentration (%)
`O.l-2.0
`0.3-2.0
`0.3-2 0
`
`8. Description
`Citric acid monohydrate occurs as colorless or translucent
`crystals, or as a white crystalline, efflorescent powder. It is
`odorless and has a strong acidic taste. Crystal structure is
`orthorhombic.
`
`I
`
`I
`
`9. P harmacopeia( Specifications
`
`Test
`Identification
`Clarity and color of solution
`Water
`(hydrous form)
`(anhydrous form)
`Bacterial endotoxins
`Residue on ignition
`Sulfated ash
`Barium
`Calcium
`Aluminum
`Oxalate
`Sulfate
`Arsenic
`Hea''Y metals
`Iron
`Chloride
`Readi ly carbonizable substances
`Polycyclic aromatic hydrocarbon
`Organic volatile impurities
`Assay (anhydrous basis)
`
`JP
`+
`
`::;; 0.1%
`
`+
`
`+
`~0.048%
`::;; l ppm
`::;; 10 ppm
`
`+
`+
`
`PhEur
`+
`+
`
`7.5-9.0%
`~ !.0%
`+
`
`+
`::;; 200 ppm
`+
`::;; 350 ppm
`::;; 150 ppm
`
`::;; 10 ppm
`::;; 50 ppm
`::;; 50 ppm
`+
`
`~ 99.5%
`
`99.5-101%
`
`USP
`+
`
`~ 8.8%
`::;; 0.5%
`
`::;; 0.05
`::;; 0.1%
`
`+
`+
`::;; 3 ppm
`::;; 0.001%
`
`+
`
`+
`99.5-100.5%
`
`10. Typical Properties
`Acidity/alkalinity:
`pH = 2.2 ( l % w/v aqueous solution)
`Dissociation constants:
`pK. 1: 3. 128 at 25°C;
`pK.2: 4.761 at 25°C;
`pK.3: 6.396 at 25°C.
`Density: 1.542 g/cm3
`Heat of combustion:
`-1972 kJ/mol (-471.4 kcal/mol)
`Heat of solution:
`-16.3 kJ/mol (-3.9 kcal/mol) at 25°C
`Hygroscopicity: at relative humidities less than about 65% cit-
`ric acid monohydrate effloresces at 25°C, the anhydrou s
`acid being formed at relative humidities less than about
`40%. At relative humidities between about 65-75%, citric
`acid monohydrate absorbs insignificant amounts of mois-
`ture but under more humid conditions substantial amounts
`of water are absorbed.
`Melting point: - 100°C (softens at 75°C)
`Particle size distribution: various grades of citric acid mono-
`hydrate with different particle sizes are commercially
`available.
`Solubility: soluble 1 in 1.5 parts of ethanol (95%) and I in
`less than 1 part of water; sparingly soluble in ether.
`Viscosity (dynamic): 6.5 mPa s (6.5 cP) for a 50% w/v aque-
`o us solution at 25°C
`See also Section 18.
`
`Exh. 1036
`
`

`
`SEM: I
`Excipient: Citric acid monohydrate
`Manufacturer: Pfizer Ltd
`MagniftcaLion: 60x
`
`SEM:2
`Bxcipicn1: Cilric acid mooohydralc
`Manufacturer: Pfizer Ltd
`Magnification: 600x
`
`Citric Acid Monohydrate 141
`
`11. Stability and Storage Conditions
`Citric acid monohydrate loses water of crystallization in dry
`air or when heated to about 40°C. Tt is slightly deliquescent
`in mo ist air. Dilute aqueous solutions of citric acid may fer-
`ment on standing.
`The bulk monohydrate or anhydrous material sho uld be stored
`in airtight containers in a cool, dry, place.
`
`12. Incompatibilities
`Citric acid is incompatible with potassium tartrate, alkali and
`alkaline earth carbonates and bicarbonates, acetates, and sul-
`fides. Incompatibilities also include oxidizing agents, bases,
`reducing agents, and nitrates. Potentially explosive in combi-
`nation with metal nitrates. On storage, sucrose may crystallize
`from syrups in the presence of c itric acid. Dilute aqueous
`solutions may ferment on standing.
`
`13. Method of Manufacture
`Citric acid occurs naturally in a number of plant species and
`may be extracted from lemon juice, which contains 5-8% cit-
`ric acid, or pineapple waste. Anhydrous citric acid may also
`be produced industrially by mycological fermentation of crude
`sugar solutio ns such as molasses, using strains of Aspergillus
`nige1: Citdc acid is purified by recrystallization; the anhy-
`drous form is obtained from a hot concentrated aqueous so-
`lution and the monohydrate from a cold concentrated aqueous
`solution.
`
`cessive or frequent consumption of citric acid has been asso-
`ciated with erosion of the teeth.(?)
`Citric acid and citrates also enha nce intestinal aluminum ab-
`sorption in renal patients which may lead to increased, harm-
`ful serum aluminum levels. It has therefore been suggested
`that patients with renal failure taking aluminum compounds
`to control phosphate absorption should not be prescribed citric
`acid or citrate-containing productsP>
`See Section 18 for anhydrous citric acid animal toxicity data.
`
`15. Handling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Eye protection and gloves
`are recommended. Contact with eyes can cause serious dam-
`age. Citric acid should be handled in a well-ventilated envi-
`ronment or a dust mask sh.ould be worn.
`
`16. Regulatory Status
`GRAS listed. The anhydrous form is accepted for use as a
`food additive in Europe. Included in the FDA Inactive Ingre-
`dients Guide (inhalations, Lvt IV, and other injections, oph-
`thalmic preparations, oral capsules, solutions, suspensions and
`tablets, topical, and vaginal preparations). Included in non-
`parenteral and parenteral medicines licensed in Japan and the
`UK.
`
`17. Pharmacopeias
`China, Eur, Jpn, Pol, and US.
`
`14. Safety
`Citric acid is found naturally in the body, mainly in the bones.
`and is commonly consumed as part of a normal diet. Orally
`ingested citric acid is absorbed and is generally regarded as
`a nontoxic material when used as an excipient. However, ex-
`
`18. Related Substances
`Anhydrous citric acid; sodium citrate dihydrate.
`Anhydrous citric acid: C6H80 7
`Molecular weight: 192.12
`
`Exh. 1036
`
`

`
`142 Citric Acid Monohydrate
`
`CAS number: [77-92-9)
`Synonyms: acidum citricum anhydricum; cttnc acid; E330;
`2-hydroxy-~1,2,3-propanetricarboxylic acid; 2-hydroxypropane
`J ,2,3-tricarboxylic acid; J-hydroxytricarballylic acid.
`Appearance: odorless or almost odorless, colorless crystals or
`a white crystalline powder. Crystal structure is monoclinic
`holohedra.
`Dissociation constants:
`pK.t= 3.128 at 25°C;
`pK.2: 4.761 at 25°C;
`pKa3: 6.396 at 25°C.
`Density: 1.665 g/cm3
`Heat of combustion:
`-1985 kJ/mol (-474.5 kcallmol)
`Hygroscopicity: at relativ.e humidities between about 25-50%
`anhydrous citric acid! absorbs insignificant amounts of
`water at 25°C. However, at relative humidities between
`50-75% it absorbs significant amounts with the monohy-
`cjrate being formed at relative humidities approaching 75%.
`At relative humidities greater than 75% substantial
`amounts of water are absorbed by the monohydrate.
`Melting point: 153°C
`Solubility: soluble 1 in 1 part of ethanol (95%) and 1 in I of
`water; sparingly soluble in ether.
`Safety:
`LD50 (mouse, IP): 0.96 g/kg<4>
`LD50 (mouse, IV): 0.04 g/kg
`LD50 (mouse, oral): 5.04 g/kg
`LD50 (mouse, SC): 2.7 .g/kg
`LDso (rabbit, IV): 0.33 g/kg
`
`LD50 (rat, IP): 0.8& g!kg
`LD50 (rat, oral): 6.73 g/kg
`LD50 (rat, SC): 5.5 g/kg
`
`19. Comments
`
`20. Specific References
`l. Anderson NR, Banker GS, Peck GE. Quantitative evaluation
`of pharmaceutical effervescent systems II: stability monitoring
`by reactivity and porosity measurements. J Pharm Sci 1982;
`71: 7-13.
`2. Citric acid: tooth enamel destruction. Clin Alert 1971, No. 151
`3. Main I, Ward MK. Potentiation of aluminium absorption by
`effervescent analgesic tablets in a haemodialysis patient. Br
`Med J 1992; 304: 1686.
`4. Sweet DV, editor. Registry of Toxic Effects of Chemical Sub-
`stanc_es Cincinnati, US Department of Health, 1987.
`
`21. General References
`Cho MJ, Scieszka JF, Burton PS. Citric acid as an adjuvant for
`transepithelial transport. Int J Pharmaceutics 1989; 52: 79-8 L.
`Timko RJ, Lordi NG. Thermal characterization of citric acid solid
`dispersions with benzoic acid and phenobarbital. J Pharm Sci
`1979; 68: 601-605.
`
`22. Authors
`GE Amidon.
`
`.-
`
`Exh. 1036