`
`tip-(V15
`m‘Handbook of
`WPharmaceutical Excipients
`
`
`
`SIXTH EDITION
`
`Edited by
`
`Raymond C Rowe BPharm, PhD, DSC, FRPharmS, FRSC, CPhys, MlnstP
`Chief Scientist
`
`Intel/igensys Ltd, Stokes/ey, 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
`
`r4!”
`’ti
`
`PhA
`
`(RP)
`
`Pharmaceutical Press
`
`London - Chicago
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1012, Page1
`__________._—_______—_
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1012, Page1
`
`

`

`Published by the Pharmaceutical Press
`An imprint of RPS Publishing
`
`1 Lambeth High Street, London SE] 7JN, UK
`100 South Atkinson Road, Suite 200, Grayslake, IL 60030-7820, USA
`
`and the American Pharmacists Association
`22l5 Constitution Avenue, NW, Washington, DC 20037-2985, USA
`
`© Pharmaceutical Press and American Pharmacists Association 2009
`
`(RP) 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
`
`|PR2018—01020 and |PR2018-01021, Exhibit 1012, Page2
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1012, Page2
`
`

`

`
`
`68 Boric Acid
`
`20 General References
`
`Gupta VD, Ho HW Quantitative determination of benzyl benzoate in
`benzyl benzoate lotion NF. Am] Hosp Pharm 1976; 33: 665—666.
`Hassan MMA, Mossa JS. Benzyl benzoate. Florey K, ed. Analytical Profiles
`ofDrug Substances, vol. 10: New York: Academic Press, 1981; 55—74.
`
`www2.mst.dk/udgiv/publications/2006/87-7052-278-2/pdf/87-7052-
`279-0.pdf (accessed 13 February 2009)
`6 Graham BE, Kuizenga MH. Toxicity studies on benzyl benzoate and
`related benzyl compounds. ] Pharmacol Exp Ther 1945; 84: 35 8—362.
`7 Draize JH et al. Toxicological investigations of compounds proposed
`for use as insect repellents. ] Pharmacol Exp Ther 1948; 93: 26—39.
`8 Sweet DV, ed. Registry of Toxic Effects of Chemical Substances.
`Cincinnati: US Department of Health, 1987: 965.
`9 Hayes W], Jr, Laws ER, Jr, eds. Handbook of Pesticide Toxicology, vol.
`3. Classes of Pesticides: New York, NY: Academic Press Inc, 1991;
`1505.
`10 Ohno O et al. Inhibitory effects of benzyl benzoate and its derivatives on
`angiotensin II-induced hypertension. Bioorg Med Chem 2008; 16(16):
`7843—7852.
`13 February 2009.
`
`
`21 Author
`
`RA Storey.
`
`22 Date of Revision
`
`Boric Acid
`
`Nonproprietary Names
`1
`BP: Boric Acid
`
`JP': Boric Acid
`PhEur: Boric Acid
`USP—NF: Boric Acid
`
`Synonyms
`2
`Acidum boricum; boracic acid; boraic acid; Borofax; boron
`trihydroxide; E284; orthoboric acid; trihydroxyborene.
`
`Chemical Name and CAS Registry Number
`3
`Orthoboric acid [10043-35-3]
`Metaboric acid [13460-50-9]
`
`Empirical Formula and Molecular Weight
`4
`H3BO3
`61.83 (for trihydrate)
`HBO;
`43.82 (for monohydrate)
`
`Structural Formula
`5
`See Section 4.
`
`Functional Category
`6
`Antimicrobial preservative; buffering agent.
`
`7
`
`Applications in Pharmaceutical Formulation or
`Technology
`Boric acid is used as an antimicrobial preservative”) in eye drops,
`cosmetic products, ointments, and topical creams. It is also used as
`an antimicrobial preservative in foods.
`Boric acid and borate have good buffering capacity and are used
`to control pH; they have been used for this purpose in external
`preparations such as eye drops.(2)
`Boric acid has also been used therapeutically in the form of
`suppositories to treat yeast infections.(3’4l In dilute concentrations it
`is used as a mild antiseptic, with weak bacteriostatic and fungistatic
`properties, although it has generally been superseded by more
`effective and less toxic disinfectants”) See Section 14.
`
`Description
`8
`Boric acid occurs as a hygroscopic, white crystalline powder,
`colorless shiny plates, or white crystals.
`
`Pharmacopeial Specifications
`9
`See Table I.
`
`liaiieiz. Ffiqrmocepéia! seésiiisationé ior'bori’é racial
`Test
`JP XV
`PhEur 6.0
`
`.
`USP32-NF27
`
`‘
`
`+
`Identification
`-—
`Characters
`+
`Appearance of solution
`<0.50%
`Loss on drying
`—
`Sulfate
`<10 ppm
`HeaVy metals
`—
`Organic matter
`<5 ppm
`Arsenic
`3.5—4.l
`pH
`Solubility in ethanol (96%) —
`Completeness of solution
`—-
`Assay
`299.5%
`
`
`
`~~
`+
`——
`—
`-—
`—
`—
`<0.50%
`$450 ppm
`—
`< l5 ppm
`<0.002%
`+
`—
`—
`—-
`3.8—4.8
`—
`+
`--
`
`—
`——
`99.0—l 00.5% 99.5—l 00.5%
`
`10 Typical Properties
`Acidity/alkalinity pH = 3.5—4.1 (5% w/v aqueous solution)
`Density
`1.435
`170.9°C. When heated slowly to 181.0°C, boric
`Melting point
`acid loses water to form metaboric acid (HBOZ); tetraboric acid
`(H2B4O7) and boron trioxide (B203) are formed at higher
`temperatures“)
`Solubility Soluble in ethanol, ether, glycerin, water, and other
`fixed and volatile oils. Solubility in water is increased by addition
`of hydrochloric, citric, or tartaric acids.
`Specific gravity
`1.517
`
`Stability and Storage Conditions
`'I 1
`Boric acid is hygroscopic and should therefore be stored in an air-
`tight, sealed container. The container must be labeled ‘Not for
`Internal Use’.
`
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`

`-—-
`
`69
`Boric Acid
`
`
`and gargles. It has also been used in US- and Japanese-approved
`intravenous products. Solutions of boric acid were formerly used to
`wash out body cavities, and as applications to wounds and ulcers,
`although the use of boric acid for these purposes is now regarded as
`inadvisable owing to the possibility of absorption”) Boric acid is
`not used internally owing to its toxicity. It is poisonous by ingestion
`and moderately toxic by skin contact. Experimentally it has proved
`to be toxic by inhalation and subcutaneous routes, and moderately
`toxic by intraperitoneal and intravenous routes.
`Boric acid is absorbed from the gastrointestinal tract and from
`damaged skin, wounds, and mucous membranes, although it does
`not readily permeate intact skin. The main symptoms of boric acid
`poisoning are abdominal pain, diarrhea, erythematous
`rash
`involving both skin and mucous membrane, and vomiting. These
`symptoms may be followed by desquamation, and stimulation or
`depression of the central nervous system. Convulsions, hy er-
`pyrexia, and renal tubular damage have been known to occur. 7)
`Death has occurred from ingestion of less than 5 g in young
`children, and of 5—20g in adults. Fatalities have occurred most
`frequently in young children after the accidental
`ingestion of
`solutions of boric acid, or after the application of boric acid powder
`to abraded skin.
`The permissible exposure limit (PEL) of boric acid is 15 mg/m3
`total dust, and 5 mg/m3 respirable fraction for nuisance dusts. 8’
`
`LdLo (man, oral): 429 mg/kgl9)
`LdLo (woman, oral): 200 mg/kgl9) .
`LdLo (infant, oral): 934 mg/kgl9)
`LdLO (man, skin): 2.43 g/kgl9’
`LdLo (infant, skin): 1.20 g/kg‘9’
`LD50 (mouse, oral): 3.45 g/kgl9)
`LD50 (mouse, IV): 1.24 g/kg
`LD50 (mouse, SC): 1.74 g/kg
`LD50 (rat, oral): 2.660 g/kg
`LD50 (rat, IV): 1.33 g/kg
`LD50 (rat, SC): 1.4 g/kg
`
`15 Handling Precautions
`
`Observe normal precautions appropriate to the circumstances and
`quantity of material handled. Boric acid is irritating to the skin and
`is potentially toxic by inhalation. Gloves, eye protection, protective
`clothing, and a respirator are recommended.
`
`16 Regulatory Status
`
`Accepted for use as a food additive in Europe. Included in the FDA
`Inactive Ingredients Database (IV injections; ophthalmic prepara-
`tions; (auricular) otic solutions; topical preparations). Reported in
`the EPA TSCA Inventory. In the UK,
`the use of boric acid in
`cosmetics and toiletries is restricted. Included in the Canadian List
`of Acceptable Non-medicinal Ingredients.
`
`17 Related Substances
`Sodium borate.
`
`18 Comments
`
`Boric acid has been used experimentally as a model oxo-acid to
`retard mannitol crystallization in the solid statello)
`The EINECS number for boric acid is 233—139-2. The PubChem
`Compound ID (CID) for boric acid includes 7628 and 24492.
`
`SEM ‘l: Excipient: boric acid; manufacturer: Alta Aesar; lot no.: 23672;
`magnification: 100x; voltage: 5 kV.
`
`
`
`SEM 2: Excipient: boric acid; manufacturer: Aldrich Chemical Company
`Inc.; lot no.: 01559BU; magnification: 100x; voltage: 5 kV.
`\
`.
`.
`
`r
`
`12
`
`lncompatibilities
`
`Boric acid is incompatible with water, strong bases and alkali
`metals. It reacts violently with potassium and acid anhydrides. It
`also forms a complex with glycerin, which is a stronger acid than
`boric acid.
`
`13 Method of Manufacture
`
`Boric acid occurs naturally as the mineral sassolite. However, the
`majority of boric acid is produced by reacting inorganic borates
`with sulfuric acid in an aqueous medium. Sodium borate and
`partially refined calcium borate (colemanite) are the principal raw
`materials. When boric acid is made from colemanite,
`the fine-
`ground ore is vigorously stirred with mother liquor and sulfuric acid
`at about 90°C. The by—product calcium sulfate is removed by
`filtration, and the boric acid is crystallized by cooling the filtrate.
`
`14 Safety
`
`Boric acid is a weak bacteriostatic and antimicrobial agent, and has
`been used in topical preparations such as eye lotions, mouthwashes
`
`19 Specific References
`1 Borokhov O, Schubert D. Antimicrobial properties of boron deriva-
`tives. ACS Symposium Series 2007; 967: 412—435.
`
`|PR2018—01020 and |PR2018—01021, Exhibit 1012, Page4
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`
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`IPR2018-01020 and IPR2018-01021, Exhibit 1012, Page4
`
`

`

`70
`BronopolWW
`
`9 Lewis R], ed. Sax’s Dangerous Properties of Industrial Materials, 11th
`edn. New York: Wiley, 2004; 536.
`10 Yoshinari T et al. Crystallisation of amorphous mannitol is retarded
`using boric acid. Int] Pharm 2003; 258: 109—120.
`
`20 General References
`
`2 Kodym A et al. Technology of eye drops containing aloe (Aloe
`arborescens M—Liliaceae) and eye drops containing both aloe and
`neomycin sulphate. Acta Pol Pharm 2003; 60(1): 31—39.
`3 Prutting SM, Cerveny JD. Boric acid vaginal suppositories: a brief
`review. Infect Dis Obstet Gynecol 1998; 6: 191—194.
`4 Sobel JD. Current treatment options for vulvovaginal candidiasis.
`Women’s Health 2005; 1(2): 253—261.
`5 Sweetman SC, ed. Martindale: The Complete Drug Reference, 36th
`edn. London: Pharmaceutical Press, 2009; 2268.
`6 Lund \W, ed. The Pharmaceutical Codex: Principles and Practice of
`Pharmaceutics, 12th edn. London: Pharmaceutical Press, 1994; 109.
`7 Hubbard SA. Comparative toxicology of borates. Biol Trace Elem Res
`1998; 66: 343—357.
`8 Dean JA, ed. Lang’s Handbook of Chemistry, 13th edn. New York:
`McGraw—Hill, 1985; 4—57.
`19 January 2009.
`m.umm:z:n;m s;_:mm..
`fizam
`
`Wm‘mm
`
`21 Authors
`
`DD Ladipo, AC Bentham.
`
`22 Date of Revision
`
`Bronopol
`
`Nonproprietary Names
`I
`BP: Bronopol
`
`2
`
`Synonyms
`
`2—Bromo-2—nitro-1,3-propanediol;
`glycol; Myacide.
`
`B—bromo-B-nitrotrimethylene-
`
`Chemical Name and CAS Registry Number
`3
`2-Bromo—2-nitr0propane-1,3-diol [52-51-7]
`
`Empirical Formula and Molecular Weight
`4
`C3H6BINO4
`2.00.00
`
`5
`
`Structural Formula
`
`Br
`
`No2
`
`H0\></OH
`
`Functional Category
`6
`Antimicrobial preservative; antiseptic.
`
`7
`
`Applications in Pharmaceutical Formulation or
`Technology
`
`Bronopol 0.01—0.1% w/v is used as an antimicrobial preservative
`either alone or in combination with other preservatives in topical
`pharmaceutical formulations, cosmetics, and toiletries; the usual
`concentration is 0.02% w/V.
`
`8
`
`Description
`
`Bronopol is a white or almost white crystalline powder; odorless or
`with a faint characteristic odor.
`
`Pharmacopeial Specifications
`9
`See Table I.
`
`10 Typical Properties
`is active against both Gram-
`Antimicrobial activity Bronopol
`positive and Gram-negative bacteria including Pseudomonas
`aeruginosa, with typical minimum inhibitory concentrations
`(MICs) between 10—50 ug/mL;(1_8) see also Table 11. At room
`temperature, a 0.08% W/V aqueous solution may reduce the
`viability of culture collection strains of Escherichia coli and
`
`. Table I: PharmacopeialSpecificationsil’bi‘ brofifipgli’ 3'1
`
`BP 2009
`
`
`Test
`
`Identification
`Characters
`Acidity or alkalinity (l % w/v solution)
`Related substances
`Sullated ash
`Water
`Assay (anhydrous basis)
`
`+
`+
`5.0—7.0
`+
`<0. 1%
`S 0.5%
`99.0—lOl .O%
`
`IImble ll: Minimum inhibitory concentrations (Mle) of bronopol.l..2j9lj
`
`MC (119/mL)
`Microorganism
`3200
`Aspergi/Ius niger
`l2.5
`Bacillus subti/is
`25
`Burkho/a’eria (Pseudomonas) cepacia
`1600
`Candida albicans
`12.5—50
`Escherichia co/i
`25
`Klebsie/ia aerogenes
`50
`Legione/la pneumophilia
`400
`Penicillium roqueforti
`1600
`Penicillium funicu/osum
`125
`Pityrosporum ova/e
`25—50
`Proteus mirabilis
`l2.5—50
`Proteus vulgaris
`l2.5—50
`Pseudomonas aeruginosa
`3200
`Saccharomyces cerevisiae
`25
`Salmonella gai/inarum
`l2.5—50
`Staphylococcus aureus
`50
`Staphylococcus epidermidis
`50
`Streptococcus faeca/is
`200
`Trichophyton mentagrophytes
`
`Trichoderma viria'e 6400
`
`|PR2018—01020 and |PR2018-01021, Exhibit 1012, Page5
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`
`IPR2018-01020 and IPR2018-01021, Exhibit 1012, Page5
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`

`
`
`210
`CyclodextrinsWWW
`
`17 Related Substances
`
`Copovidone; povidone.
`
`18 Comments
`
`Crospovidone is one of the materials that have been selected for
`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.
`Crospovidone has been studied as a superdisintegrant. The
`ability of the compound to swell has been examined directly using
`scanning electron microscopy.(9) The impact of crospovidone on
`percolation has also been examined.(10) The impact of crospovidone
`on dissolution of poorly soluble drugs in tablets has also been
`investigatedm) Crospovidone has been shown to be effective with
`highly hygroscopic drugs.(12) It continues to be examined for its uses
`in a number of tablet formulations.
`A specification for crospovidone is contained in the Food
`Chemicals Codex (FCC).(13)
`The PubChem Compound ID (CID) for crospovidone is 6917.
`
`19 Specific References
`1 Kornblum SS, Stoopak SB. A new tablet disintegrating agent: cross-
`linked polyvinylpyrrolidone. ] Pharm Sci 1973; 62: 43—49.
`2 Rudnic EM et al. Studies of the utility of cross linked polyvinylpoly-
`pyrrolidine as a tablet disintegrant. Drug Dev Ind Pharm 1980; 6: 291—
`309.
`
`3 Gordon MS, Chowhan ZT. Effect of tablet solubility and hygroscopi-
`city on disintegrant efficiency in direct compression tablets in terms of
`dissolution. ] Pharm Sci 1987; 76: 907—909.
`4 Gordon MS et al. Effect of the mode of super disintegrant incorporation
`on dissolution in wet granulated tablets. ] Pharm Sci 1993; 82: 220—
`226.
`
`5 Tagawa M et al. Effect of various disintegrants on drug release
`behavior from tablets. I Pharm Sci Tech Yakuzaigaku 2003; 63(4): 238—
`248.
`
`7 Schiermeier S, Schmidt PC. Fast dispersible ibuprofen tablets. Eur ]
`Pharm Sci 2002; 15(3): 295—305.
`8 FAQ/WHO. Evaluation of certain food additives and contaminants.
`Twenty-seventh report of the joint FAQ/WHO expert committee on
`food additives.World Health Organ Tech Rep Ser 1983; No. 696.
`9 Thibert R, Hancock BC. Direct visualization of superdisintegrant
`hydration using environmental scanning electron microscopy. ] Pharm
`Sci 1996; 85: 1255—1258.
`10 Caraballo I et al. Influence of disintegrant on the drug percolation
`threshold in tablets. Drug Dez/ Ind Pharm 1997; 23(7): 665—669.
`1 1 Yen SY et al. Investigation of dissolution enhancement of nifedipine by
`deposition on-superdisintegrants. Drug Dev Ind Pharm 1997; 23(3):
`313—317.
`
`12 Hirai N et al. Improvement of the agitation granulation method to
`prepare granules containing a high content of a very hygroscopic drug. ]
`Pharm Pharmacol 2006; 56: 1437—1441.
`,
`13 Food Chemicals Codex, 6th edn. Bethesda, MD: United States
`Pharmacopeia, 2008; 794.
`
`20 General References
`
`Barabas ES, Adeyeye CM. Crospovidone. Brittain HG, ed. Analytical
`Profiles ofDrug Substances and Excipients., vol. 24: London: Academic
`Press, 1996; 87—163.
`BASE Technical literature: Insoluble Kollidon grades, 1996.
`European Directorate for
`the Quality of Medicines and Healthcare
`(EDQM). European Pharmacopoeia — State Of Work Of International
`Harmonisation. Pharmeuropa 2009; 21(1): 142—143. http://www.edq—
`m.eu/site/-614.html (accessed 3 February 2009).
`ISP. Technical literature: Polyplasdone crospovidone NF, 1999.
`NP Pharm. Product data sheet: Crospopharm, 2008.
`Wan LSC, Prasad KPP. Uptake of water by excipients in tablets. Int] Pharm
`1989; 50: 147—153.
`
`21 Author
`AH Kibbe.
`
`6 Hipasawa N et al. Application of nilvadipine solid dispersion to tablet
`22 Date of Revision
`formulation and manufacturing using crospovidone and methylcellu-
`lose on dispersion carriers. Chem Pharm Bull 2004; 52(2): 244—247.
`3 February 2009.
`
`
`Cyclodextrins
`
`Nonproprietary Names
`l
`Alfadex Betadex
`BP:
`PhEur: Alfadex Betadex
`USP—NF: Alfadex Betadex
`Gamma Cyclodextrin
`
`Synonyms
`2
`cyclic oligosaccharide;
`Cyclodextrin Cauitron;
`cycloglucan; Encapsin; Schardinger dextrin.
`0L~Cyclodextrin
`alfadexum; alpha-cycloamylose; alpha-cyclodex—
`trin; alpha—dextrin; Caz/amax W6 Pharma; cyclohexaamylose;
`cyclomaltohexose.
`betadexum;
`beta—dextrin;
`B-Cyclodextrin
`beta-cycloamylose;
`Cavamax W7 Pharma; cycloheptaamylose; cycloheptaglucan;
`cyclomaltoheptose; Kleptose.
`
`cycloamylose;
`
`y-Cyclodextrin Cauamax W8 Pharma; cyclooctaamylose; cyclo-
`maltooctaose.
`
`Chemical Name and CAS Registry Number
`3
`oc-Cyclodextrin [10016-20-3]
`B—Cyclodextrin [75 85-39-9]
`y-Cyclodextrin [17465-86-0]
`
`Empirical Formula and Molecular Weight
`4
`OL-CYClOdCXtI'lIl C36H60030
`972
`B-CyClOdCXtrln C42H70035
`1 135
`Y-Cyclodextrin C43H80040
`1297
`
`|PR2018—01020 and |PR2018-01021, Exhibit 1012, Page6
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1012, Page6
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`

`

`Cyclodextrins
`
`21.—
`
`formulations}
`oc-Cyclodextrin is used mainly in parenteral
`However, as it has the smallest cavity of the cyclodextrins it can
`form inclusion complexes with only relatively few, small-sized
`molecules. In contrast, y-cyclodextrin has the largest cavity and can
`be used to form inclusion complexes with large molecules; it has low
`toxicity and enhanced water solubility.
`In oral tablet formulations, B-cyclodextrin may be used in both
`wet-granulation and direct-compression processes. The physical
`properties of B-cyclodextrin vary depending on the manufacturer.
`However, fi—cyclodextrin tends to possess poor flow properties and.
`requires a lubricant, such as 0.1 % w/w magnesium stearate, when it
`is directly compressed.(1’2)
`In parenteral formulations, cyclodextrins have been used to
`produce stable and soluble preparations of drugs that would
`otherwise have been formulated using a nonaqueous solvent.
`In eye drop formulations, cyclodextrins form water-soluble
`complexes with lipophilic drugs such as corticosteroids. They 'have
`been shown to increase the water solubility of the drug; to enhance
`drug absorption into the eye; to improve aqueous stability; and to
`reduce local irritation”)
`Cyclodextrins have also been used in the formulation of
`solutions,(4’5) suppositories,(6’7l and cosmetics.(8’9l
`
`LI
`
` 5
`
`Structural Formula
`RO‘
`
`[on
`
`o
`
`o
`
`[—0
`
`OR R0/
`
`x
`
`-—OR
`
`Ro— ‘.
`
`/OR
`
`RO
`OR \
`
`,OR
`
`0
`
`OR
`
`- ' 'OR
`
`OR
`
`0
`
`0
`
`
`
`0\ /O\ l CAI
`Ro/lVLo/Y OR
`
`.‘0
`
`.
`
`l
`
`Note: the structure of betadex (B-cyclodextrin) with 7 glucose units
`is shown.
`
`R=H for ‘natural’ or, B, and y-cyclodextrins with 6, 7 and 8
`glucose units, respectively
`R=H or CH3 for methyl cyclodextrins
`R=H or CHOHCH3 for 2-hydroxyethyl cyclodextrins
`R: H or CHZCHOHCH3 for 2-hydroxypropyl cyclodextrins
`
`8
`
`Description
`
`Cyclodextrins are cyclic oligosaccharides containing at least six D-
`(+)—glucopyranose units attached by oc(1—>4) glucoside bonds. The
`three natural cyclodextrins, 0c, [5, and y, differ in their ring size and
`solubility. They contain 6, 7, or 8 glucose units, respectively.
`Cyclodextrins occur as white, practically odorless, fine crystal-
`line powders, having a slightly sweet
`taste. Some cyclodextrin
`derivatives occur as amorphous powders.
`See also Table I.
`
`Functional Category
`6
`Solubilizing agent; stabilizing agent.
`
`7
`
`Applications in Pharmaceutical Formulation or
`Technology
`Cyclodextrins are crystalline, nonhygrosCopic, cyclic oligosacchar—
`ides derived from starch. Among the most commonly used forms are
`ca,
`[3-, and y—cyclodextrin, which have respectively 6, 7, and 8
`glucose units; see Section 5.
`Substituted cyclodextrin derivatives are also available;
`Section 17.
`
`see
`
`Cyclodextrins are ‘bucketlike’ or ‘conelike’ toroid molecules,
`with a rigid structure and a central cavity, the size of which varies
`according to the. cyclodextrin type; see Section 8. The internal
`surface of the cavity is hydrophobic and the outside of the torus is
`hydrophilic; this is due to the arrangement of hydroxyl groups
`within the molecule. This arrangement permits the cyclodextrin to
`accommodate a guest molecule within the cavity, forming an
`inclusion complex.
`Cyclodextrins may be used to form inclusion complexes with a
`variety of drug molecules, resulting primarily in improvements to
`dissolution and bioavailability owing to enhanced solubility and
`Improved chemical and physical stability; see Section 18.
`Cyclodextrin inclusion complexes have also been used to mask
`the unpleasant taste of active materials and to convert a liquid
`Substance into a solid material.
`B-Cyclodextrin is
`the most commonly used cyclodextrin,
`although it
`is the least soluble; see Section 10. It
`is the least
`eXpensive cyclodextrin; is commercially available from a number of
`Sources; and is able to form inclusion complexes with a number of
`molecules of pharmaceutical interest. However, B—cyclodextrin is
`r1ephrotoxic and should not be used in parenteral formulations; see
`Section 14. B-Cyclodextrin is primarily used in tablet and capsule
`fOrmulations.
`
`
`'j Table I: Pharmacopeiol specifications for «cyclodextrin lolphadex). d,“
`
`Test
`
`PhEur 6.0
`
`USP32-NF27
`
`Identification
`Characters
`Color and clarity of solution
`pH
`Specific rotation
`Microbial limits
`Sulfated ash
`Residue on ig'nition
`Heavy metals
`Light—absorbing impurities
`Loss on drying
`Related substances
`Reducing sugars
`Assay (anhydrous basis)
`
`+
`+
`+
`5.0—8.0
`+l47° to +152°
`—
`<0. I %
`—
`leppm
`+
`$11.07.:
`+
`$0.270
`98.040] .0%
`
`+
`—
`+
`5.0-8.0
`+147° to +152°
`<1000cfu/9(°l
`—
`<0.l%
`< lOug/g
`+
`<1 1.0%
`+
`$0.270
`980—10] 0%
`
`(a) Tests for Salmonella and Escherichia coli are negative.
`
`Pharmacopeial Specifications
`9
`See Tables I, II, and III.
`
`10 Typical Properties
`Compressibility 21.0—44i0% for flcyclodextrin.
`Density (bulk)
`tic-cyclodextrin: 0.526 g/cm3;
`B-cyclodextrin: 0.523 g/cm3;
`y—cyclodextrin: 0.568 g/cm3.
`Density (tapped)
`tic-cyclodextrin: 0.685 g/cm3;
`B-cyclodextrin: 0.754 g/cm3;
`y-cyclodextrin: 0.684 g/cm3.
`
`\
`
`I
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`
`

`

`
`
`Cyclodextrins
`212
`
`z 1.2
`(0.5
`FK\
`I Table'lltIPharmacopeial specifications for (Br-cyclodextrin (betadex),
`.
`j
`
` Test PhEur 6.0 USP32—NF27
`
`
`Identification /
`+
`+
`Characters
`+
`—-
`Color and clarity of solution
`+
`+
`pH
`5.0—8.0
`5.0—8.0
`Specific rotation
`+160° to +164°
`+160° to +164°
`Microbial limits
`—
`<1000cfu/gl“)
`Sulfated ash
`<0.1%
`—
`Residue an ignition
`—
`$0.1%
`Heavy metals
`S 10 ppm
`<5 ppm
`Lightclbsorbing impurities
`+
`+
`Loss on dr ing
`<16.0°/o
`s 14.0%
`Related substances
`+
`+
`Residual solvents
`+
`—
`Reducing sugars
`<0.2%
`<0.2%
`98.0—101.0°/o
`98.0—102.0°/o
`___________,/
`Assay (anhydrous basis)
`
`—0.2
`I
`I
`I
`— — .2
`1100 1300 1500 1700 1900 2100 2300 2500
`
`Wavelength/nm
`
`Figure 1: Near-infrared spectrum of acyclodextrin measured by
`reflectance.
`
`
`
`.
`
`0.5
`
`EE‘
`‘\
`
`:
`.83
`
`z 0.6
`a;
`
`\ .
`
`63
`,9
`
`2
`'—
`
`-8 0.0
`e
`E.
`
`X0OO
`
`—0.2
`I
`I
`I
`I—— .6
`1100 1300 1500 1700 1900 2100 2300 2500
`
`Wavelength/nm
`
`Figure 2: Near—infrared spectrum of chclodextrin measured by
`reflectance.
`
`A
`
`
`
`0.6
`
`'“‘
`{4
`e,
`_o
`
`,_., 0.7
`b?\
`
`33
`_.0
`>'
`'5 0 o
`1,
`'2
`51.
`
`XCOO I
`
`
`—0.2
`'
`l
`I
`_—1 .0
`1100 1300 1500 1700 1900 2100 2300 2500
`
`Wavelength/nm
`
`Figure 3: Near-infrared spectrum of ycyclodextrin measured by
`reflectance.
`
`Solubility
`oc-cyclodextrin: soluble 1 in 7 parts of water at 20°C, 1 in 3 311
`50°C.
`B-cyclodextrin: soluble 1 in 200 parts of propylene glycol, 1 in
`50 of water at 20°C, 1 in 20 at 50°C; practically insoluble 111,
`acetone, ethanol (95%), and methylene chloride.
`y—cyclodextrin: soluble 1 in 4.4 parts-0f Water at 20°C, 1 in
`45°C.
`
`2’ at:
`
`(a) Tests for Salmonella and Escherichia coli are negative.
`
`'FaBIlIeIII: Phaimacopeial,specificationsfor chyéiodeitfin (gamma
`_»_m_fl_-_
`.
`. _ _.______..___.
`I; cyclodextrin).
`
`Test USP32—NF27
`
`++ +
`
`Identification
`Color and clarity of solution
`Specific rotation
`Microbial limits
`Residue an ignition
`Heavy metals
`Loss on drying
`Related substances
`0.5%
`Reducing sugars
`98.0—102.0°/o
`Assay (anhydrous basis)
`
`174° to +180°
`s 1000 cfu/glal
`<0.1%
`<5 ppm
`$1 1.0%
`
`+ <
`
`(a) Tests for Salmonella and Escherichia cell are negative.
`
`Density (true)
`cit-cyclodextrin: 1.521 g/cm3; _
`y-cyclodextrin: 1.471 g/cm3.
`Melting point
`(it-cyclodextrin: 25 O—260°C;
`B—cyclodextrin: 25 5—265°C;
`y-cyclodextrin: 240—245 °C.
`Moisture content
`
`a-cyclodextrin: 10.2% w/W;
`(Ev—cyclodextrin: 13.0~15.0% W/W;
`y-cyclodextrin: 8—1 8% w/w.
`NIR spectra
`see Figures 1, 2, and 3.
`Particle size distribution B—cyclodextrin: 7.0—45.0 um
`Physical characteristics
`see Table IV.
`
`tWfi‘ idibaiactgrlstfcsgf cycloflixtrins.
`
`
`Characteristic
`Cyclodextrin
`
`a
`
`
`B
`
`Y
`
`Cavity diameter (A)
`Height of torus (A)
`Diameter of periphery (A)
`Approximate volume of cavity (A3)
`Approximate cavity volume
`256
`157
`104
`Per mol cyclodextrin (mL)
`
`Per 9 cyclodextrin (mL) 0.20 0.1 0.14
`
`
`Note: 1A = 0.1nm.
`
`4.7—5.3
`7.9
`14.6
`174
`
`6.0—6.5
`7.9
`15.4
`262
`
`7.5—8.3
`7.9
`17.5
`472
`
`|PR2018—01020 and |PR2018-01021, Exhibit 1012, Page8
`
`
`
`22
`’\
`
`:
`_8.’
`
`733
`.2
`
`,2
`‘—
`
`—8 0.0
`e
`
`QX0OO I
`
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`IPR2018-01020 and IPR2018-01021, Exhibit 1012, Page8
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`

`

`
`
`Cyclodextrins 213
`
`Specific rotation
`a-cyclodextrin: [on]? = +1505°;
`B-cyclodextrin: [@2135 = +162.0°;
`y-cyclodextrin: [(1]ij = +177.4°-.
`Surface tension (at 25°C)
`ot-cyclodextrin: 71 mN/m (71 dynes/cm);
`B-cyclodextrin: 71 mN/m (71 dynes/cm);
`y—cyclodextrin: 71 mN/m (71 dynes/cm).
`
`11 Stability and Storage Conditions
`
`fi-Cyclodextrin and other cyclodextrins are stable in the solid state if
`protected from high humidity.
`Cyclodextrins should be stored in a tightly sealed container, in a
`cool, dry place.
`
`Incompatibilities
`12
`The activity of some antimicrobial preservatives in aqueous solution
`.
`— 2
`can be reduced in the presence of hydroxypropyl—B— cyclodex—
`11111.00 1
`l
`
`13 Method of Manufacture
`
`Cyclodextrins are manufactured by the enzymatic degradation of
`starch using specialized bacteria. For example, B-cyclodextrin is
`produced by the action of the enzyme cyclodextrin glucosyltrans-
`ferase upon starch or a starch hydrolysate. An organic solvent is
`used to direct the reaction that produces B—cyclodextrin, and to
`prevent
`the growth of microorganisms during the enzymatic
`reaction. The insoluble complex of B—cyclodextrin and organic
`solvent is separated from the noncyclic starch, and the organic
`solvent is removed in vacuo so that less than 1ppm of solvent
`remains in the B-cyclodextrin. The B-cyclodextrin is then carbon
`treated and crystallized from water, dried, and collected.
`
`14 Safety
`Cyclodextrins are starch derivatives and are mainly used in oral and
`parenteral pharmaceutical formulations. They are also used in
`topical and ophthalmic formulations“)
`Cyclodextrins are also used in cosmetics and food products, and
`are generally regarded as essentially nontoxic and nonirritant
`materials. However, when administered parenterally, B-cyclodextrin
`is not metabolized but accumulates in the kidneys as insoluble
`Cholesterol complexes, resulting in severe nephrotoxicity.(13)
`Cyclodextrin administered orally is metabolized by microflora in
`the colon, forming the metabolites maltodextrin, maltosle, and
`glucose;
`these are themselves further metabolized before being
`finally excreted as carbon dioxide and water. Although a study
`published in 1957 suggested that orally administered cyclodextrins
`Were highly toxic,(14) more recent animal toxicity studies in rats and
`dogs have shown this not to be the case, and cyclodextrins are now
`approved for use in food products and orally administered
`Pharmaceuticals in a number of countries.
`.. Cyclodextrins are not irritant to the skin and eyes, or upon
`Inhalation. There is also no evidence to suggest that cyclodextrins
`are mutagenic or teratogenic.
`“-Cyclodextrin
`
`LD50 (rat, IP): 1.0 g/kgus)
`LD50 (rat, IV): 0.79 g/kg
`l‘l‘CyClodesvctrin
`LDso (mouse, IP): 0.33 g/kgué)
`LD50 (mouse, SC): 0.41 g/kg
`LDso (rat, 1P): 0.36 g/kg
`LDso (rat, IV): 1.0 g/kg
`LDso (rat, oral): 18.8 g/kg
`LDso (rat, so): 3.7 g/kg
`
`y-Cyclodextrin
`LD50 (rat, .IP): 4.6 g/kguS)
`LD50 (rat ,IV): 4.0 g/kg
`LD50 (rat, oral): 8.0 g/kg
`
`15 Handling Precautions
`Observe normal precautions appropriate to the circumstances and
`quantity of material handled. Cyclodextrins are fine organic
`powders and should be handled in a well-ventilated environment.
`Efforts should be made to limit the generation of dust, which can be
`explosive.
`
`16 Regulatory Status
`Included in the FDA Inactive Ingredients Database: ot-cyclodextrin
`(injection preparations); B—cyclodextrin (oral tablets, topical gels);
`y—cyclodextrin (IV injections).
`Included in the Canadian List of Acceptable Non-medicinal
`Ingredients (stabilizing agent; solubilizing agent ); and in oral and
`rectal pharmaceutical formulations licensed in Europe, Japan, and
`the USA.
`
`17 Related Substances
`
`Dimethyl-B-cyclodextrin; 2-hydroxyethyl-B-cyclodextrin; hydroxy-
`propyl betadex; sulfobutylether B—cyclodextrin; trimethyl-B-cyclo-
`dextrin.
`
`Dimetl'lyl-B-cyclodextrin
`Molecular weight
`1331
`Synonyms DM—B—CD.
`Appearance White crystalline powder.
`Cavity diameter
`6 A
`Melting point
`295.0—‘300.0°C
`Moisture content § 1% w/w
`Solubility Soluble 1 in 135 parts of ethanol (95%), and 1 in 1.75
`of water at 25 °C. Solubility decreases with increasing tempera-
`ture.
`
`62 mN/m (62 dynes/cm) at 25°C.
`Surface tension
`Method of manufacture Dimethyl-B-cyclodextrin is prepared
`from B-cyclodextrin by the selective methylation of all C2
`secondary hydroxyl groups and all C6 primary hydroxyl groups
`(C3 secondary hydroxyl groups remain unsubstituted).
`Comments Used in applications similar to those for fi-cyclodex-
`trin.
`
`2-Hydroxyethyl-B-cyclodextrin
`CAS number
`[98513-20-3]
`Synonyms
`2-HE—B—CD.
`.
`Appearance White crystalline powder.
`Density (bulk)
`0.681 g/cm3
`Density (tapped)
`0.916 g/cm3
`Density (true)
`1.378 g/cm3
`Solubility Greater than 1 in 2 parts of water at 25°C.
`Surface tension
`68.0—71.0 mN/m (68—71 dynes/cm) at 25°C.
`Comments Used in applications similar to those for B—cyclodex-
`trin. The degree of substitution of hydroxyethyl groups can
`vary.(17)
`
`Trimethyl-B-cyclodextrin
`Molecular weight 1429
`Synonyms TM-B-CD.
`Appearance White crystalline powder.
`Cavity diameter
`4.0—7.0 A
`Melting point
`157°C
`Moisture content S 1% w/w
`Solubility Soluble 1 in 3.2 parts of water at 25°C. Solubility
`decreases with increasing temperature.
`Surface tension 56 mN/m (56 dynes/cm) at 25°C.
`
`
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`|PR2018—01020 and |PR2018-01021, Exhibit 1012, Page9
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`
`

`

`
`
`
`
`214 Cyclodextrins
`
`Method of manufacture Trimethyl-B-cyclodextrin is prepared
`from B-cyclodextrin by the complete methylation of all C2 and
`C3 secondary hydroxyl groups along with all C6 primary
`hydroxyl groups.
`Comments Used in applications similar to those for B—cyclodex-
`tr1n.
`
`18 Mura P et al. Comparative study of ibuproxam complexation with
`amorphous beta-cyclodextrin derivatives in solution and in the solid
`state. Eur] Pharm Biopharm 2002; 54(2): 181.
`19 Liu X et al. Biopharmaceuticals of beta-cyclodextrin derivative—based
`formulations of acitretin in Sprague-Dawley rats. ] Pharm Sci 2004;
`93(4): 805—815.
`
`‘l 8 Comments
`
`In addition to their use in pharmaceutical formulations, cyclodex—
`trins have also been investigated for use in various industrial
`applications. Analytically, cyclodextrin polymers are used in
`chromatographic separations, particularly of chiral materials.
`B—Cyclodextrin derivatives