WM2
`
`
`
`(125-Handbook of
`-Pharmaceutical Excipients
`SIXTH EDITION
`
`
`
`Edited by
`Raymond C Rowe Pharm, PhD, DSC, FRPharmS, FRSC, CPhys, MinstP
`Chief Scientist
`Intelligensys Ltd, Stokesley, North Yorkshire, UK
`
`Paul J Sheskey Bsc, reh
`Application Development Leader
`The Dow Chemical Company, Midland, MI, USA
`
`Marian E Quinn Bsc, MSc
`DevelopmentEditor
`Royal Pharmaceutical Society of Great Britain, London, UK
`
`—h
`xfSS
`
`APhA
`
`(PP)
`
`Pharmaceutical Press
`
`london e Chicago
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1012, Page1
`(Aimer
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1012, Page1
`
`

`

`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 Pharmacisis Association
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`
`© Pharmaceutical Press and American Pharmacists Association 2009
`
`(PP) is a trade mark of RPS Publishing
`
`RPSPublishing is the publishing organisation of the Royal Pharmaceutical Society of Great Britain
`
`First published 1986
`Secondedition 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, withoutthe 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 forthis book is available from the British Library
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1012, Page2
`
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`IPR2018-01020 and IPR2018-01021, Exhibit 1012, Page2
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`

`

`
`
`68 Boric Acid
`
`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. J Pharmacol Exp Ther 1945; 84: 358-362.
`7 Draize JH et al. Toxicological investigations of compounds proposed
`for use'as insectrepellents. | 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 WJ, Jr, Laws ER,Jr, eds. Handbook ofPesticide Toxicology., vol.
`3. Classes of Pesticides: New York, NY: Academic Press Inc, 1991;
`150S.
`10 OhnoO etal. Inhibitory effects of benzyl benzoate andits derivatives on
`22 Date of Revision
`angiotensin I]-induced hypertension. Bioorg Med Chem 2008; 16(16):
`7843-7852.
`13 February 2009.
`
`
`20 General References
`
`Gupta VD, Ho HW. Quantitative determination of benzyl benzoate in
`benzy] benzoate lotion NE. Am J Hosp Pharm 1976; 33: 665-666.
`Hassan MMA,MossaJS. Benzyl benzoate. Florey-K, ed. Analytical Profiles
`of Drug Substances., vol. 10: New York: Academic Press, 1981; 55-74.
`
`21 Author
`
`RAStorey.
`
`Boric Acid
`
`Nonproprietary Names
`1
`BP: Boric Acid
`
`JP: Boric Acid
`PhEur: Boric Acid
`USP-NF:Boric Acid
`
`Description
`8
`Boric acid occurs as a hygroscopic, white crystalline powder,
`colorless shiny plates, or white crystals.
`
`Pharmacopeial Specifications
`9
`See Table I.
`
`Synonyms
`2
`Acidum boricum; boracic acid; boraic acid; Borofax; boron
`trihydroxide; E284; orthoboric acid; trinydroxyborene.
`
`Chemical Name and CAS Registry Number
`3
`Orthoboric acid [10043-35-3]
`Metaboric acid [13460-50-9]
`
`'
`
`
`
`_Table It Pharmacopeialspecifications for boric acid.
`Test
`JP XV
`PhEur 6.0
`USP32-NF27
`Identification
`+
`+
`+
`Characters
`_
`+
`-
`Appearance ofsolution
`+
`7
`=
`Loss on drying
`<0.50%
`—
`<0.50%
`Sulfate
`_
`<450 ppm
`_
`
`
`Heavy metals <10ppm=<i5ppm <0.002%
`Organic matter
`-
`+
`=
`4
`Empirical Formula and Molecular Weight
`Arsenic
`<5 ppm
`=
`-
`H3BO3
`61.83 (for trihydrate)
`pH
`3.5-4.1
`3.8-4.8
`—
`HBO,
`43.82 (for monohydrate)
`+
`Solubility in ethanol (96%) —
`+
`
`+
`Completeness of solution
` —
`99.0-100.5% 99.5-100.5%
`Assay
`299.5%
`
`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.)
`Boric acid has also been used therapeutically in the form of
`suppositories to treat yeast infections.'**)In dilute concentrationsit
`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.
`
`10. Typical Properties
`Acidity/alkalinity pH = 3.5-4.1 (5% w/v aqueoussolution)
`Density
`1.435
`170.9°C. When heated slowly to 181.0°C, boric
`Melting point
`acid loses water to form metaboric acid (HBO); tetraboric acid
`(H»B,407) and boron trioxide (B2O3) 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
`11.
`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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`

`SEM 1; Excipient: boric acid; manufacturer: Alfa Aesar; lot no.: 23672;
`
`magnification: 100; voltage: 5 kV.
`Ps
`
`SEM 2: Excipient: boric acid; manufacturer: Aldrich Chemical Company
`Inc.; lot no.: O1559BU; magnification: 100x; voltage: 5 kV.
`
`Incompatibilities
`12
`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-
`groundoreis vigorously stirred with motherliquor and sulfuric acid
`at about 90°C. The by-product calcium sulfate is removed by
`filtration, and the boric acid is crystallized by cooling thefiltrate.
`
`Boric Acid
`
`69
`
`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,
`althoughtheuse of boric acid for these purposes is now regarded as
`inadvisable owing to the possibility of absorption." Boric acid is
`not used internally owingto its toxicity. It is poisonous by ingestion
`and moderately toxic by skin contact. Experimentally it has proved
`to be toxic by inhalation and subcutaneousroutes, and moderately
`toxic by intraperitoneal and intravenousroutes.
`Boric acid is absorbed from the gastrointestinal tract and from
`damaged skin, wounds, and mucous membranes,although it does
`not readily permeateintact skin. The main symptomsof 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, hyper-
`pyrexia, and renal tubular damage have been known to occur!”
`Death has occurred from ingestion of less than 5g in young
`children, and of 5-20g in adults. Fatalities have occurred most
`frequently in young children after the accidental
`ingestion of
`solutionsof boric acid, or after the application of boric acid powder
`to abraded skin.
`The permissible exposure limit (PEL) of boric acid is 15 mg/m
`total dust, and 5 mg/m? respirable fraction for nuisance dusts.)
`Ld; (man,oral): 429 mg/kg"?
`Ld, (woman,oral): 200 mg/kg) _
`Ld,(infant, oral): 934 mg/kg")
`Ld, (man,skin): 2.43 g/kg")
`Ld, (infant, skin): 1.20 g/kg”
`LDso (mouse,oral): 3.45 g/kg!
`LDso (mouse, IV): 1.24 g/kg
`LDso (mouse, SC): 1.74 g/kg
`LD5o (rat, oral): 2.660 g/kg
`LDs5o(rat, IV): 1.33 g/kg
`LDs50 (rat, SC): 1.4 g/kg
`
`15 Handling Precautions
`Observe normal precautions appropriate to the circumstances and
`quantity of material handled. Boric acidis 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 andtoiletries 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 state.°
`The EINECS numberforboric acid is 233-139-2. The PubChem
`Compound ID (CID) for boric acid includes 7628 and 24492.
`
`14 Safety
`Boric acid is a weak bacteriostatic and antimicrobial agent, and has
`been usedin 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.
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1012, Page4
`rrSeSoeerreser
`
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`IPR2018-01020 and IPR2018-01021, Exhibit 1012, Page4
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`

`

`EEO
`
`BronopolRSRRARRRRRRE2RRARRREAPLaGAREFET
`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.
`Prutting SM, Cerveny JD. Boric acid vaginal suppositories: a brief
`review. Infect Dis Obstet Gynecol 1998; 6: 191-194.
`Sobel JD. Current treatment options for vulvovaginal candidiasis.
`Women’s Health 2005; 1(2): 253-261.
`Sweetman SC, ed. Martindale: The Complete Drug Reference, 36th
`edn. London: Pharmaceutical Press, 2009; 2268.
`Lund W, ed. The Pharmaceutical Codex: Principles and Practice of
`Pharmaceutics, 12th edn. London: Pharmaceutical Press, 1994; 109.
`Hubbard SA. Comparative toxicology of borates. Biol Trace Elem Res
`1998; 66: 343-357.
`22 Date of Revision
`8 Dean JA, ed. Lang’s Handbook of Chemistry, 13th edn. New York:
`McGraw-Hill, 1985; 4-57.
`19 January 2009.SPDIERBANTNEEDIATE RCOREAPERYENLEERTIES
`CLONENSOITNAtNCLLTCT CTT:SEES
`
`
`
`
`10
`
`9 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th
`edn. New York: Wiley, 2004; 536.
`Yoshinari T et al. Crystallisation of amorphous mannitol is retarded
`using boric acid. Int J] Pharm 2003; 258: 109-120.
`
`20 General References
`
`21 Authors
`
`DD Ladipo, AC Bentham.
`
`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;"* see also Table Il. At room
`temperature, a 0.08% w/v aqueous solution may reduce the
`viability of culture collection strains of Escherichia coli and
`
`Table I: Pharmacopeialspecifications for bronopél,
`
`
`Test
`BP 2009
`
`Identification
`Characters
`Acidity or alkalinity (1% w/v solution}
`Related substances
`Sulfated ash
`Water
`Assay (anhydrousbasis]
`
`+
`+
`5.0-7.0
`+
`<0.1%
`<0.5%
`99.0-101.0%
`
`Table tl: Minimum inhibitory concentrations (MICs) of bronopol.!2/%)
`
`MIC (ug/ml)
`Microorganism
`3200
`Aspergillus niger
`12.5
`Bacillus subtilis
`25
`Burkholderia (Pseudomonas) cepacia
`1600
`Candida albicans
`12.5-50
`Escherichia coli
`25
`Klebsiella aerogenes
`50
`Legionella pneumophilia
`400
`Penicillium roqueforti
`1600
`Penicillium funiculosum
`125
`Pityrosporum ovale
`25-50
`Proteus mirabilis
`12.5-50
`Proteus vulgaris
`12.5-50
`Pseudomonas aeruginosa
`3200
`Saccharomyces cerevisiae
`25
`Salmonella gallinarum
`12.5-50
`Staphylococcus aureus
`50
`Staphylococcus epidermidis
`50
`Streptococcusfaecalis
`200
`Trichophyton mentagrophytes
`
`Trichoderma viride 6400
`
`Bronopol
`
`Nonproprietary Names
`1
`BP: Bronopol
`
`Synonyms
`2
`2-Bromo-2-nitro-1,3-propanediol;
`glycol; Myacide.
`
`B-bromo-fB-nitrotrimethylene-
`
`Chemical Name and CAS Registry Number
`3
`2-Bromo-2-nitropropane-1,3-diol [52-51-7]
`
`Empirical Formula and Molecular Weight
`4
`C3H¢BrNO,
`200.00
`
`5
`
`Structural Formula
`
`Br
`
`Ho<n
`
`NO,
`
`‘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 B
`
`Description
`ronopol is a white or almost white crystalline powder; odorless or
`with a faint characteristic odor.
`
` Pharmacopeial Specifications
`9
`See TableI.
`
`IPR2018-01020 and IPR2018-01021,
`
`Exhibit 1012, PageS
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1012, Page5
`
`

`

`
`
`18 Comments
`
`Cyclodextrinsce
`210
`17 Related Substances
`7 Schiermeier $, Schmidt PC. Fast dispersible ibuprofen tablets. Eur J
`Pharm Sci 2002; 15(3): 295-305.
`Copovidone; povidone.
`8 FAO/WHO.Evaluation of certain food additives and contaminants,
`Twenty-seventh report of the joint FAO/WHOexpert committee on
`food additives. World Health Organ Tech Rep Ser 1983; No. 696.
`9 Thibert R, Hancock BC. Direct visualization of superdisintegrant
`hydration using environmentalscanningelectron microscopy. J] Pharm
`Sci 1996; 85: 1255-1258.
`10 Caraballo I et al. Influence of disintegrant on the drug percolation
`threshold in tablets. Drug Dev Ind Pharm 1997; 23(7): 665-669.
`11 Yen SY etal. Investigation of dissolution enhancementof 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 contentof a very hygroscopic drug.J
`Pharm Pharmacol 2006; 56: 1437-1441.
`:
`13 Food Chemicals Codex, 6th edn. Bethesda, MD: United States
`Pharmacopeia, 2008; 794.
`
`Crospovidone is one of the materials that have been selected for
`harmonization by the Pharmacopeial Discussion Group. Forfurther
`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 compoundto swell has been examined directly using
`scanning electron microscopy.) The impact of crospovidone on
`percolation hasalso been examined.) The impact of crospovidone
`on dissolution of poorly soluble drugs in tablets has also been
`investigated."”) Crospovidone has been showntobeeffective with
`highly hygroscopic drugs.”It continues to be examinedforits uses
`in a numberoftablet formulations.
`A specification for crospovidone is contained in the Food
`Chemicals Codex (FCC),
`The PubChem Compound ID (CID)for crospovidoneis 6917.
`
`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.
`BASETechnicalliterature: 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 NE, 1999.
`NPPharm. Product data sheet: Crospopharm, 2008.
`Wan LSC, Prasad KPP. Uptake of water byexcipients in tablets. Int J Pharm
`1989; $0: 147-153.
`
`19 Specific References
`1 Kornblum SS, Stoopak SB. A new tablet disintegrating agent: cross-
`linked polyvinylpyrrolidone. J Pharm Sci 1973; 62: 43-49.
`2 Rudnic EM e¢ 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. J] Pharm Sci 1987; 76: 907-909.
`4 Gordon MSetal. Effect of the mode of super disintegrant incorporation
`on dissolution in wet granulated tablets. J Pharm Sci 1993; 82: 220-
`226,
`5 Tagawa M et al. Effect of various disintegrants on drug release
`behavior from tablets. J Pharm Sci Tech Yakuzaigaku 2003; 63(4): 238-
`248.
`6 HipasawaN 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.
`
`
`21 Author
`AHKibbe.
`
`Cyclodextrins
`
`Nonproprietary Names
`1
`Alfadex Betadex
`BP:
`PhEur: Alfadex Betadex
`USP-NF: Alfadex Betadex
`Gamma Cyclodextrin
`
`Synonyms
`2
`cyclic oligosaccharide;
`Cyclodextrin Cavitron;
`cycloglucan; Encapsin; Schardinger dextrin.
`“-Cyclodextrin alfadexum; alpha-cycloamylose; alpha-cyclodex-
`trin; alpha-dextrin; Cavamax W6 Pharma; cyclohexaamylose;
`cyclomaltohexose.
`betadexum;
`beta-dextrin;
`B-Cyclodextrin
`beta-cycloamylose;
`Cavamax W7 Pharma; cycloheptaamylose; cycloheptaglucan;
`cyclomaltoheptose; Kleptose.
`
`cycloamylose;
`
`y-Cyclodextrin Cavamax W8 Pharma; cyclooctaamylose; cyclo-
`maltooctaose.
`
`Chemical Name and CASRegistry Number
`3
`o-Cyclodextrin [10016-20-3]
`B-Cyclodextrin [7585-39-9]
`y-Cyclodextrin [17465-86-0]
`
`Empirical Formula and Molecular Weight
`4
`a-Cyclodextrin C3¢H60030
`972
`B-Cyclodextrin C42H79O35
`1135
`y-Cyclodextrin CygHgqO40
`1297
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1012, Page6
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`

`Cyclodextrins
`
`21
`
` 5
`
`Structural Formula
`
`oR
`
`OR
`
`---OR
`
`OR
`
`formulations’
`a-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 watersolubility.
`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, B-cyclodextrin tends to possess poor flow properties and.
`requires a lubricant, such as 0.1% w/w magnesium stearate, whenit
`is directly compressed.”
`In parenteral formulations, cyclodextrins have been used to
`produce stable and soluble preparations of drugs that would
`otherwise have been formulated using a nonaqueoussolvent.
`In eye drop formulations, cyclodextrins form water-soluble
`complexes with lipophilic drugs such as corticosteroids. They have
`been shownto increase the watersolubility of the drug; to enhance
`drug absorption into the eye; to improve aqueousstability; and to
`reducelocalirritation.'
`Cyclodextrins have also been used in the formulation of
`solutions,(45) suppositories,'*”) and cosmetics.{®-7)
`
`Note: the structure of betadex (-cyclodextrin) with 7 glucose units
`is shown.
`
`R=H for ‘natural’ a, 8, and y-cyclodextrins with 6, 7 and 8
`glucose units, respectively
`R=H or CH;for methyl cyclodextrins
`R=H or CHOHCH;for 2-hydroxyethyl cyclodextrins
`R=H or CH,CHOHCHsfor 2-hydroxypropyl cyclodextrins
`
`Functional Category
`6
`Solubilizing agent; stabilizing agent.
`
`7
`
`see
`
`Applications in Pharmaceutical Formulation or
`Technology
`Cyclodextrins are crystalline, nonhygroscopic, cyclic oligosacchar-
`ides derived from starch. Among the most commonly used forms are
`a-, B-, and y-cyclodextrin, which have respectively 6, 7, and 8
`glucose units; see Section 5.
`Substituted cyclodextrin derivatives are also available;
`Section 17.
`Cyclodextrins are ‘bucketlike’ or ‘conelike’ toroid molecules,
`with a rigid structure and a centralcavity, 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
`substanceinto a solid material.
`B-Cyclodextrin is
`the most commonly used cyclodextrin,
`although it
`is the least soluble; see Section 10. It
`is the least
`€xpensive cyclodextrin; is commercially available from a number of
`Sources; andis able to form inclusion complexes with a number of
`Molecules of pharmaceutical interest. However, B-cyclodextrin is
`nephrotoxic and should not be used in parenteral formulations; see
`Section 14. B-Cyclodextrin is primarily used in tablet and capsule
`Ormulations.
`
`Description
`8
`Cyclodextrins are cyclic oligosaccharides containing at least six D-
`(+)-glucopyranose units attached by «(1-+4) glucoside bonds. The
`three natural cyclodextrins, a, B, and , 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.
`
`_ Table I: Pharmacopeialspecifications for a-cyclodextrin (olphadex}. ce
`
`Test
`
`PhEur 6.0
`
`USP32-NF27
`
`Identification
`Characters
`Color and clarity of solution
`pH
`Specific rotation
`Microbial limits
`Sulfated ash
`Residue onignition
`Heavy metals
`Lightabsorbing impurities
`Loss on drying
`Related substances
`Reducing sugars
`Assay (anhydrousbasis]
`
`+
`+
`+
`5.0-8.0
`+147° to +152°
`-
`<0.1%
`_
`<10ppm
`+
`<11.0%
`+
`<0.2%
`98.0-101.0%
`
`+
`-
`+
`5.0-8.0
`—-+147° to +152°
`<1000cfu/g™
`_
`<0.1%
`<10pg/g
`+
`<11.0%
`+
`<0.2%
`98.0-101.0%
`
`(a) Tests for Salmonella and Escherichia coli are negative.
`
`Pharmacopeial Specifications
`9
`See Tables I, II, and IIL.
`
`10 Typical Properties
`Compressibility 21.0-44.0% for B-cyclodextrin.
`Density (bulk)
`a-cyclodextrin: 0.526 g/cm’;
`B-cyclodextrin: 0.523 g/cm;
`y-cyclodextrin: 0.568 g/cm?.
`Density (tapped)
`a-cyclodextrin: 0.685 g/cm’;
`B-cyclodextrin: 0.754 g/cm;
`y-cyclodextrin: 0.684 g/cm?.
`
`~
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1012, Page7
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`IPR2018-01020 and IPR2018-01021, Exhibit 1012, Page7
`
`

`

`
`
`oO
`
`© >
`
`Nx
`
`fo)
`oO
`
`ro) L
`
` Cyclodextrins
`212
`
`0.5
`Tabletl: Pharmacopeial specifications for B-cyclodextrin {betadex).
`;
`\
`=ik
`
`
` Test PhEur 6.0 USP32-NF27
`
`Identification
`+
`+
`aw
`Characters
`+
`-
`‘
`=
`j
`oO
`Color and clarity of solution
`+
`+
`3a 0.0
`=Oo
`Pp
`5.0-8.0
`5.0-8.0
`
`Specific rotation 4160° to +164°=+160° to +164°
`e
`8
`Microbiallimits
`-
`<1000 cfu/g"!
`Sulfated ash
`<0.1%
`-
`Residue on ignition
`-
`<0.1%
`Heavy metals
`<10ppm
`<5 ppm
`Lightabsorbing impurities
`+
`+
`Loss on drying
`< 16.0%
`<14,0%
`Related aibsidnes
`+
`+
`Residual solvents
`+
`-
`Reducing sugars
`<0.2%
`<0.2%
`Assay (anhydrous basis}
`98.0-101.0%
`98.0-102.0%
`{a} Tests for Salmonella and Escherichia coli are negative.
`
` = 12
`log(1/R)
`
` 0.0]000x[2ndderiv.
`
`
` 1000x[2ndderiv.log(1/R)] \
`
`-1.2
`1100 1300
`
`!
`
`1500 1700
`Wavelength/nm
`
`Figure 1: Near-infrared spectrum of a-cyclodextrin measured by
`reflectance.
`]
`
`Test
`
`TableIll: Pharmacopeialspecifications for cyclodextrin (gamma
`_ cyclodextrin}.ete
`ee
`USP32-NF27
`+
`Identification
`+
`Color and clarity of solution
`+174° to +180°
`Specific rotation
`< 1000 cfu/g'"!
`Microbiallimits
`<0.1%
`Residue onignition
`<5 ppm
`Heavy metals
`<11.0%
`Loss on drying
`+
`Related substances
`<0.5%
`Reducing sugars
`
`Assay (anhydrous basis) 98.0-102.0%
`(a) Tests for Salmonella and Escherichia coli are negative.
`
`Density (true)
`a-cyclodextrin: 1.521 g/cm?-
`y-cyclodextrin: 1.471 g/cm’.
`Melting point
`a-cyclodextrin: 250-260°C;
`255~265°C;
`B-cyclodextrin:
`240-245°C.
`y-cyclodextrin:
`Moisture content
`
`10.2% wiw;
`a-cyclodextrin:
`13.0-15.0% wiw;
`6-cyclodextrin:
`y-cyclodextrin: 8-18 % wiw.
`NIR spectra
`see Figures 1, 2, and 3.
`Particle size distribution -cyclodextrin: 7.0-45.0 pm
`Physical characteristics
`see Table IV.
`
`“TableIV:Ph ysicalcharacteristicsof cyclodextrins.
`
`
`Characteristic
`Cydodextrin
`
`
`Y
`B
`o
`
`7.5-8.3
`6.0-6.5
`Cavity diameter (A)
`4,7-5.3
`7.9
`7.9
`Heightof torus (A)
`7.9
`17.5
`15.4
`Diameter of periphery (A}
`14.6
`472
`262
`Approximate volume of cavity (A°)
`174
`Approximate cavity volume
`256
`157
`Per mol cyclodextrin (mL}
`104
`
`
`0.1 0.14Per g cyclodextrin (ml) 0.20
`
`Note: 1A = 0.1 nm.
`
`Wavelength/nm
`
`Figure 2: Near-infrared spectrum of B-cyclodextrin measured by
`reflectance.
`° NX
`
`0.6
`
`log(1/R)
`
`-1.0
`1100 1300
`
`_0.
`\
`|
`|
`1500 1700 1900 2100 2300 2500
`Wavelength/nm
`
`Figure 3: Nearinfrared spectrum of y-cyclodextrin measured by
`reflectance.
`
`Solubility
`a-cyclodextrin: soluble 1 in 7 parts of water at 20°C, 1 in
`50°C.
`B-cyclodextrin: soluble 1 in 200 parts of propylene glycol, 1?
`50 of water at 20°C, 1 in 20 at 50°C; practically insoluble #
`acetone, ethanol (95%), and methylene chloride.
`y-cyclodextrin: soluble 1 in 4.4 parts-of water at 20°C, 1 in
`48°C.
`
`3 at
`
`2 at
`
`IPR2018-01020 and IPR2018-01021,
`
`Exhibit 1012, Page8
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`IPR2018-01020 and IPR2018-01021, Exhibit 1012, Page8
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`

`

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`
`Cyclodextrins 213
`
`Specific rotation
`a-cyclodextrin: [oo]? = +150.5°;
`p-cyclodextrin: [a]= +162.0°;
`y-cyclodextrin: [a]p = +177.4°.
`Surface tension (at 25°C)
`a-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
`6-Cyclodextrin and other cyclodextrins are stable in thesolid 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 aqueoussolution
`can be reduced in the presence of hydroxypropyl-B- cyclodex-
`«(10-12
`trin.
`
`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 1 ppm of solvent
`remains in the B-cyclodextrin. The B-cyclodextrin is then carbon
`treated and crystallized from water, dried, and collected.
`
`14 Safety
`Cyclodextrinsare starch derivatives and are mainly usedin 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.1?
`Cyclodextrin administeredorally is metabolized by microflora in
`the colon, forming the metabolites maltodextrin, maltosk, 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,"'*) more recent animaltoxicity studies in rats and
`dogs have shownthis notto be the case, and cyclodextrins are now
`approved for use in food products and orally administered
`pharmaceuticals in a- number of countries.
`_ Cyclodextrins are notirritant to the skin and eyes, or upon
`inhalation. There is also no evidence to suggest that cyclodextrins
`are mutagenic or teratogenic.
`&-Cyclodextrin
`LDso (rat, IP): 1.0 g/kg"?
`LDso (rat, IV): 0.79 g/kg
`-Cyclodextrin
`LDso (mouse, IP): 0.33 g/kg"!®
`LDso (mouse, SC): 0.41 g/kg
`LDso (rat, IP): 0.36 g/kg
`LDso (rat, IV): 1.0 g/kg
`LDso (rat, oral): 18.8 g/kg
`LDso (rat, SC): 3.7 g/kg
`
`y-Cyclodextrin
`LD¢o (rat, IP): 4.6 g/kg!)
`LDspo(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 madeto limit the generation of dust, which can be
`explosive.
`
`16 Regulatory Status
`Included in the FDA Inactive Ingredients Database: «-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-8-cyclodextrin; hydroxy-
`propyl betadex; sulfobutylether B-cyclodextrin; trimethyl-B-cyclo-
`dextrin.
`
`Dimethyl-f-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% wiw
`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 Usedin applications similar to those for B-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/cm?
`Density (tapped)
`0.916 g/cm?
`Density (true)
`1.378 g/cm?
`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. Be degree of substitution of hydroxyethyl groups can
`vary.
`
`Trimethyl--cyclodextrin
`Molecular weight 1429
`Synonyms TM-B-CD.
`Appearance Whitecrystalline powder.
`Cavity diameter 4.0-7.0A
`Melting point
`157°C
`Moisture content <1% wilw
`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.
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1012, Page9
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`
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`IPR2018-01020 and IPR2018-01021, Exhibit 1012, Page9
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`

`
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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-
`trin.
`
`18 Mura P et al. Comparative study of ibuproxam complexation with
`amorphousbeta-cyclodextrin derivatives in solution and in thesolid
`state. Eur J Pharm Biopharm 2002; 54(2): 181.
`19 Liu X et al. Biopharmaceuticals of beta-cyclodextrin derivative-based
`formulations of acitretin in Sprague-Dawley rats. J Pharm Sci 2004;
`93(4): 805-815.
`
`18 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 are more water-soluble than f-
`cyclodextrin, and studies have shown that
`they have greater
`solubilizing action with some drugs such as ibuproxam, a poorly
`water-soluble anti-inflammatory agent.'1®?”)
`The EINECS number
`for cyclodextrin is 231-493-2. The
`PubChem CompoundID (CID) for cyclodextrins includes 444913
`(a-cyclodextrin), 24238 (B-cyclodextrin), and 86575 (y-cyclodex-
`trin).
`
`19 Specific References
`1 El Shaboury MH.Physical properties and dissolution profiles of tablets
`directly compressed with B-cyclodextrin. Int J Pharm 1990; 63: 95—
`100.
`2 Shangraw RF et al. Characterization of the tabletin