ss
`
`Terea
`(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)
`Pharmaceutical ateoe
`
`(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)
`Sixth edition
`(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)
`Edited by
`
`rond C Rowe, PaulJ epeskeyatand Marian E oP
`
`SAB1013
`U.S. Pat. No. 10,945,970
`
`

`

`Handbook of Pharmaceutical Excipients
`
`

`

`

`

`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
`
`

`

`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
`
`

`

`56
`59
`61
`64
`66
`68
`70
`73
`75
`77
`78
`
`82
`83
`86
`89
`91
`92
`94
`96
`99
`101
`103
`105
`108
`110
`115
`117
`118
`122
`126
`128
`129
`
`134
`136
`139
`141
`143
`146
`148
`
`Benzalkonium Chloride
`Benzethonium Chloride
`Benzoic Acid
`Benzyl Alcohol
`Benzyl Benzoate
`Boric Acid
`Bronopol
`Butylated Hydroxyanisole
`Butylated Hydroxytoluene
`Butylene Glycol
`Butylparaben
`
`C C
`
`alcium Acetate
`Calcium Alginate
`Calcium Carbonate
`Calcium Chloride
`Calcium Hydroxide
`Calcium Lactate
`Calcium Phosphate, Dibasic Anhydrous
`Calcium Phosphate, Dibasic Dihydrate
`Calcium Phosphate, Tribasic
`Calcium Silicate
`Calcium Stearate
`Calcium Sulfate
`Canola Oil
`Carbomer
`Carbon Dioxide
`Carboxymethylcellulose Calcium
`Carboxymethylcellulose Sodium
`Carrageenan
`Castor Oil
`Castor Oil, Hydrogenated
`Cellulose, Microcrystalline
`Cellulose, Microcrystalline and
`Carboxymethylcellulose Sodium
`Cellulose, Powdered
`Cellulose, Silicified Microcrystalline
`Cellulose Acetate
`Cellulose Acetate Phthalate
`Ceratonia
`Ceresin
`
`1
`3
`5
`7
`8
`10
`11
`13
`14
`17
`20
`23
`28
`29
`31
`34
`35
`37
`38
`39
`41
`42
`43
`46
`48
`51
`
`53
`
`Contents
`
`Preface x
`xi
`Arrangement
`xiii
`Acknowledgments
`xiii
`Notice to Readers
`International Steering Committee xiv
`Editorial Staff
`xv
`Contributors
`xvi
`About the Editors
`New Monographs
`Related Substances
`Bibliography
`xxiv
`Abbreviations
`xxv
`Units of Measurement
`
`xx
`xxi
`xxii
`
`xxvii
`
`Monographs
`
`A A
`
`cacia
`Acesulfame Potassium
`Acetic Acid, Glacial
`Acetone
`Acetyltributyl Citrate
`Acetyltriethyl Citrate
`Adipic Acid
`Agar
`Albumin
`Alcohol
`Alginic Acid
`Aliphatic Polyesters
`Alitame
`Almond Oil
`Alpha Tocopherol
`Aluminum Hydroxide Adjuvant
`Aluminum Monostearate
`Aluminum Oxide
`Aluminum Phosphate Adjuvant
`Ammonia Solution
`Ammonium Alginate
`Ammonium Chloride
`Ascorbic Acid
`Ascorbyl Palmitate
`Aspartame
`Attapulgite
`
`B B
`
`entonite
`
`

`

`251
`253
`256
`257
`259
`261
`262
`267
`268
`270
`
`273
`276
`
`278
`282
`283
`286
`288
`290
`293
`295
`297
`298
`
`301
`303
`304
`306
`308
`309
`311
`314
`315
`317
`322
`325
`326
`330
`333
`
`337
`339
`
`Erythritol
`Ethyl Acetate
`Ethyl Lactate
`Ethyl Maltol
`Ethyl Oleate
`Ethyl Vanillin
`Ethylcellulose
`Ethylene Glycol Stearates
`Ethylene Vinyl Acetate
`Ethylparaben
`
`F F
`
`ructose
`Fumaric Acid
`
`G G
`
`elatin
`Glucose, Liquid
`Glycerin
`Glyceryl Behenate
`Glyceryl Monooleate
`Glyceryl Monostearate
`Glyceryl Palmitostearate
`Glycine
`Glycofurol
`Guar Gum
`
`H H
`
`ectorite
`Heptafluoropropane (HFC)
`Hexetidine
`Hydrocarbons (HC)
`Hydrochloric Acid
`Hydrophobic Colloidal Silica
`Hydroxyethyl Cellulose
`Hydroxyethylmethyl Cellulose
`Hydroxypropyl Betadex
`Hydroxypropyl Cellulose
`Hydroxypropyl Cellulose, Low-substituted
`Hydroxypropyl Starch
`Hypromellose
`Hypromellose Acetate Succinate
`Hypromellose Phthalate
`
`I I
`
`midurea
`Inulin
`
`150
`152
`155
`157
`159
`162
`166
`168
`171
`173
`176
`178
`181
`184
`185
`189
`196
`199
`200
`202
`203
`206
`208
`210
`215
`
`217
`218
`220
`222
`225
`227
`228
`230
`232
`233
`235
`236
`238
`241
`242
`244
`
`247
`250
`
`vi
`
`Contents
`
`Cetostearyl Alcohol
`Cetrimide
`Cetyl Alcohol
`Cetylpyridinium Chloride
`Chitosan
`Chlorhexidine
`Chlorobutanol
`Chlorocresol
`Chlorodifluoroethane (HCFC)
`Chlorofluorocarbons (CFC)
`Chloroxylenol
`Cholesterol
`Citric Acid Monohydrate
`Coconut Oil
`Colloidal Silicon Dioxide
`Coloring Agents
`Copovidone
`Corn Oil
`Corn Starch and Pregelatinized Starch
`Cottonseed Oil
`Cresol
`Croscarmellose Sodium
`Crospovidone
`Cyclodextrins
`Cyclomethicone
`
`D D
`
`enatonium Benzoate
`Dextrates
`Dextrin
`Dextrose
`Dibutyl Phthalate
`Dibutyl Sebacate
`Diethanolamine
`Diethyl Phthalate
`Difluoroethane (HFC)
`Dimethicone
`Dimethyl Ether
`Dimethyl Phthalate
`Dimethyl Sulfoxide
`Dimethylacetamide
`Disodium Edetate
`Docusate Sodium
`
`E E
`
`detic Acid
`Erythorbic Acid
`
`

`

`Contents
`
`vii
`
`436
`438
`441
`445
`447
`449
`450
`452
`454
`455
`456
`
`458
`460
`461
`463
`
`465
`466
`468
`470
`
`473
`474
`476
`478
`480
`481
`484
`485
`488
`490
`492
`494
`496
`499
`503
`504
`506
`509
`513
`515
`517
`522
`
`Methionine
`Methylcellulose
`Methylparaben
`Mineral Oil
`Mineral Oil, Light
`Mineral Oil and Lanolin Alcohols
`Monoethanolamine
`Monosodium Glutamate
`Monothioglycerol
`Myristic Acid
`Myristyl Alcohol
`
`N N
`
`eohesperidin Dihydrochalcone
`Neotame
`Nitrogen
`Nitrous Oxide
`
`O O
`
`ctyldodecanol
`Oleic Acid
`Oleyl Alcohol
`Olive Oil
`
`P P
`
`almitic Acid
`Paraffin
`Peanut Oil
`Pectin
`Pentetic Acid
`Petrolatum
`Petrolatum and Lanolin Alcohols
`Phenol
`Phenoxyethanol
`Phenylethyl Alcohol
`Phenylmercuric Acetate
`Phenylmercuric Borate
`Phenylmercuric Nitrate
`Phospholipids
`Phosphoric Acid
`Polacrilin Potassium
`Poloxamer
`Polycarbophil
`Polydextrose
`Poly (DL-Lactic Acid)
`Polyethylene Glycol
`Polyethylene Oxide
`
`340
`342
`346
`348
`350
`
`352
`
`Iron Oxides
`Isomalt
`Isopropyl Alcohol
`Isopropyl Myristate
`Isopropyl Palmitate
`
`K K
`
`aolin
`
`L L
`
`355
`actic Acid
`357
`Lactitol
`359
`Lactose, Anhydrous
`362
`Lactose, Inhalation
`364
`Lactose, Monohydrate
`370
`Lactose, Monohydrate and Corn Starch
`Lactose, Monohydrate and Microcrystalline Cellulose 371
`Lactose, Monohydrate and Povidone
`373
`Lactose, Monohydrate and Powdered Cellulose
`374
`Lactose, Spray-Dried
`376
`Lanolin
`378
`Lanolin, Hydrous
`380
`Lanolin Alcohols
`382
`Lauric Acid
`383
`Lecithin
`385
`Leucine
`387
`Linoleic Acid
`389
`
`391
`393
`397
`400
`402
`404
`408
`410
`411
`414
`416
`418
`421
`422
`424
`429
`431
`433
`
`M M
`
`acrogol 15 Hydroxystearate
`Magnesium Aluminum Silicate
`Magnesium Carbonate
`Magnesium Oxide
`Magnesium Silicate
`Magnesium Stearate
`Magnesium Trisilicate
`Maleic Acid
`Malic Acid
`Maltitol
`Maltitol Solution
`Maltodextrin
`Maltol
`Maltose
`Mannitol
`Medium-chain Triglycerides
`Meglumine
`Menthol
`
`

`

`640
`643
`645
`646
`648
`650
`651
`654
`656
`659
`661
`663
`667
`669
`671
`672
`675
`679
`682
`685
`691
`695
`697
`700
`701
`703
`707
`709
`710
`712
`714
`718
`719
`721
`722
`
`727
`728
`731
`733
`735
`736
`739
`741
`744
`
`Sodium Citrate Dihydrate
`Sodium Cyclamate
`Sodium Formaldehyde Sulfoxylate
`Sodium Hyaluronate
`Sodium Hydroxide
`Sodium Lactate
`Sodium Lauryl Sulfate
`Sodium Metabisulfite
`Sodium Phosphate, Dibasic
`Sodium Phosphate, Monobasic
`Sodium Propionate
`Sodium Starch Glycolate
`Sodium Stearyl Fumarate
`Sodium Sulfite
`Sodium Thiosulfate
`Sorbic Acid
`Sorbitan Esters (Sorbitan Fatty Acid Esters)
`Sorbitol
`Soybean Oil
`Starch
`Starch, Pregelatinized
`Starch, Sterilizable Maize
`Stearic Acid
`Stearyl Alcohol
`Sucralose
`Sucrose
`Sucrose Octaacetate
`Sugar, Compressible
`Sugar, Confectioner’s
`Sugar Spheres
`Sulfobutylether b-Cyclodextrin
`Sulfur Dioxide
`Sulfuric Acid
`Sunflower Oil
`Suppository Bases, Hard Fat
`
`T T
`
`agatose
`Talc
`Tartaric Acid
`Tetrafluoroethane (HFC)
`Thaumatin
`Thimerosal
`Thymol
`Titanium Dioxide
`Tragacanth
`
`525
`534
`536
`542
`549
`554
`557
`562
`564
`566
`567
`569
`570
`572
`574
`576
`577
`579
`581
`586
`587
`590
`592
`594
`596
`599
`600
`
`603
`
`605
`608
`610
`612
`614
`616
`619
`620
`622
`625
`627
`629
`633
`635
`637
`
`viii
`
`Contents
`
`Polymethacrylates
`Poly(methyl vinyl ether/maleic anhydride)
`Polyoxyethylene Alkyl Ethers
`Polyoxyethylene Castor Oil Derivatives
`Polyoxyethylene Sorbitan Fatty Acid Esters
`Polyoxyethylene Stearates
`Polyoxylglycerides
`Polyvinyl Acetate Phthalate
`Polyvinyl Alcohol
`Potassium Alginate
`Potassium Alum
`Potassium Benzoate
`Potassium Bicarbonate
`Potassium Chloride
`Potassium Citrate
`Potassium Hydroxide
`Potassium Metabisulfite
`Potassium Sorbate
`Povidone
`Propionic Acid
`Propyl Gallate
`Propylene Carbonate
`Propylene Glycol
`Propylene Glycol Alginate
`Propylparaben
`Propylparaben Sodium
`Pyrrolidone
`
`R R
`
`affinose
`
`S S
`
`accharin
`Saccharin Sodium
`Safflower Oil
`Saponite
`Sesame Oil
`Shellac
`Simethicone
`Sodium Acetate
`Sodium Alginate
`Sodium Ascorbate
`Sodium Benzoate
`Sodium Bicarbonate
`Sodium Borate
`Sodium Carbonate
`Sodium Chloride
`
`

`

`Contents
`
`ix
`
`779
`780
`
`782
`786
`
`790
`791
`793
`
`795
`847
`849
`852
`855
`
`Wax, White
`Wax, Yellow
`
`X X
`
`anthan Gum
`Xylitol
`
`Z Z
`
`ein
`Zinc Acetate
`Zinc Stearate
`
`Appendix I: Suppliers Directory
`Appendix II: List of Excipient ‘E’ Numbers
`Appendix III: List of Excipient ‘EINECS’ Numbers
`Appendix IV: List of Excipient Molecular Weights
`Index
`
`746
`748
`749
`751
`754
`756
`757
`
`760
`762
`764
`
`766
`770
`772
`774
`775
`777
`
`Trehalose
`Triacetin
`Tributyl Citrate
`Tricaprylin
`Triethanolamine
`Triethyl Citrate
`Triolein
`
`V V
`
`anillin
`Vegetable Oil, Hydrogenated
`Vitamin E Polyethylene Glycol Succinate
`
`W W
`
`ater
`Wax, Anionic Emulsifying
`Wax, Carnauba
`Wax, Cetyl Esters
`Wax, Microcrystalline
`Wax, Nonionic Emulsifying
`
`

`

`Cellulose, Microcrystalline
`
`129
`
`is a
`Sterotex K (Karlshamns Lipid Specialities), for example,
`mixture of hydrogenated castor oil and hydrogenated cottonseed
`oil. See Vegetable Oil, hydrogenated for further information.
`The EINECS number for hydrogenated castor oil is 232-292-2.
`
`19 Specific References
`1 Kline CH. Thixcin R-thixotrope. Drug Cosmet Ind 1964; 95(6): 895–
`897.
`2 Yonezawa Y et al. Release from or through a wax matrix system. III:
`Basic properties of release through the wax matrix layer. Chem Pharm
`Bull (Tokyo) 2002; 50(6): 814–817.
`3 Vergote GJ et al. An oral controlled release matrix pellet formulation
`containing microcrystalline ketoprofen. Int J Pharm 2002; 219: 81–87.
`4 Danish FQ, Parrott EL. Effect of concentration and size of lubricant on
`flow rate of granules. J Pharm Sci 1971; 60: 752–754.
`5 Ho¨ lzer AW, Sjo¨ gren J. Evaluation of some lubricants by the comparison
`of friction coefficients and tablet properties. Acta Pharm Suec 1981; 18:
`139–148.
`
`C
`
`20 General References
`
`— 2
`
`1 Author
`RT Guest.
`
`14 Safety
`Hydrogenated castor oil is used in oral and topical pharmaceutical
`formulations and is generally regarded as an essentially nontoxic
`and nonirritant material.
`in animals have shown that
`Acute oral
`toxicity studies
`hydrogenated castor oil is a relatively nontoxic material. Irritation
`tests with rabbits show that hydrogenated castor oil causes mild,
`transient irritation to the eye.
`LD50 (rat, oral): >10 g/kg
`
`15 Handling Precautions
`Observe normal precautions appropriate to the circumstances and
`quantity of material handled.
`
`16 Regulatory Status
`Accepted in the USA as an indirect food additive. Included in the
`FDA Inactive Ingredients Database (oral capsules, tablets, and
`sublingual tablets).
`Included in nonparenteral medicines licensed in the UK. Included
`in the Canadian List of Acceptable Non-medicinal Ingredients.
`
`17 Related Substances
`Castor oil; vegetable oil, hydrogenated.
`
`18 Comments
`Various different grades of hydrogenated castor oil are commer-
`cially available, the composition of which may vary considerably.
`
`22 Date of Revision
`11 February 2009.
`
`Cellulose, Microcrystalline
`
`Nonproprietary Names
`1
`BP: Microcrystalline Cellulose
`JP: Microcrystalline Cellulose
`PhEur: Cellulose, Microcrystalline
`USP-NF: Microcrystalline Cellulose
`
`5
`
`Structural Formula
`
`Synonyms
`2
`Avicel PH; Cellets; Celex; cellulose gel; hellulosum microcristalli-
`num; Celphere; Ceolus KG; crystalline cellulose; E460; Emcocel;
`Ethispheres; Fibrocel; MCC Sanaq; Pharmacel; Tabulose; Vivapur.
`
`Chemical Name and CAS Registry Number
`3
`Cellulose [9004-34-6]
`
`Empirical Formula and Molecular Weight
`4
`36 000
`(C6H10O5)n
`where n  220.
`
`Functional Category
`6
`Adsorbent; suspending agent; tablet and capsule diluent; tablet
`disintegrant.
`
`

`

`130
`
`Cellulose, Microcrystalline
`
`SEM 1: Excipient: microcrystalline cellulose; manufacturer: JRS Pharma
`LP; lot no.: 98662; magnification: 100.
`
`SEM 4: Excipient: microcrystalline cellulose (Avicel PH-105);
`manufacturer: FMC Biopolymer. magnification: 500; voltage: 3 kV.
`
`C
`
`SEM 2: Excipient: microcrystalline cellulose (Avicel PH-101);
`manufacturer: FMC Biopolymer. magnification: 200; voltage: 3 kV.
`
`SEM 3: Excipient: microcrystalline cellulose (Avicel PH-102);
`manufacturer: FMC Biopolymer. magnification: 200; voltage: 3 kV.
`
`SEM 5: Excipient: microcrystalline cellulose (Avicel PH-200);
`manufacturer: FMC Biopolymer. magnification: 200; voltage: 3 kV.
`
`SEM 6: Excipient: microcrystalline cellulose (Avicel PH-302);
`manufacturer: FMC Biopolymer. magnification: 200; voltage: 3 kV.
`
`7
`
`Applications in Pharmaceutical Formulation or
`Technology
`Microcrystalline cellulose is widely used in pharmaceuticals,
`primarily as a binder/diluent in oral tablet and capsule formulations
`where it is used in both wet-granulation and direct-compression
`processes.(1–7) In addition to its use as a binder/diluent, micro-
`crystalline cellulose also has some lubricant(8) and disintegrant
`properties that make it useful in tableting.
`
`

`

`Cellulose, Microcrystalline
`
`131
`
`1401
`
`1890
`
`2020
`
`0.4
`
`2292
`2246
`
`2427
`2404
`
`C
`
`log(1/R)
`
`2106
`
`2336
`
`1920
`
`2483
`
`1590 1706
`
`1367 1427
`
`4.0
`
`0.0
`
`0000 × [2nd deriv. log(1/R)]
`
`−7.01
`−0.2
`1700 1900 2100 2300 2500
`1100 1300 1500
`Wavelength/nm
`
`2273
`
`Figure 1: Near-infrared spectrum of cellulose, microcrystalline measured
`by reflectance.
`
`1.420–1.460 g/cm3 for Avicel PH-102.(11)
`Flowability 1.41 g/s for Emcocel 90M.(9)
`Melting point Chars at 260–2708C.
`Moisture content Typically less than 5% w/w. However, different
`grades may contain varying amounts of water. Microcrystalline
`cellulose is hygroscopic.(12) See Table III.
`NIR spectra see Figure 1.
`Particle size distribution Typical mean particle size is 20–200 mm.
`Different grades may have a different nominal mean particle size;
`see Table III.
`Solubility Slightly soluble in 5% w/v sodium hydroxide solution;
`practically insoluble in water, dilute acids, and most organic
`solvents.
`Specific surface area
`1.06–1.12 m2/g for Avicel PH-101;
`1.21–1.30 m2/g for Avicel PH-102;
`0.78–1.18 m2/g for Avicel PH-200.
`
`11 Stability and Storage Conditions
`Microcrystalline cellulose is a stable though hygroscopic material.
`The bulk material should be stored in a well-closed container in a
`cool, dry place.
`
`12 Incompatibilities
`Microcrystalline cellulose is incompatible with strong oxidizing
`agents.
`
`13 Method of Manufacture
`Microcrystalline cellulose is manufactured by controlled hydrolysis
`with dilute mineral acid solutions of a-cellulose, obtained as a pulp
`from fibrous plant materials. Following hydrolysis, the hydro-
`cellulose is purified by filtration and the aqueous slurry is spray-
`dried to form dry, porous particles of a broad size distribution.
`
`14 Safety
`Microcrystalline cellulose is widely used in oral pharmaceutical
`formulations and food products and is generally regarded as a
`relatively nontoxic and nonirritant material.
`Microcrystalline cellulose is not absorbed systemically following
`oral administration and thus has little toxic potential. Consumption
`of large quantities of cellulose may have a laxative effect, although
`this is unlikely to be a problem when cellulose is used as an excipient
`in pharmaceutical formulations.
`Deliberate abuse of formulations containing cellulose, either by
`inhalation or by injection, has resulted in the formation of cellulose
`granulomas.(13)
`
`Microcrystalline cellulose is also used in cosmetics and food
`products; see Table I.
`
`Description
`8
`Microcrystalline cellulose is a purified, partially depolymerized
`cellulose that occurs as a white, odorless, tasteless, crystalline
`powder composed of porous particles. It is commercially available
`in different particle sizes and moisture grades that have different
`properties and applications.
`
`Table I: Uses of microcrystalline cellulose.
`
`Use
`
`Adsorbent
`Antiadherent
`Capsule binder/diluent
`Tablet disintegrant
`Tablet binder/diluent
`
`Concentration (%)
`
`20–90
`5–20
`20–90
`5–15
`20–90
`
`Pharmacopeial Specifications
`9
`See Table II. See also Section 18.
`
`Table II: Pharmacopeial specifications for microcrystalline cellulose.
`
`Test
`
`Identification
`Characters
`pH
`Bulk density
`Loss on drying
`Residue on ignition
`Conductivity
`Sulfated ash
`Ether-soluble substances
`Water-soluble substances
`Heavy metals
`Microbial limits
`Aerobic
`Molds and yeasts
`Solubility
`Particle size distribution
`
`USP32–NF27
`þ
`
`PhEur 6.3
`JP XV
`þ
`þ
`þ—
`þ
`5.0–7.5
`5.0–7.5
`5.0–7.5
`þ
`þ
`—
`47.0%
`47.0%
`47.0%
`40.1%
`40.1%
`—
`þ
`þ
`þ
`40.1%
`—
`—
`40.05%
`40.05%
`40.05%
`þ
`40.25%
`40.25%
`40.001%
`410 ppm
`410 ppm
`þ
`þ
`þ
`4103 cfu/g 4103 cfu/g 4103 cfu/g
`4102 cfu/g 4102 cfu/g 4102 cfu/g
`þ
`—
`—
`þ
`—
`—
`
`10 Typical Properties
`Angle of repose
`498 for Ceolus KG;
`34.48 for Emcocel 90M.(9)
`Density (bulk)
`0.337 g/cm3;
`0.32 g/cm3 for Avicel PH-101;(10)
`0.80  5 g/cm3 for Cellets 100, 200, 350, 500, 700, 1000;
`0.29 g/cm3 for Emcocel 90M;(9)
`0.26–0.31 g/cm3 for MCC Sanaq 101;
`0.28–0.33 g/cm3 for MCC Sanaq 102;
`0.29–0.36 g/cm3 for MCC Sanaq 200;
`0.34–0.45 g/cm3 for MCC Sanaq 301;
`0.35–0.46 g/cm3 for MCC Sanaq 302;
`0.13–0.23 g/cm3 for MCC Sanaq UL-002;
`0.29 g/cm3 for Vivapur 101.
`Density (tapped)
`0.478 g/cm3;
`0.45 g/cm3 for Avicel PH-101;
`0.35 g/cm3 for Emcocel 90M.(9)
`Density (true) 1.512–1.668 g/cm3;
`
`

`

`132
`
`Cellulose, Microcrystalline
`
`Table III: Properties of selected commercially available grades of
`microcrystalline cellulose.
`
`Particle size analysis
`
`Moisture
`content (%)
`
`Mesh size Amount
`retained (%)
`41.0
`430.0
`48.0
`545.0
`41.0
`430.0
`41.0
`48.0
`41.0
`430.0
`510.0
`550.0
`41.0
`430.0
`48.0
`545.0
`41.0
`530.0
`40.5
`430.0
`40.25
`430.0
`48.0
`545.0
`41.0
`
`60
`200
`60
`200
`60
`200
`400
`60
`60
`200
`60
`100
`60
`200
`60
`200
`60
`200
`60
`200
`60
`200
`60
`200
`60
`
`200
`60
`
`200
`60
`
`100
`60
`
`200
`60
`
`200
`60
`
`100
`200
`60
`200
`60
`200
`38
`94
`
`430.0
`48.0
`
`545.0
`510.0
`
`550.0
`41.0
`
`530.0
`48.0
`
`545.0
`<0.5
`
`<5.0
`<5.0–30.0
`41.0
`430.0
`48.0
`545.0
`41.0
`450.0
`
`45.0
`
`45.0
`
`43.0
`
`45.0
`41.5
`41.5
`
`45.0
`
`45.0
`
`45.0
`
`45.0
`
`46.0
`
`45.0
`
`45.0
`
`46.0
`
`46.0
`
`46.0
`
`46.0
`
`46.0
`
`46.0
`
`45.0
`
`45.0
`
`45.0
`
`Grade
`
`C
`
`Nominal
`mean
`particle size
`(mm)
`
`Avicel PH-101 (a)
`
`50
`
`Avicel PH-102 (a)
`
`100
`
`Avicel PH-103 (a)
`
`50
`
`Avicel PH-105 (a)
`Avicel PH-112 (a)
`Avicel PH-113 (a)
`
`Avicel PH-200 (a)
`
`20
`100
`50
`
`180
`
`Avicel PH-301 (a)
`
`50
`
`Avicel PH-302 (a)
`
`100
`
`Celex 101 (b)
`
`75
`
`Ceolus KG-802 (c) 50
`
`Emcocel 50M (d)
`
`Emcocel 90M (d)
`
`MCC Sanaq
`101(e)
`
`MCC Sanaq
`102(e)
`
`MCC Sanaq
`200(e)
`
`MCC Sanaq
`301(e)
`
`MCC Sanaq
`302(e)
`
`MCC Sanaq UL-
`002(e)
`
`Vivapur 101 (d)
`
`Vivapur 102 (d)
`
`50
`
`91
`
`50
`
`100
`
`180
`
`50
`
`100
`
`50
`
`50
`
`90
`
`Vivapur 12 (d)
`
`160
`
`Suppliers:
`(a) FMC Biopolymer
`(b) International Specialty Products
`(c) Asahi Kasei Corporation
`(d) JRS Pharma
`(e) Pharmatrans Sanaq AG
`
`16 Regulatory Status
`GRAS listed. Accepted for use as a food additive in Europe.
`Included in the FDA Inactive Ingredients Database (inhalations;
`oral capsules, powders, suspensions, syrups, and tablets; topical and
`vaginal preparations). Included in nonparenteral medicines licensed
`in the UK. Included in the Canadian List of Acceptable Non-
`medicinal Ingredients.
`
`17 Related Substances
`Microcrystalline cellulose and carrageenan; microcrystalline cellu-
`lose and carboxymethylcellulose sodium; microcrystalline cellulose
`and guar gum; powdered cellulose;
`silicified microcrystalline
`cellulose.
`Microcrystalline cellulose and carrageenan
`Synonyms Lustre Clear.
`Comments Lustre Clear (FMC Biopolymer) is an aqueous film
`coating combining microcrystalline cellulose and carrageenan.
`Microcrystalline cellulose and guar gum
`Synonyms Avicel CE-15.
`Comments Avicel CE-15 (FMC Biopolymer) is a coprocessed
`mixture of microcrystalline cellulose and guar gum used in
`chewable tablet formulations.
`
`18 Comments
`Microcrystalline cellulose 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.
`Several different grades of microcrystalline cellulose are com-
`mercially available that differ in their method of manufacture,(15,16)
`particle size, moisture, flow, and other physical properties.(17–29)
`The larger-particle-size grades generally provide better flow proper-
`ties in pharmaceutical machinery. Low-moisture grades are used
`with moisture-sensitive materials. Higher-density grades have
`improved flowability.
`Several coprocessed mixtures of microcrystalline cellulose with
`other excipients such as carrageenan, carboxymethylcellulose
`sodium, and guar gum are commercially available; see Section 17.
`Celphere (Asahi Kasei Corporation) is a pure spheronized
`microcrystalline cellulose available in several different particle size
`ranges. Balocel Sanaq (Pharmatrans Sanaq AG) is an excipient used
`mainly in the production of pellets and granulates in direct
`tableting, which contains lactose, microcrystalline cellulose, and
`sodium carboxymethylcellulose.
`According to PhEur 6.3, microcrystalline cellulose has certain
`functionality related characteristics that are recognised as being
`relevant control parameters for one or more functions of the
`substance when used as an excipient. Non-mandatory testing
`procedures have been described for particle size distribution (2.9.31
`or 2.9.38) and powder flow (2.9.36).
`A specification for microcrystalline cellulose is contained in the
`Food Chemicals Codex (FCC).(30) The PubChem Compound ID
`(CID) for microcrystalline cellulose is 14055602.
`
`15 Handling Precautions
`Observe normal precautions appropriate to the circumstances and
`quantity of material handled. Microcrystalline cellulose may be
`irritant to the eyes. Gloves, eye protection, and a dust mask are
`recommended. In the UK, the workplace exposure limits for
`cellulose have been set at 10 mg/m3 long-term (8-hour TWA) for
`total inhalable dust and 4 mg/m3 for respirable dust; the short-term
`limit for total inhalable dust has been set at 20 mg/m3.(14)
`
`19 Specific References
`1 Ene´zian GM. [Direct compression of tablets using microcrystalline
`cellulose.] Pharm Acta Helv 1972; 47: 321–363[in French].
`2 Lerk CF, Bolhuis GK. Comparative evaluation of excipients for direct
`compression I. Pharm Weekbl 1973; 108: 469–481.
`3 Lerk CF et al. Comparative evaluation of excipients for direct
`compression II. Pharm Weekbl 1974; 109: 945–955.
`4 Lamberson RF, Raynor GE. Tableting properties of microcrystalline
`cellulose. Manuf Chem Aerosol News 1976; 47(6): 55–61.
`
`

`

`C
`
`5 Lerk CF et al. Effect of microcrystalline cellulose on liquid penetration
`in and disintegration of directly compressed tablets. J Pharm Sci 1979;
`68: 205–211.
`6 Chilamkurti RN et al. Some studies on compression properties of tablet
`matrices using a computerized instrumented press. Drug Dev Ind
`Pharm 1982; 8: 63–86.
`7 Wallace JW et al. Performance of pharmaceutical filler/binders as
`related to methods of powder characterization. Pharm Technol 1983;
`7(9): 94–104.
`8 Omray A, Omray P. Evaluation of microcrystalline cellulose as a
`glidant. Indian J Pharm Sci 1986; 48: 20–22.
`9 Celik M, Okutgen E. A feasibility study for the development of a
`prospective compaction functionality test and the establishment of a
`compaction data bank. Drug Dev Ind Pharm 1993; 19: 2309–2334.
`10 Parker MD et al. Binder–substrate interactions in wet granulation 3: the
`effect of excipient source variation. Int J Pharm 1992; 80: 179–190.
`11 Sun CC. True density of microcrystalline cellulose. J Pharm Sci 2005;
`94(10): 2132–2134.
`12 Callahan JC et al. Equilibrium moisture content of pharmaceutical
`excipients. Drug Dev Ind Pharm 1982; 8: 355–369.
`13 Cooper CB et al. Cellulose granulomas in the lungs of a cocaine sniffer.
`Br Med J 1983; 286: 2021–2022.
`14 Health and Safety Executive. EH40/2005: Workplace Exposure Limits.
`Sudbury: HSE Books, 2005 (updated 2007). http://www.hse.gov.uk/
`coshh/table1.pdf (accessed 5 February 2009).
`15 Jain JK et al. Preparation of microcrystalline cellulose from cereal straw
`and its evaluation as a tablet excipient. Indian J Pharm Sci 1983; 45:
`83–85.
`16 Singla AK et al. Evaluation of microcrystalline cellulose prepared from
`absorbent cotton as a direct compression carrier. Drug Dev Ind Pharm
`1988; 14: 1131–1136.
`17 Doelker E et al. Comparative tableting properties of sixteen micro-
`crystalline celluloses. Drug Dev Ind Pharm 1987; 13: 1847–1875.
`18 Bassam F et al. Effect of particle size and source on variability of
`Young’s modulus of microcrystalline cellulose powders. J Pharm
`Pharmacol 1988; 40: 68P.
`19 Dittgen M et al. Microcrystalline cellulose in direct tabletting. Manuf
`Chem 1993; 64(7): 17, 19, 21.
`20 Landin M et al. Effect of country of origin on the properties of
`microcrystalline cellulose. Int J Pharm 1993; 91: 123–131.
`21 Landin M et al. Effect of batch variation and source of pulp on the
`properties of microcrystalline cellulose. Int J Pharm 1993; 91: 133–141.
`22 Landin M et al. Influence of microcrystalline cellulose source and batch
`variation on tabletting behavior and stability of prednisone formula-
`tions. Int J Pharm 1993; 91: 143–149.
`23 Podczeck F, Re´ve´sz P. Evaluation of the properties of microcrystalline
`and microfine cellulose powders. Int J Pharm 1993; 91: 183–193.
`24 Rowe RC et al. The effect of batch and source variation on the
`crystallinity of microcrystalline cellulose. Int J Pharm 1994; 101: 169–
`172.
`
`Cellulose, Microcrystalline
`
`133
`
`25 Hasegawa M. Direct compression: microcrystalline cellulose grade 12
`versus classic grade 102. Pharm Technol 2002; 26(5): 50, 52, 54, 56,
`58, 60.
`26 Kothari SH et al. Comparative evaluations of powder and mechanical
`properties of low crystallinity celluloses, microcrystalline celluloses, and
`powdered celluloses. Int J Pharm 2002; 232: 69–80.
`27 Levis SR, Deasy PB. Production and evaluation of size-reduced grades
`of microcrystalline cellulose. Int J Pharm 2001; 213: 13–24.
`28 Wu JS et al. A statistical design to evaluate the influence of
`manufacturing factors on the material properties and functionalities
`of microcrystalline cellulose. Eur J Pharm Sci 2001; 12: 417–425.
`29 Suzuki T, Nakagami H. Effect of crystallinity of microcrystalline
`cellulose on the compactability and dissolution of tablets. Eur J Pharm
`Biopharm 1999; 47: 225–230.
`30 Food Chemicals Codex, 6th edn.
`Pharmacopeia, 2008; 187.
`
`Bethesda, MD: United States
`
`20 General References
`Asahi Kasei Corporation. Ceolus KG, Celphere. http://www.ceolus.com
`(accessed 6 November 2008).
`Doelker E. Comparative compaction properties of various microcrystalline
`cellulose types and generic products. Drug Dev Ind Pharm 1993; 19:
`2399–2471.
`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 5 February 2009).
`FMC Biopolymer. Problem Solver: Avicel PH, 2000.
`International Specialty Products. Material Safety data sheet: Celex 101,
`2003.
`JRS Pharma LP. Technical literature: Emcocel, 2003.
`Pharmatrans Sanaq AG. Product literature: Cellets. http://www.cellets.com
`(accessed 6 November 2008).
`Pharmatrans Sanaq AG. Product literature: MCC Sanaq. http://www.phar-
`matrans-sanaq.com/prod.html (accessed 6 November 2008).
`Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipients. Boca
`Raton, FL: CRC Press, 1992; 71–74.
`Staniforth JN et al. Effect of addition of water on the rheological and
`mechanical properties of microcrystalline celluloses. Int J Pharm 1988;
`41: 231–236.
`
`21 Author
`A Guy.
`
`22 Date of Revision
`5 February 2009.
`
`

`

`C
`
`Colloidal Silicon Dioxide
`
`185
`
`18 Comments
`A specification for coconut oil (unhydrogenated) is contained in the
`Food Chemicals Codex (FCC).(13)
`
`19 Specific References
`1 Hung CF et al. The effect of oil components on the physicochemical
`properties and drug delivery of emulsions: tocol emulsion versus lipid
`emulsion. Int J Pharm 2007; 335(1–2): 193–202.
`2 Garti N, Arkad O. Preparation of cloudy coconut oil emulsions
`containing dispersed TiO2 using atomizer. J Dispersion Sci Technol
`1986; 7(5): 513–523.
`3 Fang JY et al. Lipid nano/submicron emulsions as delivery vehicles for
`topical flurbiprofen delivery. Drug Deliv 2004; 11(2): 97–105.
`liquid
`4 Nielsen HW et al.
`Intranasal administration of different
`formulations of bumetanide to rabbits. Int J Pharm 2000; 204(1–2):
`35–41.
`5 Tanabe K et al. Effect of different suppository bases on release of
`indomethacin. J Pharm Sci Technol Jpn 1984; 44: 115–120.
`6 Broda H et al. Preparation and testing of suppositories with cephradine
`– evaluation of pharmaceutical availability and biological availability.
`Farm Pol 1993; 49(11–12): 1–8.
`7 Ogbolu DO et al. In vitro antimicrobial properties of of coconut oil on
`Candida species in Ibadan, Nigeria. J Med Food 2007; 10(2): 384–387.
`8 Anonymous. Nitlotion. Pharm J 2000; 265: 345.
`9 Pajoumand A et al. Survival following severe aluminium phosphide
`poisoning. J Pharm Pract Res 2002; 32(4): 297–299.
`10 Patel HR. Sales of coconut oil. Pharm J 1992; 249: 252.
`11 Todd RG, Wade A, eds. The Pharmaceutical Codex, 11th edn. London:
`Pharmaceutical Press, 1979; 214.
`12 Dexter MB, Shott MJ. The evaluation of the force to expel oily injection
`vehicles from syringes. J Pharm Pharmacol 1979; 31: 497–500.
`13 Food Chemicals Codex, 6th edn.
`Bethesda, MD: United States
`Pharmacopiea, 2008; 222.
`
`20 General References
`
`— 2
`
`1 Author
`CG Cable.
`
`22 Date of Revision
`27 February 2009.
`
`It has been shown that the increased force required to expel
`coconut oil from plastic syringes was due to uptake of the oil into
`the rubber plunger; this resulted in swelling of the rubber plunger
`and an increased resistance to movement down the syringe
`barrel.(12)
`
`13 Method of Manufacture
`Coconut oil is the fixed oil obtained from the seeds of Cocos
`nucifera Linn. (Palmae). This oil is then refined to produce refined
`coconut oil, which is referred to in the coconut industry as RBD
`(refined, bleached, and deodorized) coconut oil.
`
`14 Safety
`is essentially nontoxic,
`When administered orally, coconut oil
`although ingestion of
`large amounts may cause digestive or
`gastrointestinal
`irritation or upset. Coconut oil can act as an
`irritant when applied to the skin and when in contact with the eyes;
`it may be absorbed through the skin. Inhalation of mist or vapor
`may cause respiratory tract irritation.
`
`15 Handling Precautions
`Observe normal precautions appropriate to the circumstances and
`quantity of the material handled. Coconut oil should be kept away
`from heat and sources of ignition, and contact with oxidizing
`agents, acids, and alkalis should be avoided.
`If in the solid form, large spillages of coconut oil should be dealt
`with by shoveling the material into a waste disposal container. For
`liquid spillages, the oil should be absorbed with an inert material
`before removal for disposal.
`
`16 Regulatory Status
`Included in the FDA Inactive Ingredients Database (oral capsules
`and tablets; topical creams, solutions,