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Pharmaceutical dosage forms contain both pharmacologically active compounds and excipients added to aid the formulation and manufacture of the subsequent dosage form for administration to patients. Indeed, the properties of the final dosage form (i.e. its bioavailability and stability) are, for the most part, highly dependent on the excipients chosen, their concentration and interaction with both the active compound and each other. No longer can excipients be regarded simply as inert or inactive ingredients, and a detailed knowledge not only of the physical and chemical properties but also of the safety, handling and regulatory status of these materials is essential for formulators throughout the world. In addition, the growth of novel forms of delivery has resulted in an increase in the number of the excipients being used and suppliers of excipients have developed novel excipient mixtures and new physical forms to improve their properties. The Handbook of Pharmaceutical Excipients has been conceived as a systematic, comprehensive resource of information on all of these topics The first edition of the Handbook was published in 1986 and contained 145 monographs. This was followed by the second edition in 1994 containing 203 monographs, the third edition in 2000 containing 210 monographs and the fourth edition in 2003 containing 249 monographs. Since 2000, the data has also been available on CD-ROM, updated annually, and from 2004 online. This new printed edition with its companion CDROM, Pharmaceutical Excipients 5, contains 300 monographs compiled by over 120 experts in pharmaceutical formulation or excipient manufacture from Australia, Europe, India and the USA. All the monographs have been reviewed and revised in the light of current knowledge. There has been a greater emphasis on including published data from primary sources although some data from laboratory projects included in previous editions have been retained where relevant. Variations in test methodology can have significant effects on the data generated (especially in the case of the compactability of an excipient), and thus cause confusion. As a consequence, the editors have been more selective in including data relating to the physical properties of an excipient. However, comparative data that show differences between either source or batch of a specific excipient have been retained as this was considered relevant to the behavior of a material in practice. The Suppliers Directory (Appendix I) has also been completely updated with many more international suppliers included. In a systematic and uniform manner, the Handbook of Pharmaceutical Excipients collects essential data on the physical properties of excipients such as: boiling point, bulk and tap density, compression characteristics, hygroscopicity, flowability, melting point, moisture content, moisture-absorption isotherms, particle size distribution, rheology, specific surface area, and solubility. Scanning electron microphotographs (SEMs) are also included for many of the excipients. The Handbook contains information from various international sources and personal observation and comments from monograph authors, steering committee members, and the editors. All of the monographs in the Handbook are thoroughly cross-referenced and indexed so that excipients may be identified by either a chemical, a nonproprietary, or a trade name. Most monographs list related substances to help the formulator to develop a list of possible materials for use in a new dosage form or product. Related substances are not directly substitutable for each other but, in general, they are excipients that have been used for similar purposes in various dosage forms. The Handbook of Pharmaceutical Excipients is a comprehensive, uniform guide to the uses, properties, and safety of pharmaceutical excipients, and is an essential reference source for those involved in the development, production, control, or regulation of pharmaceutical preparations. Since many pharmaceutical excipients are also used in other applications, the Handbook of Pharmaceutical Excipients will also be of value to persons with an interest in the formulation or production of confectionery, cosmetics, and food products.
Contents
International Steering Committee ix
Editorial Staff ix
Contributors x
About the Editors xii
New Monographs xiii
Related Substances xiv
Preface xvi
Arrangement xvii
Acknowledgments xix
Notice to Readers xix
Bibliography xx
Abbreviations xx
Units of Measurement xxii
Monographs
Acacia 1
Acesulfame Potassium 4
Acetic Acid, Glacial 6
Acetone 8
Acetyltributyl Citrate 10
Acetyltriethyl Citrate 12
Agar 14
Albumin 16
Alcohol 18
Alginic Acid 21
Aliphatic Polyesters 24
Alitame 28
Almond Oil 30
Alpha Tocopherol 32
Aluminum Hydroxide Adjuvant 36
Aluminum Oxide 38
Aluminum Phosphate Adjuvant 40
Aluminum Stearate 42
Ammonia Solution 44
Ammonium Alginate 46
Ascorbic Acid 48
Ascorbyl Palmitate 51
Aspartame 53
Attapulgite 56
Bentonite 58
Benzalkonium Chloride 61
Benzethonium Chloride 64
Benzoic Acid 66
Benzyl Alcohol 69
Benzyl Benzoate 72
Boric Acid 74
Bronopol 76
Butylated Hydroxyanisole 79
Butylated Hydroxytoluene 81
Butylparaben 83
Calcium Alginate 86
Calcium Carbonate 89
Calcium Phosphate, Dibasic Anhydrous 93
Calcium Phosphate, Dibasic Dihydrate 96
Calcium Phosphate, Tribasic 100
Calcium Stearate 102
Calcium Sulfate 105
Canola Oil 108
Carbomer 111
Carbon Dioxide 116
Carboxymethylcellulose Calcium 118
Carboxymethylcellulose Sodium 120
Carrageenan 124
Castor Oil 128
Castor Oil, Hydrogenated 130
Cellulose, Microcrystalline 132
Cellulose, Powdered 136
Cellulose, Silicified Microcrystalline 139
Cellulose Acetate 142
Cellulose Acetate Phthalate 145
Ceratonia 148
Cetostearyl Alcohol 150
Cetrimide 152
Cetyl Alcohol 155
Cetylpyridinium Chloride 157
Chitosan 159
Chlorhexidine 163
Chlorobutanol 168
Chlorocresol 171
Chlorodifluoroethane (HCFC) 174
Chlorofluorocarbons (CFC) 176
Chloroxylenol 180
Cholesterol 182
Citric Acid Monohydrate 185
Colloidal Silicon Dioxide 188
Coloring Agents 192
Copovidone 201
Corn Oil 204
Cottonseed Oil 206
Cresol 208
Croscarmellose Sodium 211
Crospovidone 214
Cyclodextrins 217
Cyclomethicone 222
Denatonium Benzoate 224
Dextrates 226
Dextrin 228
Dextrose 231
Dibutyl Phthalate 234
Dibutyl Sebacate 236
Diethanolamine 238
Diethyl Phthalate 240
Difluoroethane (HFC) 242
Dimethicone 244
Dimethyl Ether 246
Dimethyl Phthalate 248
Dimethyl Sulfoxide 250
Dimethylacetamide 253
Disodium Edetate 255
Docusate Sodium 257
Edetic Acid 260
Erythorbic Acid 264
Erythritol 266
Ethyl Acetate 268
Ethyl Lactate 270
Ethyl Maltol 272
Ethyl Oleate 274
Ethyl Vanillin 276
Ethylcellulose 278
Ethylene Glycol Palmitostearate 283
Ethylene Vinyl Acetate 285
Ethylparaben 287
Fructose 290
Fumaric Acid 293
Gelatin 295
Glucose, Liquid 299
Glycerin 301
Glyceryl Behenate 304
Glyceryl Monooleate 306
Glyceryl Monostearate 308
Glyceryl Palmitostearate 311
Glycofurol 313
Guar Gum 315
Hectorite 318
Heptafluoropropane (HFC) 321
Hexetidine 323
Hydrocarbons (HC) 325
Hydrochloric Acid 328
Hydroxyethyl Cellulose 330
Hydroxyethylmethyl Cellulose 334
Hydroxypropyl Cellulose 336
Hydroxypropyl Cellulose, Low-substituted 341
Hydroxypropyl Starch 344
Hypromellose 346
Hypromellose Acetate Succinate 350
Hypromellose Phthalate 354
Imidurea 359
Inulin 362
Iron Oxides 364
Isomalt 366
Isopropyl Alcohol 371
Isopropyl Myristate 374
Isopropyl Palmitate 376
Kaolin 378
Lactic Acid 381
Lactitol 383
Lactose, Anhydrous 385
Lactose, Monohydrate 389
Lactose, Spray-Dried 396
Lanolin 399
vi Contents
Lanolin Alcohols 402
Lanolin, Hydrous 404
Lauric Acid 406
Lecithin 409
Leucine 412
Linoleic Acid 414
Macrogol 15 Hydroxystearate 416
Magnesium Aluminum Silicate 418
Magnesium Carbonate 422
Magnesium Oxide 426
Magnesium Silicate 428
Magnesium Stearate 430
Magnesium Trisilicate 434
Malic Acid 436
Maltitol 438
Maltitol Solution 440
Maltodextrin 442
Maltol 445
Maltose 447
Mannitol 449
Medium-chain Triglycerides 454
Meglumine 457
Menthol 459
Methylcellulose 462
Methylparaben 466
Mineral Oil 471
Mineral Oil, Light 474
Mineral Oil and Lanolin Alcohols 476
Monoethanolamine 478
Monosodium Glutamate 480
Monothioglycerol 482
Myristic Acid 484
Neohesperidin Dihydrochalcone 486
Nitrogen 488
Nitrous Oxide 490
Octyldodecanol 492
Oleic Acid 494
Oleyl Alcohol 496
Olive Oil 498
Palmitic Acid 501
Paraffin 503
Peanut Oil 505
Pectin 507
Petrolatum 509
Petrolatum and Lanolin Alcohols 512
Phenol 514
Phenoxyethanol 517
Phenylethyl Alcohol 519
Phenylmercuric Acetate 521
Phenylmercuric Borate 524
Phenylmercuric Nitrate 526
Phosphoric Acid 530
Polacrilin Potassium 532
Poloxamer 535
Polycarbophil 539
Polydextrose 542
Polyethylene Glycol 545
Polyethylene Oxide 551
Polymethacrylates 553
Poly(methyl vinyl ether/maleic anhydride) 561
Polyoxyethylene Alkyl Ethers 564
Polyoxyethylene Castor Oil Derivatives 572
Polyoxyethylene Sorbitan Fatty Acid Esters 580
Polyoxyethylene Stearates 585
Polyvinyl Acetate Phthalate 589
Polyvinyl Alcohol 592
Potassium Alginate 594
Potassium Benzoate 596
Potassium Bicarbonate 598
Potassium Chloride 600
Potassium Citrate 603
Potassium Hydroxide 605
Potassium Metabisulfite 607
Potassium Sorbate 609
Povidone 611
Propionic Acid 617
Propyl Gallate 619
Propylene Carbonate 622
Propylene Glycol 624
Propylene Glycol Alginate 627
Propylparaben 629
2-Pyrrolidone 633
Raffinose 635
Saccharin 638
Saccharin Sodium 641
Saponite 644
Sesame Oil 646
Shellac 649
Contents vii
Simethicone 652
Sodium Acetate 654
Sodium Alginate 656
Sodium Ascorbate 659
Sodium Benzoate 662
Sodium Bicarbonate 665
Sodium Borate 669
Sodium Chloride 671
Sodium Citrate Dihydrate 675
Sodium Cyclamate 678
Sodium Hyaluronate 681
Sodium Hydroxide 683
Sodium Lactate 685
Sodium Lauryl Sulfate 687
Sodium Metabisulfite 690
Sodium Phosphate, Dibasic 693
Sodium Phosphate, Monobasic 696
Sodium Propionate 699
Sodium Starch Glycolate 701
Sodium Stearyl Fumarate 705
Sodium Sulfite 708
Sorbic Acid 710
Sorbitan Esters (Sorbitan Fatty Acid Esters) 713
Sorbitol 718
Soybean Oil 722
Starch 725
Starch, Pregelatinized 731
Starch, Sterilizable Maize 734
Stearic Acid 737
Stearyl Alcohol 740
Sucralose 742
Sucrose 744
Sugar, Compressible 748
Sugar, Confectioner’s 750
Sugar Spheres 752
Sulfobutylether b-Cyclodextrin 754
Sulfuric Acid 758
Sunflower Oil 760
Suppository Bases, Hard Fat 762
Talc 767
Tartaric Acid 770
Tetrafluoroethane (HFC) 772
Thaumatin 775
Thimerosal 777
Thymol 780
Titanium Dioxide 782
Tragacanth 785
Trehalose 788
Triacetin 790
Tributyl Citrate 792
Triethanolamine 794
Triethyl Citrate 796
Vanillin 798
Vegetable Oil, Hydrogenated 800
Water 802
Wax, Anionic Emulsifying 807
Wax, Carnauba 809
Wax, Cetyl Esters 811
Wax, Microcrystalline 813
Wax, Nonionic Emulsifying 815
Wax, White 817
Wax, Yellow 819
Xanthan Gum 821
Xylitol 824
Zein 828
Zinc Acetate 830
Zinc Stearate 832
Appendix I: Suppliers’ Directory 835
Appendix II: List of Excipient ‘E’ Numbers 882
Appendix III: List of Excipient ‘EINECS’ Numbers 884
Appendix IV: List of Excipient Molecular Weights 886
Index 889
viii Contents
International Steering Committee
Gregory E Amidon
Pharmacia Corporation
Kalamazoo, MI, USA
Graham Buckton
University of London
London, UK
Colin G Cable
Western General Hospital
Edinburgh, UK
Brian A Carlin
FMC Biopolymer
Princeton, NJ, USA
Walter Cook
AstraZeneca
Loughborough, UK
Henk J de Jong
Servier International Research Institute
Courbevoie, France
Stephen Edge
DMV International
Veghel, The Netherlands
Roger T Guest
GlaxoSmithKline
Ware, Hertfordshire, UK
Bruno Hancock
Pfizer Inc
Groton, CT, USA
Stephen W Hoag
University of Maryland at Baltimore
Baltimore, MD, USA
Arthur H Kibbe
Wilkes University
Wilkes-Barre, PA, USA
William J Lambert
Eisai Inc
Research Triangle Park, NC, USA
M Jayne Lawrence
King’s College, University of London
London, UK
John MacLaine
Boots Contract Manufacturing
Nottingham, UK
Colin P McCoy
Queens University Belfast
Belfast, UK
R Christian Moreton
Idenix Pharmaceuticals
Cambridge, MA, USA
Sandeep Nema
Pfizer Inc
Chesterfield, MO, USA
Siaˆ n C Owen
Royal Pharmaceutical Society of Great
Britain
London, UK
Anthony Palmieri III
University of Florida
Gainesville, FL, USA
Raymond C Rowe
Intelligensys Ltd
Billingham, UK
Shirish A Shah
Watson Pharmaceuticals
Corona, CA, USA
Bob Sherwood
JRS Pharma
Patterson, NY, USA
Paul J Sheskey
The Dow Chemical Co
Midland, MI, USA
Kamalinder K Singh
SNDT Women’s University
Mumbai, India
Paul J Weller
Royal Pharmaceutical Society of Great
Britain
London, UK
Tim Wood
GlaxoSmithKline
Ware, Hertfordshire, UK
Mukund Yelvigi
Wyeth Research
Pearl River, NY, USA
Editorial Staff
Editorial Staff of the Pharmaceutical Press:
Laurent Y Galichet
Louise ME McIndoe
Siaˆn C Owen
Paul J Weller
Contributors
O AbuBaker
Pfizer Inc
Ann Arbor, MI, USA
KS Alexander
University of Toledo
Toledo, OH, USA
LV Allen
International Journal of Pharmaceutical
Compounding
Edmond, OK, USA
GE Amidon
Pharmacia Corporation
Kalamazoo, Michigan, USA
GP Andrews
The Queen’s University of Belfast
Belfast, UK
NA Armstrong
Harpenden, Hertfordshire, UK
ME Aulton
De Montford University
Leicester, UK
S Behn
AstraZeneca
Macclesfield, UK
M Bond
Danisco Sweeteners Ltd
Redhill, Surrey, UK
CG Cable
Western General Hospital
Edinburgh, UK
E Cahill
AstraZeneca
Macclesfield, UK
W Camarco
ISP Corp
Wayne, NJ, USA
WG Chambliss
University of Mississippi
University, MS, USA
RK Chang
Shire Laboratory
Rockville, MD, USA
R Chen
Pfizer Inc
Groton, CT, USA
JH Chu
Pfizer Inc
Groton, CT, USA
JH Collett
University of Manchester
Manchester, UK
JT Colvin
Pfizer Inc
Groton, CT, USA
W Cook
AstraZeneca
Loughborough, UK
DQM Craig
The University of East Anglia
Norwich, UK
TC Dahl
Gilead Sciences
Foster City, CA, USA
A Day
AstraZeneca
Loughborough, UK
HJ de Jong
Servier International Research Institute
Courbevoie, France
SP Denyer
University of Cardiff
Cardiff, UK
X Duriez
Roquette Fre`res
Lestrem, France
S Edge
DMV International
Veghel, The Netherlands
K Fowler
Schering-Plough Healthcare Products
Memphis, TN, USA
SO Freers
Grain Processing Corporation
Muscatine, IA, USA
B Fritzsching
Palatinit GmbH
Mannheim, Germany
G Frunzi
Bristol-Myers Squibb
New Brunswick, NJ, USA
LY Galichet
Royal Pharmaceutical Society of Great
Britain
London, UK
SR Goskonda
Sunnyvale, CA, USA
JL Gray
The Queen’s University of Belfast
Belfast, UK
RT Guest
GlaxoSmithKline
Ware, Hertfordshire, UK
RR Gupta
SNDT Women’s University
Mumbai, India
VK Gupta
Tyco HealthCare Mallinckrodt
St Louis, MO, USA
G Haest
Cargill Cerestar BVBA
Mechelen, Belgium
BC Hancock
Pfizer Inc
Groton, CT, USA
RJ Harwood
Bensalem, PA, USA
S Hem
Purdue University
West Lafayette, IN, USA
L Hendricks
Rhodia Inc
Cranbury, NJ, USA
SE Hepburn
Bristol Royal Infirmary
Bristol, UK
NA Hodges
University of Brighton
Brighton, UK
JT Irwin
Perrigo Corporation
MI, USA
BR Jasti
University of the Pacific
Stockton, CA, USA
R Johnson
AstraZeneca
Loughborough, UK
DS Jones
The Queen’s University of Belfast
Belfast, UK
AS Kearney
GlaxoSmithKline
King-of-Prussia, PA, USA
SW Kennedy
Morflex Inc
Greensboro, NC, USA
VL Kett
The Queen’s University of Belfast
Belfast, UK
AH Kibbe
Wilkes University
Wilkes-Barre, PA, USA
V King
Rhodia Inc
Cranbury, NJ, USA
PB Klepak
Reheis Inc
Berkley Heights, NJ, USA
JJ Koleng
University of Texas at Austin
Austin, TX, USA
K Kussendrager
DMV International
Veghel, The Netherlands
WJ Lambert
Eisai Inc
Research Triangle Park, NC, USA
BA Langdon
Pfizer Inc
Groton, CT, USA
MJ Lawrence
King’s College, University of London
London, UK
JC Lee
Cellegy
San Jose´, CA, USA
MG Lee
Medicines and Healthcare products
Regulatory Agency
London, UK
X Li
University of the Pacific
Stockton, CA, USA
EB Lindblad
Brenntag Biosector
Frederikssund, Denmark
O Luhn
Palatinit GmbH
Mannheim, Germany
PE Luner
Pfizer Inc
Groton, CT, USA
HJ Mawhinney
The Queen’s University of Belfast
Belfast, UK
CP McCoy
The Queen’s University of Belfast
Belfast, UK
OS McGarvey
The Queen’s University of Belfast
Belfast, UK
JW McGinity
University of Texas at Austin
Austin, TX, USA
LME McIndoe
Royal Pharmaceutical Society of Great
Britain
London, UK
LA Miller
Pfizer Inc
Groton, CT, USA
RW Miller
Bristol-Myers Squibb
New Brunswick, NJ, USA
J-P Mittwollen
BASF Aktiengesellschaft
Ludwigshafen, Germany
RC Moreton
Idenix Pharmaceuticals
Cambridge, MA, USA
G Mosher
CyDex Inc
Lenexa, KS, USA
C Mroz
Colorcon Ltd
Dartford, Kent, UK
MP Mullarney
Pfizer Inc
Groton, CT, USA
S Murdande
Pfizer Inc
Groton, CT, USA
RA Nash
St John’s University
Jamaica, NY, USA
S Nema
Pfizer Inc
Chesterfield, MO, USA
SC Owen
Royal Pharmaceutical Society of Great
Britain
London, UK
A Palmieri
University of Florida
Gainesville, FL, USA
D Parsons
ConvaTec Ltd
Clwyd, UK
Y Peng
University of Tennessee
Memphis, TN, USA
JD Pipkin
CyDex Inc
Lenexa, KS, USA
D Pipkorn
Pfizer Inc
Ann Arbor, MI, USA
JC Price
University of Georgia
Athens, GA, USA
MA Repka
University of Mississippi
University, MS, USA
B Sarsfield
Bristol-Myers Squibb
New Brunswick, NJ, USA
T Schmeller
BASF Aktiengesellschaft
Ludwigshafen, Germany
A Schoch
Palatinit GmbH
Mannheim, Germany
CJ Sciarra
Sciarra Laboratories Inc
Hicksville, NY, USA
Contributors xi
JJ Sciarra
Sciarra Laboratories Inc
Hicksville, NY, USA
SA Shah
Watson Pharmaceuticals
Corona, CA, USA
RM Shanker
Pfizer Inc
Groton, CT, USA
PJ Sheskey
The Dow Chemical Co
Midland, MI, USA
AJ Shukla
University of Tennessee
Memphis, TN, USA
KK Singh
SNDT Women’s University
Mumbai, India
R Steer
AstraZeneca
Loughborough, UK
JT Stewart
University of Georgia
Athens, GA, USA
Y Sun
University of Tennessee
Memphis, TN, USA
AK Taylor
Baton Rouge, LA, USA
MS Tesconi
Wyeth Research
Pearl River, NY, USA
D Thassu
UCB Pharma Inc
Rochester, NY, USA
BF Truitt
Pfizer Inc
Groton, CT, USA
CK Tye
Pfizer Inc
Kalamazoo, MI, USA
HM Unvala
Bayer Corporation
Myerstown, PA, USA
KD Vaughan
Boots Healthcare International
Nottingham, UK
H Wang
Pfizer Inc
Groton, CT, USA
PJ Weller
Royal Pharmaceutical Society of Great
Britain
London, UK
AJ Winfield
Aberdeen, UK
AW Wood
GlaxoSmithKline
Research Triangle Park, NC, USA
M Yelvigi
Wyeth Research
Pearl River, NY, USA
PM Young
University of Sydney
Sydney, Australia
About the Editors
Raymond C Rowe
BPharm, PhD, DSc, FRPharmS, CChem, FRSC, CPhys, MInstP
Raymond Rowe has been involved in the Handbook of
Pharmaceutical Excipients since the first edition was published
in 1986, initially as an author then as a Steering Committee
member. In addition to his position as Chief Scientist at
Intelligensys, UK, he is also Professor of Industrial Pharmaceutics at the School of Pharmacy, University of Bradford, UK. He
was formerly Senior Principal Scientist at AstraZeneca, UK. In
1998 he was awarded the Chiroscience Industrial Achievement
Award, and in 1999 he was the British Pharmaceutical
Conference Science Chairman. He has contributed to over
350 publications in the pharmaceutical sciences including a
book and eight patents.
Paul J Sheskey
BSc, RPh
Paul Sheskey has been involved in the Handbook of Pharmaceutical Excipients as an author and member of the Steering
Committee since the third edition. He is a Technical Service
Leader in the Water Soluble Polymers, Pharmaceutical R&D
Group at The Dow Chemical Company in Midland, Michigan,
USA. Paul received his BSc degree in pharmacy from Ferris
State University. Previously, he has worked as a research
pharmacist in the area of solid dosage form development at the
Perrigo Company and the Upjohn (Pharmacia) Company. Paul
has authored numerous journal articles in the area of
pharmaceutical technology. He is a member of the AAPS,
Controlled Release Society, and the Institute for Briquetting and
Agglomeration.
Siaˆn C Owen
BSc, MA
Siaˆn Owen has been involved with the Handbook of
Pharmaceutical Excipients since the fourth edition, as a
contributor and Steering Committee member. Siaˆn received
her BSc degree in pharmacology from the University of
Sunderland, and her MA in biotechnological law and ethics
from the University of Sheffield.
xii Contributors
New Monographs
The following new monographs have been added to the Handbook of Pharmaceutical Excipients, 5th edition.
Acetone
Agar
Aluminum Hydroxide Adjuvant
Aluminum Oxide
Aluminum Phosphate Adjuvant
Ammonium Alginate
Aluminum Stearate
Boric Acid
Calcium Alginate
Cetylpyridinium Chloride
Copovidone
Dimethylacetamide
Disodium Edetate
Erythorbic Acid
Erythritol
Ethyl Lactate
Ethylene Vinyl Acetate
Hectorite
Hydroxypropyl Starch
Hypromellose Acetate Succinate
Inulin
Iron Oxides
Isomalt
Lactose, Anhydrous
Lactose, Monohydrate
Lactose, Spray-Dried
Lauric Acid
Leucine
Linoleic Acid
Macrogol 15 Hydroxystearate
Myristic Acid
Neohesperidin Dihydrochalcone
Octyldodecanol
Oleyl Alcohol
Palmitic Acid
Pectin
Polycarbophil
Poly(methylvinyl ether/maleic anhydride)
Potassium Alginate
2-Pyrrolidone
Raffinose
Saponite
Sodium Acetate
Sodium Borate
Sodium Hyaluronate
Sodium Lactate
Sodium Sulfite
Sulfobutylether b-Cyclodextrin
Thaumatin
Thymol
Zinc Acetate
Related Substances
Acetic acid
Activated attapulgite
Aleuritic acid
d-Alpha tocopherol
d-Alpha tocopheryl acetate
dl-Alpha tocopheryl acetate
d-Alpha tocopheryl acid succinate
dl-Alpha tocopheryl acid succinate
Aluminum distearate
Aluminum monostearate
Amylopectin
a-Amylose
Anhydrous citric acid
Anhydrous sodium citrate
Anhydrous sodium propionate
Artificial vinegar
Bacteriostatic water for injection
Bentonite magma
Beta tocopherol
Beta-carotene
n-Butyl lactate
Butylparaben sodium
Calcium ascorbate
Calcium cyclamate
Calcium polycarbophil
Calcium propionate
Calcium silicate
Calcium sorbate
Calcium sulfate hemihydrate
Capric acid
Carbon dioxide-free water
Cationic emulsifying wax
Ceratonia extract
Cetylpyridinium bromide
Chlorhexidine acetate
Chlorhexidine gluconate
Chlorhexidine hydrochloride
Chlorodifluoromethane
Chlorophenoxyethanol
Corn syrup solids
m-Cresol
o-Cresol
p-Cresol
Crude olive-pomace oil
Cyclamic acid
De-aerated water
Dehydrated alcohol
Delta tocopherol
Denatured alcohol
Dextrose anhydrous
Diazolidinyl urea
Dibasic potassium phosphate
Diethylene glycol monopalmitostearate
Dilute acetic acid
Dilute alcohol
Dilute ammonia solution
Dilute hydrochloric acid
Dilute phosphoric acid
Dilute sulfuric acid
Dimethyl-b-cyclodextrin
Dioctyl phthalate
Dipotassium edetate
Docusate calcium
Docusate potassium
Dodecyl gallate
Dodecyltrimethylammonium bromide
Edetate calcium disodium
Eglumine
Ethyl gallate
Ethylene glycol monopalmitate
Ethylene glycol monostearate
Ethyl linoleate
Ethylparaben potassium
Ethylparaben sodium
Extra virgin olive oil
Fine virgin olive oil
Fuming sulfuric acid
Gamma tocopherol
Hard water
Hesperidin
Hexadecyltrimethylammonium bromide
High-fructose syrup
Hyaluronic acid
Hydrogenated lanolin
Hydrogenated vegetable oil, type II
2-Hydroxyethyl-b-cyclodextrin
2-Hydroxypropyl-b-cyclodextrin
3-Hydroxypropyl-b-cyclodextrin
Indigo carmine
Invert sugar
Isotrehalose
Lampante virgin olive oil
Lanolin alcohols ointment
DL-Leucine
Liquefied phenol
Liquid fructose
Magnesium carbonate anhydrous
Magnesium carbonate hydroxide
Magnesium lauryl sulfate
Magnesium metasilicate
Magnesium orthosilicate
Magnesium trisilicate anhydrous
D-Malic acid
L-Malic acid
d-Menthol
l-Menthol
Methyl lactate
Methyl linoleate
Methyl methacrylate
Methyl oleate
Methylparaben potassium
Methylparaben sodium
N-Methylpyrrolidone
Microcrystalline cellulose and carboxymethylcellulose sodium
Microcrystalline cellulose and carrageenan
Microcrystalline cellulose and guar gum
Modified lanolin
Monobasic potassium phosphate
Montmorillonite
Myristyl alcohol
Neotrehalose
Normal magnesium carbonate
Octyl gallate
Oleyl oleate
Olive-pomace oil
Palmitin
Pharmaceutical glaze
Phenoxypropanol
Polacrilin
Poly(methyl methacrylate)
Potassium bisulfite
Potassium myristate
Potassium propionate
Powdered fructose
Propan-1-ol
(S)-Propylene carbonate
Propylparaben potassium
Propylparaben sodium
Purified bentonite
Purified stearic acid
Quaternium 18-hectorite
Rapeseed oil
Refined almond oil
Refined olive-pomace oil
Saccharin ammonium
Saccharin calcium
Self-emulsifying glyceryl monostearate
Shellolic acid
Sodium bisulfite
Sodium borate anhydrous
Sodium edetate
Sodium erythorbate
Sodium laurate
Sodium myristate
Sodium palmitate
Sodium sorbate
Sodium sulfite heptahydrate
Soft water
Sorbitol solution 70%
Spermaceti wax
Stearalkonium hectorite
Sterile water for inhalation
Sterile water for injection
Sterile water for irrigation
Sunset yellow FCF
Synthetic paraffin
DL-()-Tartaric acid
Tartrazine
Theobroma oil
Tocopherols excipient
Tribasic sodium phosphate
Trimethyl-b-cyclodextrin
Trimethyltetradecylammonium bromide
Trisodium edetate
Virgin olive oil
Water for injection
White petrolatum
Zinc propionate
Related Substances xv
Preface
Pharmaceutical dosage forms contain both pharmacologically
active compounds and excipients added to aid the formulation
and manufacture of the subsequent dosage form for administration to patients. Indeed, the properties of the final dosage
form (i.e. its bioavailability and stability) are, for the most part,
highly dependent on the excipients chosen, their concentration
and interaction with both the active compound and each other.
No longer can excipients be regarded simply as inert or inactive
ingredients, and a detailed knowledge not only of the physical
and chemical properties but also of the safety, handling and
regulatory status of these materials is essential for formulators
throughout the world. In addition, the growth of novel forms of
delivery has resulted in an increase in the number of the
excipients being used and suppliers of excipients have developed novel excipient mixtures and new physical forms to
improve their properties. The Handbook of Pharmaceutical
Excipients has been conceived as a systematic, comprehensive
resource of information on all of these topics
The first edition of the Handbook was published in 1986 and
contained 145 monographs. This was followed by the second
edition in 1994 containing 203 monographs, the third edition
in 2000 containing 210 monographs and the fourth edition in
2003 containing 249 monographs. Since 2000, the data has
also been available on CD-ROM, updated annually, and from
2004 online. This new printed edition with its companion CDROM, Pharmaceutical Excipients 5, contains 300 monographs
compiled by over 120 experts in pharmaceutical formulation or
excipient manufacture from Australia, Europe, India and the
USA. All the monographs have been reviewed and revised in the
light of current knowledge. There has been a greater emphasis
on including published data from primary sources although
some data from laboratory projects included in previous
editions have been retained where relevant. Variations in test
methodology can have significant effects on the data generated
(especially in the case of the compactability of an excipient),
and thus cause confusion. As a consequence, the editors have
been more selective in including data relating to the physical
properties of an excipient. However, comparative data that
show differences between either source or batch of a specific
excipient have been retained as this was considered relevant to
the behavior of a material in practice. The Suppliers Directory
(Appendix I) has also been completely updated with many more
international suppliers included.
In a systematic and uniform manner, the Handbook of
Pharmaceutical Excipients collects essential data on the
physical properties of excipients such as: boiling point, bulk
and tap density, compression characteristics, hygroscopicity,
flowability, melting point, moisture content, moisture-absorption isotherms, particle size distribution, rheology, specific
surface area, and solubility. Scanning electron microphotographs (SEMs) are also included for many of the excipients. The
Handbook contains information from various international
sources and personal observation and comments from monograph authors, steering committee members, and the editors.
All of the monographs in the Handbook are thoroughly
cross-referenced and indexed so that excipients may be
identified by either a chemical, a nonproprietary, or a trade
name. Most monographs list related substances to help the
formulator to develop a list of possible materials for use in a
new dosage form or product. Related substances are not
directly substitutable for each other but, in general, they are
excipients that have been used for similar purposes in various
dosage forms.
The Handbook of Pharmaceutical Excipients is a comprehensive, uniform guide to the uses, properties, and safety of
pharmaceutical excipients, and is an essential reference source
for those involved in the development, production, control, or
regulation of pharmaceutical preparations. Since many pharmaceutical excipients are also used in other applications, the
Handbook of Pharmaceutical Excipients will also be of value to
persons with an interest in the formulation or production of
confectionery, cosmetics, and food products.
Arrangement
The information consists of monographs that are divided into
22 sections to enable the reader to find the information of
interest easily. Although it was originally intended that each
monograph contain only information about a single excipient,
it rapidly became clear that some substances or groups of
substances should be discussed together. This gave rise to such
monographs as ‘Coloring Agents’ and ‘Hydrocarbons’. In
addition, some materials have more than one monograph
depending on the physical characteristics of the material, e.g.
Starch versus Pregelatinized Starch. Regardless of the complexity of the monograph they are all divided into 22 sections as
follows:
1 Nonproprietary Names
2 Synonyms
3 Chemical Name and CAS Registry Number
4 Empirical Formula and Molecular Weight
5 Structural Formula
6 Functional Category
7 Applications in Pharmaceutical Formulation or
Technology
8 Description
9 Pharmacopeial Specifications
10 Typical Properties
11 Stability and Storage Conditions
12 Incompatibilities
13 Method of Manufacture
14 Safety
15 Handling Precautions
16 Regulatory Status
17 Related Substances
18 Comments
19 Specific References
20 General References
21 Authors
22 Date of Revision
Descriptions of the sections appear below with information
from an example monograph if needed.
Section 1, Nonproprietary Names, lists the excipient names
used in the current British Pharmacopoeia, European Pharmacopeia, Japanese Pharmacopeia, and the United States Pharmacopeia/National Formulary.
Section 2, Synonyms, lists other names for the excipient,
including trade names used by suppliers (shown in italics).
The inclusion of one supplier’s trade name and the absence of
others should in no way be interpreted as an endorsement of
one supplier’s product over the other. The large number of
suppliers internationally makes it impossible to include all the
trade names.
Section 3, Chemical Name and CAS Registry Number, indicates the unique Chemical Abstract Services number for an
excipient along with the chemical name, e.g., Acacia [9000-
01-5].
Sections 4 and 5, Empirical Formula and Molecular Weight
and Structural Formula, are self-explanatory. Many excipients
are not pure chemical substances, in which case their composition is described either here or in Section 8.
Section 6, Functional Category, lists the function(s) that an
excipient is generally thought to perform, e.g., diluent, emulsifying agent, etc.
Section 7, Applications in Pharmaceutical Formulation or Technology, describes the various applications of the excipient.
Section 8, Description, includes details of the physical appearance of the excipient, e.g., white or yellow flakes, etc.
Section 9, Pharmacopeial Specifications, briefly presents the
compendial standards for the excipient. Information included
is obtained from the British Pharmacopoeia (BP), European
Pharmacopeia (PhEur), Japanese Pharmacopeia (JP), and the
United States Pharmacopeia/National Formulary (USP/
USPNF). Information from the JP, USP and USPNF are
included if the substance is in those compendia. Information
from the PhEur is also included. If the excipient is not in the
PhEur but is included in the BP, information is included from
the BP. Pharmacopeias are continually updated with most
now being produced as annual editions. However, although
efforts were made to include up-to-date information at the
time of publication of this edition, the reader is advised to
consult the most current pharmacopeias or supplements.
Section 10, Typical Properties, describes the physical properties of the excipient which are not shown in Section 9. All
data are for measurements made at 208C unless otherwise
indicated. Where the solubility of the excipient is described in
words, the following terms describe the solubility ranges:
Very soluble 1 part in less than 1
Freely soluble 1 part in 1–10
Soluble 1 part in 10–30
Sparingly soluble 1 part in 30–100
Slightly soluble 1 part in 100–1000
Very slightly soluble 1 part in 1000–10 000
Practically insoluble 1 part in more than 10 000
or insoluble
Where practical, data typical of the excipient or comparative
data representative of different grades or sources of a material
are included, the data being obtained from either the primary or
the manufacturers’ literature. In previous editions of the
Handbook a laboratory project was undertaken to determine
data for a variety of excipients and in some instances this data
has been retained. For a description of the specific methods
used to generate the data readers should consult the appropriate previous edition(s) of the Handbook.
Section 11, Stability and Storage Conditions, describes the
conditions under which the bulk material as received from
the supplier should be stored. In addition some monographs
report on storage and stability of the dosage forms that contain the excipient.
Section 12, Incompatibilities, describes the reported incompatibilities for the excipient either with other excipients or with
active ingredients. If an incompatibility is not listed it does
not mean it does not occur but simply that it has not been
reported or is not well known. Every formulation should be
tested for incompatibilities prior to use in a commercial product.
Section 13, Method of Manufacture, describes the common
methods of manufacture and additional processes that are
used to give the excipient its physical characteristics. In some
cases the possibility of impurities will be indicated in the
method of manufacture.
Section 14, Safety, describes briefly the types of formulations
in which the excipient has been used and presents relevant
data concerning possible hazards and adverse reactions that
have been reported. Relevant animal toxicity data are also
shown.
Section 15, Handling Precautions, indicates possible hazards
associated with handling the excipient and makes recommendations for suitable containment and protection methods. A
familiarity with current good laboratory practice (GLP) and
current good manufacturing practice (GMP) and standard
chemical handling procedures is assumed.
Section 16, Regulatory Status, describes the accepted uses in
foods and licensed pharmaceuticals where known. However,
the status of excipients varies from one nation to another,
and appropriate regulatory bodies should be consulted for
guidance.
Section 17, Related Substances, lists excipients similar to the
excipient discussed in the monograph.
Section 18, Comments, includes additional information and
observations relevant to the excipient. Where appropriate, the
different grades of the excipient available are discussed. Comments are the opinion of the listed author(s) unless referenced
or indicated otherwise.
Section 19, Specific References, is a list of references cited
within the monograph.
Section 20, General References, lists references which have
general information about this type of excipient or the types
of dosage forms made with these excipients.
Section 21, Authors, lists the current authors of the monograph in alphabetical order. Authors of previous versions of
the monograph are shown in previous printed editions of the
text.
Section 22, Date of Revision, indicates the date on which
changes were last made to the text of the monograph.
xviii Arrangement
Acknowledgments
A publication containing so much detail could not be produced
without the help of a large number of pharmaceutical scientists
based world-wide. The voluntary support of over 120 authors
has been acknowledged as in previous editions, but the current
editors would like to thank them all personally for their
contribution. Grateful thanks also go to the members of the
International Steering Committee who advised the editors and
publishers on all aspects of the Handbook project. Steering
Committee members also diligently reviewed all of the
monographs before their publication. Many authors and
Steering Committee members have been involved in previous
editions of the Handbook. For others, this was their first edition
although not, we hope, their last. Walter Chambliss and John
Hogan retired from the International Steering Committee
during the preparation of this edition and we extend our
thanks for their support over many years. Thanks are also
extended to excipient manufacturers and suppliers who
provided helpful information on their products.
Thanks are also gratefully extended to the staff of the
Pharmaceutical Press and American Pharmacists Association
who were involved in the production of the Handbook: Eric
Connor, Tamsin Cousins, Simon Dunton, Laurent Galichet,
Julian Graubart, Louise McIndoe, Karl Parsons, Paul Weller,
and John Wilson. Once again, the diligent copy-editing and
challenging questions asked by Len Cegielka helped the authors
and editors, we hope, to express their thoughts clearly,
concisely, and accurately.
Raymond C Rowe, Paul J Sheskey and Siaˆ n C Owen
August 2005
Notice to Readers
The Handbook of Pharmaceutical Excipients is a reference
work containing a compilation of information on the uses and
properties of pharmaceutical excipients, and the reader is
assumed to possess the necessary knowledge to interpret the
information that the Handbook contains. The Handbook of
Pharmaceutical Excipients has no official status and there is no
intent, implied or otherwise, that any of the information
presented should constitute standards for the substances. The
inclusion of an excipient, or a description of its use in a
particular application, is not intended as an endorsement of
that excipient or application. Similarly, reports of incompatibilities or adverse reactions to an excipient, in a particular
application, may not necessarily prevent its use in other
applications. Formulators should perform suitable experimental studies to satisfy themselves and regulatory bodies that a
formulation is efficacious and safe to use.
While considerable efforts were made to ensure the accuracy
of the information presented in the Handbook, neither the
publishers nor the compilers can accept liability for any errors
or omissions. In particular, the inclusion of a supplier within the
Suppliers Directory is not intended as an endorsement of that
supplier or its products and, similarly, the unintentional
omission of a supplier or product from the directory is not
intended to reflect adversely on that supplier or its product.
Although diligent effort was made to use as recent
compendial information as possible, compendia are frequently
revised and the reader is urged to consult current compendia, or
supplements, for up-to-date information, particularly as efforts
are currently in progress to harmonize standards for excipients.
Data presented for a particular excipient may not be
representative of other batches or samples.
Relevant data and constructive criticism are welcome and
may be used to assist in the preparation of any future editions
or electronic versions of the Handbook. The reader is asked to
send any comments to the Editor, Handbook of Pharmaceutical
Excipients, Royal Pharmaceutical Society of Great Britain, 1
Lambeth High Street, London SE1 7JN, UK, or Editor,
Handbook of Pharmaceutical Excipients, American Pharmacists Association, 2215 Constitution Avenue, NW, Washington,
DC 20037-2985, USA.
Bibliography
A selection of publications and websites which contain useful information on pharmaceutical excipients is listed below:
Ash M, Ash I. Handbook of Pharmaceutical Additives, 2nd
edn. Endicott, NY: Synapse Information Resources, 2002.
Aulton ME, ed. Pharmaceutics: the Science of Dosage Form
Design, 2nd edn. Edinburgh: Churchill Livingstone, 2002.
Banker GS, Rhodes CT, eds. Modern Pharmaceutics, 4th edn.
New York: Marcel Dekker, 2002.
British Pharmacopoeia 2004. London: The Stationery Office,
2004.
Bugay DE, Findlay WP. Pharmaceutical Excipients Characterization by IR, Raman, and NMR Spectroscopy. New York:
Marcel Dekker, 1999.
European Pharmacopoeia, 5th edn. and supplements. Strasbourg: Council of Europe, 2005.
Florence AT, Salole EG, eds. Formulation Factors in Adverse
Reactions. London: Butterworth, 1990.
Food and Drug Administration. Inactive Ingredient Guide.
http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm
(accessed 11 July 2005).
Food Chemicals Codex, 4th edn. Washington, DC: National
Academy Press, 1996.
Health and Safety Executive. EH40/2002: Occupational
Exposure Limits 2002. Sudbury: Health and Safety Executive, 2001.
Health Canada. Canadian List of Acceptable Non-medicinal
Ingredients. http://www.hc-sc.gc.ca/hpfb-dgpsa/nhpd-dpsn/
nmi_list1_e.html (accessed 11 July 2005)
Hoepfner E, Reng A, Schmidt PC, eds. Fiedler Encyclopedia of
Excipients for Pharmaceuticals, Cosmetics and Related
Areas. Aulendorf, Germany: Editio Cantor, 2002.
Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical Excipients 2004. Tokyo: Yakuji Nippo, 2004.
Japanese Pharmacopeia, 14th edn. and supplement. Tokyo:
Yakuji Nippo, 2001.
Kemper FH, Luepke N-P, Umbach W, eds. Blue List Cosmetic
Ingredients. Aulendorf, Germany: Editio Cantor, 2000.
Lewis RJ, ed. Sax’s Dangerous Properties of Industrial
Materials, 11th edn. New York: John Wiley, 2004.
Lund W, ed. The Pharmaceutical Codex: Principles and
Practice of Pharmaceutics, 12th edn. London: Pharmaceutical Press, 1994.
National Library of Medicine. TOXNET.
http://toxnet.nlm.nih.gov (accessed 11 July 2005)
O’Neil MJ, Smith A, Heckelman PE, eds.The Merck Index: an
Encyclopedia of Chemicals, Drugs, and Biologicals, 13th
edn. Whitehouse Station, NJ: Merck, 2001.
Smolinske SC. Handbook of Food, Drug and Cosmetic
Excipients. Boca Raton, FL: CRC Press, 1992.
Swarbrick J, Boylan JC, eds. Encyclopedia of Pharmaceutical
Technology, 2nd edn. New York: Marcel Dekker, 2002.
Sweetman SC, ed. Martindale: the Complete Drug Reference,
34rd edn. London: Pharmaceutical Press, 2005.
United States Pharmacopeia 28 and National Formulary 23.
and supplement. Rockville, MD: United States Pharmacopeial Convention, 2005.
University of the Sciences in Philadelphia. Remington: the
Science and Practice of Pharmacy, 21st edn. Baltimore:
Lippincott Williams and Wilkins, 2005.
Weiner M, Bernstein IL. Adverse Reactions to Drug Formulation Agents: a Handbook of Excipients. New York: Marcel
Dekker, 1989.
Weiner ML, Kotkoskie LA, eds. Excipient Toxicity and Safety.
New York: Marcel Dekker, 2000.
Abbreviations
Some units, terms, and symbols are not included in this list as they are defined in the text. Common abbreviations have been omitted.
The titles of journals are abbreviated according to the general style of the Index Medicus.
approximately.
Ad Addendum.
ADI acceptable daily intake.
approx approximately.
atm atmosphere.
BAN British Approved Name.
bp boiling point.
BP British Pharmacopoeia.
BS British Standard (specification).
BSI British Standards Institution.
cal calorie(s).
CAS Chemical Abstract Service.
CFC chlorofluorocarbon.
cm centimeter(s).
cm2 square centimeter(s).
cm3 cubic centimeter(s).
cmc critical micelle concentration.
CNS central nervous system.
cP centipoise(s).
cSt centistoke(s).
CTFA Cosmetic, Toiletry, and Fragrance Association.
D&C designation applied in USA to dyes permitted for use
in drugs and cosmetics.
DoH Department of Health (UK).
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