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handbook of pharmaceutical excipients sixth edition edited by raymond c rowe chief scientist bpharm phd dsc frpharms frsc cphys minstp intelligensys ltd stokesley north yorkshire uk paul j sheskey bsc rph application development leader the dow chemical company midland mi usa marian e quinn development editor bsc msc royal pharmaceutical society of great britain london uk london chicago[close]
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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[close]
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contents preface x arrangement xi acknowledgments xiii notice to readers xiii international steering committee editorial staff xv contributors xvi about the editors xx new monographs xxi related substances xxii bibliography xxiv abbreviations xxv units of measurement xxvii monographs a acacia 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 bentonite 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 c calcium 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 53 ceratonia ceresin 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 xiv benzoic acid benzyl alcohol benzyl benzoate boric acid bronopol butylated hydroxyanisole butylated hydroxytoluene butylene glycol butylparaben 56 59 61 64 66 68 70 73 75 77 78[close]
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vi contents 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 erythritol ethyl acetate ethyl lactate ethyl maltol ethyl oleate ethyl vanillin ethylcellulose ethylene glycol stearates ethylene vinyl acetate ethylparaben f fructose fumaric acid g gelatin glucose liquid glycerin glyceryl behenate glyceryl monooleate glyceryl monostearate glyceryl palmitostearate glycine glycofurol guar gum h hectorite 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 247 250 imidurea inulin 337 339 273 276 251 253 256 257 259 261 262 267 268 270 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 denatonium 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 edetic acid erythorbic acid 278 282 283 286 288 290 293 295 297 298 217 218 220 222 225 227 228 230 232 233 235 236 238 241 242 244 301 303 304 306 308 309 311 314 315 317 322 325 326 330 333[close]
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contents iron oxides isomalt isopropyl alcohol isopropyl myristate isopropyl palmitate k kaolin l lactic acid lactitol lactose anhydrous lactose inhalation lactose monohydrate lactose monohydrate and corn starch 352 340 342 346 348 350 methionine methylcellulose methylparaben mineral oil mineral oil light mineral oil and lanolin alcohols monoethanolamine monosodium glutamate monothioglycerol myristic acid myristyl alcohol n neohesperidin dihydrochalcone neotame nitrogen nitrous oxide o octyldodecanol oleic acid oleyl alcohol olive oil p palmitic acid paraffin peanut oil pectin 391 393 397 400 402 404 408 410 411 414 416 418 421 422 424 429 431 433 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 vii 436 438 441 445 447 449 450 452 454 455 456 355 357 359 362 364 370 458 460 461 463 lactose monohydrate and microcrystalline cellulose 371 lactose monohydrate and povidone 373 lactose monohydrate and powdered cellulose lactose spray-dried lanolin lanolin hydrous lanolin alcohols lauric acid lecithin leucine linoleic acid m macrogol 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 374 376 378 380 382 383 385 387 389 465 466 468 470 473 474 476 478 480 481 484 485 488 490 492 494 496 499 503 504 506 509 513 515 517 522[close]
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viii contents 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 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 tagatose talc tartaric acid tetrafluoroethane hfc thaumatin thimerosal thymol titanium dioxide tragacanth 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 polymethacrylates polymethyl 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 raffinose s saccharin 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 603 605 608 610 612 614 616 619 620 622 625 627 629 633 635 637 727 728 731 733 735 736 739 741 744[close]
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contents trehalose triacetin tributyl citrate tricaprylin triethanolamine triethyl citrate triolein 746 748 749 751 754 756 757 x xanthan gum xylitol wax white wax yellow ix 779 780 782 786 v vanillin vegetable oil hydrogenated vitamin e polyethylene glycol succinate 760 762 764 z zein zinc acetate zinc stearate 790 791 793 795 847 849 852 855 w water wax anionic emulsifying wax carnauba wax cetyl esters wax microcrystalline wax nonionic emulsifying 766 770 772 774 775 777 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[close]
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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 coprocessed 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 the fifth edition with its companion cd-rom pharmaceutical excipients 5 contained 300 monographs and was published in 2006 this new edition contains 340 excipient monographs with a new text design and enhanced online features compiled by over 140 experts in pharmaceutical formulation or excipient manufacture from australia europe india japan 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 over the past few years there has been an increased emphasis on the harmonization of excipients for information on the current status for each excipient selected for harmonization the reader is directed to the general information chapter <1196 in the usp32nf27 the general chapter 5.8 in pheur 6.0 along with the `state of work document on the pheur edqm website http www.edqm.eu and also the general information chapter 8 in the jp xv 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 this edition contains over 130 near-infrared nir spectra specifically generated for the handbook 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 crossreferenced 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 x[close]
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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 functions 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 freely soluble soluble sparingly soluble slightly soluble very slightly soluble practically insoluble or insoluble 1 1 1 1 1 1 1 part in part in part in part in part in part in part in less than 1 110 1030 30100 1001000 100010 000 more than 10 000 for this edition near-infrared nir reflectance spectra of samples as received i.e the samples were not dried or reduced in particle size were measured using a foss nirsystems 6500 spectrophotometer foss nirsystems inc laurel md usa fitted with a rapid content analyser against a ceramic standard supplied with the instrument the instrument was controlled by vision version 2.22 software spectra were recorded over the wavelength range 11002498 nm 700 data points and each saved spectrum was the average of 32 scans solid powdered samples were measured in glass vials of approximately 20 mm diameter each sample was measured in triplicate and the mean spectrum taken when more than one batch of a material was available the mean of all the batches is presented liquid samples were measured by transflectance using a gold reflector 2 Â 0.5 mm optical path-length foss placed in a 45 mm silica reflectance cell against air as the reference spectra are presented as plots of a log1/r vs wavelength dashed line scale on right-hand side and b second-derivative log1/r vs wavelength solid line scale on left-hand side r is the reflectance and log1/r represents the apparent absorbance second-derivative spectra were calculated from the log1/r values using an 11 point savitzky-golay filter with second-order polynomial smoothing xi[close]
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xii arrangement 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 authors 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 note peak positions and amplitudes in the second-derivative spectrum are very sensitive to the method used to calculate the second-derivative 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 editions 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.[close]
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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 140 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.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 we extend our thanks to all for their support thanks are also extended to roger jee kelly palmer and tony moffat at the school of pharmacy university of london for supplying the nir spectra to pfizer pgrd sandwich uk for supplying sems and 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 tamsin cousins simon dunton rebecca garner julian graubart karl parsons linda paulus jo watts paul weller and john wilson the diligent copy-editing and proofreading by len cegielka and janet pascoe respectively helped the authors and editors we hope to express their thoughts clearly concisely and accurately raymond c rowe paul j sheskey marian e quinn july 2009 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 the most recent compendial information 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 xiii[close]
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international steering committee gregory e amidon university of michigan ann arbor mi usa graham buckton university of london london uk colin g cable royal pharmaceutical society of great britain edinburgh uk walter cook pfizer global r d kent uk henk j de jong puteaux france stephen edge novartis pharma ag basel switzerland robert t forbes university of bradford bradford uk julian i graubart american pharmacists association washington dc usa roger t guest glaxosmithkline ware hertfordshire uk bruno c hancock pfizer inc groton ct usa karen p hapgood monash university clayton victoria australia stephen w hoag university of maryland at baltimore baltimore md usa jennifer c hooton astrazeneca cheshire uk anne juppo university of helsinki helsinki finland arthur h kibbe wilkes university school of pharmacy wilkes-barre pa usa bruce r kinsey ashland aqualon functional ingredients harleysville pa usa william j lambert pacira pharmaceuticals inc san diego ca usa jian-xin li evonik degussa corporation piscataway nj usa brian r matthews alcon laboratories uk ltd hertfordshire uk r christian moreton finnbrit consulting waltham ma usa gary moss university of hertfordshire hertfordshire uk marian e quinn royal pharmaceutical society of great britain london uk raymond c rowe intelligensys ltd stokesley uk niklas sandler university of helsinki helsinki finland shirish a shah icon development solutions phoenix az usa catherine m sheehan united states pharmacopeia rockville md usa paul j sheskey the dow chemical company midland mi usa kamalinder k singh sndt women s university mumbai india hirofumi takeuchi gifu pharmaceutical university gifu japan paul j weller royal pharmaceutical society of great britain london uk xiv[close]
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