1
`
`EX 1012
`IPR of U.S. Pat. No. 7,829,595
`
`

`
`Published by the American Pharmaceutical Association
`2215 Constitution Avenue NW, Washington, DC 20037-2985, USA
`www.aphanet.org
`and the Pharmaceutical Press
`1 Lambeth High Street, London SE1 7JN, UK
`www.pharmpress.com
`
`© 1986, 1994, 2000 American Pharmaceutical Association and Pharmaceutical Press
`
`First edition 1986
`Second edition 1994
`Third edition 2000
`
`Printed in the United States of America
`
`ISBN: O-85369-381-1 (UK)
`ISBN: O-917330-96-X (USA)
`
`Library of Congress Cataloging-in-Publication Data
`Handbook of pharmaceutical excipients / edited by Arthur H. Kibbe.--3rd ed.
`p.
`; cm.
`Includes bibliographical references and index.
`ISBN 0—9l7330-96-X
`1. Excipients--Handbooks. manuals, etc.
`Pharmaceutical Association.
`IDNLM: 1. Excipients--Handbooks. QV 735 H236 2000]
`RSZOLEB7 H36 2000
`615119--dc21
`
`I. Kibbe, Arthur H. II. American
`
`A catalogue record for this book is available from the British Library.
`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.
`
`Managing Editor: Melanie Segala
`Copyeditor:
`Paul Gottehrer
`Indexer:
`Lillian Rodberg
`compositor:
`Roy Barnhill
`Cover Designer:
`Tim Kaage
`
`2
`
`

`
`SEM: 1
`Exeipient: Microcrystalline cellulose
`Manufacturer: Penwest Pharmaceuticals
`Lot: 98662
`Magnification: 100x
`
`102 Cellulose, Microcrystalline
`
`Cellulose,
`Microcrystalline
`
`1. Nonproprietary Names
`BP: Microcrystalline cellulose
`JP: Microcrystalline cellulose
`PhEur: Cellulosum microcrystallinum
`USP: Microcrystalline cellulose
`
`2. Synonyms
`
`Avicel; cellulose gel; crystalline cellulose; E460; Emcocel;
`Fibrocel; Tabulose; Vivacel.
`
`3. Chemical Name and CAS Registry Number
`Cellulose [9004—34-6]
`
`4. Empirical Formula and Molecular Weight
`
`(C5H.ioO5)n
`Where n = 220.
`
`3 35 000
`
`5. Structural Formula
`
`6. Functional Category
`
`Adsorbent; suspending agent; tablet and capsule diluent; tablet
`disintegrant.
`
`8. Description
`Microcrystalline cellulose is a purified, partially dcpolymcr—
`ized cellulose that occurs as a white, odorless, tasteless, crys-
`talline powder composed of porous particles. It
`is
`commercially available in different particle sizes and moisture
`grades which have different properties and applications.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`
`Test
`
`9. Pharrnacopeial Specifications
`
`Microcrystallinc cellulose is widely used in pharmaceuticals,
`primarily as a binder/diluent in oral tablet and capsule for-
`mulations where it is used in both wet granulation and direct-
`compression processes.“‘7) In addition to its use as a bind-
`er/diluent, microcrystalline cellulose also has some lubricant“)
`and disintcgrant properties that make it useful in tableting.
`Microcrystalline cellulose is also used in cosmetics and food
`products.
`
`Use
`Adsorbent
`Anti-adherent
`Capsule binder/diluent
`Tablet clisintegrant
`Tablet binder/diluent
`
`Concentration (%)
`20-90
`5-20
`20-90
`5-15
`2090
`
`4-
`
`5.0-7.0
`+
`-
`S 7.0%
`S 0.05%
`+
`—
`
`Identification
`Characters
`pH
`Bulk density
`Solubility
`Loss on drying
`Residue on ignition
`Conductivity
`Sulfated ash
`Ether—soluble substances
`Water-soluble substances
`Heavy metals
`Starch
`Organic volatile impurities
`Microbial limits
`Assay
`
`+
`97 .O- 1 02.0%
`
`3
`
`

`
`SEM: 2
`Excipienl: Microcrysmlline cellulose
`Manufacturer: Penwest Pharmaceuticals
`Lot: 98662
`Magnification: 300x
`
`SEM: 3
`Excipienx: Microcrystalline cellulose
`Manufacturer; FMC Corp
`Magnification: 100x
`
`Cellulose, Microcrystalline
`
`I03
`
`Table 1: Properties of some commercially available grades of
`microcrystalline cellulose.
`
`10. Typical Properties
`Angle of repose: 34.4” for Emcocel 90M.‘9)
`Density (bulk):
`0.337 g/cm3;(‘*)
`0.32 g/cm3 for Avicel PH—10l;(1°)
`0.29 g/cm3 for Emcocel 90M.(9)
`Density (tapped):
`0.478 g/cm3;‘“’
`0.45 g/cm3 for Avicel PH-10];“°l
`0.35 g/cm3 for Emcocel 90M.(9)
`Density (true): 1.512-1.668 g/cm3(‘l
`Compressibility: See Figs. 1, 2, and 3.“)
`Mechanical properties“)
`9.84 kN/cmz
`Compression pressure:
`0.8711 kN/cm:
`Tensile strength:
`15.3
`Permanent deformation pressure:
`0.0821
`Brittle fracture index:
`0.0571
`Bonding index:
`1472
`Reduced modulus of elasticity:
`Flowabilityz 1.41 gls for Emcocel 90M.(9l
`Melting point: chars at 260-270°C.
`Moisture content: typically, less than 5% w/w. However, different
`grades may contain varying amounts of water. Microcrystalline
`cellulose is hygroscopic.“” See Fig. 4“) and Table L
`Particle size distribution: typical mean particle size is 20400 um.
`Different grades may have a different nominal mean par
`ticle size, see Table I.
`Solubility: slightly soluble in 5% w/v sodium hydroxide solu-
`tion; 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 mz/g for Avicel PH—]02.‘“l
`0.78-1.18 m2/g for Avicel PH-200.“)
`"> Results of laboratory project for third edition.
`
`Nominal
`mean
`particle size Mesh
`(um)
`size
`50
`60
`200
`60
`200
`60
`200
`400
`60
`60
`200
`60
`100
`60
`200
`60
`200
`60
`200
`60
`200
`50
`150
`50
`150
`so
`500
`50
`150
`
`Particle Size Analysis
`Amount
`retained
`(96) '
`S 1.0
`S 30.0
`S 8.0
`2 45.0
`S 1.0
`S 30.0
`S 1.0
`S 3.0
`S 1.0
`S 30.0
`2 10.0
`2 50.0
`S 1.0
`S 30.0
`S 8.0
`2 45.0
`S 0.25
`S 30.0
`S 8.0
`2 45.0
`2 35.0
`S 10.0
`2 50.0
`s 30.0
`2 70.0
`s 1.0
`S 2.0
`S 0.1
`
`Moisture
`content
`(96)
`S 5.0
`
`S 5.0
`
`S 3.0
`
`S 5.0
`S 15
`S 1.5
`
`s 5.0
`
`S 5.0
`
`Grade
`Avicel PH-101i"
`
`Avicel PH-I02“)
`
`100
`
`Avicel PH-103“) 50
`'
`Avicel PH-I05“) 20
`Avicel PH-I120’
`100
`Avicel PH-I13“)
`50
`
`Avicel PH-200“)
`
`Avicel PH-301"’ 50
`
`Avicel PH-302“)
`
`Emcocel 50M“”
`
`Emcocel 90M("l
`
`Vivace! 1010:)
`
`Vivace! 102°)
`
`Vivacel 120
`
`Vivacel 20“)
`
`100
`
`51
`
`91
`
`50
`
`100
`
`180
`
`20
`
`Suppliers: la’ FMC Corporation; (5) Edward Mendell Co Inc; W1. Reticu-
`maier & Siihne Gmbl-1
`
`4
`
`

`
`I04 Cellulose. Microcrysralline
`
`
`
`
`
`CrushingStrength(MPa)
`
`(dx)sseup1eH
`
`120
`
`240
`
`350
`
`480
`
`Mean applied pressure (MPa)
`
`Fig. 1: Crushing strength.
`(Reprinted with permission from Marcel Dekker, [ne., to be
`published in Compaction of Pharmaceutical Excipients by Metin
`Celik, in press, 1999.)
`I : Microcrystalline cellulose, Emcocel 90M (Lot # 1037X.
`Mendell) at V 2 I00 mm/s
`A : Microcrystalline cellulose, Emcocel 90M (Lot # l037X.
`Mendell) at V : 300 mm/s
`
`40
`
`‘is
`
`35
`
`55
`
`95
`75
`Pressure (MPa)
`
`115
`
`135
`
`Fig. 3: Heckel plot for microcrystalline cellulose.
`O: lnl/(1-D)
`I: Hardness
`
`-5 M
`
`.n. O
`
`
`
` W%Equilibriummoisture
`
`.uca
`
`CD-4MO)ts
`
`Ir]uouaeduioolomom|e;o_L
`
`120
`
`480
`360
`240
`Mean applied pressure (MPa)
`
`Kg. 2: Total work of compaction.
`(Reprinted with permission from Marcel Dekker, lnc., to be
`published in Compaction of Pharmaceutical Excipients by Metin
`Celik, in press, 1999.)
`I : Percentage porosity (E) vs. pressure plot for microcrystalline
`cellulose, Emcacel 90M (Lot # l037X. Mendell) at V = 100 mm/s
`A : Total work of compaction (TWC) vs. pressure plot for
`microcrystalline cellulose, Emcocel 90M (Lot # l037X, Mendell)
`at V = 100 mm/s
`
`4050 607080 90100
`% Relative Humidity
`
`Fig. 4: Sorbtiorbdesorption isotherm for microcrystalline cellulose.
`O: Sorption
`I : Desorption
`
`11. Stability and Storage Conditions
`
`Microcrystalline cellulose is a stable, though hygroscopic ma-
`terial. The bulk material should be stored in a well-closed
`container in a cool, dry, place.
`
`12. Incompatibilities
`Incompatible with strong oxidizing agents.
`
`5
`
`

`
`13. Method of Manufacture
`
`Microcrystalline cellulose is manufactured by the controlled
`hydrolysis, with dilute mineral acid solutions of or-cellulose,
`obtained as a pulp from fibrous plant materials. Following
`hydrolysis, the hydrocellulose 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 pharmaceu-
`tical formulations and food products and is generally regarded
`as a nontoxic and nonirritant material.
`
`Microcrystalline cellulose is not absorbed systemically fol-
`lowing oral administration and thus has little toxic potential.
`Consumption of large quantities of cellulose may, however,
`have a laxative effect, although this is unlikely to be a prob-
`lem when cellulose is used as an excipient in pharmaceutical
`formulations.
`
`Deliberate abuse of formulations containing cellulose, either
`by inhalation or injection, has resulted in the formulation of
`cellulose granulomasflm
`
`15. Handling Precautions
`
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Mierocrystalline cellulose
`may be irritant to the eyes. Gloves. eye protection. and a dust
`mask are recommended. In the UK, the occupational exposure
`limits for cellulose has been set at 10 mg/m3 long-term
`(8—hour TWA) for total inhalable dust and 5 mg/m3 for respi-
`rable dust; short-term limit for total inhalable dust has been
`set at 20 mglm3.“3)
`
`16. Regulatory Status
`
`GRAS listed. Accepted in Europe for use as a food additive.
`Included in the FDA Inactive Ingredients Guide (inhalations,
`oral capsules, powders, suspensions, syrups and tablets. top-
`ical, and vaginal preparations). Included in nonparenteral
`medicines licensed in the UK.
`
`17. Pharrnacopeias
`Eur, Int, Jpn, Pol, and US.
`
`18. Related Substances
`
`Microcrystalline cellulose and carboxymethylcellulose sodi-
`um: powdered cellulose.
`
`Microcrystalline cellulose and carboxymethylcellulose sodium
`
`Synonyms: Avicel RC-581; Avicel RC-591; Avicel CL-611; col-
`loidal cellulose; dispersible cellulose.
`Appearance: white colored, odorless and tasteless hygroscopic
`powder.
`Pharmacopeias: Br and US.
`S1011.
`Acidity/alkalinity: pH = 6-8 for a 1.2% wlv aqueous disper-
`Moisture content: not more than 6.0% wlw.
`Particle size distribution: 5 0.1% retained on a #60 mesh and
`S 50% retained on #325 mesh for Avicet CL-611; S 0.1%
`retained on a #60 mesh and S 35% retained on a #200
`mesh for Avicel RC-581; S 0.l% retained on a #60 mesh
`and S. 45% retained on a #325 mesh for Avicel RC-591.
`
`Cellulose, Micrvcryrxalline 105
`
`Solubility: practically insoluble in dilute acids and organic
`solvents. Partially soluble in dilute alkali and water (car-
`boxymethylcellulose sodium fraction).
`Viscosity (dynamic): 5-20 mPa s (5-20 cP) for a 1.2% wlv
`aqueous dispersion of Avicel CL-611; 72-168 mPa s
`(72—168 cP) for Aviccl R058] and 39-91 mPa s (39-91
`cP) for Avicel RC—59l at the same concentration.
`Comments: mixtures of microcrystalline cellulose and car-
`boxymethylcellulose sodium that are dispersible in water
`and produce thixotropic gels are suitable as suspending
`vehicles in pharmaceutical formulations. The amount of
`carboxymethylcellulose present can vary between
`8.3-18.8% wlw depending upon the grade of material.
`
`19. Comments
`
`Several different grades of microcrystalline cellulose are com-
`mercially available which differ in their method of manufac-
`ture,“"‘5) particle size, moisture, how. and other physical
`properties.“‘*23’ The larger particle-size grades generally pro-
`vide better flow properties in pharmaceutical machinery. Low-
`moisture grades are used with moisture-sensitive materials.
`Higher density grades improve flowability and weight unifor-
`mtty.
`
`20. Specific References
`1. Enéziau GM. Direct compression of tablets using rnicrocrys-
`talline cellulose [in French]. Pharm Acta Helv 1972; 47:
`321-363.
`. Lerk CF, Bolhuis GK. Comparative evaluation of excipients
`for direct compression 1. Pharm Weelcbl 1973; 108: 469-481.
`. Lerk CF, Bolhuis GK, de Boer AH. Comparative evaluation
`of excipients for direct compression II. Phann Weekbl 1974;
`109: 945-955.
`. Lamberson RF. Raynor GE. Tableting properties of microc-
`rystalline cellulose. Mfg Chem Aerosol News 1976; 47(6):
`55—6l.
`. Lerk CF, Bolhuis GK, de Boer AH. Effect of microcrystalline
`cellulose on liquid penetration in and disintegration of
`directly compressed tablets. J Phann sci 1979; 68: 205-211.
`. Chilamltutti RN. Rhodes CT. Schwartz J8. Some studies on
`compression properties of tablet matrices using a computer-
`ized instrumented press. Drug Dev Ind Phann 1982; 8:
`63-86.
`. Wallace JW. Capozzi IT, Shangraw RF. Performance of phar-
`maceutical filler/binders as related to methods of powder
`characterization. Phannaceut Technol 1983; 7(9): 94-104.
`. Omray A, Omray P. Evaluation of microcrystalline cellulose
`as a glidant Indian J Pharm Sci 1986; 48: 20-22.
`. Celik M. Okutgen B. A feasibility study for the development
`of a prospective compaction functionality test and the estab-
`lishment of a compaction data bank. Drug Dev Ind Pharm
`1993; 19: 2309-2334.
`. Parker MD, York P. Rowe RC. Binder-substrate interactions
`in wet granulation 3: the effect of excipient source variation.
`Int J Pharmaceutics 1992; 80: 179-190.
`. Callahan JC. Cleary GW. Elefant M, Kaplan G, Kensler T,
`Nash RA. Equilibrium moisture content of pharmaceutical
`excipients. Drug Dev Ind Pharm 1982; 8: 355-369.
`. Cooper CB. Bai TR. Heyderman E. Corrin B. Cellulose gran-
`ulomas in the lungs of a cocaine sniffer. Br Med J 1983;
`286: 2021-2022.
`. Health and Safety Executive. EH40/98: Occupational Expo-
`sure Lirnits 1998. Sudbury. Health & Safety Executive, 1998.
`. Jain IK, Dixit VK, Varma KC. Preparation of microcrystal—
`line cellulose from cereal straw and its evaluation as a tablet
`excipient. Indian J Pharm Sci 1983; 45: 83-85.
`
`6
`
`

`
`Colloidal Silicon Dioxide
`
`143
`
`8. Description
`
`Colloidal silicon dioxide is a submicroscopic fumed silica
`with a particle size of about 15 nm.
`It
`is a light,
`loose,
`bluish—white colored, odorless, tasteless, nongritty amorphous
`powder.
`
`SEM: 1
`Excipient: Colloidal silicon dioxide (Aerosil A-200)
`Manufacturer: Degussa
`Lot No: 87A-I (04l69C)
`Magnification: 600><
`Voltage: 20 kV
`
`Excipient: Colloidal silicon dioxide (Acrosil A—200)
`Manufacturer: Degussa
`rm No: 87A-l (O4l69C)
`Magnification: 2400><
`Voltage: 20 kV
`
`Colloidal Silicon
`
`Dioxide
`
`1. Nonproprietary Names
`BP: Colloidal anhydrous silica
`PhEur: Silica colloidalis anhydrica
`USP: Colloidal silicon dioxide
`
`2. Synonyms
`
`light anhydrous
`Aerosil; Cab-0-Sil; colloidal silica; fumed silica;
`silicic acid; silicic anhydride; silicon dioxide fumed; Wacker HDK.
`
`3. Chemical Name and CAS Registry Number
`Silica [763l—86—9]
`
`4. Empirical Formula Molecular Weight
`SiO2
`60.08
`
`5. Structural Formula
`
`SiO2
`
`6. Functional Category
`
`Adsorbent; anticaking agent; glidant; suspending agent; tablet
`disintegrant; viscosity-increasing agent.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`
`Colloidal silicon dioxide is widely used in pharmaceuticals,
`cosmetics, and food products. lts small particle size and large
`specific surface area give it desirable flow characteristics
`which are exploited to improve the [low properties of dry
`powders in a number of processes, e.g.,
`tableting.<"-‘iv’
`Colloidal silicon dioxide is also used to stabilize emulsions
`and as a thixotropic thickening and suspending agent in gels
`and semisolid preparations“) With other ingredients of similar
`refractive index transparent gels may be formed. The degree
`of Viscosity increase depends on the polarity of the liquid
`(polar liquids generally require a greater concentration of col-
`loidal silicon dioxide than nonpolar liquids). Viscosity is
`largely independent of temperature. However, changes to the
`pH of a system may affect the Viscosity, see Section 11.
`In aerosols, other than those for inhalation, colloidal silicon
`dioxide is used to promote particulate suspension. eliminate
`hard settling and minimize the clogging of spray nozzles. Col-
`loidal silicon dioxide is also used as a tablet disintegrant and
`as an adsorbent dispersing agent for liquids in powders or
`supp0sitories.(5’
`
`jj_
`Use
`Concentration ( %)
`Aerosols
`0.5 -2
`Emulsion stabilizer
`1-5
`Glidant
`0.1-0.5
`Suspending and thickening agent
`2-l0
` _m_jm_
`
`7
`
`

`
`I44 Colloidal Silicon Dioxide
`
`\lO
`
`O)O
`
` 01O%Equilibriummoisture
`
`
`I\)on4:-0OO 7
`
`_i. O
`
`0
`
`0
`
`I
`
`10
`
`IiJ_JIi__L_l
`20
`30
`40
`50
`60
`70
`80
`90
`% Relative humidity
`
`100
`
`Fig. 1: Sorption desorption isotherm for colloidal silicon dioide.
`(Results of laboratory project for third edition.)
`0: Sorption
`I : Desorption
`
`9. Pharmacopeial Specifications
`
`
`
`PhEurTest USP
`Identification
`+
`+
`pH
`4.0-7.0
`3.5-5.5
`Arsenic
`—
`S 8 ppm
`Chloride
`S 250 ppm
`——
`l-leavy metals
`S 25 ppm
`—
`Loss on drying
`—
`S 2.5%
`Loss on ignition
`S 5.0%
`S 2.0%
`Organice voltile impurities
`—
`+
`Assay (on ignited sample)
`99.0—]00.5%
`99.0-100.5%
`
`10. Typical Properties
`Acidity/alkalinity:
`pH = 3.5-4.4 (4% w/v aqueous dispersion)
`Density (bulk): 0.029-0.042 g/cm3
`Density (tapped): see Tables I-III.
`Flowability: 35.52% (Carr compressibility index).
`Moisture content: See Fig. 1.(5v7)
`Particle size distribution: 7-16 nm. See also Fig. 2.
`Refractive index: 1.46
`
`
`
`Masspercent
`
`[00:OO
`
`O
`
`10
`
`20
`
`70
`60
`50
`40
`30
`Particle size, microns
`
`80 90100
`
`Fig. 2: Particle size distributin of colloidal silicon dioxide.
`(Aerosil A-200)
`
`size, surface areas, and densities are affected. The physical prop-
`erties of three commercially available colloidal silicon diox-
`ides, Aerosil (Degussa), Cab-0-Sil (Cabot Corporation), and
`Wucker HDK (Wacker—Chemic GmbH) are shown below in
`Tables I,
`ii, and III, respectively.
`
`Table I: Aerosil physical properties.
`
`Density (tapped)
`Specific surface areata)
`Grade
`__j___jj€___
`(mz/g)
`(g/cm’)
`130 : 25
`0.05
`130
`130Vs
`130 i 25
`0.12
`200
`200 i 25
`0.05
`200vs
`200 i 25
`0.12
`300
`300 1' 30
`0.05
`
`380 J: 30380 0.05
`
`(3) BET method.
`
`Table II: Cab-0-Sil physical propertiesfsl
`
`Solubility: practically insoluble in organic solvents, water, and
`acids, except hydrofluoric acid; soluble in hot solutions of
`alkali hydroxide. Forms a colloidal dispersion with water.
`Specific gravity: 2.2
`Specific surface area: 200-400 ml/g (Stroehlein apparatus, single
`point); 50-380 m2/g (BET method). See also Tables l-HI.
`
`Several grades of colloidal silicon dioxide are commercially
`available which are produced by modifying the manufacturing pro-
`cess. The modifications do not affect the silica content, specific grav-
`ity, refractive index, color or amorphous form. However, particle
`
`Grade
`
`LM—5
`LM—50
`M—5
`H-5
`Ell-5
`M-7D
`
`(31 BET method.
`
`Specific surface area”)
`(ml/g)
`130 i 25
`150 i 25
`200 i 25
`325 i 25
`390 i 40
`200 i 25
`
`Density (tapped)
`(g/cm3)
`0.04
`0.04
`0.04
`0.04
`0.04
`0.10
`
`8
`
`

`
`Table III: Wacker HDK physical properties.“”_m
`
`Density (tapped)
`Specific surface area*“"
`Grade
`
`(ml/g) (g/cm3)
`125 i 15
`S13
`0.05
`V15
`150 i 20
`0.05
`N20
`200 i 30
`0.04
`T30
`300 i 30
`0.04
`T40
`400 i 40
`0.04
`H15
`120 i 20
`0.04
`H20
`170 i’ 30
`0.04
`H30
`250 i 30
`0.04
`H2000
`140 i 30
`0.22
`H2000/4
`120 1' 20
`0.23
`H3004
`200 i 30
`0.08
`H20l5EP
`100 i 30
`0.20
`
`100 i 30H2050EP 0.20
`
`W BET method.
`
`11. Stability and Storage Conditions
`
`Colloidal silicon dioxide is hygroscopic, but adsorbs large
`quantities of water without liquefying. When used in aqueous
`systems at a pH between 0-7.5 colloidal silicon dioxide is
`effective in increasing the viscosity of a system. However, at
`a pH greater than 7.5 the viscosity-increasing properties of
`colloidal silicon dioxide are reduced and at a pH greater than
`10.7 this ability is lost entirely since the silicon dioxide dis-
`solves to form silieateslgl Colloidal silicon dioxide powder
`should be stored in a well-closed container.
`
`Some grades of colloidal silicon dioxide have hydrophobic
`surface treatments which greatly minimizes its hygroscopicity.
`
`12. Incompatibilities
`
`Incompatible with diethylstilbestrol preparations.‘1‘°’
`
`13. Method of Manufacture
`
`Colloidal silicon dioxide is prepared by the vapor hydrolysis
`of chlorosilanes, such as silicon tetrachloride, at l800°C using
`a hydrogen-oxygen flame.
`
`14. Safety
`
`Colloidal silicon dioxide is widely used in oral and topical
`pharmaceutical products and is generally regarded as an es-
`sentially nontoxic and nonirritant excipient. However, intrap-
`eritoneal and subcutaneous injection may produce local tissue
`reactions and/or granulomas. Colloidal silicon dioxide should
`therefore not be administered parenterally.
`LD50 (rat, IV): 15 mg/kg(“)
`LD50 (rat, oral): 3.16 g/kg
`
`15. Handling Precautions
`
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Eye protection and gloves
`are recommended. Precautions should be taken to avoid inha-
`lation of colloidal silicon dioxide. In the absence of suitable
`containment facilities, a dust mask should be worn when han-
`dling small quantities of material. For larger quantities, a dust
`respirator is recommended.
`
`Colloidal Silicon Dioxide
`
`I45
`
`fibrosis of the lungs (silicosis) which can occur upon exposure
`to crystalline silica. In the UK, the 8-hour TWA occupational
`exposure limits for colloidal silicon dioxide are 6 mg/m3 for
`total inhalablc dust and 3 mg/m3 for respirable dustf”)
`
`16. Regulatory Status
`
`GRAS listed. Included in the FDA Inactive Ingredients Guide
`(oral capsules, suspensions and tablets, transdermal and vag-
`inal preparations). Included in nonparentcral medicines li-
`censed in the UK.
`
`17. Pharmacopeias
`Eur and US.
`
`18. Related Substances
`
`19. Comments
`
`The incidence of microbial contamination of colloidal silicon
`dioxide is low.
`
`20. Specific References
`l. Lerk CF, Bolhuis GK, Smedema SS. Interaction of lubricants
`and colloidal silica during mixing with excipients I: its effect
`on tabletting. Pharm Acm Helv 1977; 52: 33-39.
`. Lerk CF, Bolhuis GK. Interaction of lubricants and colloidal sil-
`ica during mixing with excipients II: its effect on wettability and
`dissolution velocity. Pharm Acta Helv 1977; 52: 39-44.
`. Gore AY, Banker GS. Surface chemistry of colloidal silica
`and a possible application to stabilize aspirin in solid
`matrixes. J Pharm Sci 1979; 68: 197-202.
`. Daniels, R, Kerstiens B, Tishinger-Wagner H, Rupprecht H.
`The stability of drug absorbates on silica. Drug Dev Ind
`Pharm 1986; 12: 2127-2156.
`
`. Sherriff M, Enever RP. Rheological and drug release prop-
`erties of oil gels containing colloidal silicon dioxide. J
`Pharm Sci 1979; 68: 842-845.
`. Ettlinger M, Ferch l-I, Mathias 1. Adsorption at the surface
`of fumed silica [in German]. Arch Pharm 1987; 320: 1-15.
`. Callahan JC, Cleary GW, Elefant M, Kaplan G, Kensler T.
`Nash RA. Equilibrium moisture content of pharmaceutical
`excipients. Drug Dev Ind Pharm 1982; 8: 355-369.
`. Cabot Corporation. Technical literature: Cab-0-Sil fumed sil-
`ica, properties and functions, 1990.
`. Wacker-Chemie GmbH. Technical
`the fumed silica, 1993.
`
`literature: Wacker HDK
`
`. Johansen H, Muller N. Solvent deposition of drugs on excip-
`ients II: interpretation of dissolution, adsorption and absorp-
`tion characteristics of drugs. Arch Pharm Chemi (Sci) 1977;
`5: 33-42.
`
`. Sweet DV, editor. Registry of Toxic Effects of Chemical Sub-
`stances. Cincinnati, US Department of Health, 1987
`. Health and Safety Executive. EH40/98: Occuptional exposure
`limits 1998. Sudbury, Health and Safety Executive, 1998.
`
`21. General References
`
`Yang KY, Glemza R, Iarowski CI. Effects of amorphous silicon
`dioxides on drug dissolution. J Pharm Sci 1979; 68: 560-565.
`
`Inhalation of colloidal silicon dioxide dust may cause irrita-
`tion to the respiratory tract but
`it
`is not associated with
`
`22. Authors
`E Morefield.
`
`.
`
`....u...ummulil1lllmllllnmmlmul..ll~ .1.
`
`.
`
`'
`
`9
`
`

`
`Crospovidone
`
`I 63
`
`SEM: 1
`Excipient: Crospovidone (Kollidon CL‘)
`Manufacturer: BASF Corp
`Lot No: 80-3077
`Magnification:
`l50><
`Voltage: 20 kV
`
`40.00
`35.00
`
`30.00 A
`m01 "oO (K
`20.00
`
`15.00 Hardness
`
`10.00
`5.00
`
`120
`
`14° 0.00
`
`60
`
`l
`1
`100
`80
`Pressure (MPa)
`
`Fig. 1: Heckel plot of crospovidone.
`I :
`lnl/(l—D)
`9 zhardness
`
`10. Typical Properties
`Acidity/alkalinity:
`pH = 5.0-8.0 (1% w/v aqueous slurry)
`Compressibility: see Fig. 1.“)
`Compression pressure: 20.39 kN/CIHZ
`Tensile strength: 0.7471 kN/cmz
`Permanent deformation pressure: 140.4 kN/cm2
`Brittle fracture index: 0.2371
`Bonding index: 0.0053
`Reduced modulus of elasticity: 10621
`Density: 1.22 g/cm?
`Density (bulk):
`0.363 g/cm3 for Kollidon CL;
`0.213 g/cm‘ for Polyplasdone XL;
`0.323 g/cn13 for Polyplasdane XL-10.
`Density (tapped):
`0.534 g/cm‘ For Kollidon CL;
`
`Crospovidone
`
`1. Nonproprietary Names
`BP: Crospovidone
`PhEur: Crospovidon
`USP: Crospovidone
`
`2. Synonyms
`
`Cross-linked povidone; Kollidon CL; Polyplasdone XL; Poly-
`plasdone XLv]0; polyvinylpolypyrrolidonc; PVPP; 1-vinyl-
`2-pyrrolidinone homopolymer.
`
`3. Chemical Name and CAS Registry Number
`1-Ethcnyl-2-pyrrolidinone homopolymer [9003—39—8]
`
`4. Empirical Formula Molecular Weight
`(CfiH9NO)n
`> 1 000 000
`
`Crospovidone is a water-insoluble synthetic crosslinked ho-
`mopolymer of N-vinyl—2-pyrrolidinone. An exact determina-
`tion of the molecular weight has not been established because
`of the insolubility of the material.
`
`5. Structural Formula
`See Povidone.
`
`6. Functional Category
`Tablet disintegrant.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`
`Crospovidone is a water—insoluble tablet disintegrant used at
`2—5% concentration in tablets prepared by direct compression
`or wet and dry granulation methods.“‘4> lt rapidly exhibits
`high capillary activity and pronounced hydration Capacity with
`little tendency to form gels.
`
`8. Description
`
`Crospovidone is a white to creamy—white, finely divided, free-
`flowing, practically tasteless, odorless or nearly odorless, hy-
`groscopic powder.
`
`9. Pharmacopeial Specifications
`
`<——
`—
`S 0.001%
`S 0.1%
`ll.0—l2.8%
`
`PhEur
`
`++
`
`—
`S 5.0%
`—
`S 1.5%
`S 400 ppm
`S 01%
`S 10 ppm
`S 0.1%
`—
`
`Test
`Identification
`Characters
`pH (1% solution)
`Water
`Residue on ignition
`Water-soluble substances
`Peroxides
`Sulfated ash
`Heavy metals
`Vinylpyrrolidinone
`Nitrogen content
`(anhydrous basis)
`
`10
`
`

`
`162 Croscurmellose Sodium
`
`The WHO has not specified an acceptable daily intake for the
`related substance carboxymethylcellulose sodium, used as a
`food additive, since the levels necessary to achieve a desired
`effect were not considered sufficient
`to be a hazard to
`health.(”)
`'
`
`See also Carboxymethylcellulose Sodium.
`
`15. Handling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Croscarmellose sodium may
`be irritant to the eyes; eye protection is recommended.
`
`16. Regulatory Status
`Included in the FDA Inactive Ingredients Guide (oral capsules
`and tablets). Included in nonparenteral medicines licensed in
`the UK.
`
`17. Pharmacopeias
`Eur and US.
`
`18. Related Substances
`
`Carboxymethylcellulose calcium: carboxyrnethylcellulose so-
`dium.
`
`19. Comments
`
`Typically, the degree of substitution (DS) for croscarmellose
`sodium is 0.7.
`
`20. Specific References
`1. Botzolakis IE, Augsburger LL. Disintegrating agents in hard
`gelatin capsules part I: mechanism of action. Drug Dev Ind
`Pharm 1988; 14: 29-41.
`. Dahl TC, Sue IT, Yum A. The influence of disintegrant level
`and capsule size on dissolution of hard gelatin capsules
`stored in high humidity conditions. Drug Dev Ind Pharm
`1991; 17: 1001-1016.
`. Gissinger D, Stamm. A comparative evaluation of the prop-
`erties of some tablet disintegrants. Drug Dev Ind Pharm
`1980; 6: 511-536.
`. Shangraw R, Mitrevej A, Shah M. A new era of tablet dis-
`integrants. Pharmaceut Technol 1980; 4(l0): 49-57.
`
`. Rudnic EM, Rhodes CT, Bavitz JF, Schwartz JB. Some
`effects of relatively low levels of eight tablet disintegrants
`on a direct compression system. Drug Dev Ind Pharm 1981;
`7: 347-358.
`. Gorman EA, Rhodes CT, Rudnic EM. An evaluation of cros-
`carmellose as a tablet disintegrant in direct compression sys-
`tems. Drug Dev Ind Pharm 1982; 8: 397-410.
`. Rudnic EM, Rhodes CT, Welch S, Bernado P. Evaluations
`of the mechanism of disintegrant action. Drug Dev Ind
`Pharm 1982; 8: 87-109.
`. Gordon MS, Chowhan ZT. Effect of tablet solubility and
`hygroscopicity on disintegrant efficiency in direct compres-
`sion tablets in terms of dissolution. J Phurm Sci 1987; 76:
`907-909.
`. Gordon MS, Chowhan ZT. The effect of aging on disintegrant
`efficiency in direct compression tablets with varied solubility
`and hygroscopicity,
`in terms of dissolution. Drug Dev Ind
`Phurm 1990; 16: 437-447.
`. Johnson JR, Wang L-H, Gordon MS, Chowhan ZT. Effect of
`formulation solubility and hygroscopicity on disintegrant
`efficiency in tablets prepared by wet granulation, in terms of
`dissolution. J Pharm Sci 1991; 80: 469-471.
`. Gordon MS, Rudraraju VS, Dani K, Chowhan ZT. Effect of
`the mode of super disintegrant incorporation on dissolution
`in wet granulated tablets. J Pharm Sci 1993; 82: 220-226.
`. Khattab I, Menon A, Sakr A. Effect of mode of incorporation
`of disintcgrants on the characteristics of fluid—bed wet—gran-
`ulated tablets. J Pharm Pharmacol 1993; 45: 687-691.
`. Ferrero C, Mufioz N, Velasco MV, Mufioz—Ruiz A, Jimenez-
`Castellanos R. Disintegrating efficiency of croscarmellose
`sodium in a direct compression formulation. In! J Pharma-
`ceutics 1997; 147: 11-21.
`. FAO/WHO. Evaluation of certain food additives and contam-
`inants: thirty-fifth report of the joint FAO/WHO expert com-
`mittee on food additives. Tech Rep Ser Wld Hlth Org 1990;
`No. 789.
`
`21. General References
`DMV International. Technical literature: Phurmucel XL, 1997.
`FMC Corporation. Technical literature: Ac-D1-Sol, 1995.
`Metsa-Serla Chemicals BV. Technical
`literature: Nymcel ZSX,
`1995.
`
`22. Authors
`P] Weller.
`
`11
`
`

`
`Magnesium Stearate
`
`SEM: 1
`Excipiem: Magnesium stcarate
`coax
`
`Magnesium Stearate 305
`
`1. Nonproprietary Names
`BP: Magnesium stearate
`JP: Magnesium stearate
`PhEur: Magnesii stearas
`USP: Magnesium stearate
`
`2. Synonyms
`572; Magnesium octadecanoate; stearic acid magnesium salt;
`octadecanoic acid, magnesium salt.
`
`3. Chemical Name and CAS Registry Number
`Octadecanoic acid magnesium salt [557-04-0]
`
`4. Empirical Formula Molecular Weight
`C36H7oMgO4
`59 1
`The USP describes magnesium stearate as a compound of
`magnesium with a mixture of solid organic acids and consists
`chiefly of variable proportions of magnesium stearate and
`magnesium palmitate (C32H62MgO4). The PhEur describes
`magnesium stearate as consisting mainly of magnesium stear-
`ate with variable proportions of magnesium palmitate and
`magnesium oleate (C36H65MgO4).
`
`5_ Sn-“gnu-a] Formuja
`
`[CH3(CH2)i6C00]2Mg
`
`6. Functional Category
`Tablet and capsule lubricant.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`Magnesium stearate is widely used in cosmetics. foods, and
`pharmaceutical formulations. It is primarily used as a lubri—
`cant in capsule and tablet manufacture at concentrations be-
`tween 0.25-5.0%. It is also used in barrier creams.
`
`8. Description
`Magnesium stearate is a fine. white, precipitated or milled,
`impalpable powder of low bulk density, having a faint odor
`of stearic acid and a characteristic taste. The powder is greasy
`to the touch and readily adheres to the skin.
`
`SEM: 2
`Excipient: Magnesium stearatc
`
`Magnification: 2400K
`
`12
`
`

`
`306 Magnesium Stearate
`
`9. Pharmacopeial Specifications
`
`Test
`Identification
`Characters
`Microbial limits
`Acidity or alkalinity
`Acid value of the
`fatty acid
`Clarity and color of
`solution of the
`fatty acids
`Color of solution
`Loss on drying
`Chloride
`Sulfate
`Lead
`Heavy metals
`Relative stearicl
`palmitic content
`Organic volatile
`impurities
`Assay (dried, as Mg) 4.0-5.0%
`
`195-210
`
`10. Typical Properties
`Crystalline forms: high purity magnesium stearatc has been
`isolated as a trihydrate, a dihydratc, and an anhydrate.
`Density (bulk): 0.159 g/cm3(“)
`Den.rr'ty(tapped): 0.286 g/cm3(‘)
`Density (true): 1.092 g/cm3(“l
`Flash point: 250°C
`Flawability: poorly flowing, cohesive powder.
`Melting range: 117-150°C (commerical samples);
`l26—l30°C (high purity magnesium stearate).
`Moisture content: see Fig. 1.“)
`Solubility: practically insoluble in ethanol. ethanol (95%).
`ether and water; slightly soluble in warm benzene and
`warm ethanol (95%).
`
`Specific sufiace area: 1.6-14.8 ml/g.
`('9 Results from laboratory project for third cdtion.
`
`11. Stability and Storage Conditions
`Magnesium steararc is stable and should be stored in a
`well-closed container in a cool, dry place.
`
`12. Incompatibilities
`
`Incompatible with strong acids, alkalis and iron salts. Avoid
`mixing with strong oxidizing materials. Magnesium stearate
`cannot be used in products containing aspirin, some vitamins,
`and most alkaloidal salts.
`
`13. Method of Manufacture
`
`Magnesium stearate is prepared either by the interaction of
`aqueous solutions of magnesium chloride with sodium stea.r-
`atc. or by the interaction of magnesium oxide, hydroxide or
`carbonate with stearic acid at elevated temperatures.
`
`
`
`
`
`Equilibriummoisture(°/0)
`
`20
`
`15
`10
`
`5
`
`0‘l0203040506070809010O
`Relative humidity (‘’/a)
`Fig. 1: Sorption-desorption isotherm for magnesium stearate.
`I : sorption
`O : desorption
`
`14. Safety
`
`Magnesium stearate is widely used as a pharmaceutical ex-
`cipient and is generally regarded as being nontoxic fol