en,
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`Edited by
`
`Rayir ond C Rowe, PaulJ gpeskeyatand Marian E Quinn aeayf
`
`MYLAN - EXHIBIT 1008
`
`

`

`Handbook of
`Pharmaceutical Excipients
`
`S I X T H E D I T I O N
`
`Edited by
`Raymond C Rowe BPharm, PhD, DSC, FRPharmS, FRSC, CPhys, MInstP
`Chief Scientist
`Intelligensys Ltd, Stokesley, North Yorkshire, UK
`Paul J Sheskey BSc, RPh
`Application Development Leader
`The Dow Chemical Company, Midland, MI, USA
`Marian E Quinn BSc, MSc
`Development Editor
`Royal Pharmaceutical Society of Great Britain, London, UK
`
`London . Chicago
`
`

`

`Published by the Pharmaceutical Press
`An imprint of RPS Publishing
`
`1 Lambeth High Street, London SE1 7JN, UK
`100 South Atkinson Road, Suite 200, Grayslake, IL 60030-7820, USA
`
`and the American Pharmacists Association
`2215 Constitution Avenue, NW, Washington, DC 20037-2985, USA
`
`# Pharmaceutical Press and American Pharmacists Association 2009
`
`is a trade mark of RPS Publishing
`
`RPS Publishing is the publishing organisation of the Royal Pharmaceutical Society of Great Britain
`
`First published 1986
`Second edition published 1994
`Third edition published 2000
`Fourth edition published 2003
`Fifth edition published 2006
`Sixth edition published 2009
`
`Typeset by Data Standards Ltd, Frome, Somerset
`Printed in Italy by L.E.G.O. S.p.A.
`
`ISBN 978 0 85369 792 3 (UK)
`ISBN 978 1 58212 135 2 (USA)
`
`All rights reserved. No part of this publication may be
`reproduced, stored in a retrieval system, or transmitted in any
`form or by any means, without the prior written permission
`of the copyright holder.
`The publisher makes no representation, express or implied,
`with regard to the accuracy of the information contained in
`this book and cannot accept any legal responsibility or
`liability for any errors or omissions that may be made.
`
`A catalogue record for this book is available from the British Library
`
`

`

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

`

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

`

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

`

`132
`
`Cellulose, Microcrystalline
`
`Table III: Properties of selected commercially available grades of
`microcrystalline cellulose.
`
`Particle size analysis
`
`Moisture
`content (%)
`
`Mesh size Amount
`retained (%)
`41.0
`430.0
`48.0
`545.0
`41.0
`430.0
`41.0
`48.0
`41.0
`430.0
`510.0
`550.0
`41.0
`430.0
`48.0
`545.0
`41.0
`530.0
`40.5
`430.0
`40.25
`430.0
`48.0
`545.0
`41.0
`
`60
`200
`60
`200
`60
`200
`400
`60
`60
`200
`60
`100
`60
`200
`60
`200
`60
`200
`60
`200
`60
`200
`60
`200
`60
`
`200
`60
`
`200
`60
`
`100
`60
`
`200
`60
`
`200
`60
`
`100
`200
`60
`200
`60
`200
`38
`94
`
`430.0
`48.0
`
`545.0
`510.0
`
`550.0
`41.0
`
`530.0
`48.0
`
`545.0
`<0.5
`
`<5.0
`<5.0–30.0
`41.0
`430.0
`48.0
`545.0
`41.0
`450.0
`
`45.0
`
`45.0
`
`43.0
`
`45.0
`41.5
`41.5
`
`45.0
`
`45.0
`
`45.0
`
`45.0
`
`46.0
`
`45.0
`
`45.0
`
`46.0
`
`46.0
`
`46.0
`
`46.0
`
`46.0
`
`46.0
`
`45.0
`
`45.0
`
`45.0
`
`Grade
`
`C
`
`Nominal
`mean
`particle size
`(mm)
`
`Avicel PH-101 (a)
`
`50
`
`Avicel PH-102 (a)
`
`100
`
`Avicel PH-103 (a)
`
`50
`
`Avicel PH-105 (a)
`Avicel PH-112 (a)
`Avicel PH-113 (a)
`
`Avicel PH-200 (a)
`
`20
`100
`50
`
`180
`
`Avicel PH-301 (a)
`
`50
`
`Avicel PH-302 (a)
`
`100
`
`Celex 101 (b)
`
`75
`
`Ceolus KG-802 (c) 50
`
`Emcocel 50M (d)
`
`Emcocel 90M (d)
`
`MCC Sanaq
`101(e)
`
`MCC Sanaq
`102(e)
`
`MCC Sanaq
`200(e)
`
`MCC Sanaq
`301(e)
`
`MCC Sanaq
`302(e)
`
`MCC Sanaq UL-
`002(e)
`
`Vivapur 101 (d)
`
`Vivapur 102 (d)
`
`50
`
`91
`
`50
`
`100
`
`180
`
`50
`
`100
`
`50
`
`50
`
`90
`
`Vivapur 12 (d)
`
`160
`
`Suppliers:
`(a) FMC Biopolymer
`(b) International Specialty Products
`(c) Asahi Kasei Corporation
`(d) JRS Pharma
`(e) Pharmatrans Sanaq AG
`
`16 Regulatory Status
`GRAS listed. Accepted for use as a food additive in Europe.
`Included in the FDA Inactive Ingredients Database (inhalations;
`oral capsules, powders, suspensions, syrups, and tablets; topical and
`vaginal preparations). Included in nonparenteral medicines licensed
`in the UK. Included in the Canadian List of Acceptable Non-
`medicinal Ingredients.
`
`17 Related Substances
`Microcrystalline cellulose and carrageenan; microcrystalline cellu-
`lose and carboxymethylcellulose sodium; microcrystalline cellulose
`and guar gum; powdered cellulose;
`silicified microcrystalline
`cellulose.
`Microcrystalline cellulose and carrageenan
`Synonyms Lustre Clear.
`Comments Lustre Clear (FMC Biopolymer) is an aqueous film
`coating combining microcrystalline cellulose and carrageenan.
`Microcrystalline cellulose and guar gum
`Synonyms Avicel CE-15.
`Comments Avicel CE-15 (FMC Biopolymer) is a coprocessed
`mixture of microcrystalline cellulose and guar gum used in
`chewable tablet formulations.
`
`18 Comments
`Microcrystalline cellulose is one of the materials that have been
`selected for harmonization by the Pharmacopeial Discussion
`Group. For further information see the General
`Information
`Chapter <1196> in the USP32–NF27, the General Chapter 5.8
`in PhEur 6.0, along with the ‘State of Work’ document on the PhEur
`EDQM website, and also the General Information Chapter 8 in the
`JP XV.
`Several different grades of microcrystalline cellulose are com-
`mercially available that differ in their method of manufacture,(15,16)
`particle size, moisture, flow, and other physical properties.(17–29)
`The larger-particle-size grades generally provide better flow proper-
`ties in pharmaceutical machinery. Low-moisture grades are used
`with moisture-sensitive materials. Higher-density grades have
`improved flowability.
`Several coprocessed mixtures of microcrystalline cellulose with
`other excipients such as carrageenan, carboxymethylcellulose
`sodium, and guar gum are commercially available; see Section 17.
`Celphere (Asahi Kasei Corporation) is a pure spheronized
`microcrystalline cellulose available in several different particle size
`ranges. Balocel Sanaq (Pharmatrans Sanaq AG) is an excipient used
`mainly in the production of pellets and granulates in direct
`tableting, which contains lactose, microcrystalline cellulose, and
`sodium carboxymethylcellulose.
`According to PhEur 6.3, microcrystalline cellulose has certain
`functionality related characteristics that are recognised as being
`relevant control parameters for one or more functions of the
`substance when used as an excipient. Non-mandatory testing
`procedures have been described for particle size distribution (2.9.31
`or 2.9.38) and powder flow (2.9.36).
`A specification for microcrystalline cellulose is contained in the
`Food Chemicals Codex (FCC).(30) The PubChem Compound ID
`(CID) for microcrystalline cellulose is 14055602.
`
`15 Handling Precautions
`Observe normal precautions appropriate to the circumstances and
`quantity of material handled. Microcrystalline cellulose may be
`irritant to the eyes. Gloves, eye protection, and a dust mask are
`recommended. In the UK, the workplace exposure limits for
`cellulose have been set at 10 mg/m3 long-term (8-hour TWA) for
`total inhalable dust and 4 mg/m3 for respirable dust; the short-term
`limit for total inhalable dust has been set at 20 mg/m3.(14)
`
`19 Specific References
`1 Ene´zian GM. [Direct compression of tablets using microcrystalline
`cellulose.] Pharm Acta Helv 1972; 47: 321–363[in French].
`2 Lerk CF, Bolhuis GK. Comparative evaluation of excipients for direct
`compression I. Pharm Weekbl 1973; 108: 469–481.
`3 Lerk CF et al. Comparative evaluation of excipients for direct
`compression II. Pharm Weekbl 1974; 109: 945–955.
`4 Lamberson RF, Raynor GE. Tableting properties of microcrystalline
`cellulose. Manuf Chem Aerosol News 1976; 47(6): 55–61.
`
`

`

`C
`
`5 Lerk CF et al. Effect of microcrystalline cellulose on liquid penetration
`in and disintegration of directly compressed tablets. J Pharm Sci 1979;
`68: 205–211.
`6 Chilamkurti RN et al. Some studies on compression properties of tablet
`matrices using a computerized instrumented press. Drug Dev Ind
`Pharm 1982; 8: 63–86.
`7 Wallace JW et al. Performance of pharmaceutical filler/binders as
`related to methods of powder characterization. Pharm Technol 1983;
`7(9): 94–104.
`8 Omray A, Omray P. Evaluation of microcrystalline cellulose as a
`glidant. Indian J Pharm Sci 1986; 48: 20–22.
`9 Celik M, Okutgen E. A feasibility study for the development of a
`prospective compaction functionality test and the establishment of a
`compaction data bank. Drug Dev Ind Pharm 1993; 19: 2309–2334.
`10 Parker MD et al. Binder–substrate interactions in wet granulation 3: the
`effect of excipient source variation. Int J Pharm 1992; 80: 179–190.
`11 Sun CC. True density of microcrystalline cellulose. J Pharm Sci 2005;
`94(10): 2132–2134.
`12 Callahan JC et al. Equilibrium moisture content of pharmaceutical
`excipients. Drug Dev Ind Pharm 1982; 8: 355–369.
`13 Cooper CB et al. Cellulose granulomas in the lungs of a cocaine sniffer.
`Br Med J 1983; 286: 2021–2022.
`14 Health and Safety Executive. EH40/2005: Workplace Exposure Limits.
`Sudbury: HSE Books, 2005 (updated 2007). http://www.hse.gov.uk/
`coshh/table1.pdf (accessed 5 February 2009).
`15 Jain JK et al. Preparation of microcrystalline cellulose from cereal straw
`and its evaluation as a tablet excipient. Indian J Pharm Sci 1983; 45:
`83–85.
`16 Singla AK et al. Evaluation of microcrystalline cellulose prepared from
`absorbent cotton as a direct compression carrier. Drug Dev Ind Pharm
`1988; 14: 1131–1136.
`17 Doelker E et al. Comparative tableting properties of sixteen micro-
`crystalline celluloses. Drug Dev Ind Pharm 1987; 13: 1847–1875.
`18 Bassam F et al. Effect of particle size and source on variability of
`Young’s modulus of microcrystalline cellulose powders. J Pharm
`Pharmacol 1988; 40: 68P.
`19 Dittgen M et al. Microcrystalline cellulose in direct tabletting. Manuf
`Chem 1993; 64(7): 17, 19, 21.
`20 Landin M et al. Effect of country of origin on the properties of
`microcrystalline cellulose. Int J Pharm 1993; 91: 123–131.
`21 Landin M et al. Effect of batch variation and source of pulp on the
`properties of microcrystalline cellulose. Int J Pharm 1993; 91: 133–141.
`22 Landin M et al. Influence of microcrystalline cellulose source and batch
`variation on tabletting behavior and stability of prednisone formula-
`tions. Int J Pharm 1993; 91: 143–149.
`23 Podczeck F, Re´ve´sz P. Evaluation of the properties of microcrystalline
`and microfine cellulose powders. Int J Pharm 1993; 91: 183–193.
`24 Rowe RC et al. The effect of batch and source variation on the
`crystallinity of microcrystalline cellulose. Int J Pharm 1994; 101: 169–
`172.
`
`Cellulose, Microcrystalline
`
`133
`
`25 Hasegawa M. Direct compression: microcrystalline cellulose grade 12
`versus classic grade 102. Pharm Technol 2002; 26(5): 50, 52, 54, 56,
`58, 60.
`26 Kothari SH et al. Comparative evaluations of powder and mechanical
`properties of low crystallinity celluloses, microcrystalline celluloses, and
`powdered celluloses. Int J Pharm 2002; 232: 69–80.
`27 Levis SR, Deasy PB. Production and evaluation of size-reduced grades
`of microcrystalline cellulose. Int J Pharm 2001; 213: 13–24.
`28 Wu JS et al. A statistical design to evaluate the influence of
`manufacturing factors on the material properties and functionalities
`of microcrystalline cellulose. Eur J Pharm Sci 2001; 12: 417–425.
`29 Suzuki T, Nakagami H. Effect of crystallinity of microcrystalline
`cellulose on the compactability and dissolution of tablets. Eur J Pharm
`Biopharm 1999; 47: 225–230.
`30 Food Chemicals Codex, 6th edn.
`Pharmacopeia, 2008; 187.
`
`Bethesda, MD: United States
`
`20 General References
`Asahi Kasei Corporation. Ceolus KG, Celphere. http://www.ceolus.com
`(accessed 6 November 2008).
`Doelker E. Comparative compaction properties of various microcrystalline
`cellulose types and generic products. Drug Dev Ind Pharm 1993; 19:
`2399–2471.
`European Directorate for the Quality of Medicines and Healthcare
`(EDQM). European Pharmacopoeia – State Of Work Of International
`Harmonisation. Pharmeuropa 2009; 21(1): 142–143. http://www.edq-
`m.eu/site/-614.html (accessed 5 February 2009).
`FMC Biopolymer. Problem Solver: Avicel PH, 2000.
`International Specialty Products. Material Safety data sheet: Celex 101,
`2003.
`JRS Pharma LP. Technical literature: Emcocel, 2003.
`Pharmatrans Sanaq AG. Product literature: Cellets. http://www.cellets.com
`(accessed 6 November 2008).
`Pharmatrans Sanaq AG. Product literature: MCC Sanaq. http://www.phar-
`matrans-sanaq.com/prod.html (accessed 6 November 2008).
`Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipients. Boca
`Raton, FL: CRC Press, 1992; 71–74.
`Staniforth JN et al. Effect of addition of water on the rheological and
`mechanical properties of microcrystalline celluloses. Int J Pharm 1988;
`41: 231–236.
`
`21 Author
`A Guy.
`
`22 Date of Revision
`5 February 2009.
`
`

`

`Magnesium Stearate
`
`Nonproprietary Names
`1
`BP: Magnesium Stearate
`JP: Magnesium Stearate
`PhEur: Magnesium Stearate
`USP-NF: Magnesium Stearate
`
`Synonyms
`2
`Dibasic magnesium stearate; magnesium distearate; magnesii
`stearas; magnesium octadecanoate; octadecanoic acid, magnesium
`salt; stearic acid, magnesium salt; Synpro 90.
`
`Chemical Name and CAS Registry Number
`3
`Octadecanoic acid magnesium salt [557-04-0]
`
`Empirical Formula and Molecular Weight
`4
`591.24
`C36H70MgO4
`The USP32–NF27 describes magnesium stearate as a compound
`of magnesium with a mixture of solid organic acids that consists
`chiefly of variable proportions of magnesium stearate and
`magnesium palmitate (C32H62MgO4). The PhEur 6.5 describes
`magnesium stearate as a mixture of solid organic acids consisting
`mainly of variable proportions of magnesium stearate and
`magnesium palmitate obtained from sources of vegetable or animal
`origin.
`
`M
`
`Structural Formula
`5
`[CH3(CH2)16COO]2Mg
`
`Functional Category
`6
`Tablet and capsule lubricant.
`
`7
`
`Applications in Pharmaceutical Formulation or
`Technology
`foods, and
`Magnesium stearate is widely used in cosmetics,
`pharmaceutical formulations. It is primarily used as a lubricant in
`capsule and tablet manufacture at concentrations between 0.25%
`and 5.0% w/w. It is also used in barrier creams. See also Section 18.
`
`Description
`8
`Magnesium stearate is a very fine, light 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.
`
`Pharmacopeial Specifications
`9
`See Table I. See also Section 18.
`
`10 Typical Properties
`Crystalline forms High-purity magnesium stearate has been
`isolated as a trihydrate, a dihydrate, and an anhydrate.
`Density (bulk) 0.159 g/cm3
`Density (tapped) 0.286 g/cm3
`Density (true) 1.092 g/cm3
`Flash point 2508C
`Flowability Poorly flowing, cohesive powder.
`Melting range
`117–1508C (commercial samples);
`
`404
`
`SEM 1: Excipient: magnesium stearate; magnification: 600.
`
`SEM 2: Excipient: magnesium stearate; magnification: 2400.
`
`126–1308C (high purity magnesium stearate).
`NIR spectra see Figure 1.
`Solubility Practically insoluble in ethanol, ethanol (95%), ether
`and water; slightly soluble in warm benzene and warm ethanol
`(95%).
`Specific surface area 1.6–14.8 m2/g
`
`11 Stability and Storage Conditions
`Magnesium stearate is stable and should be stored in a well-closed
`container in a cool, dry place.
`
`

`

`M
`
`Magnesium Stearate
`
`405
`
`0.2
`
`2325
`2295
`
`2363
`
`log(1/R)
`
`2440
`2387
`
`2351
`
`1.5
`
`0.0
`
`1214
`
`1747
`
`1764
`
`1730
`
`−3.0
`−0.2
`1100 1300 1500 1700 1900 2100 2300 2500
`Wavelength/nm
`
`2311
`
`1000 × [2nd deriv. log(1/R)]
`
`Figure 1: Near-infrared spectrum of magnesium stearate measured by
`reflectance.
`
`tions; intravitreal implants and injections). Included in nonpar-
`enteral medicines licensed in the UK. Included in the Canadian List
`of Acceptable Non-medicinal Ingredients. Listed on the US TSCA
`inventory.
`
`17 Related Substances
`Calcium stearate; magnesium aluminum silicate; stearic acid; zinc
`stearate.
`
`18 Comments
`Magnesium stearate is one of the materials that have been selected
`for harmonization by the Pharmacopeial Discussion Group. For
`further information see the General Information Chapter <1196>
`in the USP32–NF27, the General Chapter 5.8 in PhEur 6.0, along
`with the ‘State of Work’ document on the PhEur EDQM website,
`and also the General Information Chapter 8 in the JP XV.
`Magnesium stearate is hydrophobic and may retard the
`dissolution of a drug from a solid dosage form; the lowest possible
`concentration is therefore used in such formulations.(5–10) Capsule
`dissolution is also sensitive to both the amount of magnesium
`stearate in the formulation and the mixing time; higher levels of
`magnesium stearate and long mixing times can result in the
`formation of hydrophobic powder beds that do not disperse after
`the capsule shell dissolves.(11,12)
`An increase in the coefficient of variation of mixing and a
`decrease in the dissolution rate have been observed following
`blending of magnesium stearate with a tablet granulation. Tablet
`dissolution rate and crushing strength decreased as the time of
`blending increased; and magnesium stearate may also increase
`tablet friability. Blending times with magnesium stearate should
`therefore be carefully controlled.(13–29) A variety of online analytical
`techniques have been investigated to monitor magnesium stearate in
`powder blends and tablets.(30–32) Inverse gas chromatography has
`been used to examine the surface coverage of magnesium stearate
`on powder blends.(33) Magnesium stearate also affects the flow
`properties of blends.(34)
`The existence of various crystalline forms of magnesium stearate
`has been established.(35–39) A trihydrate, a dihydrate, and an
`anhydrate have been isolated,(5,37,38,40) and an amorphous form has
`been observed.(41) While the hydrated forms are stable in the
`presence of moisture, the anhydrous form adsorbs moisture at
`relative humidity up to 50%, and at higher humidities rehydrates to
`form the trihydrate. The anhydrate can be formed by drying either
`of the hydrates at 1058C.(38)
`It has not been conclusively established which form of pure
`magnesium stearate possesses
`the best
`lubricating proper-
`ties.(36,37,41–43) Commercial lots of magnesium stearate generally
`
`Table I: Pharmacopeial specifications for magnesium stearate.
`
`Test
`
`Identification
`Characters
`Microbial limits
`Aerobic microbes
`Fungi and yeasts
`Acidity or alkalinity
`Acid value of the fatty
`acid
`Freezing point
`Nickel
`Cadmium
`Specific surface area
`Loss on drying
`Chloride
`Sulfate
`Lead
`Heavy metals
`Relative stearic/palmitic
`content
`Assay (dried, as Mg)
`
`USP32–NF27
`PhEur 6.5
`JP XV
`þ
`þ
`þ
`þ
`—
`—
`þ
`þ
`þ
`41000 cfu/g 4103 cfu/g 41000 cfu/g
`4500 cfu/g 4102 cfu/g 4500 cfu/g
`þ
`þ
`þ
`—
`195–210
`—
`
`—
`—
`—
`—
`46.0%
`40.1%
`41.0%
`—
`420 ppm
`þ
`
`5538C
`45 ppm
`43 ppm
`—
`46.0%
`40.1%
`41.0%
`410 ppm
`—
`þ
`
`—
`—
`—
`þ
`46.0%
`40.1%
`41.0%
`40.001%
`—
`þ
`
`4.0–5.0%
`
`4.0–5.0%
`
`4.0–5.0%
`
`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 stearate or by the
`interaction of magnesium oxide, hydroxide, or carbonate with
`stearic acid at elevated temperatures.
`
`14 Safety
`Magnesium stearate is widely used as a pharmaceutical excipient
`and is generally regarded as being nontoxic following oral
`administration. However, oral consumption of large quantities
`may produce a laxative effect or mucosal irritation.
`No toxicity information is available relating to normal routes of
`occupational exposure. Limits for heavy metals in magnesium
`stearate have been evaluated in terms of magnesium stearate worst-
`case daily intake and heavy metal composition.(1)
`Toxicity assessments of magnesium stearate in rats have
`indicated that it is not irritating to the skin, and is nontoxic when
`administered orally or inhaled.(2,3)
`Magnesium stearate has not been shown to be carcinogenic
`when implanted into the bladder of mice.(4)
`LD50 (rat, inhalation): >2 mg/L(2)
`LD50 (rat, oral): >10 g/kg
`
`15 Handling Precautions
`Observe normal precautions appropriate to the circumstances and
`quantity of material handled. Eye protection and gloves are
`recommended. Excessive inhalation of magnesium stearate dust
`may cause upper respiratory tract discomfort, coughing, and
`choking. Magnesium stearate should be handled in a well-ventilated
`environment; a respirator is recommended. In the USA, the OSHA
`limit is 10 mg/m3 TWA for magnesium stearate.
`
`16 Regulatory Acceptance
`GRAS listed. Accepted as a food additive in the USA and UK.
`Included in the FDA Inactive Ingredients Database (oral capsules,
`powders, and tablets; buccal and vaginal tablets; topical prepara-
`
`

`

`M
`
`406
`
`Magnesium Stearate
`
`consist of mixtures of crystalline forms.(37,39,41,42,44–46) Because of
`the possibility of conversion of crystalline forms during heating,
`consideration should be given to the pretreatment conditions
`employed when determining physical properties of magnesium
`stearate powders such as surface area.(47,48)
`Physical properties of magnesium stearate can vary among
`batches from different manufacturers(46) because the solid-state
`characteristics of the powder are influenced by manufacturing
`variables.(36) Variations in the physical properties of different lots of
`magnesium stearate from the same vendor have also been
`observed.(46) Presumably because of these variations, it has not
`been possible to conclusively correlate the dissolution rate retarda-
`tion with observed lubricity.(49)
`However, various physical properties of different batches of
`magnesium stearate, such as specific surface area, particle size,
`crystalline structure, moisture content, and fatty acid composition,
`have been correlated with lubricant efficacy.(37,41,45,46,50–55) Due to
`variations in the specific surface area, the labeling states that specific
`surface area and the method specified for its determination should
`be listed on the label. Reduction in dissolution caused by the effects
`of magnesium stearate in some cases can be overcome by including a
`highly swelling disintegrant in the formulation.(56)
`The impact of magnesium stearate levels on tablet compaction
`properties and performance of roller compacted granulations has
`been examined.(57–59) In other compaction studies performed with
`granules, magnesium stearate has been shown to exert an influence
`on granule relaxation and may help to prevent capping.(60)
`There is evidence to suggest that the hydrophobic nature of
`magnesium stearate can vary from batch to batch owing to the
`presence of water-soluble, surface-active impurities such as sodium
`stearate. Batches containing very low concentrations of these
`impurities have been shown to retard the dissolution of a drug to
`a greater extent than when using batches that contain higher levels
`of impurities.(49) One study related lubricity to the fatty acid
`composition (stearate : palmitate) of
`lubricant
`lots
`for
`tablet
`formulations based on compaction data and tablet material
`properties.(54) However, other studies have indicated that fatty
`acid composition has no influence on lubricant activity(37) and high-
`purity magnesium stearate was as effective a lubricant as the
`commercial material.(10) Moisture sorption at different relative
`humidities can result in morphological changes in the magnesium
`stearate.(61,62)
`Magnesium stearate has been investigated for use in inhalation
`powders to control their performance.(63)
`A specification for magnesium stearate is included in the Food
`Chemicals Codex (FCC).(64) The EINECS number for magnesium
`stearate is 209-150-3.
`
`19 Specific References
`1 Chowhan ZT. Harmonization of excipient standards. Weiner ML,
`Kotkoskie LA, eds. Excipient Toxicity and Safety. New York: Marcel
`Dekker, 2000; 321–354.
`2 Anonymous. Final report of the safety assessment of lithium stearate,
`aluminum distearate, aluminum stearate, aluminum tristearate, ammo-
`nium stearate, calcium stearate, magnesium stearate, potassium
`stearate, sodium stearate, and zinc stearate. J Am Coll Toxicol 1982;
`1: 143–177.
`3 Sondergaard D et al. Magnesium stearate given perorally to rats: a short
`term s