Handbook of
`
`~
`
`PHARMACEUTICAL
`
`EXCIPIENTS
`
`
`
`Second Edition
`
`Edited by
`Ainley Wade and Paul J Weller
`
`aimefilcan Pharmaceutical Association
`a5h“1Et0Il
`
`I
`
`1994
`
`The Pharmaceutical Press
`London
`
`Amerigen Ex. 1059, p. 1
`Amerigen Ex. 1059, p.
`1
`
`

`
`I ‘
`
`iIIInIInIiIn n InIn n
`
`
`
`
`
`© Copyright 1986, 1994 by the American Pharmaceutical Association, 2215 Constitution Avenue NW, Washington,
`DC 2003'?-2985, USA, and The Pharmaceutical Press, Royal Pharmaceutical Society of Great Britain, 1 Lambeth High
`Street, London, SE1 "LIN, England.
`
`A catalogue record for this book is available from the British Library.
`
`Library of Congress Catalog Card Number: 94-79492. _
`
`International Standard Book Number (ISBN) in the UK: 0 85369 305 6
`International Standard Book Number (ISBN) in the USA: 0 91730 66 8
`
`No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical,
`including photocopy, recording, or any information storage or retrieval system, without prior written permission from
`the joint publishers.
`'
`
`Typeset in Great'Britain by Alden Multimedia, Northampton.
`Printed and bound in Great Britain by
`
`Amerigen Ex. 1059, p. 2
`Amerigen Ex. 1059, p. 2
`
`

`
`
`
`Hydmxypropyl Methylcellulose
`
`229
`
`In oral products, hydroxy ropyl rnethylcellulose is primarily
`used as a tablet binder, 1)
`in filrr:—coating(2’?) and as an
`extended release tablet matrix.(s'm Concentrations of between
`2—5% wfw may be used as a binder in either wet or dry
`granulation processes. High viscosity grades may be used to
`retard the release of water-soluble drugs from a matrix.
`Depending upon the viscosity grade, concentrations between
`2—l0% w_.I'w are used as filrn~forniing solutions to film—coat
`tablets. Lower viscosity grades are used in aqueous film-
`coating solutions while higher viscosity grades are used with
`orgnic solvents.
`Hydroxypropyl methylcellulose is also used as a suspending
`and thickening agent
`in topical formulations, particularly
`ophthalmic preparations. Compared with methyloellulose,
`hydroxypropyl methylcellulose produces solutions of greater
`clarity, with fewer undispersed fibres present, and is therefore
`preferred in formulations for ophthalmic use. Concentrations
`of between 0.45— l .0% wfw may be added as a thickening agent
`to vehicles for eye—drops and artificial tear solutions.
`Hydroxypropyl methylcellulose is also used as an emulsifier,
`suspending agent and stabilizing agent in topical gels and
`ointrnents. As a protective colloid, it can prevent droplets and
`particles from coalescing or agglomerating thus inhibiting the
`formation of sediments.
`
`In addition, hydroxypropyl rnethylcellulose is used as an
`adhesive in plastic bandages and as a wetting agent for hard
`contact lenses. It is also widely used in cosmetics and food
`products.
`
`8. Description
`
`Hydroxypropyl methylcellulose is an odorless and tasteless,
`white or creamy-white colored fibrous or granular powder.
`
`9. Pharmacopeial Specifications
`
`Test
`
`_
`
`?|lEur 1992
`
`
`
`Hydroxypropyl
`Methylcellulose
`
`1. Nonproprietary Names
`BP: Hypromellose
`PhEur: Methylhydroxypropylcellulosum
`USP: Hydroxypropyl rnethylcellulose
`
`2. Synonyms
`-Cubm'nn2' MHPC;
`Cellulose, hydroxypropyl methyl ether;
`E464; HPMC; Methocef;
`rnethylcellulose propylene glycol
`ether; methyl hydroxypropylcellulose; Metolose; Phzzrmacomf.
`
`3. Chemical Name and CAS Registry Number
`Cellulose, 2—Hydroxypropyl methyl ether
`[9004~65~3]
`
`4. Empirical Formula Molecular Weight
`The Phliur 1992 describes hydroxypropyl methylcellulose as a
`partly 0—methylated and 0-(2—hydroxypropylated) cellulose.
`It is available in several grades which vary in viscosity and
`extent of substitution. Grades may be distinguished by
`appending a number indicative of the apparent viscosity, in
`mPa s, of a 2% wftv aqueous solution at 20°C. Hydroxypropyl
`inethylcellulose defined in the USP XXII specifies the
`substitution type by appending a four digit number to the
`nonproprietary name, e.g. hydroxypropyl methylcellulose
`1823. The first two digits refer to the approximate percentage
`content of the methoxy group (OCI-I3). The second two digits
`refer to the approximate percentage content of the hydroxy-
`propoxy group (0CH2CHOHCH3), calculated on a dried
`basis. Molecular weight is approximately 10000-1 500 000. i
`
`5. Structural Formula
`
`on
`
`£211,011
`
`on
`
`0
`
`c
`
`0R
`
`0
`
`on
`
`cH,oR
`
`.
`
`11
`
`Where R is H, CH3 or [CI-I3CH{0H)CH2].
`
`6. Functional Category
`Coating agent;
`filn1—forrner; stabilizing agent; suspending
`386111; tablet binder; viscosity—increasing agent.
`
`7- Applications in Pharmaceutical Formulation or
`Technology
`HY<_1roxypropyl methyloellulose is widely used in oral and
`1*’-‘P1381 pharmaceutical formulations.
`
`-—
`--
`5.5-8.0
`--
`S 10.0%
`'
`
`Identification
`Appearance of solution
`pH (1% w,-’w solution]
`Apparent viscosity
`Loss Drt drying
`Residue on ignition
`-~-~
`for viscosity grade > 50 mPa s
`for viscosity grade ..<, 50 mPa s —
`for type 1828 of all viscositios
`—
`Sulfatcd ash
`g 1.0%
`Arsenic
`-——
`Chlorides
`é 0.5%
`Heavy metals
`Q 20 ppm
`Mcthoxy content
`Type 1823
`Type 2:203
`Type 2906
`Type 2910
`Hydroxypropoxy content
`Type 1828
`Type 2208
`Type 2906
`Type 2910
`
`—
`—
`—
`—
`
`—
`—-
`—
`—
`
`USP XXII
`(Suppl 2)
`+
`—--
`—
`+
`Q 5.0%
`
`3 1.5%
`g 3.0%
`5, 5.0%
`—
`..<__ 3 ppm_
`——
`g 0.001%
`
`I6.5—20.0”x’o
`19.0-24.0‘:/..
`27.0-30.0%
`23.0-30.0%
`
`23.0—32.0%
`4.0-12.0"/'o
`4.0-7.5%
`7.0-12.0%
`
`10. Typical Properties
`Acidityfalkafinily:
`pH = 5.5—8.0 for a 1% wfw aqueous solution.
`
`Amerigen Ex. 1059, p. 3
`Amerigen Ex. 1059, p. 3
`
`

`
`
`230 Hydroxypropyl Methylcellulose
`
`
`
`.....5.-.....-..-_..../.-vs...:.-.'::.:_-..1".-...'-..~..'..
`
`
`
`
`
`Ash: 1.5-3.0%, depending upon the grade.
`Aufoignuian temperature: 360°C
`Density (rapped): 0.50-030 g,"cm3 for Pharmacoat.
`Melting point: browns at 190-200°C; chars at 225—230°C. Glass _
`transition temperature is l70—180°C.
`Moisture content: hydroxypropyl methylcellulose absorbs
`moisture from the atmosphere, the amount of water absorbed
`depending upon the initial moisture content and the
`temperature and relative humidity of the surrounding air.
`See also HPE Data.
`Solubility: soluble in cold water, forming a viscous colloidal I
`solution; practically insoluble in chloroform, ethanol (95%)
`and ether, but soluble in mixtures of ethanol and dichlor— '
`omethane, and mixtures of methanol and dichloromethane
`Certain grades of hydroxypropyl methylcellulose are soluble in
`aqueous acetone solutions, mixtures of dichloromethane and
`propan—2-ol, and other organic solvents. See also Section 11.
`Spemfic gravity: 1.26
`Viscosity (dynamic): a wide range of viscosity types are
`commercially available Aqueous solutions are most com-
`monly prepared although hydroxypropyl methylcellulose may
`also be dissolved in aqueous alcohols such as ethanol and
`propan-2-01 provided the alcohol content is less than 50% wfw.
`Dichloromethane and ethanol mixtures may also be used to
`prepare viscous hydroxypropyl methyloellulose solutions.
`Solutions prepared using organic solvents tend to be more
`viscous; increasing concentration also produces more viscous
`solutions, see Table I.
`recommended that
`is
`it
`To prepare an aqueous solution,
`hydroxypropyl methyloellulose is dispersed and thoroughly
`hydrated in about 20~30".-in of the requ.ired amount of water.
`The water should be vigorously stirred and heated to 80-90°C
`then the remaining hydroxypropyl methylcellulose added.
`‘Cold water should then be added to produce the required
`volume.
`
`.
`
`When a water—miscible organic solvent such as ethanol, glycol,
`or mixtures of ethanol and dichloromethane is used,
`the
`hydroxypropyl methylcellulose should first be dispersed into
`the organic solvent, at a ratio of 5-8 parts of solvent to 1 part
`of hydroxypropyl methylcellulose. Cold water is then added to
`produce the required volume.
`
`Table I: Dynamic viscosity (mPa s) of Plaarmacoar 603 (Shin-Emu
`Clrernical Co Ltd) solutions in various solvents at 20°C.
`
`Solvent
`
`Viscosity (mPa s) at 20°C
`Concentration (‘Va win)
`2
`' 6
`10
`14
`
`Dichloromethane: ethanol (50:50)
`Ethanol: water (50:50)
`Water
`
`4
`8
`3
`
`28
`32
`15
`
`150
`120
`45
`
`580
`350
`100
`
`Moisture content
`Moisture content
`Moisture content
`
`HPE Laboratory Project Data
`
`Method
`
`M020
`M020
`EMC—l
`
`Lab #
`
`Results
`
`is
`is
`15
`
`2.10% ‘*3
`3.10% ‘"1
`See Fig. 1. 0*’
`
`Supplier; a. Dow Chemical Company; b. Aqualon.
`
`11. Stability and Storage Conditions
`Hydroxypropyl methylcellulose powder is a stable material
`although it is hygroscopic after drying.
`
`Amerigen Ex. 1059, p. 4
`Amerigen Ex. 1059, p. 4
`
`SEM: I
`Excipient: Hydroxypropyl methylocllulose
`Manufacturer: Shin-Etsn Cbernical Co Ltd
`Lot Nfl.I 83214
`Magnification: 60::
`Voltage: l0IkV
`
`
`
`SEM: 2
`Excipient: Hydroxypropyl methyloeiiulose
`Manufacturer: Shin-E1511 Chemical Co Ltd
`Lot No; 83214
`Magnification: 6001
`Voltage: 101:‘?
`
`
`
`

`
`
`
`Hydroxypropyl methylcellulose is generally’ egarded as a
`nontoxic and nonirritant material althou
`' excessive oral
`
`consumption may have a laxative effect ll‘) The WHO has not
`specified an acceptable daily intake for hydroxypropyl
`methylcellulose since the levels consumed were not considered
`to represent a hazard to health.u5)
`LD50 (mouse, IP): 5 gfkgl 16)
`LD50 (rat, IP): 5.2 g/kg
`
`15. Handling Precautions
`Observe normal precautions appropriate to the circumstances_
`and quantity of material handled. Hydroxypropyl methylcel-
`lulose dust may be irritant to the eyes and eye protection is
`recommended. Excessive dust generation should be avoided to
`minimize the risks of explosions. Hydroxypropyl ruetl1ylcellu—
`lose is combustible.
`
`16. Regulatory Status
`GRAS listed. Accepted as a food additive in Europe. Included
`in the FDA Inactive Ingredients Guide (ophthalmic prepara-
`tions,-oral capsules, suspensions, syrups and tablets,
`topical
`and vaginal preparations). Included in nouparenteral n1edi—
`cines licensed in the UK.
`
`17. Phannacopeias
`Br, Bu1', Fr, Gr, It, Jpn, Neth, Port, Swiss and US.
`
`18. Related Substances
`
`Hydroxyethyl Cellulose; I-lydroxypropyl Cellulose; I-Iydroxy—
`propyl Methylcellulose Phthalate.
`
`19. Comments
`
`Powdered or granular, surface-treated grades of hydroxypro-
`pyl methylnxllulose are also available which are dispersible in
`cold water. The dissolution rate of these materials can be
`controlled by a shift in pH and they are thus useful for slow-
`release or enteric coated formulations.
`
`20. Specific References
`1. Chowhan ZT. Role of binders in moistureinduced hardness
`increase in compressed tablets and its effect on in were
`disintegration and dissolution. J Pharm Sci 1980; 59: 1-4.
`2. Rowe RC. The adhesion of film coatings to tablet surfaces - the
`effect of some direct compression excipients and lubricants. J
`Pharm Pharmacol 1977; 29: 723-725.
`3. Rowe RC. The molecular weight and molecular weight
`distribution of hydroxypropyl rnethylcellulose used in the film
`coating of tablets. J Pharm Pharmacol 1930; 32: 116-119.
`4. Banker G, Peck G, Jan S, Piralcitilculr P. Evaluation of
`hydroxypropyl cellulose and hydroxypropyl methyl cellulose as
`aqueous based film coatings. Drug Dev Ind Pharm 1981; 7: 693-
`716.
`5. Okhamafe A0, York P. Moisture permeation mechanism of
`some aqueous-based film coats. J Pharm Pharmaeol 1982;
`34(S1.1p1:Il]: 53?.
`6. Alderman DA, Schulz GJ. Method of making a granular, cold
`water dispersible eoating eomposition for tablets. US Patent
`4816298, 1939.
`7. Patell MK. Taste masking pharrilsceutical agents. US Patent
`4916161, 1990.
`8. Hardy JG, Kennerley JW, Taylor MJ, Wilson CG, Davis SS.
`Release rates from sustained-release buceal
`tablets in man. J
`Pharm Pharmacol 1982; 34{Suppl): 9lP.
`
`Amerigen Ex. 1059, p. 5
`Amerigen Ex. 1059, p. 5
`
`
`
`Hydroxypropyl Me£hyl¢eH&S.if:Eé.I'
`
`2.'1'l,__
`
`125
`
`29
`
`15
`
`..
`
`O
`
`_1
`
`10
`
`5
`
`U0
`
`33
`
`G)
`E.-2D
`E
`
`5§D
`
`’(D
`
`E»
`
`EII.
`
`D10 20
`
`30
`
`40
`
`50
`
`60
`
`?O
`
`30
`
`90100
`
`Percent rerative humidity
`
`Fig. 1: Equilibrium moisture content of hydroxypropyl methyl-
`oellulose, Methane! E15 (Dow Chemical Company, Lot Nu.:
`QP0502-801-E).
`
`Solutions are stable between pH 3—ll. Increasing temperature
`reduces the viscosity of solutions. Hydroxypropyl rnethylcel—
`lulose undergoes a reversible sol to gel transformation upon
`heating and cooling rtspectively. The gel point is 5l}—9D"C,
`depending upon the grade of material.
`Aqueous solutions are comparatively enzyme-resistant, pro-
`viding good viscosity stability during long—terIn storagef”)
`However, aqueous solutions are liable to microbial spoilage
`and should be preserved with an antimicrobial preservative.
`When used as a viscosityvincreasing agent
`in ophthalmic
`solutions, benzalkonitun chloride is commonly used for this
`purpose. Aqueous solutions may also be sterilized by
`autoelaving; the coagulated polymer must be redispersed on
`cooling by shaking.
`Hydroxypropyl methylcellulose powder should be stored in a
`well—closed container, in a cool, dry, place.
`
`12. Incornpatibilities
`incompatible with some
`I-Iydroxypropyl methylcellulose is
`oxidizing agents. Since it is nonionic, hydroxypropyl methyl-
`cellulose will not complex with metallic salts and ionic organics
`to form insoluble precipitates.
`
`13. Method of Manufacture
`
`A purified form of cellulose, obtained from cotton waste or
`Wood pulp,
`is reacted with sodium hydroxide solution to
`Pmduce a swollen alkali cellulose which is chemically more
`1'eactive than untreated cellulose. The alkali cellulose is then
`
`treated with chloromethane and propylene oxide to produce
`methylhydroxypropyl ethers of cellulose. The fibrous reaction
`]31‘0duct is then purified and ground to a fine, uniform powder
`01‘ granules.
`
`14. Safety
`Hydroxypropyl methylcellulose is widely used as an excipient
`In oral and topical pharmaceutical formulations. It is also used
`extensively in cosmetics and food products.
`
`

`
`232 Hydroxypropyl Methyiceiiuiose
`
`9. Hogan JE. Hydroxypropylmethyloellulose sustained release
`technology. Drug Dev Ind Pharm 1989; 15: 975-999.
`10. Shah AC, Britten NJ, Olanoff LS, Badalamenti JN. Gel-matrix
`systems exhibiting bimodal controlled release for oral delivery. J
`Controlled Release 1989; 9: 169-175.
`_
`ll. Wilson HC, Cuff GW. Sustained release of isomazole from
`matrix tablets administered to dogs, J Pharm Sci 1939; 78: 582-
`584.
`
`l4.
`
`l2. Dahl TC, Calderwood T, Bormeth A, Trimble K, Piepmeicr E.
`Influence of physicochemical properties of hydroxypropyl
`methylcellulose on naproxen release from sustained release
`matrix tablets. J Controlled Release i990; 14:
`l—lU.
`13. Banker G, Peck G, Williams E, Taylor D, Pirakitikulr P.
`Microbiological considerations of polymer solutions used in
`aqueous fi‘m coating. Drug Dev Ind Pharm i982; 8: 4l—5l.
`final report on the safety assessment of hydroxyethylocllulose,
`hydroxypropylcellulose, methylcellulose, hydroxypropyl methyl-
`oellulose and cellulose gum. J Am Coll Toxicol i986; 5(3): l-60.
`l5. FAO,/WHO. Evaluation of certain food additives and contami—
`nants:
`thirty-fifth report of the joint_ IJAOIWHO expert
`committee on food additives. Tech Rep Ser Wld Hlth Org
`i990; No. 789.
`_
`16. Sweet DV, editor. Registry of toxic effects of chemical
`substances. Cincinnati: US Department of Health, 1987.
`
`21. General References
`
`Dow Chemical Company. Technical literature: Methocel, 1993.
`Doelker E. Cellulose derivatives. Adv Polymer Sci 1993; 107: l99-265.
`Malamataris S, Karidas T, Goidas P. Effect of particle size and sorbed
`moisture on the compremion behavior of some hydroxypropyl
`
`
`
`methylccllulose (HPMC) polymers. Int J Pharmaceutics 1994; 103:
`2{)S—2l S.
`
`Papadimitriou E, Buckton G, Efentakis M. Probing the mechanisms of
`swelling of hydroxypropylmethylcellulose matrices. Int J Pharma.
`ceutics i993; 98: 57-62.
`Parab PV. Nayak MP, Ritschel WA. Influence of hydroxypropyl
`methylcellulose and of manufacturing technique on in vitro
`performance of selected antacids. Drug Dev Ind Pharrn i985; 1];
`i69—l85.
`
`Radebaugh GW, Murtha JL, Julian TN, Bondi JN. Methods for
`evaluating the puncture and shear properties of pharmaoeutiea]
`polymeric films. Int J Pharmaceutics 1988; 45: 39-46.
`Rowe RC. Materials used in the film coating of oral dosage forms. In;
`Florence AT, editor. Critical reports on applied chemistry, volume
`6: materials used in pharmaceutical formulation. Oxford: Blackwell
`Scientific Publications, 1984:
`l—36.
`Sebert P, Andrianoff N. Rollet M. Effect of gamma irradiation on
`hydroxypropylmethylcellulose powders: consequences on physical,
`rheological and pharmacotechnical properties. Int J Pharmaceutics
`1993; 99: 37-42.
`Shin—Etsu Chemical Co Ltd. Technical literature: Mefoiose, I977.
`Shin-Etsu Chemical Co Ltd. Technical
`literature: Pharmacoar
`hydroxypropyl methylcellulose, 1990.
`'-
`Wan LSC, Heng PWS, Wong LF. The effect of hyI:|roxypropylmethyl-
`cellulose on water penetration into a matrix system.
`Int J
`Pharmaceutics I991; 73: lll~ll6.
`
`22. Authors
`
`USA: RI Harwood, JL Johnson.
`
`Amerigen Ex. 1059, p. 6
`Amerigen Ex. 1059, p. 6
`
`
`
`
`
`r'u
`
`
`
`

`
`510 Sugar Spheres
`
`
`
`Sugar Spheres
`
`1. Nonproprietary Names
`USPNF: Sugar spheres
`
`2. Synonyms
`Non-pareil; Non-pareil I03; non—pareil seeds; Nu-Core; Nu-
`Pareil; sugar seeds.
`
`3. Chemical Name and CAS Registry Number
`
`4. Empirical Formula Molecular Weight
`See Section 8.
`
`5. Structural Formula
`See Section 8.
`
`6. Functional Category
`Tablet and capsule diluent.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`Sugar spheres are used as inert cores in capsule and tablet
`formulations particularly niultiparticulate sustained release
`fo11nulati0ns.( 3) They form the base upon which a drug is
`coated, usually followed by a release modifying polymer
`coating. Alternatively, a drug and matrix polymer may be
`coated onto the cores simultaneously. The active drug is
`released over an extended period either via diffusion through
`the polymer, or due to the controlled erosion of the polymer
`coating. Complex drug mixtures contained within a single
`dosage form may be prepared by coating the drugs onto
`different batches of sugar spheres with different protective
`polymer coatings.
`Sugar spheres are also used in confectionery products.
`
`8. Description
`
`The USPNF XVII describes sugar spheres as approximately
`spherical granules of a labelled nominal size range with a
`uniform diameter and containing not less than 62.5% and not
`more than 91.5% of sucrose, calculated on the dried basis. The
`remainder is chiefly starch. Usually white in color, sugar
`spheres may also contain approved coloring agents.
`
`9. Pharniacopeial Specifications
`
`Test
`
`USPNF XVII
`
`.
`
`+
`Identification (starch)
`+41“ to +61“
`Specific rotation
`+
`Microbial limits
`Q 4.0%
`Loss on drying
`a 0.25%
`Residue on ignition
`$ 5 ppm
`Heavy metals
`- Particle size distribution
`S. 10% oversize,
`g 10% undcrsiae
`
`10. Typical properties
`Particle size distribution: sugar spheres are of a uniform
`diameter. The following sizes are commercially available (US
`standard sieves):
`35-40 mesh (425600 pm)
`30-35 mesh (500-600 um)
`25-30 mesh (600-710 um)
`20-25 mesh (710-850 min)
`I3-20 mesh (850—l000 ,u.rn)
`16-20 mesh (850—1l80 pm)
`14-18 mesh (1000-1400 um)
`Solubility: solubility in water varies according to the sucrose to
`starch ratio. The sucrose component is freely soluble in water
`whereas the starch component is insoluble in cold water.
`
`11. Stability and Storage Conditions
`Sugar spheres are stable when stored in a well-closed container
`in a cool, dry, place.
`
`12. Inconlpatibilities
`
`See Starch and Sucrose for information concerning the
`incompatibilities of the component materials of sugar spheres.
`
`13. Method of Manufacture
`
`Sugar spheres are prepared from crystalline sucrose which is
`coated using sugar syrup and a starch dusting powder.
`
`14. Safety
`
`Sugar spheres are used in oral pharmaceutical forinulations.
`The sucrose and starch components of sugar spheres are
`widely used in edible food products and oral pharmaceutical
`formulations.
`
`The adverse reactions and precautions necessary with the
`starch and sucrose components should be considered in any
`product containing sugar spheres. For example, sucrose is
`generally regarded as more cariogenic than other carbohy-
`drates and in higher doses is also contraindicated in diabetic
`patients.
`See Starch and Sucrose for further information.
`
`15. Handling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled.
`
`16. Regulatory Status
`
`Included in the FDA Inactive Ingredients Guide (oral capsules
`and tablets). Included in nonparenteral medicines licensed in
`the UK. and Europe. The sucrose and starch components of
`sugar spheres are individually approved for use as food
`additives in Europe and the US.
`
`17. Pharmacopeias
`USPNF.
`
`18. Related Substances
`
`Compressible Sugar; Confectioners Sugar; Starch; Sucrose.
`
`19. Comments
`
`Amerigen Ex. 1059, p. 7
`Amerigen Ex. 1059, p. 7
`
`

`
`
`Sugar Spheres
`511
`
`_
`2,0. Specific References
`1, Narsimhan R, Labhasetwar VD, Lakhotia CL, Dorle A. Timed-
`release noscapine microcapsules. Indian J Pharm Sci 1988; 50: 120-
`122.
`
`’
`
`2. Bansal AK, Kakkar AP. Solvent deposition of diazepam over
`sucrose pellets. Indian J Phann Sci 1990; 52: l86~l8'.".
`
`21. General References
`Birch GG, Parker KJ, editors. Sugar: science and technology. London:
`Applied Science publications Ltd, 1979.
`
`22. Authors
`UK: RC Moreton.
`
`
`
`Amerigen Ex. 1059, p. 8
`Amerigen Ex. 1059, p. 8
`
`

`
`
`
`634 Index
`
`Anhydrite, 55
`1,4-Anhydro-D—glucito1, 6-hexadecanoate,
`473
`1,4—Anhyciro—o-glucitol, 6-isooctadecanoate,
`473
`1,4-Anhydro-o-glucitol, 6-octadecanoate,
`473
`Anhydrosorbitol monoisostcarate, 473
`Anhydrosorbitol monostearate, 473
`Anhydrous citric acid, 125
`Anhydrous dextrose, 156
`Anhydrous dibasic sodium phosphate, 454
`Anhydrous D-( + )—g1ucopyranose, 156
`Anhydrous glucose, 156
`Anhydrous gypsum, 66
`Anhydrous lactose, 252
`Anhydrous oc—1actose, 252
`Anhydrous ,6-lactose, 252
`Anhydrous lanolin, 262
`Anhydrous monobasio sodium phosphate,
`457
`Anhydrous sodium citrate, 444
`Anhydrous sodium propionate, 460
`Anhydrous sodium sulfite, 452
`Anhydrous sulfate of lime, 66
`Anhydrous trisodium citrate, 444
`Anionic emulsifying wax, S50
`Anionic surfactants,
`Docusate sodium, 173
`Sodiurn lauryl sulfate, 448
`Annalin, 68
`Annato extract, 129
`Ammlex BHT, 47
`Anthocyanins, 126
`Anticaking agents,
`Colloidal silicon dioxide, 4-24
`Magnesium trisilioate, 283
`Talc, 519
`Tribasic calcium phosphate, 61
`Antimicrobial preservatives see Preservatives
`Antioxidant 30, 47
`Antioxidants,
`Alpha tocopherol, 12
`Ascorbic acid, 15
`Ascorbyl palmitate, 19
`Butylated hydroxyanisole, 45
`Butylated hydroxytoluene, 47
`Furnaric acid, 197
`Malia: acid, 285
`Propyl gallate, 402
`Sodium ascorbate, 431
`Sodium metabisulfite, 451
`Antiseptics,
`Benzalkoniurn chloride, 27
`Benzethonimn chloride, 30
`Bronopol, 40
`Cetrimide, 96
`Chlorhexidine, 106
`Phenylrncrcuric acetate, 342
`Phenylrnercuric boratc, 344
`Phenyhnercuric nitrate, 346
`Thimerosal, 526
`Amrancine 8, 47
`Amrancine I2, 45
`APM, 21
`Apple acid, 285
`Aqua, 546
`Aqua purificata, 546
`Aquacom‘, 186, 603, 606, 613, 618
`Aquateric, 91, 606, 613, 618
`Aqueous cream BP, 550
`Arabic acid,
`1
`Arachiclis oleum, 329
`
`Arachfs hypogaea, 329
`Arachis oil, 329
`Aragonite, 54
`Arcran I1, 536, 606, 619
`Arclon I2, 160, 606, 619
`Arcton 22, 119, 606, 619
`Arcton H4, 163, 606, 619
`Argilla, 247
`-
`Argobase ED’, 334-, 610
`Argawox, 264, 610
`Arltrcel 20, 473
`Arlacef 40, 473
`Arlacel 60, 473
`Ariacel 80, 473
`Arlacet 83-, 473
`Arlacef 85, 473
`Arlacef 729, 209, 613
`Arlacel I65, 210
`Arfacel I36, 207, 613
`Arlacel 937, 473
`Arlacel C, 4-73
`Adamo! grades, 613
`Arlatane, 3'71
`Ariatone 235, 613
`Arlatone 289, 613
`Ariarorre 650, 613
`Arlatarle 983, 210, 613
`Armotrm ML, 473, 602
`Armotarr MO, 473, 602
`Armortm MP, 473, 602
`Armoton MS, 4-73, 602
`Armotan PML 20, 375, 602
`Armotan PMO 20, 375, 602
`Armaran PMS 20, 375, 602
`Ascorbic acid, 15
`L—(+)-Ascorbic acid, 15
`L-Ascorbic acid 6-hexadecanoate, 19
`L-Ascorbic acid monosodium salt, 431
`L-Ascor'oic_ acid 6—palr11.itate, 19
`Ascorbyl palrnitate, 19
`Ascorbylis pahnitas, 19
`Aspartame, 21
`a~Aspa1'tan1e, 22
`fi—Aspartamc, 22
`Aspartic acid, 22
`Asparty] phenylamine methyl ester, 21
`N—o:—L—Aspartyl-L-phenylalanine 1—rnethyl
`ester, 21
`As.-mgrin, 446
`Asrragaius gflmmrfer, 533
`A—TAB, 59, 609, 621
`ATBC, 540
`ATEC, S40
`Atlas G-695, 207, 613
`Arias G‘-2153, 379
`Atlas G~37I3, 367, 613
`Arias G4829, 613
`Atlas 614909, 613
`Almos 150, 209, 613
`Armin’ 8416, 614
`Avatech, 314, 616
`Avebe, 602, 612, 616
`Avedex, 151, 602, 612, 616
`Avicel, 84, 606, 613, 613
`Avicel C'L~6II, 86
`Avfce! RC—58I, 86
`Avfcel RC-591, 86
`Ayrex P, 433
`Azote, 321
`
`Bacteriostatic water for injection, 54-8
`Baking soda, 436
`Basic phenylrnercury nitrate, 346
`
`Beeswax,
`White, 558
`Yellow, 560
`Beet sugar, 500
`Beetroot red, 126
`Benecei, 306, 606, 616
`Benne oil, 420
`Bentonite, 24
`Magma, 26
`Purified, 26
`Bentonitum, 24-
`BentoPhorm, 24, 603
`Benzalkonii cltloridum, 27
`Benzalkonium chloride, 27
`Benzenecarboxylic acid, 32
`l,2—BenzenedicarboxyZic acid dibutyl ester,
`167
`1,2-Benzenedicarboxylic acid diethyi ester,
`16'!
`Benzeneethanol, 340
`Benzeneforrnic acid, 32
`Benzenemethanol, 35
`Benzethoniurn chloride, 30
`1,2-Benz.isothiazolin~3—one 1,1-dioxide, 415
`1,2—Benzisothiazol.in—3-one 1,1-dioxide,
`sodium salt‘, 418
`1,2-Benzisothiazol-3(2H]-one l,1—dioxide,
`415
`1,2—Benzisoth.iazo1—3[2H)-o ne 1,1-dioxide,
`sodium salt, 418
`Benzoate soda, 433
`Benzoit: acid, 32
`Bcnzoic acid benzyl ester, 38
`Benzoic acid phenylrnethyl ester, 38
`Benzoic acid potassium salt, 434
`Benzoie acid sodium salt, 433
`Benzoic sultirnide, 415
`Bcnzosulfiinide, 415
`Benzyl alcohol, 35
`Benzyl benzoate, 38
`Benzyl carbi.nol, 340
`Benzyl phenylformate, 38
`Benzylbenzenecarboxylate, 38
`Benzy1dimethy1[2-[2-{p—1,1,3,3-tetramethyl-
`bulylphenoxy)ethoxy]cthyl]a.mmor1ium
`chloride, 30
`Benzylmethanol, 340
`Bergabesr, 602
`Beta cyclodcxtrin, 145
`Beta tocopherol, 13
`Beta vtdgarir, 500
`Beta—apo-8' carotenal, 126
`Beta-carotene, 129, 131
`Betacarotene, 131
`Beta-cycloamylosc, 145
`Betadex, 145
`Beta—de:Ittrin, 145
`Betanin, 126
`BHA, 45
`BHT, 47
`Binders,
`Acacia, 1
`Alginic acid, 10
`Carbomer, 71
`Carboxymethylcellulose sodium, 78
`Dextrin, 151
`Ethyloellulose, 186
`Gelatin, 199
`Guar gum, 215
`Hydrogenated vegetable oil, type 1, 544
`Hydroxyethyl cellulose, 219
`Hydroxypropyl cellulose, 23
`Hydroxypropyl methylcellulose, 229
`
`Amerigen Ex. 1059, p. 9
`Amerigen Ex. 1059, p. 9
`
`

`
`Binders (Continued)
`Liquid glucose, 202
`Magnesium aluminum silicate, 269
`Maltodextrin, 289
`Methylcellulcse, 306
`Polymetlracrylates, 362
`Pcvidcne, 392
`Pregelatinized starch, 491
`Sodium alginate, 428
`Starch, 483
`Zein, 563
`Biopare 100, 233, 608, 620
`Bio-sarb, 489
`1,613is[N’—(p—cl11orophenyl)-N5-biguanido]
`hexane, 106
`N,N"-Bis(4-chlorophcnyl)—3,12—diimino-
`2,4,11,13-tet1*aazatetradecanediimid-
`amide, 106
`2,6-Bis(1,1-dirnctllylethyl)-4—methylphenoI, 4-7
`Bis(2-ethylhexyl) sodium sulfosuccinate, 173
`1,4-Bis(2-ethylhexyl) sulfosuccinate, calcium
`salt, 1'14
`Bis(h5rdroxyethyl]amine, 165
`Bismuth oxychloride, 129
`Brlsomel, 243
`Bixin, 126
`BKC, 27
`Blzmose, 78, 606, 616
`Bleached shellac, 423
`Bleached wax, 558
`Blood sugar, 154
`Bloom strength, 201
`BNPD, 40
`Boletic acid, 197
`Bolus alba, 247
`Boseral, 614
`Bovine serum albumin, 6
`Brassica napus, 69
`Brazil wax, 552
`Breox PEG, 355, 603, 606
`Brrj grades, 36?‘, 614
`Brilliant black BN, 126
`Brilliant black PN, 126
`Brilliant blue FCF, 127, 128
`Brilliant lake red R, 127, 128
`British gum-, 151
`Brirml, 418, 603
`Bram.-Jr, 96
`2-Bromo-2-m'tro-1,3-propanodiol, 40
`2—Bromo-2-nitropropane-1,3-diol, 40
`,8—Bromo-,6‘-nitrotrimetllyleneglycol, 40
`Bronchoconstriction,
`Bcnzalkoniurn chloride, 28
`Edetic acid, 177
`Bronopol, 40
`Bronapol—Boat.r, 40, 603
`Branosoi, 40
`-
`Brcnzc powder, 129
`Brookite titanium dioxide, 52.9
`Buffering agents,
`See also acidifying agents -
`See also alkalizing agents
`Citric acid monohydratc, 123
`Dibasic sodium phosphate, 454
`Monobasic sodium phosphate, 457
`Potassium citrate, 388
`Sodium citrate dillydrate, 443
`Bulk Density see Laboratory methods
`Bulk sweeteners see sweetening agents
`Bulk volume see Laboratory methods
`Bamimzte, 5
`Butane, 43
`rI—Butane, 43
`
`(E)~2«Butenedioic acid, 197
`rm.-is-Butenedicic acid, 197
`2-Butenedioic, monooctadecyl ester, sodium
`salt, 46?
`Butoben, 49
`Butolic acid, 422
`Batyl chemosept, 49
`Butyl citrate, 541
`Billy] hydroxybenzoate, 49
`Butyl parahydroxybenzoate, 49
`Bury.’ paras-ept, 49
`rt-Butyl phthalate, 16'?
`Butyl sebacate, 158
`Butylated hydroxyanisole, 45
`Butylated hydroxytoluene, 47
`Butyl—4—hydroxybenzoate, 49
`n-Buty1—p-hydroxybenzoate, 49
`Butylhydroxytolucne, 4’?
`Butylhydroxytoluenurn, 4'7
`terr-Buty1—4—methoxyphenol, 45
`2-Ierr-Butyl-4-methoxyphcnol, 4-5
`3—tert—Butyl-4-methoxypbenol, 45
`Butylparaben, 49
`Butylparaben sodium, 50
`BZT, 30
`
`097, 15, 605, 615
`Cab-0-Sit, 424, 603, 612, 617
`Cachalot, 620
`Cafes, 56, 612
`Cal-Corb, 52, 617
`Calcfiem C-I02, 69, 61?
`Calckem H402, 69, 617
`Catchem IVOJ08, 135, 61?
`Calcfzem IVO-1'09, 137, 617 ‘
`Calchem W0-112, 329, 61?
`Cclchem IVOJI4, 481 617
`Calcii carbonas, 52
`Calcii hydrogenophosphas, 56
`Calcined magnesia, 278
`Calcite, 54
`Calcium 90, 55
`Calcium alginate, 429
`Calcium ascorbate, 432
`Calcium L-[+)-ascorbate, 432
`Calcium carbonate, 52, 126, 129
`Precipitated, 52
`Calcium carhoxymethylcclluloae, 76
`Calcium CMC, 76
`Calcium cyclarnate, 447
`Calcium Neyclohexylsulfamate dihydrate,
`447
`Calcium dipropionate, 460
`Calcium disodiuru edetate, 178
`Calcium disodium ethy1cnediaminetctra—
`acetate, 178
`Calcium disodium (ethy1euedinitri—
`lo)tctraaoctatc, 173
`Calcium diatearate, 63
`Calcium hydrogen orthophosphate
`dihydratc, 56
`Calcium hydrogen phosphate, 56
`Calcium hydroxide phosphate, 61
`Calcium rnonohydrogen phosphate
`dihydrate, 56
`Calcium orthophosphate, 61
`Calcium palmitate, 63
`Calcium phosphate, 61
`Dibasic, 56
`Anhydrous, 59
`Dihydratc, 56
`Secondary, 56
`Tribasic, 61
`
`Index 635
`
`Calcium polyrnannuronate, 429
`Calcium propionate, 460
`Calcium silicate, 283
`Calcium sorbate, 471
`Calcium stearate, 63
`Calcium sulfate, 66
`Anhydrous, 66
`Dihydratc, 66
`Dried, 68
`Exsiccated, 63
`Hemihydrate, 68
`Calginate, 429
`Caloreen, 151
`Calsrur, 56, 606, 613, 618
`Cal-Tab, 66, 61'?
`Canary dextrin, 151
`Canbra oil, 69
`Czmderel, 21
`Cane sugar, 500
`Canola oil, 69
`Canthaxanthin, 126, 129
`CAP, 91
`CAP30, 44, 401
`Cap-locking, 194, 287, 477
`Capmul, 607, 614, 619
`Cayman‘ 0, 473
`Capmul POE—L, 375
`C.-zpmyl POE—0, 375
`Copmnl POE-S, 375
`Cupmul S, 473
`Capric acid, 299
`Caprylic acid, 299
`Caprylicfcapric triglyceride, 299
`Capaantbin, 126
`Capsorubin, 126
`CapsuLoc, 614
`Capsule and tablet dilucnts see Diluents
`Capsule and tablet disintegrants see
`Disintegranta
`Capsule and tablet lubricants see Lubricants
`Caprcx, 607, 614, 619
`Caramauia gum, 533
`Caramel, 126, 129
`Caranda wax, 552
`Carbo medicinalis vegetabilis, 126
`Carbolic acid, 336
`Carbomer, 71
`Carbon dioxide, 74
`Carbon dioxide-free water, 548
`Carbonei dioxidurn, '.-'4
`_ Carbonic acid,
`Calcium salt (1:1), 52
`Cyclic propylene ester, 4-05
`Gas, 74
`Magnesium salt,
`Anhydrous (1:1), 276
`Hydrate (1:1), 276
`Monosodium salt, 436
`Carbonic anhydride, 74
`Ccrbopol, T1, 603, 617
`Corbowcx, 355, 622
`Carboxybenzene, 32
`Carboxyethane, 460
`Carbcxymethyl starch, sodium salt, 462
`Carboxymethylcellulose calcium, 76
`Carboxymethylccllulcse sodium, 78, 81
`And microcrystalline cellulose, 86
`Cross—1inked, 141
`Carboxymethylcellulosum natricum, 78
`[{0-Carboxypheny1)tbic]ethyIlI1ercury
`sodium salt, 526
`Carboxypolyrnethylene, 71
`Carboxyvinyl polymer, 71
`
`Amerigen Ex. 1059, p. 10
`Amerigen Ex. 1059, p. 10