Handbook ol
`Pharmaceutical
`Granulation Technology ·
`
`edited by
`Dilip M. Parikh
`Atlantic Pharmaceutical Services Inc.
`. Owings Mills, Maryland
`
`M 1\ R <. l
`
`n MARCEL DEKKER, I N c
`
`l
`
`OEKKER
`
`NEW YoRK . BASEL
`
`Par Pharm., Inc.
`Exhibit 1022
`Page 001
`
`

`

`Library of Congress Cataloging-in-Publication Data
`
`Handbook of pharmaceutical granulation technology I edited by Dilip M.
`Parikh.
`p. em. -
`(Drugs and the pharmaceutical sciences; 81)
`Includes bibliographical references and index.
`ISBN 0-8247-9882 -1 (hardcover : alk. paper)
`1.· Drugs-Granulation- Handbooks, manuals, etc.
`M.
`II. Series.
`fDNLM : I. Technology, Pharmaceutical 2 Powders. WI DR893B
`v . 81 1997 I QV 778 H2 36 1997)
`RS 199. G73H36 1997
`6 15'.4--dc21
`DNLM/DLC
`for Library of Congress
`
`I. Parikh, Dilip
`
`97-11743
`CIP
`
`The publisher offers discounts on this book when ordered in bulk quantities .
`For more information, write to Special Sales/Professional Market ing at the
`address below .
`
`This book is printed on acid-free paper.
`
`Copyright© 1997 by MARCEL DEKKER, INC. All Rights Reserved.
`
`Neither this book nor any part may be reproduced or transmitted in any form
`or by any means , electronic or mechanical , including photocopying, micro(cid:173)
`filming, and recording, or by any information storage and retrieval system,
`without permission in writing from the publisher.
`
`MARCEL DEKKER , INC.
`270 Madison Avenue, New York , New York 10016
`Imp: / /www.dekker. com
`
`Current printing (last digit ):
`10987654
`
`PRINTED IN THE UNITED STATES OF AMERICA
`
`Par Pharm., Inc.
`Exhibit 1022
`Page 002
`
`

`

`4
`Binders and Solvents
`
`Rajendra K. Khankari
`CIMA LABS INC., Brooklyn Park, Minnesota
`
`John Hontz
`Glaxo Wei/come Company, Greenville, North Carolina
`
`INTRODUCfiON
`I.
`II. TYPES OF BINDERS
`A. Natural Polymers
`B. Synthetic Polymers
`c. Sugars
`III. FACTORS INFLUENCING BINDER EFFICIENCY
`A. Binder Concentration
`B. Mechanical Properties of the Binder
`c. Properties of the Drug and Other Excipients in the
`Formulation
`D. Binder-Substrate Interactions
`E. Binder Distribution
`REFERENCES
`
`60
`60
`60
`63
`66
`67
`67
`68
`
`70
`71
`71
`72
`
`59
`
`Par Pharm., Inc.
`Exhibit 1022
`Page 003
`
`

`

`60
`
`Khankari and Hontz
`
`I.
`
`INTRODUCTION
`
`Binders are the adhesives that are added to the tablet formulations. The role
`of binders is to provide the cohesiveness essential for the bonding of the
`solid particles under compaction to form a tablet. In a wet granulation pro(cid:173)
`cess, binders promote size enlargement to provide granules and, thereby,
`improve ftowability of the blend during the manufacturing process. Binders
`may also improve the hardness of the tablets by enhancing intragranular as
`well as intergranular forces. In a direct compression process, binders often
`act as fillers and impart compressibility to the powder blend. The cohesive
`properties of binders may reduce friability of the tablets and, thus, aid in
`their elegance. Although the purpose of using binders in a tablet formulation
`is not to influence its disintegration and dissolution rate, these properties
`may be modified owing to the altered wettability of the formulation.
`
`II. TYPES OF BINDERS
`
`Binders are classified as natural polymers, synthetic polymers, or sugars.
`The selection of a binder for a particular system is mostly empirical and
`depends on the previous experience of the formulator. Selection of the quan(cid:173)
`tity of binder required in a particular system can be determined by optimi(cid:173)
`zation studies, using parameters such as granule friability, tablet friability,
`hardness, disintegration time, and the drug dissolution rate. Some commonly
`used binders in wet granulation, with their usual concentration range along
`with the granulating system, are listed in Table 1.
`The basic properties of some widely used binders, with their method
`of incorporation, will be discussed in this section [ 1- 4].
`
`A. Natural Polymers
`
`1. Starch
`
`Starch is a polymeric carbohydrate obtained from various plant sources, such
`as potato, wheat, maize; rice, and tapioca. It is a generally regarded as safe
`(GRAS)-Iisted material and one of the most widely used tablet binders. It
`is insoluble in cold water and in alcohol, but it gelatinizes (hydrolyzes) in
`hot water to form a paste. Starch paste can be prepared by dispersing starch
`in 1- 1.5 parts of cold water for initial wetting, followed by addition of 2
`to 4 times as much boiling water, with continuous stirring, until a translucent
`paste is obtained. This is further diluted by cold water to the desired con(cid:173)
`centration . Alternatively, starch paste can also be prepared by heating the
`
`Par Pharm., Inc.
`Exhibit 1022
`Page 004
`
`

`

`Binders and Solvents
`
`Table 1 Commonly Used Granulating Systems
`
`Binder
`
`Method of % used in
`incorporation
`formula
`
`Solvent
`
`61
`
`%used in
`granulating
`system
`
`Natural polymers
`Wet mixing
`Starch
`Pregelatinized starch Wet mixing
`Dry mixing
`Wet mixing
`Wet mixing
`Dry mixing
`Wet mixing
`
`Gelatin
`Acacia
`Alginic acid
`Sodium alginate
`
`2-5
`2-5
`5-10
`1-3
`3-5
`1-5
`1-3
`
`Synthetic polymers
`Polyvinylpyrrolidone Wet mixing
`
`0.5-5
`
`Methylcellulose
`
`HPMC
`
`Na-CMC
`
`Ethylcellulose
`
`Sugars
`Glucose
`Sucrose
`Sorbitol
`
`Source: Ref. 3.
`
`Dry mixing
`Wet mixing
`Dry mixing
`Wet mixing
`
`Dry mixing
`Wet mixing
`Dry mixing
`Wet mixing
`Dry mixing
`
`Wet mixing
`Wet mixing
`Wet mixing
`
`5-10
`1-5
`5-10
`2-5
`
`5-10
`1-5
`5-10
`1-5
`5-10
`
`2-25
`2-25
`2-10
`
`Water
`Water
`Water
`Water
`Water
`Water
`Water
`
`Water or
`hydroalcoholic
`solution
`
`Water
`
`Water or
`hydroalcoholic
`solution
`
`Water
`
`Ethanol
`
`Water
`Water
`Water
`
`5-25
`10-15
`
`5-lO
`10-15'
`
`3-5
`
`5-10
`
`2-15
`
`5..:-. 10
`
`5-15
`
`2-10
`
`25-50
`50-67
`2-25
`
`cold water suspension of starch to boiling in a steam-jacketed kettle with
`constant . stirring.
`Freshly prepared starch paste is used at a concentration of 5-25%
`w/w in a tablet granulation. Relatively soft and friable granules are pro(cid:173)
`duced when starch paste is used as a binder. Consequently, it yields tablets
`that disintegrate readily. During the wet-massing process, the high viscos(cid:173)
`ity of the starch paste makes it difficult to evenly distribute the binder m
`the powder blend.
`
`Par Pharm., Inc.
`Exhibit 1022
`Page 005
`
`

`

`62
`
`Khankari and Hontz
`
`2.
`
`. Pregelatinized Starch
`
`Pregelatinized starch is a modified starch used in tablet formulations as a
`binder, diluent, and disintegrant. It is obtained by chemically and mechan(cid:173)
`ically processing starch to rupture all or parts of the starch granules. This
`process renders starch granules ftowable, and soluble in warm water without
`boiling. As a binder in a wet granulation process, pregelatinized starch can
`be used either as a solution reconstituted in water or by dry blending, fol(cid:173)
`lowed by wetting with water. The latter process requires two to four times
`more binder to achieve the same binding effect.
`Pregelatinized starch is available in fully or partially pregelatinized
`forms. The degree of pregelatinization determines its solubility in cold water.
`Cold water-soluble matter for a partially pregelatinized starch is 10-20%.
`Starch 1500 is partially pregelatinized starch containing 20% maximum cold
`water-soluble fraction, which makes it useful for wet granulation. The water(cid:173)
`soluble fraction acts as a binder, whereas the remaining fraction facilitates
`the tablet disintegration process.
`
`3. Gelatin
`
`Gelatin is a mixture of purified protein fractions obtained by partial acid
`hydrolysis (type A gelatin) or alkali hydrolysis (type B gelatin) of animal
`collagens. It is insoluble in cold water and in alcohol, but is soluble in hot
`water. In hot water, gelatin forms a gel on cooling to 35 - 40°C. At temper(cid:173)
`atures higher than 40°C, the system exists as a solution. Therefore, the gel(cid:173)
`atin solutions must be used when wann to avoid gel formation.
`During the preparation of gelatin solution, the gelatin must be wetted
`in cold water and then heated with gentle agitation to ensure dissolution.
`The agitation intensity must be controlled to prevent air entrapment in the
`viscous solution. Use of gelatin as a binder is limited in general-purpose
`tablets because it produces tablets characterized by high hardness and slow
`disintegration. However, these properties of gelatin, along with its smooth
`mouthfeel, can be advantageous in a lozenge formulation.
`Gelatin reacts with aldehydes, aldehydic sugars, anionic and cationic
`polymers, electrolytes, metal ions, plasticizers, preserVatives, and surfac(cid:173)
`tants. In a wet granulation process of a formulation containing color, the
`migration of dyes toward the upper surface of the static bed during the
`drying operation is often amplified by the presence of gelatin owing to its
`high affinity for dyes. The gelatin solutions are susceptible to microbial
`contamination on storage; therefore, freshly prepared solutions should al(cid:173)
`ways be used.
`
`l
`
`J
`
`Par Pharm., Inc.
`Exhibit 1022
`Page 006
`
`

`

`Binders and Solvents
`
`4. Acacia
`
`63
`
`Acacia, also named as gum arabic, is a natural gum obtained from the acacia
`trees. It is a complex, loose aggregate of sugars and hemicelluloses. It is
`commercially available in a powdered form, a granular form, or as a spray (cid:173)
`dried product. As a tablet binder, it is used in an aqueous solution or added
`in dried form before moistening with water. Acacia forms very hard tablets
`that disintegrate slowly. Aqueous solutions are susceptible to bacterial and
`enzymatic degradation. It is incompatible with amidopyrine, cresol, phenol,
`ethanol, ferric salts, and with several other substances. Acacia, which was
`widely used in the past as a tablet binder, has been replaced by many syn(cid:173)
`thetic polymers.
`
`5. Tragacanth
`
`Tragacanth is a naturally occurring dried gum. It poses problems similar to
`those of acacia. Dry addition to the blend followed by addition of water
`works better than addition in solution, this is because of the difficulty in
`preparing the solution and the use of mucilage.
`
`6. Alginic Acid
`
`Alginic acid is a polymannuronic acid extracted from seaweed. It is used as
`a binder and disintegrating agent at concentration between 1 and 5%. It
`slowly hydrolyzes at room temperature and is insoluble in water. Therefore,
`it is best incorporated in a dry state. It is incompatible with strong-oxidizing
`agents. It forms insoluble alginates with the alkaline earth metals and group
`III metals, with the exception of magnesium. These alginates may delay
`disintegration of the tablets owing to their geling properties.
`
`7. Sodium Alginate
`
`Sodium alginate slowly dissolves in water to form a viscous solution. A
`3-5% solution is used in wet granulation process. It has also been used
`in sustained-release formulations because it delays the dissolution of a ·
`drug from tablets. It is hygroscopic, and its aqueous solution is susceptible
`to microbial contamination.
`
`B. Synthetic Polymers
`
`1 . Polyvinylpyrrolidone
`
`Polyvinylpyrrolidone (PVP, povidone) is a versatile and one of the most
`commonly used binders. It is readily soluble in water and freely soluble in
`
`Par Pharm., Inc.
`Exhibit 1022
`Page 007
`
`

`

`64
`
`Khankari and Hontz
`
`alcohol and many other organic solvents. It is available in variety of grades
`of different molecular weight. Povidone is generally used in the form of a
`solution; however, it can be added to the blends in the dry form and then
`granulated in situ. The in situ method generally requires a higher concen(cid:173)
`tration of povidone to achieve the same binding effect of a solution. Povi(cid:173)
`done is frequently used as a binder in effervescent and chewable tablets
`because the tablets manufactured using PVP generaJly harden with age.
`Aqueous or hydroalcoholic solutions of povidone are used to granulate
`water-insoluble materials, and alcoholic solutions are used for granulating
`water-soluble materials. It is used as a binder at concentration between 0.5
`and 5%. Low- to medium-viscosity grades are preferred for its use as a
`binder. It is highly hygroscopic and picks up significant amounts of moisture
`at low relative humidities.
`
`2. Methylcellulose
`
`Methylcellulose is a long-chain, substituted cellulose in which approxi(cid:173)
`mately 27-32% of the hydroxyl groups are in the form of methyl ether. It
`is available in a variety of grades of different degrees of substitution and
`average molecular weight. Therefore, it offers considerable latitude in bind(cid:173)
`ing strength. Efficiency of methylcellulose as a binder improves with the
`increasing molecular weight. Low or medium viscosity grades are preferred
`when used as a binder. It may be added as a dry powder or in solution.
`Although an aqueous solution of 1-5 % can be used to granulate soluble or
`insoluble excipients, it is a better binder for soluble excipients, such as
`lactose and mannitol. Methylcellulose produces granulations that compress
`easily. Granulations produced using 5% methylcelluJose solution are equiv(cid:173)
`alent in hardness to 10% starch paste. It produces robust tablets, with a
`moderate hardness that does not increase with age.
`Methylcellulose is practically insoluble in hot water, ethanol , chloro(cid:173)
`form , ether, and saturated salt solutions. In cold water, it swells and disperses
`slowly to form clear to opalescent, viscous dispersion. To produce aqueous
`solution, an appropriate quantity of methylcellulose powder is suspended in
`25 % of the required amount of water at 80°C. The remaining amount of
`water is added cold, or ice water is added to the hot slurry, with vigorous
`stirring to cool it to 20°C. A clear aqueous solution of methylcellulose is
`obtained. Methylcellulose can also be added as a dry powder to another
`powder before mixing with cold water. The methylcellulose can be mois(cid:173)
`tened with .an organic solvent, such as 95 % ethanol before addition of water.
`
`3. Hydroxypropylmethylcellulose
`
`Hydroxypropylmethylcellulose (HPMC) is a propyleneglycol ether of meth(cid:173)
`ylcellulose . It is available in variety of viscosity grades. Its binding prop-
`
`Par Pharm., Inc.
`Exhibit 1022
`Page 008
`
`

`

`Binders and Solvents
`
`65
`
`erties are comparable with those of methylcellulose. Concentrations of 2-
`5% w/w may be used as a binder in either wet or dry granulation processes.
`It is soluble in cold water and forms a viscous colloidal solution. To prepare
`an aqueous solution, HPMC is first hydrated in 20 - 30% of required amount
`of water at 80- 90°C with vigorous stirring. Cold water is added to produce
`the required volume. Hydroalcoholic solutions or mixtures of water and
`other water-miscible solvent, such as glycol, can also be used to dissolve
`HPMC. HPMC is first dispersed in the organic solvent, at a ratio of five to
`eight parts of solvent to one part of HPMC. Cold water is then added to
`produce the required volume. HPMC is incompatible with some oxidizing
`agents .
`
`4. Sodium Carboxymethylcellulose
`
`Sodium carboxymethylcellulose (Na-CMC) is a sodium salt of carboxy(cid:173)
`methyl ethers of cellulose. It is available in variety of molecular weights,
`which influence the viscosity of the solution and its swelling properties. It
`easily disperses in water at all temperatures to form a clear colloidal solution.
`Its aqueous solubility varies with its degree of substitution, which is the
`average number of hydroxyl groups substituted per anhydroglucose unit. A
`5-15 % solution may be used for the granulation of powders, regardless of
`their water solubility. The granulations produced using Na-CMC as a binder
`are softer, but have good compressibility. It forms tough tablets of moderate
`hardness. Na-CMC is highly hygroscopic material. It can adsorb a large
`quantity (> 50%) of water at high relative humidities. Therefore, the tablets
`using Na-CMC as a binder have tendency to harden with age. Na-CMC is
`incompatible with strongly acidic solutions and with metal salts of iron,
`aluminum, zinc, and others.
`
`5. Ethylcellulose
`
`Ethylcellulose, an ethyl ether of cellulose, is available in variety of grades
`that differ in their viscosity. Low-viscosity grades are used as binders in
`concentrations of 2-10% in ethanol. Ethylcellulose produces softer granules
`that compress into tablets that easily disintegrate. However, the dissolution
`of the active ingredient from these tablets may be slower because ethylcel(cid:173)
`lulose is insoluble in water. Ethylcellulose may be used in a dry form or as
`an ethanolic solution for wet granulation. It is a good nonaqueous binder
`for water-sensitive formulations. Aqueous polymeric dispersions of ethyl(cid:173)
`cellulose, which were introduced for controlled-release coating application
`in the 1980s, have been used a binding agent for granulating products re(cid:173)
`quiring sustained-release properties.
`
`Par Pharm., Inc.
`Exhibit 1022
`Page 009
`
`

`

`66
`
`Khankari and Hontz
`
`6. Polyethylene Glycol
`
`Polyethylene glycols (PEGs), by themselves, have limited-binding action;
`however, they can enhance effectiveness of tablet binders and impart plas(cid:173)
`ticity to granules. They can also be used in thermoplastic granulations. In
`this process, a powder blend containing 10-15% w/w of PEG-6000 is heated
`to 70°-75°C to obtain a paste-like mass that forms granules if stirred while
`cooling. This technique is used in lozenge formulations.
`
`7. Polymethacrylates
`
`Polymethacrylates (Eudragit NE 30D and Eudragit RS 30D) can be used as
`binders in aqueous or nonaqueous wet granulation processes. They are sup(cid:173)
`plied as 30% aqueous dispersions. Dilution with water before use is rec(cid:173)
`ommended. Eudragit RS 30D is incompatible with magnesium stearate.
`
`8. Polyvinyl Alcohol
`
`Polyvinyl alcohols (PYAs) are available in variety of viscosity grades. Vis(cid:173)
`cosity ranges from 10 to 100 cp lend themselves for tablet granulations.
`PYAs are water-soluble polymers. They form softer granulations which yield
`tablets that do not harden with age.
`
`C. Sugars
`
`1. Glucose (Dextrose)
`
`Glucose, . when applied as syrup in concentrations above 50% in wet gran(cid:173)
`ulation processes, exhibits good-bonding properties. It produces moderately
`strong granules and tablets that are, however, hard and brittle. Glucose is
`also used as a direct compression tablet diluent and binder, primarily in
`chewable tablets. Anhydrous dextrose adsorbs substantial amounts of mois(cid:173)
`ture at 25°C and 85% relative humidity to form a monohydrate. The mono(cid:173)
`hydrate also absorbs moisture at 85 % relative humidity. Dextrose is a re(cid:173)
`ducing sugar and, in its aldehyde form, can react with amines, amides, amino
`acids, and such. Brown coloration may occur in the tablets containing dex (cid:173)
`trose and strong alkali or amines. This browning is called a Maillard reac(cid:173)
`tion, which is a reaction between reducing sugars and proteins and is most
`common in candy preparation.
`
`2. Sucrose
`
`Sucrose is commercially available in several forms, such as granular, fine
`granular, fine, superfine, and confectioners sugar. The confectioners sugar
`
`Par Pharm., Inc.
`Exhibit 1022
`Page 010
`
`

`

`Binders and Solvents
`
`67
`
`(contains 5% starch) is most commonly used in wet granulation formula(cid:173)
`tions. Sucrose syrup, containing 50- 67% w/w sucrose, is used as a binder
`in wet granulation processes. lt can also be used as a dry binder in which
`it is granulated with water or hydroalcoholic solutions. Similar to glucose,
`sucrose produces strong, but hard and brittle, tablets. The amount of binder
`determines . the tablet hardness. Softer granules can be obtained by using
`hydroalcoholic mixtures as granulating solutions. Finely divided sugar is
`hygroscopic. Tablets containing large amounts of sucrose may harden with
`age, which may result in slower disintegration. In the systems in which quick
`overwetting occurs, the amount and the rate of addition of the sucrose syrup
`must be carefully monitored. Use of sucrose with starch paste may improve
`the tablet quality. Sucrose is incompatible with aluminum. It hydrolyzes in
`the presence of acids. Contamination of powdered sucrose with heavy metals
`may lead to incompatibility with substances such as ascorbic acid.
`
`3. Sorbitol
`
`Sorbitol, a sugar alcohol, is the optical isomer of mannitol. It is highly
`hygroscopic at relative humidities of 65 % and higher; therefore, it is used
`as a humectant in pharmaceutical formulations. Whenever this property of
`sorbitol as a moisture-control agent is desirable, it can be used as a binder.
`Up to 2-20% of sorbitol can be added as l0- 25 % aqueous solution in wet
`granulation formulations .
`
`Ill. FACTORS INFLUENCING BINDER EFFICIENCY
`
`The function of binders in a tablet formulation is to impart strength and to
`reduce friability of granules and tablets. A multitude of factors influence the
`effectiveness of a binder in a formulation. Some of these factors are con(cid:173)
`centration, viscosity, mechanical properties of the binder, properties of a drug
`and other excipients in the formulation , interparticulate interactions between
`the binder and the substrate, and binder distribution.
`
`A. Binder Concentration
`
`During wet granulation process, binder form s an internal matrix. Conse(cid:173)
`quentl y, the granule strength and the tablet strength increases as the binder
`concentration in a formulation increases.
`Figure 1 shows a plot of crushing strength of dicalcium phosphate
`granules versus binder concentration for various binding agents [5) . As the
`binder concentration increases, the crushing strength of the granules in-
`
`Par Pharm., Inc.
`Exhibit 1022
`Page 011
`
`

`

`68
`
`2.5
`
`2.0
`
`Khankari and Hontz
`
`01
`.:.1!
`.c
`c;,
`c:
`CIJ
`
`.... -"' en
`
`.S
`~
`....
`::J
`u
`CIJ
`
`::J c .., ....
`
`(.:J
`
`Binder content in dry granules, % w/w
`
`Fig. 1 Crushing strength of wet granulated dicalcium phosphate. Binders: •. gel(cid:173)
`atin; o, potato starch mucilage; x, acacia; ~ . povidone; o , PEG 4000. (From
`Ref. 5.)
`
`creases. The plot also shows that starch and gelatin can produce much
`stronger granules with lower concentrations, compared with acacia, PVP, or
`PEG 4000. As expected, the particle size of granules also increases as the
`binder concentration increases. Figure 2 shows a plot of mean particle size
`of lactose granules versus binder concentration [6] .
`lntragranular bonds (formed during drying of granules) that are not
`fractured during compaction, cohesion of binder film and particles, and
`binder substrate adhesion are the types of bondings that contribute to the
`tablet strength. Jarosz and Parrott [7] showed that the radial and axial tensile
`strengths of the dicalcium phosphate tablets increased with increasing con(cid:173)
`centrations of povidone in the formulation (Fig. 3).
`
`B. Mechanical Properties of the Binder
`
`The mechanical and film-forming properties · of a binder determines the
`strength and deformation behavior of a binder matrix . These properties of
`
`Par Pharm., Inc.
`Exhibit 1022
`Page 012
`
`

`

`Binders and Solvents
`
`69
`
`800
`
`700
`
`600
`
`E'
`..=.
`
`II)
`. ~
`"'
`~ 500
`:::1
`~
`~
`~
`
`00
`
`400
`
`300
`
`a PVP
`
`• ACACIA
`
`a GElATIN
`
`200
`
`0
`
`2
`
`4
`
`6
`
`8
`
`10
`
`12
`
`14
`
`16
`
`Binder concentration (% w/ w)
`
`Fig. 2 Plot of the mean granule size as a function of binder concentration for the
`granulation of lactose. (From Ref. 6.)
`
`I I~
`
`I
`
`I
`
`40
`
`...
`E
`~
`"'
`-"' JO
`:r
`I-
`t:> z
`w a:
`1-
`"' 20
`w
`...1
`;:;;
`z
`w
`1-
`
`10
`
`2
`
`J
`4
`POVIDONE,%
`
`5
`
`6
`
`7
`
`Fig. 3 The influence of povidone on the tensile strength of tablets of dibasic cal(cid:173)
`cium phosphate dihydrate compressed at 226R (solid line) and at 4536 kg (dashed
`line); ,\,axial ; o , radial. (From Ref. 7.)
`
`Par Pharm., Inc.
`Exhibit 1022
`Page 013
`
`

`

`70
`
`80
`
`70
`
`Khankari and Hontz
`
`N
`
`I 60
`E
`z
`! 50
`:!: L.O
`Ol c
`<II .:: 30
`
`lll
`
`<II
`
`·- 20
`lll
`c
`<II
`1- 10
`
`0
`
`0
`
`.
`r
`T
`T
`L-.!.---o-o T
`o
`1''-o
`1
`. \
`1
`~
`'
`~-c:~
`~/
`~ ~~T
`i
`T ,~'
`o - - c
`1
`'
`
`' 0
`
`5
`
`10
`15
`Moisture content ("/. w/w)
`
`20
`
`Fig. 4 The effect of moisture content on the tensile strength of binder tilms: •,
`gelatin; &, methylhydroxyethylcellulose; • . starch; o, acacia; o, PVP. The vertcal
`hars show the limits of error of the means at P = 0.95 . (From Ref. 8.)
`
`the binder matrix primarily determine the effectiveness of the binder. Healey
`et al. [8] measured the tensile strengths of the films of acacia, gelatin, meth- .
`ylhydroxyethylcellulose, PVP, and starch prepared with varying moisture
`levels by equilibration at different relative humidities. Figure 4 shows the
`effect of moisture content on the tensile strength of these binders. The results
`show that acacia and PVP form weak films, whereas gelatin films possess
`the highest tensile strength. These results compare well with the crushing
`strength results shown earlier in Fig. 1. Healey et al. [8] also showed that
`PVP exhibited low values of Young's modulus, showing that it is the most
`deformable binder. This high deformability of PVP aids consolidation during
`compaction. Consequently, PVP is the most preferred wet binder of choice
`[9]. These results show that the efficiency of a granule binder is determined
`by its film-forming properties and deformation behavior [10].
`
`C. Properties of the Drug and Other Excipients in the
`Formulation
`
`The process of wet granulation is dependent on the wetting of the powder
`by the granulating fluid, surface tension of the lenticular bridge films formed,
`
`Par Pharm., Inc.
`Exhibit 1022
`Page 014
`
`

`

`Binders and Solvents
`
`71
`
`and the viscosity of the solution. During wet massing and the stages of
`drying, the drug and any soluble excipients will dissolve and then recrys(cid:173)
`talize, forming solid interparticulate bridges as the binder vehicle is evapo(cid:173)
`rated. The strength of the crystalline bridges depends on the amount depos(cid:173)
`ited and rate of crystallization. Both these properties are dependent on the
`solubility of the drug and other excipients in the granulating solvent. Con(cid:173)
`sequently, the binder solvent will influence the granule formation and growth
`during wet massing, and the structure of the granules if the drug is soluble
`in the vehicle.
`Wells and Walker [ 11 J reported the effect of wet-massing acetylsali(cid:173)
`cylic acid with aqueous and hydroalcoholic solutions of PVP. The greater
`drug solubility produced granules of larger size, tighter particle size distri(cid:173)
`bution, and reduced friability. The friability of the tablets was not reduced
`by secondary binding caused by solute deposition. High drug solubility in
`the binder solution produced tablets with poor disintegration properties.
`
`D. Binder-Substrate Interactions
`
`Major determinants of granule and tablet strength are wettability of the sub(cid:173)
`the binder, binder cohesion, and binder-substrate adhesion
`strate by
`[10,12,13]. Rowe [14-16) , in a series of publications, presented theoretical
`approaches to predict the binder- substrate interactions. Rowe showed that
`for a low-polarity substrate, such as griseofulvin, either PVP or starch would
`be the optimal binder, whereas for high-polarity substrates, such as theoph(cid:173)
`ylline, acacia or HPMC would be the optimal binder. This approach is based
`solely on the hypothesis that optimum spreading of the binder is the main
`criterion for successful formulation. It does not take into account other
`equally important factors, such as disintegration, dissolution, and flow prop(cid:173)
`erties. However, the study shows the potential of using the theoretical ap(cid:173)
`proach in binder selection and formulation optimization.
`Parker et a!. [17] studied the interactions during wet granulation be(cid:173)
`tween microcrystalline cellulose and aqueous solutions of two molecular
`weight grades of PVP and of HPMC. They showed that the rheological
`behavior of the granulations indicated that the behavior of the two molecular
`weight grades of the same polymer at equivalent viscosity was different. The
`differences were explained on the basis of differences in the surface tension,
`intragranule porosity, and polymer adsorption of HPMC on microcrystalline
`cellulose.
`
`E. Binder Distribution
`
`The distribution of binder in the granules influences its ability to produce
`strong and nonfriable granules. The factors that resist the distribution of the
`
`Par Pharm., Inc.
`Exhibit 1022
`Page 015
`
`

`

`72
`
`Khankari and Hontz
`
`binder solution during wet granulation reduce the efficiency of the binder.
`For example, very viscous binder solutions, such as starch paste, may pro(cid:173)
`duce more friable granules and tablets.
`The processing methods used to distribute the binder can influence the
`binder efficiency. Seager et al. [18,19] and Rue et al. [20] compared the
`granules and tablets of acetaminophen prepared by wet massing, dry gran(cid:173)
`ulation (i.e., roller compaction), and spray-drying of the substrate - binder
`slurry. Hydrolyzed gelatin was used as a binder. The · distribution of the
`binder influenced the strength and rate of disintegration and dissolution of
`the tablets. Wet massing produced a sponge-like matrix that embedded sub(cid:173)
`strate particles, whereas the roller compaction produced a distribution of
`discrete particles in the substrate particles. Spray-drying coated the granules
`with an outer shell of the binder. Spray-drying produced tablets that were
`superior to the other two methods.
`During wet massing, the binder may be dissolved in the granulating
`solvent, which is then added to the powder blend. The binder can also be
`mixed dry with the powder blend, and the granulating solvent is added to
`the mixture. During the latter process, the binder is dissolvt:d in the solvent
`in situ. This process may produce local points of high viscosity in the blend
`that may oppose distribution of the binder. This may lead to incomplete
`dissolution of the binder. Consequently, the dry blending of the binders,
`generally, requires higher concentration of the binder in the formula.
`In a fluid bed granulation process, the factors influencing the droplet
`size of the binder solution must be carefully controlled because the granule
`size is directly related to the droplet size . Thus, ·the concentration and vis(cid:173)
`cosity of the binder solution and the type of binder used will determine the
`particle size of the granules in a fluidized bed process.
`The effectiveness of the binder is related to various factors related to
`the properties of the binder, properties of the drug substance, type of gran(cid:173)
`ulating solution, interaction between the binder and the substrate, and the
`processing method used. Consequently, it is difficult to predict the effect of
`a particular binder in a particular system. Thus, the effectiveness of a binder
`must be experimentally evaluated.
`
`REFERENCES
`
`1. A Wade, PJ Walker, eds. Handbook of Pharmaceutical Excipients. 2nd ed.
`London: Pharmaceutical Press, 1994.
`2. HA Lieberman, L Lachman, JB Schwartz, eds. Pharmaceutical Dosage Forms:
`Tablets. Vol 1, 2nd ed. New York: Marcel Dekker, 1989.
`
`Par Pharm., Inc.
`Exhibit 1022
`Page 016
`
`

`

`Binders and Solvents
`
`73
`
`8.
`
`10.
`
`3. HG Kristensen. In: Binders; Encyclopedia of Pharmaceutical Technology. New
`York: Marcel Dekker, 1993, pp. 451-465.
`4. RW Mendes, SB Roy. Tableting cxcipients, Part II. Pharm Techno! 3:6 1, 197K
`5. NA Armstrong, GA March. J Pharrn Sci 65:200, 1976
`6. BD Rohera, A Zahir. Granualtions in a fluidized-bed : effect of binders and
`their concentrations on the granule growth and modeling relationship between
`granule size and binder concentration. Drug Dev lnd Pharm 19:773, 1993.
`7. PJ Jarosz, EL Parrott. Factors influencing axial and radial strength of tablets.
`J Pharm Sci 71 :607, 1982.
`JNC Healey, MH Rubinstein, V Walter. The mechanical properties of some
`binders used in tableting. J Pharm Pharmacol Suppl 26:41 P, 1974.
`9. RF Shangraw, DA Demarest Jr. A survey of current industrial practices in the
`formulation and manufacture of tablets and capsules. Pharm Techno! 17:32,
`1993.
`I Krycer, DG Pope, JA Hersey. An evaluation of tablet binding agents. Part I.
`Solution binders. Powder Techno! 34:39, 1983.
`JI Wells, CV Walker. The influence of granulating tluids upon granule and
`tablet properties: the role of secondary binding. lnt J Pharrn 15:97, 1983.
`I Krycer, DG Pope, JA Hersey. An evaluation of tablet binding agents. Part II.
`Pressure binders. Powder Techno! 34:53.