`
`CIP2107
`Argentum Pharmaceuticals LLC v. Cipla Ltd.
`IPR2017-00807
`
`
`
`NNNNNNNNNNNNNR0
`
`2
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`
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`
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`
`Printed in the United States of America
`
`Entered according to Act of Congress, in the year 1885 by Joseph P Remington,
`in the Office of the Librarian of Congress, at Washington DC
`
`Copyright 1889, 1894, 1905, 1907, 1917, by Joseph P Remington
`
`Copyright 1926, 1936, by the Joseph P Remington Estate
`
`Copyright 1948, 1951, by the Philadelphia College of Pharmacy and Science
`Copyright 1956, 1960, 1965, 1970, 1975, 1980, 1985, 1990, 1995, by the Phila-
`delphia College of Pharmacy and Science
`
`Copyright 2000, by the University of the Sciences in Philadelphia
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`The use of structural formulas from USAN and the USP Dictionary of Drug
`Names is by permission of The USP Convention. The Convention is not respon.
`sible for any inaccuracy contained herein.
`Notice—This text is not intended to represent, nor shall it be interpreted to be, the
`equivalent of or a substitute for the official United States Pharmacopeia (USP)
`and/or the National Formulary (NF). In the event of any difference or discrep-
`ancy between the current official USP or NF standards of strength, quality,
`purity, packaging and labeling for drugs and representations ofthem herein, the
`context and effect of the official compendia shall prevail.
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`1 02 03 O4
`6 7 8 9 10
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`3
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`
`
`. A treatise on the theory
`.
`Remington: The Science and Practice of Pharmacy .
`and practice of the pharmaceutical sciences, with essential
`information about pharmaceutical and medicinal agents; also, a
`guide to the professional responsibilities of the pharmacist as the
`drug information specialist of the health team .
`.
`. A textbook and
`reference work for pharmacists, physicians, and other practitioners of
`the pharmaceutical and medical sciences.
`
`EDITORS
`
`Alfonso R Gennaro, Chair
`Ara H Der Marderosian
`
`Glen R Hanson
`
`Thomas Medwick
`
`Nicholas G Popovich
`Roger L Schnaare
`
`Joseph B Schwartz
`
`H Steve White
`
`AUTHORS
`
`The 119 chapters of this edition of Remington were written by the
`editors, by members of the Editorial Board, and by the authors
`
`listed on pages viii to x.
`
`Managing Editor
`Editorial Assistant
`
`John E Hoover, BSc (Pharm)
`Bonnie Brigham Packer, RNC, BA
`
`Director
`
`Philip P Gerbino 199542000
`
`Twentieth Edition——2000
`
`Published in the 180th year of the
`PHILADELPHIA COLLEGE OF PHARMACY AND SCIENCE
`
`4
`
`
`
`
`
`CHAPTERZZ
`
`Coarse Dispersions
`
`James Swarbrick, DSc, PhD
`Vice President for Research and Development
`Applied Analytical Industries, lnc
`Wilmington, NC 28405
`
`Joseph T Rubino, PhD
`Section Head, Chemical Biological Pharmaceutical
`Development
`Wyeth-Ayerst Research
`Pearl River, NY 10965
`
`Orapin P Rubino, PhD
`Process Development Scientist
`Glatt Air Techniques, lnc
`Ramsey, NJ 07446
`
`
`
`Once the process of dispersion begins there develops simul-
`taneously a tendency for the system to revert to an energeti-
`cally more stable state, manifested by flocculation, coalescence,
`sedimentation, crystal growth, and caking phenomena. If these
`physical changes are not inhibited or controlled, successful
`dispersions will not be achieved or will be lost during shelf-life.
`
`
`
`INTERFACIAL PROPERTIES
`
`” B
`
`ecause suspensions and emulsions are dispersions of one
`phase Within another, the process of dispersion creates a tre—
`mendous increase in interfacial area between the dispersed
`particles or droplets and the dispersion medium. When consid—
`ering the interfacial properties of dispersed particles, two fac-
`tors must be taken into account, regardless of whether the
`dispersed phase is solid or liquid. The first relates to an in—
`crease in the free energy of the surface as the particle size is
`reduced and the specific surface increased. The second deals
`with the presence of an electrical charge on the surface of the
`dispersed particles.
`SURFACE FREE ENERGY—When solid and liquid ma-
`terials are reduced in size, they tend to agglomerate or stick
`together. This clumping, which can occur either in an air or
`liquid medium, is an attempt by the particles to reduce the
`excess free energy of the system. The increase in surface free
`energy is related to the increase in surface area produced when
`the mean particle size is reduced. It may be expressed as
`
`AF = yAA
`
`(1)
`
`where AF is the increase in surface free energy in ergs, AA is the
`increase in surface area in cm2, and y is the interfacial tension in
`dyn/cm, between the dispersed particle or droplet and the disper—
`sion medium. The smaller AF is, the more thermodynamically
`stable is the suspension of particles. A reduction in AF is effected
`often by the addition of a wetting agent (discussed in Chapter 20),
`which is adsorbed at the interface between the particle and the
`vehicle, thereby reducing the interfacial tension. This causes the
`particles to remain dispersed and settle relatively slowly. Unfor-
`tunately, in solid—liquid suspensions, the particles can form a
`hard cake at the bottom of the container when they eventually
`settle. Such a sediment, which can be extremely difficult to redis—
`perse, can lead to dosing errors when the product is administered
`to the patient.
`SURFACE POTENTIAL—As discussed in Chapter 20, both
`attractive and repulsive forces exist between particles in a liquid
`medium. The balance between these opposing forces determines
`Whether two particles approaching each other actually make con-
`tact or are repulsed at a certain distance of separation. Although
`much of the theoretical work on electrical surface potentials has
`been carried out on lyophobic colloids, the theories developed in
`this area have been applied to suspensions and emulsions.
`
`This chapter includes the formation of suspensions and emul-
`sions and the factors that influence their stability and perfor-
`mance as dosage forms. For the purpose of the present discus—
`sion, a dispersed system, or dispersion, will be regarded as a
`two-phase system in which one phase is distributed as particles
`or droplets in the second, or continuous, phase. In these sys—
`tems, the dispersed phase frequently is referred to as the dis-
`continuous or internal phase, and the continuous phase is
`called the external phase or dispersion medium. Discussion
`will be restricted to those solid—liquid and liquid—liquid disper—
`sions that are of pharmaceutical significance, namely, suspen—
`sions and emulsions. However, more complicated phase sys—
`tems (eg, a combination of liquid and liquid crystalline phases)
`can exist in emulsions. This situation will be discussed in the
`section dealing with emulsions.
`All dispersions may be classified into three groups based of
`the size of the dispersed particles. Chapter 21 deals with one
`such group—colloidal dispersions—in which the size of the
`dispersed particles is in the range of approximately 1 nm to 0.5
`pm. Molecular dispersions, the second group in this classifica-
`tion, are discussed in Chapter 20. The third group, consisting of
`coarse dispersions in which the particle size exceeds 0.5 um, is
`the subject of this chapter. Knowledge of coarse dispersions is
`essential for the preparation of both pharmaceutical suspen—
`sions (solid—liquid dispersions) and emulsions (liquid—liquid
`dispersions).
`
`
`
`THE DISPERSION STEP
`
`# T
`
`he pharmaceutical formulator is concerned primarily with
`producing a smooth, uniform, easily flowing (pouring or spread-
`ing) suspension or emulsion in Which dispersion of particles can
`be effected with minimum expenditure of energy.
`In preparing suspensions, particle—particle attractive forces
`need to be overcome by the high shearing action of such devices
`as the colloid mill, or by use of surface-active agents. The latter
`greatly facilitate wetting of lyophobic powders and assist in the
`removal of surface air that shearing alone may not remove;
`thus, the clumping tendency of the particles is reduced. More—
`over, lowering of the surface free energy by the adsorption of
`these agents directly reduces the thermodynamic driving force
`opposing dispersion of the particles.
`In emulsification, shear rates are frequently necessary for
`dispersion of the internal phase into fine droplets. The shear
`forces are opposed by forces operating to resist distortion and
`subsequent breakup of the droplets. Again surface-active
`agents help greatly by lowering interfacial tension, which is the
`primary reversible component resisting droplet distortion.
`Surface-active agents also may play an important role in de-
`termining whether an oil-in-Water (O/W) or a water—in-oil
`(W/O) emulsion preferentially survives the shearing action.
`
`316
`
`5
`
`
`
`COARSE DISPERSIONS
`
`317
`
`
`
`A pharmaceutical suspension may be defined as a coarse dis-
`persion containing finely divided insoluble material suspended
`in a liquid medium. Suspension dosage forms are given by the
`oral route,
`injected intramuscularly or subcutaneously,
`in—
`stilled intranasally, inhaled into the lungs, applied to the skin
`as topical preparations, or used for ophthalmic purposes in the
`eye. They are an important class of dosage form. Because some
`products occasionally are prepared in a dry form to be placed in
`suspension at the time of dispensing by the addition of an
`appropriate liquid vehicle, this definition is extended to include
`these products.
`There are certain criteria that a well-formulated suspension
`should meet. The dispersed particles should be of such a size
`that they do not settle rapidly in the container. However, in the
`event that sedimentation does occur, the sediment must not
`form a hard cake. Rather, it should be capable of redispersion
`with a minimum of effort on the part of the patient. Finally, the
`product should be easy to pour, have a pleasant taste, and be
`resistant to microbial attack.
`The three major concerns associated with suspensions are
`1. Ensuring adequate dispersion of the particles in the vehicle.
`2. Minimizing settling of the dispersed particles.
`3. Preventing caking of these particles when a sediment forms.
`
`Much of the following discussion will deal with the factors
`that influence these processes and the ways in which settling
`and caking can be minimized.
`FLOCCULATION AND DEFLOCCULATION—Zeta po-
`tential, (pz, is a measurable indication of the potential existing
`at the surface of a particle. When (pz is relatively high (25 mV
`or more), the repulsive forces between two particles exceed the
`attractive London forces. Accordingly, the particles are dis-
`persed and are said to be deflocculated. Even when brought
`close together by random motion or agitation, defiocculated
`particles resist collision due to their high surface potential.
`The addition of a preferentially adsorbed ion whose charge
`is opposite in sign to that on the particle leads to a progressive
`lowering of 932. At some concentration of the added ion, the
`electrical forces of repulsion are lowered sufficiently and
`the forces of attraction predominate. Under these conditions
`the particles may approach each other more closely and form
`loose aggregates, termed flocs. Such a system is said to be
`flocculated.
`Some workers restrict the term “flocculation” to the aggre-
`gation brought about by chemical bridging; aggregation involv-
`ing a reduction of repulsive potential at the double layer is
`referred to as coagulation. Other workers regard flocculation as
`aggregation in the secondary minimum of the potential energy
`curve of two interacting particles and coagulation as aggrega~
`
`tion in the primary minimum. In the present chapter the term
`flocculation is used for all aggregation processes, irrespective of
`mechanism.
`The continued addition of the flocculating agent can reverse
`the above process, if the zeta potential increases sufficiently in
`the opposite direction. Thus, the adsorption of anions onto
`positively charged, deflocculated particles in suspension will
`lead to flocculation. The addition ofmore anions eventually can
`generate a net negative charge on the particles. When this has
`achieved the required magnitude, deflocculation may occur
`again. The only difference from the starting system is that the
`net charge on the particles in their deflocculated state is neg-
`ative rather than positive. Some of the major differences be-
`tween suspensions offlocculated and deflocculated particles are
`presented in Table 22—1.
`FLOCCULATION KINETICS—The rate at which floccu-
`lation occurs is a consideration in the stability of suspended
`dispersions. Whether flocculation is judged to be rapid or slow
`depends on the presence of a repulsive barrier between adja-
`cent particles. In the absence of such a barrier, and for a
`monodispersed system, rapld flocculation occurs at a rate given
`by the Smoluchowski equation
`
`SN/St = ~417DRA72
`
`(2)
`
`where 8N/5t is the disappearance rate of particles/mL, R is
`the distance between the centers of the two particles in
`contact, N is the number of particles per mL, and D is the
`diffusion coefficient. Under these conditions the rate is pro-
`portional to the square of the particle concentration. The
`presence or absence of an energy barrier is influenced
`strongly by the type and concentration of any electrolyte
`present. When an energy barrier does exist between adjacent
`particles, the flocculation rate likely will be much smaller
`than predicted by Equation 2.
`
`________________________.__———-—————————-—
`
`SETTLING AND ITS CONTROL
`
`To control the settling of dispersed material in suspension, the
`pharmacist must be aware of those physical factors that will
`affect the rate of sedimentation of particles under ideal and
`nonideal conditions. Also important are the various coefficients
`used to express the amount of flocculation in the system and
`the effect flocculation will have on the structure and volume of
`the sediment.
`
`Table 22-1. Relative Properties of Flocculated and Deflocculated Particles in Suspension
`
`FLOCCULATED
`DEFLOCCULATED
`
`. Particles form loose aggregates.
`1. Particles exist in suspension as separate entities.
`. Rate of sedimentation is high, as particles settle as a floc, which
`2. Rate of sedimentation is slow, as each particle settles
`is a collection of particles.
`separately and particle size is minimal.
`. A sediment is formed rapidly.
`3. A sediment is formed slowly.
`. The sediment is packed loosely and possesses a scaffold-like
`4. The sediment eventually becomes very closely packed, due to
`structure. Particles do not bond tightly to each other and a
`weight of upper layers of sedimenting material. Repulsive
`hard, dense cake does not form. The sediment is easy to
`forces between particles are overcome and a hard cake is
`redisperse, so as to reform the original suspension.
`formed that is difficult, if not impossible, to redisperse.
`. The suspension is somewhat unsightly, due to rapid
`5. The suspension has a pleasing appearance, as the suspended
`sedimentation and the presence of an obvious, clear
`material remains suspended for a relatively long time. The
`supernatant region. This can be minimized if the volume of
`supernate also remains cloudy, even when settling is
`sediment is made large. Ideally, volume of sediment should
`apparent.
`encompass the volume of the suspension.
`
`
`6
`
`
`
`318
`
`CHAPTER 22
`
`Sedimentation Rate
`
`The rate at which particles in a suspension sediment is related
`to their size and density and the viscosity of the suspension
`medium. Brownian movement may exert a significant effect, as
`will the absence or presence of flocculation in the system.
`STOKES’ LAW—The velocity of sedimentation of a uni-
`form collection of spherical particles is governed by Stokes’ law,
`expressed as
`
`_ 27'20’1 " 92M
`v — m9“
`
`(3)
`
`where v is the terminal velocity in cm/sec, r is the radius of the
`particles in cm, p1 and p2 are the densities (g/cmg) of the
`dispersed phase and the dispersion medium, respectively, g is
`the acceleration due to gravity (980.7 cm/sec2), and n is the
`Newtonian viscosity of the dispersion medium in poises (g/cm
`sec). Stokes’ law holds only if the downward motion of the
`particles is not sufficiently rapid to cause turbulence. Micelles
`and small phospholipid vesicles do not settle unless they are
`subjected to centrifugation.
`While conditions in a pharmaceutical suspension are not in
`strict accord with those laid down for Stokes’ law, Equation 3
`provides those factors that can be expected to influence the rate
`of settling. Thus, sedimentation velocity will be reduced by
`decreasing the particle size, provided that the particles are
`kept in a deflocculated state. The rate of sedimentation will be
`an inverse function of the viscosity of the dispersion medium.
`However, too high a viscosity is undesirable, especially if the
`suspending medium is Newtonian rather than shear—thinning
`(see Chapter 23), because it then becomes difficult to redisperse
`material that has settled. It also may be inconvenient to re-
`move a Viscous suspension from its container. When the size of
`particles undergoing sedimentation is reduced to approxi-
`mately 2 ,um, random Brownian movement is observed and the
`rate of sedimentation departs markedly from the theoretical
`predictions of Stokes’ law. The actual size at which Brownian
`movement becomes significant depends on the density of the
`particle as well as the viscosity of the dispersion medium.
`EFFECT OF FLOCCULATION—In a deflocculated sys—
`tem containing a distribution of particle sizes, the larger par-
`ticles naturally settle faster than the smaller particles. The
`very small particles remain suspended for a considerable
`length of time, with the result that no distinct boundary is
`formed between the supernatant and the sediment. Even when
`a sediment becomes discernible,
`the supernatant remains
`cloudy.
`When the same system is flocculated (in a manner to be
`discussed later), two effects are immediately apparent. First,
`the fines tend to fall together, so a distinct boundary between
`the sediment and the supernatant is readily observed; second,
`the supernatant is clear, showing that the very fine particles
`have been incorporated into the flocs. The initial rate of settling
`in flocculated systems is determined by the size of the flocs and
`the porosity of the aggregated mass. Under these circum-
`stances it is perhaps better to use the term subsidence, rather
`than sedimentation.
`
`Quantitative Expressions
`of Sedimentation and Flocculation
`
`Frequently, the pharmacist needs to assess a formulation in
`terms of the amount of flocculation in the suspension and
`compare this with that found in other formulations. The two
`parameters commonly used for this purpose are outlined below.
`SEDINIENTATION VOLUNIE—The sedimentation vol-
`ume, F, is the ratio of the equilibrium volume of the sediment,
`V,,, to the total volume of the suspension, V0. Thus,
`
`l
`l
`
`lI
`II
`‘1
`
`l"I'In‘“.I
`
`Deflocculated
`
`Flocculated
`
`Figure 22—1. Sedimentation parameters of suspensions. Defloccu~
`Iated suspension: F,c = 0.15. Flocculated suspension: F = 0.75;
`e = 5.0.
`
`F : VII/V0
`
`(4)
`
`impart
`
`As the volume of suspension that appears occupied by the
`sediment increases, the value of F, which normally ranges from
`nearly 0 to 1, increases. In the system where F = 0.75, for
`example, 75% of the total volume in the container is apparently
`occupied by the loose, porous flocs forming the sediment. This is
`illustrated in Figure 22-1. WhenF = 1, no sediment is apparent
`even though the system is flocculated. This is the ideal suspen-
`sion for, under these conditions, no sedimentation will occur.
`Caking also will be absent. Furthermore, the suspension is
`esthetically pleasing, there being no visible, clear supernatant.
`DEGREE OF FLOCCULATION—A better parameter for
`comparing flocculated systems is the degree of flocculation, [3,
`which relates the sedimentation volume of the flocculated sus-
`pension, F,
`to the sedimentation volume of the suspension
`when deflocculated, Fm. It is expressed as
`
`e = F/Fx
`
`(5)
`
`The degree of flocculation is, therefore, an expression of the
`increased sediment volume resulting from flocculation. If, for
`example, ,8 has a value of 5.0 (see Fig 22—1), this means that the
`volume of sediment in the flocculated system is five times that
`in the deflocculated state. If a second flocculated formulation
`results in a value for [3 of say 6.5, this latter suspension obvi—
`ously is preferred, if the aim is to produce as flocculated a
`product as possible. As the degree of flocculation in the system
`decreases, B approaches unity, the theoretical minimum value.
`
`FORMULATION OF SUSPENSIONSm
`
`The formulation of a suspension possessing optimal physical
`stability depends on whether the particles in suspension are to
`be flocculated or to remain deflocculated. One approach in—
`volves use of a structured vehicle to keep deflocculated parti-
`cles in suspension; a second depends on controlled flocculation
`as a means of preventing cake formation. A third, a combina-
`tion of the two previous methods, results in a product with
`optimum stability. The various schemes are illustrated in
`Figure 22—2.
`DISPERSION OF PARTICLES—The dispersion step has
`been discussed earlier in this chapter. Surface—active agents
`commonly are used as wetting agents; maximum efficiency is
`obtained when the HLB value lies within the range of 7 to 9. A
`concentrated solution of the wetting agent in the vehicle may
`be used to prepare a slurry of the powder; this is diluted with
`the required amount of vehicle. Alcohol and glycerin may be
`used sometimes in the initial stages to disperse the particles,
`thereby allowing the vehicle to penetrate the powder mass.
`Only the minimum amount of wetting agent should be used,
`compatible with producing an adequate dispersion of the par—
`ticles. Excessive amounts may lead to foaming or
`
`7
`
`
`
`COARSE DISPERSIONS
`
`319
`
`This principle is illustrated by reference to the following
`example, taken from the work of Haines and Martin.2 Particles
`of sulfamerazine in water bear a negative charge. The serial
`addition of a suitable electrolyte, such as aluminum chloride,
`causes a progressive reduction in the zeta potential of the
`particles. This is due to the preferential adsorption of the
`trivalent aluminum cation. Eventually, the zeta potential Will
`reach zero and then become positive as the addition of A1013 is
`continued.
`If sedimentation studies are run simultaneously on suspen—
`sions containing the same range of A1013 concentrations, a
`relationship is observed (Fig 22-3) between the sedimentation
`volume F, the presence or absence of caking, and the zeta
`potential of the particles. To obtain a flocculated, noncaking
`suspension with the maximum sedimentation volume, the zeta
`potential must be controlled so as to lie within a certain range
`(generally less than 25 mV).This is achieved by the judicious
`use of an electrolyte. A comparable situation is observed when
`a negative ion such as P043” is added to a suspension of
`positively charged particles such as bismuth subnitrate.
`Work by Matthews and Rhodes3"5 involving both experi-
`mental and theoretical studies has confirmed the formulation
`principles proposed by Martin and Haines. The suspensions
`used by Matthews and Rhodes contained 2.5% w/u of griseo-
`fulvin as a fine powder together with the anionic surfactant
`sodium dioxyethylated dodecyl sulfate (10'3 molar) as a wet—
`ting agent. Increasing concentrations of aluminum chloride
`were added and the sedimentation height (equivalent to the
`sedimentation volume, see Chapter 21) and the zeta potential
`recorded. Flocculation occurred when a concentration of 10‘3
`molar aluminum chloride was reached. At this point the zeta
`potential had fallen from ~46.4 to —17.0 mV. Further reduction
`of the zeta potential, to ——4.5 mV by use of 10’2 molar aluminum
`chloride did not increase sedimentation height, in agreement
`with the principles shown in Figure 22-3.
`Matthews and Rhodes then went on to show, by computer
`analysis, that the DLVO theory (see Chapter 21 ) predicted the
`results obtained—namely, that the griseofulvin suspensions
`under investigation would remain deflocculated when the con-
`centration of aluminum chloride was 10“4 molar or less. Only
`at concentrations in the range of 10‘3 to 10‘2 molar aluminum
`chloride did the theoretical plots Show deep primary minima,
`indicative of flocculation. These occurred at a distance of sep-
`aration between particles of approximately 50 A, which led
`
`Caking
`
`INocakingI
`
`Caking
`
`
`
`J'aLunwAuoneiuawipas
`
`(D
`
`
`
`Zeta-potential(mv)
`
`
`
`Cationic fiocculating
`agent
`
`Figure 22-3. Typical relationship between caking, zeta potential,
`and sedimentation volume, as a positively charged flocculating
`agent is added to a suspension of negatively charged particles. 0:
`zeta potential. I: sedimentation volume.
`
`Addition of wetting agent and dispersion medium
`
` r—"
`
`Uniform dispersion of
`deflocculated particles
`
`A
`Incorporation of
`structured vehicle
`
`B
`Addition of
`flocculating agent.
`
`—‘-1
`(I:
`Addition of
`flocculating agent
`
`
`
`Flacculated
`Flocculated
`suspensmn
`suspension
`as final product
`
`
`as final product.
`
`Incorporation of
`structured vehicle
`
`Flocculated
`suspension
`in structured vehicle
`
`
`
`
`Deflocculated
`
`’ suspension
`
`in structured vehicle
`as final product
`
`
`
`
`Figure 22-2. Alternative approaches to the formulation of
`suspensions.
`
`an undesirable taste or odor to the product. Invariably, as a result of
`wetting, the dispersed particles in the vehicle are deflocculated.
`STRUCTURED VEHICLES—Structured vehicles are gen-
`erally aqueous solutions of polymeric materials, such as the
`hydrocolloids, that are usually negatively charged in aqueous
`solution. Typical examples are methylcellulose, carboxymeth-
`ylcellulose, bentonite, and carbomer. The concentration em—
`ployed will depend on the consistency desired for the suspen—
`sion that, in turn, will relate to the size and density of the
`suspended particles. They function as viscosity-imparting sus-
`pending agents and, as such, reduce the rate of sedimentation
`of dispersed particles.
`The rheological properties of suspending agents are consid-
`ered elsewhere (Chapter 23). Ideally, these form pseudo—plastic
`or plastic systems that undergo shear—thinning. Some degree of
`thixotropy is also desirable. Non-Newtonian materials of this
`type are preferred over Newtonian systems because, if the
`particles eventually settle to the bottom of the container, their
`redispersion is facilitated by the vehicle thinning when shaken.
`When the shaking is discontinued, the vehicle regains its orig-
`inal consistency and the redispersed particles are held sus—
`pended. This process of redispersion, facilitated by a shear-
`thinning vehicle, presupposes that the deflocculated particles
`have not yet formed a cake. If sedimentation and packing have
`proceeded to the point where considerable caking has occurred,
`redispersion is virtually impossible.
`CONTROLLED FLOCCULATION—When using the con-
`trolled flocculation approach (see Fig 22—23 and C), the formuv
`lator takes the deflocculated, wetted dispersion of particles and
`attempts to bring about flocculation by the addition of a floc-
`culating agent; most commonly, these are electrolytes, poly-
`mers, or surfactants. The aim is to control flocculation by add—
`ing that amount of flocculating agent that results in the
`maximum sedimentation volume.
`FLOCCULATION USING ELECTROLYTES—Electro-
`lytes are probably the most widely used flocculating agents.
`They act by reducing the electrical forces of repulsion between
`particles, thereby allowing the particles to form the loose flocs
`so characteristic of a flocculated suspension. As the ability of
`particles to come together and form a floc depends on their
`surface charge, zeta potential measurements on the suspen-
`sion, as an electrolyte is added, provide valuable information as
`to the extent of flocculation in the system.
`
`8
`
`
`
`320
`
`CHAPTER 22
`
`Matthews and Rhodes to conclude that coagulation had taken
`place in the primary minimum.
`Schneider et al6 have published details of a laboratory in—
`vestigation (suitable for undergraduates) that combines calcu-
`lations based on the DLVO theory carried out with an interac-
`tive computer program with actual sedimentation experiments
`performed on simple systems.
`FLOCCULATION BY POLYMERS—Polymers can play
`an important role as flocculating agents in pharmaceutical
`suspensions. As such, polymers can have an advantage over
`ionic flocculating agents in that they are less sensitive to added
`electrolytes. This leads to a greater flexibility in the use of
`additives such as preservatives, flavoring, and coloring agents
`that might be needed for the formulation.
`The effectiveness of a polymer as a stabilizing agent for
`suspensions primarily depends on the affinity of the polymer
`for the particle surface as well as the charge, size, and orien—
`tation of the polymer molecule in the continuous phase. Many
`pharmaceutically useful polymers contain polar functional
`groups that are separated by a hydrocarbon backbone. As a
`result of this structure, many active centers exist on a given
`polymer molecule that are capable of interacting with a particle
`surface. If one considers that each of these active centers is
`reversibly adsorbed to the surface of the particle, then numer—
`ous equilibria are established between each of the active cen-
`ters of a given polymer molecule and a particle. At any partic—
`ular time, some active centers will be adsorbed and others will
`be desorbed, but due to the large numbers of active centers, it
`is highly unlikely that all sites will be desorbed at the same
`time. This model may account for the strong attraction of many
`pharmaceutically useful polymers for dispersed solids.
`Although DLVO theory provides the most successful de—
`scription of suspension stability in general, it does not always
`predict the behavior of suspensions that are formulated with
`polymeric stabilizing agents. This is because factors other than
`electrostatic interactions are responsible for flocculation and
`other interparticle interactions in suspensions. As observed
`with ionic flocculating agents, polymers can produce both floc-
`culated and deflocculated suspensions. It is believed that the
`primary mechanism by which polymers act as flocculants is due
`to the bridging of the polymer between the surfaces of two
`different particles. The effect can be highly concentration de—
`pendent as illustrated in Figure 22-4. The effect has been
`interpreted as follows.
`At very low concentrations of polymer, a large number of
`sites on the surface of the dispersed solid are available for
`adsorption of polymer. Bridging between particles occurs as a
`result of the simultaneous adsorption of a polymer molecule
`onto the surfaces of different particles. At low polymer concen-
`trations, the number of particle-particle bridges is relatively
`low. At somewhat higher concentrations of polymer, sufficient
`binding sites are still available on the particles, permitting
`additional interparticle attachments to form. It is these inter-
`mediate concentrations that result in optimum flocculation and
`sedimentation volume. At high concentrations of polymer, com-
`plete coverage of the particle surface with polymer occurs and
`insufficient binding sites remain on the particles to permit
`interparticle bridging. In this instance, the polymer can lead to
`the formation of a deflocculated or peptized system because
`adsorbed layers of polymer on separate particles will prevent
`close attraction of the particles via the phenomenon of steric
`stabilization (di