PHARMACEUTICAL
`DOSAGE FORMS
`Disperse Systems
`In Three Volumes
`VOLUME2
`Second Edition, Revised and Expanded
`
`EDITED BY
`Herbert A. Lieberman
`H. H. Lieberman Associates, Inc.
`Livingston, New Jersey
`Martin M. Rieger
`M. & A. Rieger Associates
`Morris Plains, New Jersey
`Gilbert S. Banker
`University of Iowa
`Iowa City, Iowa
`
`Marcel Dekker, Inc.
`
`New York • Basel• Hong Kong
`
`LUYE1014
`IPR of Patent No. 6,667,061
`
`

`
`ISBN: 0-8247-9713-2
`The publisher offers discounts on this book when ordered in bulk quantities. For more
`information, write to Special Sales/Professional Marketing at the address below.
`This book is printed on acid-free paper.
`Copyright © 1996 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, microfilming, 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
`Current printing (last digit):
`10 9 8 7 6 5 4 3 2 1
`PRINTED IN THE UNITED STATES OF AMERICA
`
`LUYE1014
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`3. Dissolve preservative in sufficient purified water and slowly add to step 1 with
`agitation.
`4. Mix calamine, zinc oxide, and colorant together and suspend in step l with agi-
`tation.
`5. Add fragrance and pass suspension through a colloid mill or homogenizer rinsing
`through with purified water.
`6. Bring suspension to final volume with purified water.
`
`1,'
`
`Formula 6 Barium Sulfate Oral Suspension
`
`Barium sulfate, microcrystals
`Docusate, sodium
`Colloidal microcrystalline cellulose
`Emulsifying wax NF
`Preservative blend
`Flavor
`Saccharin, sodium
`High fructose corn syrup (SpG = 1.4 i)
`Purified water, qs ad
`
`35.0% w/v
`0.16% w/v
`1.5% w/v
`2.0% w/v
`qs
`qs
`qs
`20.0% w/v
`100%
`
`Procedure
`1. Dissolve docusate, sodium, in a portion of purified water and thoroughly wet
`barium sulfate overnight.
`2. Dissolve preservative blend and saccharin, sodium, in a separate portion of puri-
`fied water.
`3. Disperse colloidal microcrystalline cellulose imd emulsifying wax in step 2 with
`agitation.
`4. Add the barium sulfate slurry (step l) to step 3 with agitation.
`5. Add flavor and high fructose corn syrup to step 4.
`6. Pass suspension through a colloidal mill or homogenizer, rinsing through with
`purified water.
`7. Add purified water to final volume.
`
`V. FORMULATION OF SUSPENSIONS
`During the preparation of physically .stable pharmaceutical suspensions, a number of
`formulation components are employed to help keep the solid particles in a state of sus-
`pension (suspending agents), whereas other components are merely part of the liquid
`vehicle itself. These formulation components are classified as follows:
`1. Components of the suspending system
`a. Wetting agents
`b. Dispersants or deflocculation agents
`c. Flocculating agents
`d. Thickeners
`2. Components of the suspending vehicle or external phase
`e. pH control agents and buffers
`f. Osmotic agents
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`Pharmaceutical Suspensions
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`g. Coloring agents, flavors and fragances
`h. Preservatives to control microbial growth
`i. Liquid vehicles
`Not all of the components listed above are required in each of the three types of phar-
`maceutical suspensions: oral, topical, and parenteral.
`
`A. Wetting Agents
`According to Idson and Scheer [62], certain solids are readily wet by liquids, whereas
`others are not. The degree of wettability depends on the affinity of drugs for water, and
`whether the solids are hydrophilic or hydrophobic. Hydrophilic solids are easily wet-
`ted by water and can increase the viscosity of aqueous suspensions. Hydrophobic sol-
`ids repel water but can be wetted by nonpolar liquids. When properly wetted, the lat-
`ter usually do not alter the viscosity of aqueous suspensions. Hydrophilic solids usually
`can be incorporated into suspensions without the use of wetting agents. The majority
`of drugs in aqueous suspension are, however, hydrophobic. These are extremely diffi-
`cult to suspend and frequently float on the surface of water and polar liquids due to
`entrapped air and poor wetting.
`Wetting agents are surfactants that lower the interfacial tension and contact angle
`between solid particles and liquid vehicle. If, according to Hiestand [8], a wetting agent
`is present when the powder is added to the liquid vehicle, penetration of the liquid phase
`into powder will be sufficiently rapid to permit air to escape from the particles and the
`resulting wetted particles will either sink en masse or separate with low shear agitation.
`According to hydrophile-lipophile balance (HLB) theory [9], the best range for wetting
`and spreading by nonionic surfactants lies between 7 and 10.
`A number of surfactants that may be used as pharmaceutical wetting agents are listed
`in Table 8. Note that the 7-10 HLB values listed in the table for optimum wetting are
`greater than the range normally recommended. The usual concentration of surfactant
`varies from 0.05% to 0.5% and depends on the solids content intended for suspension.
`The use of surfactants as wetting agents will also retard crystal growth in the range
`of 0.05% to 0.5%. On the other hand, employing surfactants at concentrations less than
`about 0.05% can result in incomplete wetting. Concentrations greater than 0.5% sur-
`factant may solubilize ultrafine particles and lead eventually to changes in particle size
`distribution and crystal growth.
`The high HLB surfactants are also foaming agents; however, foaming is an unde-
`sirable property during wetting of a suspension formulation. In addition, the ionic types,
`even though claimed to be more effective at the preferred concentration range than
`nonionic types, are considered pH sensitive and incompatible with many excipients.
`Most of the surfactants, except poloxamers, have a bitter taste that often rules against
`their use in oral suspensions. Nevertheless, polysorbate 80 is still the most widely used
`surfactant for suspension formulation because of its lack of toxicity and compatibility
`with most formulation ingredients. Steric stabilization of suspensions with poloxamers
`was reviewed by Rawlins and Kayes [63]. Nonoxynols and poloxamers were also found
`to be effective agents below their critical micelle concentration.
`The rate of wetting is often determined by placing a measured amount of powder
`on the undisturbed surface of water containing a given concentration of surfactant and
`measuring the time required to completely wet and sink the powder. For example, Carino
`and Mollet [64] found the most rapid sinking time for a hydrophobic solid (SpG > 1)
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`Table 8 Surfactants Used as Pharmaceutical Wetting Agents
`Surface tension
`(dynes cm- 1 at
`0.1% w/v in water)
`
`HLB• value
`
`Surfactant
`
`Anionic type
`docusate sodium
`sodium Iaury! sulfate
`Nonionic type
`polysorbate 65
`octoxynol-9
`nonoxynol-10
`polysorbate 60
`polysorbate 80
`polysorbate 40
`poloxamer 235
`polysorbate 20
`polyoxamer 188
`
`>24
`40
`
`10.5
`12.2
`13.2
`14.9
`15.0
`15.6
`16
`16.7
`29
`
`41
`43
`
`33
`30
`29
`44
`42
`41
`42
`37
`50
`
`Comment
`
`Bitter taste, foaming agent
`Bitter taste, foaming agent
`
`Bitter taste
`Bitter taste
`Bitter taste
`Bitter taste
`Most widely used, bitter taste
`Low toxicity, bitter taste
`Low toxicity, good taste
`Bitter taste
`Foaming agent
`
`•Term introduced by W. Griffin to describe the hydrophilic-lipophilic balance or properties of nonionic surfactants; it
`has a numerical value between I and 20.
`
`was at a concentration of 0.018% docusate sodium USP in water, which is above the
`critical micelle concentration of the surfactant. The authors also showed that wetting
`proceeds via liquid penetration into powder pores followed by spreading of wetted pow-
`der aggregates prior to sinking.
`The addition of smaller amounts of neutral electrolyte, such as potassium chloride,
`has been found [65] to lower the critical micelle concentration and the interfacial ten-
`sion of surfactant solutions and thus improve wetting. The resultant suspensions, how-
`ever, are more susceptible to aggregate or floc formation.
`Two simple tests have been devised by the paint industry for wetting agent evalu-
`ation.
`I. The wet point method, which measures the amount of suspending vehicle required
`to just wet all of the powder. The reduction of the wet point by an additive, such
`as a wetting agent at a particular concentration, is a practical test of wettability.
`2. The flow point method measures the amount of suspending vehicle used to achieve
`pourability, i.e., rheologic flow beyond the yield-stress value. The extent to which
`the flow point of a powder-vehicle system is reduced by a particular concentra-
`tion of wetting agent is related to the wetting agent's ability to deflocculate the
`system or its ability to inhibit the buildup of networklike structures (agglomerates).
`Both these test methods are best designed for high solids containing topical suspensions.
`
`B. Deflocculants or True Dispersing Agents
`Mitsui and Takada [66] showed that the dispersibility of a powder in water depends
`largely on the magnitude of its surface charge and" particle density, whether the pow-
`der was forcibly dispersed by applying mechanical shear or not. Deflocculating agents
`are polymerized organic salts of sulfonic acid of both alkyl-aryl or aryl-alkyl types that
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`can alter the surface charge of particles through physical adsorption. These special
`polyelectrolytes are marketed under the following trade names: Daxad (Dewey and
`Almay Chemical Co., Cambridge, MA), Darvan (R. T. Vanderbilt Co., New York,
`NY), Marasperse (Marathon Corp., Rothschild, WI), and Orzan (Crown Zellerbach,
`Camas, W A). Their mechanism of action is not completely understood, but they appear
`to function by producing a negatively charged particle or increasing the negative charge
`already present in order to aid dispersibility. The reduction of cohesive forces between
`primary particles through the repulsion of like charge helps break up floes and agglom-
`erates and also aids dispersion.
`Unlike surfactants, these agents do not appreciably lower surface and interfacial
`tension; hence they have little or no tendency to create foam or wet particles. Most
`deflocculants, however are not generally considered safe for internal use and, as a re-
`sult, the only acceptable dispersant for internal products is lecithin (a naturally occur-
`ring mixture of phosphatides and phospholipids), which is related in activity to the
`deflocculants listed above. Because lecithins are natural-occurring substances and vary
`in their water solubility and dispersibility characteristics, in order to obtain reproduc-
`ible results, proper raw material specifications of lecithins must be rigidly controlled.
`
`C. Flocculating Agents
`Simple neutral (1: 1) and cation to anion (2: 1 or 3: 1) electrolytes in solution that are
`capable of reducing the zeta potential of suspended charged particles to zero are con-
`sidered to be primary flocculating agents. The mechanism of their activity in stable floc
`formation has been described previously in this chapter. Small concentrations (0.01-1 %)
`of neutral electrolytes, such as sodium chloride or potassium chloride, are often suffi-
`cient to induce flocculation of weakly charged, water-insoluble, organic nonelectrolytes,
`such as steroids. In the case of more highly charged, insoluble polymers and polyelec-
`trolytes species, similar concentrations (0.0 1-1%) of water-soluble divalent or trivalent
`ions, such as calcium salts and alums or sulfates, citrates, and phosphates, are usually
`required to achieve floc formation depending on particle charge, positive or negative.
`Often these salts can be used jointly in formulations as pH buffers and flocculating
`agents.
`
`D. Thickeners and Protective Colloids
`Protective or hydrophilic colloids, such as gelatin, natural gums (tragacanth, xanthan,
`etc.) and cellulose derivatives (sodium carboxymethylcellulose, hydroxypropylcellulose,
`and hydroxypropylmethylcellulose), which are adsorbed, increase the strength of the
`.hydration layer formed around suspended particles through hydrogen bonding and
`molecular interaction. Since these agents do not reduce surface and interfacial tension
`greatly, they function best in the presence of a surfactant. Many of these agents are
`protective colloids in low concentrations ( < 0.1%) and viscosity builders in relatively
`high concentrations ( > 0.1 %) .
`
`E. pH Control Agents and Buffers
`A properly formulated pharmaceutical suspension should exhibit excellent physical sta-
`bility over a wide range of pH values. On the other hand, if a specific pH value is found
`necessary to provide for optimum stability and/or to minimize solubility in the suspending
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`vehicle, the system can be maintained at this desired pH value by the use of a speci-
`fied concentration of a pharmaceutically acceptable buffer. This is especially important
`for drugs that possess ionizable acidic or basic groups; then the pH of the vehicle of-
`ten influences drug stability and/or solubility. Careless or indiscriminate use of salts and
`buffers however, should be avoided, because small changes in electrolyte concentration
`will often alter the surface charge of suspended particles. Such effects can influence the
`nature and stability of flocculated suspensions. This is especially noticeable when poly-
`valent ions, such as citrates and phosphates, are used in buffering systems. Suspensions
`of stable, neutral drugs, which possess no formal charge, such as corticosteroids, are
`usually insensitive to pH change. The control of pH by buffering of these particular
`suspensions is normally required as a quality control procedure for maintaining a de-
`sired pH specification. Again, buffering components and their concentrations are often
`selected on an experimental basis so as not to adversely affect the physical stability of
`the final suspension.
`
`F. Osmotic Agents and Stabilizers
`The previous discussion also applies to the use of osmotic agents (sodium chloride, etc.)
`and stabilizers (disodium edetate, etc.), many of which are electrolytes or potential
`electrolytes in suspension products. Substituting organic nonelectrolytes, such as dex-
`trose, mannitol, or sorbitol, for inorganic salts and electrolytes to adust osmolarity or
`tonicity in an ophthalmic or injectable suspension will often reduce batch variation with
`respect to physical stability when these materials are used as osmotic agents and stabi-
`lizers.
`
`G. Colorants, Flavors, and Fragrances
`Organoleptic agents, such as colorants, flavors, or fragrances, should not normally affect
`the physical stability of topical or oral suspensions as long as the formulator realizes that
`cationic materials will interact with negatively charged suspension particles and thereby
`adversely affect physical stability.
`On the other hand, since many flavoring agents and fragrances are water-insoluble,
`oily liquids that are usually added to the batch in the final phase after the primary physi-
`cal stability of the suspension has been established, the formulator should be alert to the
`possibility that these oily materials may be adsorbed on the surface of suspended par-
`ticles and thereby influence the physical stability of the final suspension.
`
`H. Preservatives to Control Microbial Growth
`Preservation against microbial growth is an important consideration, not only in terms
`of its effect on the chemical stability of the ingredients and the safety and acceptability
`of the products but also on the physical integrity of the system. Riddick [67] indicated
`that many colloidal dispersed systems were judged unstable because they agglomerated
`in time. The effect apparently was not due to aging but to continued microbial activ-
`ity, which gradually decreased the zeta potential of the system. If such systems had been
`properly preserved, they would not have agglomerated but would have remained in a
`colloidal state of dispersion. The same may be said of systems that are prepared initially
`by controlled flocculation procedure and later deflocculate in the absence of adequate
`preservation. Adequacy of preservation is a particularly troublesome problem in antacid
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`suspensions where pH values greater than 6 or 7 often compromise the effectiveness of
`commonly used, orally accepted preservatives, such as parabens, benzoates, and sorbates.
`Sweeteners, .nonionic surfactants, and suspending agents, such as clays, gelatin,
`lecithin, natural gums, and cellulose derivatives, are particularly susceptible to micro-
`bial growth. The use of cationic antimicrobial agents, such as benzalkonium chloride,
`is usually contraindicated, because cationic agents may be inactivated by formulation
`components or they may alter the charge of the suspended particles.
`A well-preserved oral or topical suspension does not have to be sterile to prevent
`microbial growth. The use of small amounts of propylene glycol (5-15%) disodium
`edetate (about 0.1%) or a decrease of pH all have been used to increase the efficiency
`of preservative systems without adversely affecting physical stability of pharmaceutical
`suspensions [68]. A list of commonly used antimicrobial preservatives in pharmaceuti-
`cal suspensions is presented in Table 9.
`
`I. External Phase
`The suspending vehicle chosen also governs the selection of the suspending agent(s) to
`be employed. For example, in the case of nonpolar liquids, such as aliphatic or halo-
`genated hydrocarbons, fatty esters, and oils, the best suspending agents are low HLB
`surfactants, stearalkonium hectorite, water-insoluble resins, and water-insoluble film-
`formers. On the other hand, in the case of polar liquids such as water, alcohols, polyols,
`and glycols, the higher HLB surfactants, clays, silicates, gums, and cellulose derivatives
`are usually preferred. The physically most stable systems are designed to wet particles
`and then to disperse them in a gelled liquid formed by the interaction between suspending
`agent(s) and vehicle component(s). Liquid vehicles are selected based on safety, den-
`sity, viscosity, taste, and stability considerations.
`
`J. Sterile Suspensions
`In most reviews of pharmaceutical suspensions very little space is devoted to a discus-
`sion of sterile suspensions. Yet there are factors peculiar to this dosage form, which are
`not commonly shared by other suspension systems. Some of these are sterility, syringe-
`ability, ease of resuspension, slow settling after shaking, and drainage, as well as ab-
`sence of pyrogens and foreign particulate matter. Akers et a!. presented an excellent
`review of the topic [69].
`Preparation of a sterile parenteral suspension is a very difficult procedure. It requires
`complete attention to detail during the following broad phases of manufacture:
`Final recrystallization of the drug
`Size reduction of the drug
`Sterilization of the drug
`Sterilization of the vehicle
`Aseptic wetting of the powder with a portion of the sterile vehicle
`Aseptic dispersion and milling of the bulk suspension
`Aseptic filling of the finished suspension into sterile containers
`Alternate procedures for the manufacture of sterile suspensions have been reported
`separately by Akers et a!. [ 69], Grimes [70], and Portnoff [71]. At the present time,
`there is no pharmaceutically acceptable chemical agent that can be added to the finished
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`LUYE1014
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`:::r-
`(/)
`OJ
`<:
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`1\)
`c.u
`
`•The preservatives phenol, chlorocresol, phenylmercuric acetate, and chlorobutanol are rarely used in present-day pharmaceutical formulations.
`
`and topical preservative
`inactivated by high concentrations of surfactants, injectable
`large-volume parenterals is restricted, soluble in water,
`
`ophthalmic preservative
`salts, and chlorhexidine, soluble in water, topical and
`Potentiates activity of parabens, quaternary ammonium
`
`borates, rapid kill time, ophthalmic preservative
`
`Active above pH 7, soluble in water, illcompatible with
`
`properties
`
`Poor activity above pH 5, soluble in water, good taste
`
`Low sensitizing potential, active at neutral pH, use in
`by EDT A, rapid kill time, ophthalmic preservative
`charged particles, soluble in water, activity potentiated
`anionic surfactants and polymers, will affect negatively
`
`Low sensitizing potential, poor activity above pH 6, unstable
`
`poor taste properties
`water, active against molds and yeasts, slow kill time,
`by high concentration of surfactants, poor solubility in
`Potential sensitizer, poor activity above pH 7, inactivated
`
`with surfactants, good taste properties
`in polyethylene containers, soluble in water, compatible
`
`Potential sensitizer, good activity above pH 7, inactivated
`
`by EDT A and sulfites, slow kill time, used in injectables
`
`Potential sensitizer, active at neutral pH, inactivated by
`
`Comments
`
`1.0
`
`0.01
`
`0.2
`
`1.0
`
`0.01
`
`0.01
`
`0.2
`
`Pheny !ethanol
`
`Chlorhexidine gluconate
`
`Benzoic acid
`
`Benzyl alcohol
`
`Quaternary ammonium salts
`
`Thimerosal
`
`Sorbic acid
`
`Concentration
`
`0.2
`(%)
`
`Parabens (Me, Et, Pr, Bu)
`
`Agent
`
`Table 9 List of Preservatives Used in Pharmaceutical Suspensions•
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`suspension to render it both sterile and safe. Therefore, an elaborate program of steril-
`ity checks at critical phases of the operation is required. There is no simple way to
`prepare sterile parenteral suspensions other than reliance on sound parenteral techniques
`and aseptic practices.
`Special facilities to handle the preparation of sterile powders for parenteral suspen-
`sions should be made available for this purpose. Pharmaceuticals that are handled in this
`manner include antibiotics, biological materials, and steroids. The final workup and
`purification steps of such drugs are conducted in sterile rooms. Aseptic techniques and
`sterile or particle-free solvents are used for the purpose of performing final recrystalli-
`zations.
`There are several advantages in establishing such a program. The foreign matter
`content of sterile powders for parenteral use is greatly reduced through the extra care
`involved in such an operation. The chance of preparing pyrogenic materials or contami-
`nating with pyrogens is greatly reduced. Sterile powder can be provided for the manu-
`facture of parenteral products, thereby greatly simplifying the subsequent sterilization
`operations.
`
`I. Selection of Milling Equipment
`Some type of mechanical dispersion equipment is often required to break up agglom-
`erates of poorly wetted, hydrophobic particles shortly after a primary slurry is formed
`between the sterile powder and a portion of the sterile suspending vehicle. For most
`efficient handling in production, a one-pass dispersion step is desirable through the use
`of a colloidal mill that can be sterilized prior to use, with either ethylene oxide gas or
`live steam. The principal advantage of this particular mill is that the head, which is
`composed entirely of stainless steel, can be detached from the motor housing and ster-
`ilized in an autoclave. The hopper of the mill is removed, and a stainless steel plate and
`baffle are inserted in its place for parenteral operation. Mill heads are relatively inex-
`pensive, and, therefore, several units can be purchased to provide continuous trouble-
`free operation. Piston-type homogenizers have also been used for the preparation of
`parenteral dispersions [72]. These units, however, lack the flexibility of a colloid miJJ
`and are more difficult to sterilize. Ultrasonic devices [73] and high speed mixers [68]
`have been used experimentally for the same purpose.
`
`2. Syringeability
`One of the most important properties of a good parenteral suspension is syringeability,
`the ability o( a parenteral solution or suspension to pass easily through a hypodermic
`needle, especially during the transfer of product from vial to hypodermic syringe prior
`to injection. Increases in the following characteristics tend to reduce syringeability or
`make material transfer through the needle more difficult:
`The viscosity of the vehicle
`The density of the vehicle
`The size of suspended particulate matter
`The concentration of suspended drug
`Probably the most important of these factors is viscosity. Fortunately, with
`parenteral suspensions, viscosity is perhaps the easiest parameter for the formulator to
`control. The preparation of a stable floc contributes little to the overall viscosity of the
`system and hence does not adversely influence syringeability. Even though the individual
`
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`suspension particles are loosely held together in large multiple aggregates, they are easily
`broken up and reformed during their passage from vial to syringe, and from syringe to
`injection site.
`To give the physician flexibility in selecting hypodermic needles for various routes
`of parenteral injection, the following standard for syringeability can be established: the
`entire contents of a parenteral suspension is expected to pass through a 25 gauge needle
`without difficulty where the needle's internal diameter is 0.3 mm and no individual
`particle size is greater than about one-third the needle's internal diameter. The needle
`size of such a specification can be extended to 27, 28, and 30 gauge only when extreme
`care is exercised by the physician. Making routine injections with very fine bore hypo-
`dermic needles (>25 gauge), however, is not normally recommended.
`
`3. Drainage
`The ability of the suspension to break cleanly away from the inner walls of the primary
`container-closure system is another important characteristic of a well-formulated
`parenteral suspension. Completely peptized to flocculated systems show this property,
`while overflocculated systems exhibit some degree of poor drainage. Poor drainage is
`further characterized by the use of the term "buttermilk appearance," an expression that
`aptly describes this unsightly condition. The effect is produced by the rapid drainback
`of vehicle through channels created by the residual adhering flocculant.
`The process of silicone coating of containers, vials, and plugs with dimethicone
`makes good suspensions drain better and helps reverse the tendency toward poor drainage
`by slightly overflocculated systems [74].
`
`4. Resuspendability
`Resuspendability is defined as the ability to resuspend settled particles with a minimum
`amount of shaking after a suspension has stood for some time. The difficulty lies in
`estimating how much effort will be required to resuspend the solids in a suspension after
`reading a "shake well" label. Unless a suspension can be prepared in which the sus-
`pended particles do not settle-in other words, the "permanent suspension"-the best
`answer to the problem is preparation of a physically stable, flocculated suspension. This
`is especially important in the case of parenteral suspensions, for which the structured
`vehicle approach cannot be considered because of the poor syringeability of such sys-
`tems. Preparation of a stable floc offers the formulator a convenient method of over-
`coming this problem. Stable, flocculated parenteral suspensions that have stood undis-
`turbed for prolonged periods of storage are therefore the easiest systems to resuspend.
`
`5. Compatibility with Diluents and Other Injectable Products
`Unlike other pharmaceutical suspensions, dilution of parenteral suspensions prior to use
`is often necessary, especially if only small concentrations of drug are required. Often
`times, parenteral suspensions are mixed and injected with solutions of a local anesthetic
`agent, such as Lidocaine Hydrochloride Injection USP, to diminish the pain associated
`with administration. For this reason some sort of compatibility testing is extremely
`useful.
`Dilution of the suspension with water or normal saline will often cause the system
`to deflocculate. This is not necessarily detrimental, since dilutions are often made prior
`to administration, long before "caking and cementing" can take place. On the other hand,
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`if dilution or mixing with other injectable preparations causes the suspension to agglomer-
`ate or coagulate, this will result in a more serious incompatibility. Therefore, some basic
`compatibility testing is recommended with common injectable diluents during the devel-
`opment of a parenteral suspension. Increasing the solids content of suspensions 1 O-fo1d
`(from, say, 0.5% to 5%) will often increase the physical stability of the system itself
`as well as its compatibility with diluents and other injectable products.
`
`K. Cosmetic Suspensions
`There are basically two types of cosmetic suspension system used at the present time.
`The first are the pigmented products that are suspended in aqueous vehicles (such as
`liquid makeups, eyeliners, mascaras, and blushers). These products feature high solids
`content, high density, impalpable powders, and pigments permanently suspended in either
`a primary oil-in-water, emulsion type base or a complex system of hydrophilic cellu-
`losic derivatives, clays, and/or polymeric film-formers, in which the gelling and sus-
`pending properties of the vehicle often are reinforced by the presence of a small amount
`of a Bingham-type plastic, such as carbomer [75].
`The second type of cosmetic suspension consists of the pigment-containing nail
`enamels. The coloring tints, pigments, pearls, and lakes in the latter system are sus-
`pended with the aid of organophilic, thixotropic gellant, such as stearalkonium hectorite
`(Bentone 38: trademark of NL Industries, Inc., Hightstown, NJ), in a nonaqueous vehicle
`consisting of a mixture of butyl acetate, ethyl acetate, and isopropyl alcohol solvents in
`which the primary plasticized nitrocellulose and toluene sulfonamide-formaldehyde resin
`film-formers are dissolved. Patents covering such products have been reviewed separately
`by Markland [76] and Kahn and Eichhorn [77].
`Examples of cosmetic-type suspensions are given in Tables 10 through 13.
`
`L. Manufacturing Guidelines
`Technical guidelines with respect to the formulation, manufacture, and testing of phar-
`maceutical suspensions have been published separately by Scheer [78] and Idson and
`)
`
`Ingredients
`
`Table 10 Typical Aqueous Cream Makeup Formula
`% w/w
`10
`2
`2
`2
`1
`12
`2
`8
`1
`qs
`. qs
`60
`100
`
`Stearic acid
`Glyceryl monostearate
`Cetyl alcohol
`Isopropyl myristate
`Polyethylene glycol 400 monostearate
`Propylene glycol
`Titanium dioxide
`Talc
`Pigment blend
`Preservative
`Fragrance
`Water
`
`Function
`
`Gelling agent/suspending agent
`Emulsifier I suspending agent
`Thickener/suspending agent
`Emollient
`Emulsifier/suspending agent
`Dispersant and humectant
`
`Suspensoid mixture
`
`Primary vehicle
`
`LUYE1014
`IPR of Patent No. 6,667,061
`
`

`
`40
`
`Nash
`
`bility of certain suspensions. Great care must be exercised in the use of graduated cyl-
`inders because decreases in the diameter of small containers produce a "wall effect,"
`which can often affect the settling rate or ultimate sedimentation height of flocculated
`suspensions. Such small vessels have a tendency to hold up suspensions due to the
`adhesive forces acting between the inner surface of the container and the suspended
`particles.
`
`5. Broolifield Viscometer with Helipath Attachment
`The Helipath attachment used with a Brookfield viscometer is a valuable piece of rheo-
`logical equipment for measuring the settling behavior and structure of pharmaceutical
`suspensions. A description of the apparatus was presented in the paper by Tingstad [79].
`The instrument consists of a slowly rotating T-bar spindle, which while descending
`slowly into suspensions encounters new, essentially undisturbed material as it rotates.
`The dial reading of the viscometer measures resistance to flow that the spindle encounters
`from the structure at various levels in the sediment. Taking rheograms at various time
`intervals, under standard conditions of sample preparation, gives a description of the
`suspension and its physical stability. The technique is most useful for viscous suspen-
`sions high in solids, that d