Section 14
`
`Avicel® RC/CL, Microcrystalline Cellulose
`and Carboxymethylcellulose Sodium, NF, BP
`By Sheila M. Dell, Ph.D. and John A. Colliopoulos, M.S.
`
`Table of Contents
`
`Avicel RC/CL, Microcrystalline Cellulose and Carboxymethylcellulose Sodium, NF, BP..............1
`Table of Contents.......................................................................................................................1
`Introduction ....................................................................................................................................3
`Disperse Systems ......................................................................................................................3
`Guidelines for Suspension Formulation.....................................................................................3
`Particle Size ...........................................................................................................................4
`Wetting ...................................................................................................................................4
`Viscosity .................................................................................................................................4
`Flocculation and Deflocculation ............................................................................................5
`Characteristics of Commonly Used Suspending Agents ..........................................................6
`Avicel RC and CL, Microcrystalline Cellulose
`and Carboxymethylcellulose Sodium, NF, BP....................................................................6
`Carrageenan, NF....................................................................................................................7
`Algins and Alginate ................................................................................................................7
`Other Commonly Used Suspending Agents .........................................................................8
`Other Suspension Excipients.................................................................................................9
`Avicel RC and Microcrystalline Cellulose, NF..............................................................................11
`Introduction ..............................................................................................................................11
`Structure and Properties..........................................................................................................11
`Chemical and Physical Specifications.................................................................................12
`Microbiological Specifications .............................................................................................13
`Effect of pH and Temperature on the Viscosity of Colloidal Avicel .........................................13
`Effect of Other Hydrocolloids on Viscosity ..............................................................................13
`Advantages of Formulating Disperse Systems with Colloidal Avicel ......................................14
`Preparation of Colloidal Avicel.....................................................................................................15
`Dry Mix Dispersion...................................................................................................................15
`Liquid Mix Dispersion ..............................................................................................................15
`Rheology of Avicel Dispersions ...................................................................................................15
`Viscoelastic Properties.............................................................................................................15
`Pharmaceutical Applications .......................................................................................................21
`Example of Use of Colloidal Avicel as a Suspending Agent ...................................................21
`Example of an Analgesic Oral Suspension Using Colloidal Avicel RC-591 ............................21
`Example of an Antacid Suspension Using Colloidal Avicel RC-591 .......................................22
`
`1
`
`Exhibit 1146
`IPR2017-00807
`ARGENTUM
`
`000001
`
`

`

`Example of Use of Colloidal Avicel® as an Oil/Water Emulsifier..............................................22
`Example of Use of Colloidal Avicel as a Thickener, Emulsion Stabilizer
`and Opacifier for Pharmaceutical Creams and Gels ...........................................................23
`Example of Use of Colloidal Avicel as an Oil/Water Emulsifier
`for Cosmetic Lotions............................................................................................................23
`Example of Use of Colloidal Avicel as a Suspending Agent
`for Reconstitutable Suspensions.........................................................................................24
`Suspension Powder for Reconstitution ...............................................................................24
`Example of a Drug (Active) Powder Formualtion for Reconstitution...................................24
`Equipment and Suppliers.............................................................................................................25
`Mixers.......................................................................................................................................25
`Mills .........................................................................................................................................25
`Deaerator-Defoamer.................................................................................................................26
`Micronizer-Pulverizer................................................................................................................26
`Viscometers..............................................................................................................................26
`Rheometers..............................................................................................................................26
`Special Equipment ...................................................................................................................26
`Particle Size Analyzer...............................................................................................................26
`References ...................................................................................................................................27
`Acknowledgement .......................................................................................................................27
`
`2
`
`000002
`
`

`

`Introduction
`
`Disperse Systems
`
`The science of suspensions and dispersions
`is fundamental in the field of food, drugs and
`cosmetics where the drug or actives are neither
`soluble nor precipitated. Disperse systems are
`classified broadly as systems in which one
`substance, the dispersed phase, is distributed
`throughout another substance, the continuous
`phase. Examples of disperse systems are
`suspensions, emulsions, creams, ointments,
`aerosols, pastes, etc. These dosage forms
`can be administered by oral, ophthalmic,
`intranasal, dermatological or by parental
`routes of administration.
`
`One of the most important challenges of a
`disperse system is to have the dispersed
`phase remain dispersed in the dispersion
`medium. Thus, the control of sedimentation
`is of primary importance in maintaining the
`integrity of a disperse system.The most
`practical method of controlling sedimentation
`is by the use of viscosity building agents.
`Various substances, such as sugars and
`polyols, have been used over the years to
`build viscosity in aqueous drug systems.
`However, they needed to be used in large
`amounts to achieve the required viscosity
`and these solutions are usually Newtonian
`in nature. Polymers, on the other hand, are
`needed in small amounts to meet the viscosity
`requirements and have the added advantage
`of being non-Newtonian in nature, i.e., they
`have a yield point or are thixotropic. These
`properties are advantageous in overcoming
`sedimentation and are easier to process. Thus,
`polymers are used in suspensions, emulsions
`and other dispersions mainly to control or
`minimize sedimentation. Various substances
`such as natural, synthetic and semi-synthetic
`polymers, have been used over the years to
`build viscosity in aqueous drug systems.
`
`The objective of this chapter is to highlight the
`features of colloidal Avicel®, a polymer that is
`a combination of microcrystalline cellulose and
`
`sodium carboxymethylcellulose as a suspending
`agent/thickener, etc. in oral suspensions, creams
`and lotions. The bulk of the information present-
`ed is from reviews of FMC literature, brochures
`technical reports, Kennon and Storz (1), Nash (2),
`Boylan (3), Macek (4) and Haines and Martin (5).
`
`Guidelines for Formulation
`of a Suspension
`
`Oral aqueous suspensions constitute the
`largest portion of suspensions marketed in the
`pharmaceutical industry. Drugs are dispensed
`as suspensions for various reasons, the primary
`one being poor aqueous solubility. Suspensions
`also improve the taste since less of the drug is
`in solution. In addition, greater chemical stability
`is achieved since the drug is not in solution and,
`in some cases, bioavailability is enhanced. This
`is of particular importance to children and
`geriatric patients. Suspensions also offer
`advantages for those patients who have
`difficulty swallowing tablets or capsules.
`
`A suspension can be defined as a two-phase
`system consisting of a finely divided solid
`dispersed in a solid, liquid or gas. Oral
`suspensions usually have the active drug,
`which is insoluble or poorly water soluble,
`dispersed in water (liquid), which is the
`continuous phase.
`
`The main objective in suspension formulation
`is to ensure that the dispersed particles do not
`settle on standing, or if the particles do settle,
`the particles should be easily dispersed on
`shaking and should produce a uniform dose on
`administration. The suspension should also be
`pleasant tasting, and be stable physically and
`chemically. Since the specific properties of
`various suspended drugs differ, no single
`procedure will always produce a successful
`suspension product. However, certain principles
`are affirmed to be fundamental in all successful
`formulations.
`
`3
`
`000003
`
`

`

`They are:
`1. Particle size of the suspended drug
`2. Wetting/surfactants
`3. Viscosity
`4. Flocculation/deflocculation
`
`Particle Size
`
`A major goal of a suspension formulation is
`to slow or prevent sedimentation of the drug
`particle to avoid a non-uniform distribution of
`the drug. The particle size of the drug plays a
`significant part in determining formulation
`elegance, rate of settling, absence of caking,
`rate of drug release and final stability of the
`product.
`
`Particle size of the suspended drug is a
`critical parameter in a suspension formulation.
`According to Stokes’ Law, the rate of settling
`of the insoluble drug is directly proportional
`to the square of the particle diameter.
`
`V ⫽ d2
`
`共␳1 ⫺ ␳2兲g
`18␩
`
`where V = sedimentation rate of a particle
`d = mean particle diameter
`␳1 = particle density
`␳2 = density of the dispersion medium
`g = acceleration due to gravity
`␩ = viscosity of the dispersion medium
`
`Therefore, smaller particles will settle more
`slowly than larger particles. The majority of
`pharmaceutical suspensions have drug particles
`in the range of 1-50 microns in diameter. If
`particles are less than about 3 microns and their
`density does not differ by more than 20% from
`that of the dispersion vehicle, the particles will
`remain suspended due to Brownian motion.
`Therefore, reduction of particle size has a
`beneficial effect upon the physical stability of
`the suspension. In practice, however, there is
`a limit to particle size reduction because, after
`reaching a certain particle size, further reduction
`can be expensive due to the time and equipment
`involved. Moreover, movement of small particles
`due to Brownian motion often produces particle
`
`aggregation, followed by settling of the
`aggregates and frequently caking. Redispersion
`of the drug after caking is often impossible.
`
`Wetting
`
`Since most drugs in a suspension are
`hydrophobic, they float on the surface of
`the dispersion medium due to poor wetting.
`A wetting agent helps disperse the poorly
`soluble drug in the dispersion medium. Wetting
`of the solid phase by the suspended liquid is
`necessary to produce a good suspension. Low
`concentrations of surfactants are commonly
`used as wetting agents to aid dispersion of the
`particles in the suspension vehicle. However,
`excess amounts of surfactants may impart
`foaming or an unpleasant taste.
`
`Viscosity
`
`Stokes’ Law describes the inverse relationship
`between viscosity of the dispersion medium
`and rate of particle settling. An increase in
`viscosity produces a slower sedimentation
`rate and increases physical stability. The most
`common method of increasing viscosity is by
`adding a suspending agent. Suspending agents
`with high viscosity do not always prevent
`sedimentation. Meyer and Cohen in 1959 (6)
`suggested that yield value is an important
`mechanism to keep a particle suspended.
`The yield value for a suspension must balance
`or exceed the force of gravity on the settling
`particles. This mechanism is gaining recognition
`and was reviewed by Hem and White. (7)
`The yield value of a dispersion medium can
`be determined experimentally by using a rota-
`tional viscometer and plotting shear stress
`(dyne/cm2 ) as a function of shear rate (sec-1).
`The curve as shown in the Figure 1 does not
`pass through the origin, but intersects the axis
`of shear stress as in curves A and B. The inter-
`section at C or D is the yield value. The slope
`of the curve is the apparent viscosity, which
`varies with shear rate, and therefore, the entire
`curve is required to describe the viscosity of
`these systems. Additional information on the
`
`4
`
`000004
`
`

`

`One such process is flocculation. Flocculation
`is a process in which particles are allowed to
`come together and form loose agglomerates.
`The chief advantage of a flocculated suspension
`is in its redispersibility. The goal of controlled
`flocculation is to maintain reasonably sized
`aggregates or flocs. In this way, redispersibility
`and sedimentation rate are kept in balance.
`
`Flocculation can be achieved by various
`means. One of the methods is based on electric
`charge. Charged particles of the same charge
`will repel each other and thus resist forming
`flocs. Reduction of particle repulsion permits
`the particles to get close enough to allow the
`attractive forces to dominate.
`
`The use of polymers is another method to
`achieve flocculation. Polymers containing
`chemical groups that interact with the
`suspended particles can be added to the
`continuous phase. Polymer segments can
`then attach to individual particles to form a
`polymer-particle complex. As the polymer
`connects across two or more particles a floc
`is formed. Other ingredients such as protective
`colloids (e.g., carboxymethylcellulose), wetting
`agents such as polysorbates, and electrolytes
`such as sodium chloride can also act as
`flocculating agents.
`
`The final suspension product should be
`evaluated for its stability in the final package
`after manufacture, at various temperature
`conditions for a given period of time to ensure
`physical and chemical stability. Several physical
`tests are employed to determine the stability
`of a suspension. The list below shows the
`various tests a formulator would conduct to
`determine the stability of a suspension, Ofner,
`Schnaare and Schwartz (8).
`
`rheological properties of suspending agents and
`suspensions will be covered in this chapter.
`
`Figure 1: Yield Value
`
`Reducing the difference in density between the
`particles and the dispersion medium can also
`lower the rate of sedimentation. However, water
`is usually the dispersion medium, and since
`added ingredients do not change its density
`to a great extent, i.e., this has not been a partic-
`ularly successful method. Therefore, particle
`size and viscosity have been the properties
`that most formulators focus on to obtaining
`an optimum suspension formulation.
`
`Flocculation and Deflocculation
`
`The basic concern in developing a suitable
`suspension is to control adequately the rate of
`settling and ease of redispersion, as well as to
`prevent caking of the particles as a dense
`mass at the bottom of the container. Particle
`size reduction produces slower, more uniform
`rates of settling. Frequently, caking cannot be
`prevented by adding a suspending agent or
`reducing the particle size; in fact, these
`measures sometimes aggravate the problem
`of caking. The best approach to this problem
`is to achieve a controlled flocculation of the
`particles, where they appear as floccules or
`like tufts of wool with a loose fibrous structure.
`When such a system settles, two distinct layers
`form, a clear particle-free supernatant and a
`sediment. The particles are held together by
`weak van der Waals forces. Maintaining a drug
`in suspension with little or no separation results
`in a more elegant and permanent suspension.
`
`5
`
`000005
`
`

`

`Avicel® RC and CL Microcrystalline Cellulose
`and Carboxymethylcellulose Sodium, NF;
`Dispersible Cellulose, BP
`
`FMC BioPolymer
`1735 Market Street
`Philadelphia, PA 19103
`
`Derivation
`Colloidal Avicel is a modified microcrystalline
`cellulose product. It has a composition, on a
`dry basis, of 82-89% microcrystalline cellulose
`and 11-18% sodium carboxymethylcellulose,
`medium viscosity.
`
`Water Dispersibility
`Colloidal Avicel is a water-dispersible anionic
`hydrocolloid.
`
`pH Stability
`Colloidal Avicel is stable over a pH range of
`3.5-11.
`
`Rheology
`1. Colloidal Avicel systems form thixotropic
`gels which have a finite yield value at low
`concentrations.
`2. These gels are shear thinning and upon
`resting the yield value increases to re-estab-
`lish the equilibrium value. Colloidal Avicel is
`a stable product. Its viscosity is unaffected
`by temperature.
`
`Incompatibilities
`Colloidal Avicel being anionic by nature
`flocculates when small amounts of electrolyte,
`cationic polymers or surfactants are added.
`
`Advantages
`The advantages and uses of Avicel RC and CL
`will be discussed in detail in the following
`sections of this chapter.
`
`Summary of Physical Tests for Suspension
`Stability; The Stability of Actives is Assumed
`
`1. Appearance
`2. Sedimentation rate
`3. Sedimentation volume
`4. Redispersibility
`5. Zeta potential measurement
`6. Dissolution
`7. Rheological measurements
`8. Stress tests-Vibration-Transportation
`9. pH
`10. Specific gravity
`11. Odor
`12. Taste
`13. Color-Light
`14. Microbiological examination
`15. Freeze-thaw cycles
`16. Compatibility with container
`17. Compatibility with cap liner
`18. Torque
`19. Microscopic-Photomicrographs
`20. Crystal size
`21. Uniform drug distribution
`22. Toxicity
`23. Use tests
`
`Characteristics of Commonly Used
`Suspending Agents
`
`One of the most important factors in
`formulating a suspension is selection of the
`proper suspending agent. It is the suspending
`agent that is used primarily to control or mini-
`mize sedimentation. The formulator must
`select the suspending agent best suited to
`support the drug in either a flocculated or
`deflocculated state.
`
`The following listing of suspending agents and
`protective hydrocolloids most commonly used
`in the pharmaceutical industry provides pertinent
`functional, rheological and incompatibility
`characteristics, and is designed to give the
`formulator a quick overview. The many grades
`available for some particular hydrocolloids are
`not dealt with in this overview, and the formula-
`tor is referred to company literature, Idson and
`Scheer (9).
`
`6
`
`000006
`
`

`

`Carrageenan, NF
`
`FMC BioPolymer
`1735 Market Street
`Philadelphia, PA 19103
`
`Algins and Alginate
`
`FMC BioPolymer
`1735 Market Street
`Philadelphia, PA 19103
`
`Derivation
`Carrageenan is an anaerobic polysaccharide
`derived from seaweed. Different types of
`Carrageenan have been identified such as
`kappa, iota and lambda Carrageenan. (See
`Chapter on carrageenan in Problem Solver).
`
`Water Dispersibility
`All forms of carrageenan are soluble in hot water,
`but only the sodium salts of iota carrageenan
`and lambda carrageenan are soluble in cold
`water. In the presence of certain ions such as
`calcium or potassium, gels of great strength
`are formed with definite melting temperatures.
`
`pH Stability
`Carrageenans are stable over a pH range of
`4-10. They are least stable under either strongly
`acidic or alkaline solutions. Carrageenan
`solutions generally have a pH of 6-10.
`
`Rheology
`1. Carrageenans, especially the iota and kappa
`types, form thixotropic gels with a yield point
`at low concentrations.
`2. A reversible loss in viscosity is seen at higher
`temperatures.
`
`Incompatibilities
`Carrageenans are anionic in nature and
`therefore are incompatible with cationics.
`Mono- and divalent ions such as potassium
`and calcium will crosslink the polymer to
`form gels. They hydrolyze and degrade in
`the presence of strong acids.
`
`Advantages
`1. Carrageenans are thickeners, film formers
`and suspending agents.
`
`Derivation
`Alginates are purified hydrocolloids obtained
`from brown seaweed (Kelp extract). (See chapter
`on Algins/Alginate in Problem Solver).
`
`Water Dispersibility
`Alginate is readily water dispersible and can be
`either pre-blended with other drug excipients like
`sucrose or wetted with glycols prior to
`water addition. High speed stirring is indicated.
`
`pH Stability
`Alginate is stable over a pH range of 4-10.
`
`Rheology
`1. Alginate systems exhibit pseudoplastic
`behavior.
`2. Long term accelerated temperature
`conditions produce some viscosity losses
`(depolymerization).
`
`Incompatibilities
`Alginate is anionic in nature and therefore
`are incompatible with cationics. Calcium salts
`precipitate algins. Polyvalent ions will crosslink
`the polymer to form gels.
`
`Algins are incompatible with heavy metal ions.
`They are sensitive to strong acids.
`
`Advantages
`1. Alginates are colloidal electrolytes.
`2. Alginates are stabilizers, film formers
`and reasonable suspending agents.
`
`Note: The formulator must strictly monitor rheological
`properties of alginate suspensions.
`
`7
`
`000007
`
`

`

`Other Commonly Used Suspending Agents
`
`The pH stability, rheology, incompatibilities and uses of other common suspending agents
`are listed in alphabetical order.
`
`Suspending Agent
`
`pH Stability (Range)
`
`Rheology
`
`Carbomer, NF
`
`5.0 - 11
`
`Systems exhibit plastic
`flow
`
`Methylcellulose, USP
`
`3.0 - 11
`
`Dispersions are
`pseudoplastic
`
`Sodium Carboxy-
`methylcellulose, NF
`(Cellulose gum)
`(NaCMC)
`
`4.0 - 10.0
`
`Acacia, NF
`(Gum Arabic)
`
`Viscosity is
`affected by pH
`
`CMC systems exhibit
`pseudoplastic behavior.
`Viscosity of CMC systems
`is dependent upon
`temperature.
`
`Newtonian flow exhibited
`at concentrations below
`40%. High concentrations
`are pseudoplastic.
`
`Guar Gum, NF
`
`4 - 10
`Maximum viscosity
`is obtained at pH 6
`
`Pseudoplastic behavior
`with no yield point.
`
`Incompatibilities
`Sensitive to soluble salts;
`mono-, di- and polyvalent
`and to cationic polymers.
`
`High levels of electrolytes
`and surfacants affect MC
`dispersions.
`
`Incompatible with di- and
`trivalent salts.
`
`Acacia is anionic.
`It flocculates with small
`amounts of electrolytes,
`cationic polymers and
`surfacants.
`
`May degrade irreversibly
`with time at elevated
`temperatures.
`
`Uses
`
`Good suspending agent
`at a pH value of 5.0
`
`Effective stabilizer and
`protective colloid. Usually
`used in conjunction with
`other suspending agents,
`not as a primary
`suspending agent.
`
`Effective stabilizer
`and protective colloid
`especially for Avicel®
`RC-591 MCC.
`
`—
`
`—
`
`Xanthan Gum, NF
`
`3.0 - 11.0
`
`Dispersions are extremely
`pseudoplastic with
`significant yield value.
`
`Incompatible with cationic
`dyes and polyvalent ions
`at high pH.
`
`Effective suspending
`agent especially when
`used in conjunction
`with Avicel CL-611 MCC.
`
`Should the formulator decide to use a natural gum either as a sole or adjunct suspending agent, strict
`attention must be given to the natural source derivation and rigid specifications regarding lot-to-lot
`uniformity must be implemented.
`
`8
`
`000008
`
`

`

`Other Suspension Excipients
`
`• Functions
`• Use levels
`• Problems
`
`The function, percent use level and problems that could surface relative to commonly used suspension
`excipients are listed in alphabetical order.
`
`Percent levels used are approximate and represent general use levels.
`
`Excipient
`
`Purpose
`
`% W/V Range Used
`
`Problem
`
`Could solubilize small percentage of drug.
`Incompatibility with suspending agent.
`
`pH of the system should be below 4.5
`for the preservative to be effective.
`Solubility, precipitation not uncommon.
`
`Incompatibility with drug or suspending
`agent.
`
`Excessive levels may cause staining
`of teeth, skin, or clothing.
`Quaternary ammonium compounds
`interact with FD&C Blue #1 and FD&C
`Yellow #10
`
`— R
`
`eactions with drug and/or other flavors.
`Excessive levels impart bitterness,
`burning sensation.
`
`Could impart hot acrid taste at high
`levels.
`
`0.1-0.2
`
`0.01-0.1
`
`Can impart an objectionable taste and a
`feeling of numbness at high levels.
`
`Poor water solubility.
`
`5-10
`
`Unpleasant taste.
`
`Sodium Benzoate
`
`Preservative.
`
`0.05-0.25
`
`See Benzoic Acid
`
`9
`
`Alcohol 95%, USP
`
`Solvent for preservatives,
`flavors, or other insolubles.
`
`Benzoic Acid
`
`Preservative.
`
`3-10
`
`0.05-0.25
`
`Buffer Acids
`
`pH adjustment buffer system.
`
`Depends on pH of system
`
`Colorants
`
`Provides color-system.
`
`q.s.
`
`Disodium Edetate
`(Na2 EDTA)
`
`Sequesterant.
`
`0.001-0.005
`
`q.s.
`
`5-15
`
`Flavors
`
`Taste improvement.
`
`Glycerin
`
`Solvent for preservatives.
`Bodying agent.
`Drug dispersing vehicle.
`Used with Sorbitol in
`combination to produce
`cap lock resistant blends.
`
`Methyl Paraben
`
`Propyl Paraben
`
`Preservative.
`Preservative.
`
`Propylene Glycol
`
`Solvent for preservative
`or flavors.
`Drug dispersing vehicle.
`
`000009
`
`

`

`Other Suspension Excipients Continued.....
`
`Excipient
`
`Sodium Chloride
`
`Sorbitol
`Solution, 70%
`
`Purpose
`Modification of bitterness.
`Taste modifier.
`Improves flavor.
`Imparts sweet cool taste.
`Bodying agent.
`Helps retard cap locking
`tendency.
`
`Sucrose
`
`Natural sweetener.
`
`Pluronic Polyol – F68
`(HLB = 5.8)
`
`Wetting agent.
`Defoamer.
`
`Polyoxyethylene (8)
`Stearate (HLB = 11.1)
`
`Polyoxyethylene (20)
`Sorbitan Monostearate
`(HLB = 14.9)
`
`Polyoxyethylene (20)
`Sorbitan Monooleate
`(HLB = 15.0)
`
`Wetting agent.
`Increases hydrophilic
`properties of clay suspending
`agents.
`
`Wetting agent.
`
`Wetting agent.
`Solubilizer for flavors.
`Viscosity control.
`
`Sodium Lauryl Sulfate
`(HLB = 40)
`
`Wetting agent.
`
`Sorbitan Monolaurate
`(HLB = 8.6)
`
`Wetting agent.
`
`% W/V Range Used
`
`0.1-0.3
`
`Problem
`Incompatibility with drug, suspending
`agent, or protective colloid.
`
`10-40
`
`—
`
`10-60
`
`0.1-1.0
`
`0.1-0.5
`
`0.05-0.1
`
`0.1-0.5
`
`Cap locking.
`Incompatibility with suspending agent.
`Drug incompatibility possible but rare.
`
`—
`
`—
`
`—
`
`Can solubilize small percentage of drug.
`Taste is soapy and bitter.
`
`0.001-0.05
`
`Powerful solubilizer.
`Can solubilize some drugs.
`
`0.001-0-05
`
`—
`
`10
`
`000010
`
`

`

`Avicel® RC and CL Microcrystalline Cellulose, NF
`
`Introduction
`
`Colloidal Avicel is not a water-soluble cellulose
`derivative, but a water-dispersible organic
`hydrocolloid. It is prepared by chemical
`depolymerization of highly purified wood pulp.
`The original crystalline areas of the fiber are
`combined with sodium carboxymethylcellulose
`(NaCMC) to produce the colloidal Avicel product.
`NaCMC serves as a protective colloid and also
`aids in dispersion of the product. Soluble
`hydrocolloids (e.g., NaCMC) are produced by
`chemical substitution of functional groups in
`cellulose. Other types of cellulose products
`(e.g., flocs) are made by mechanical grinding
`of pulp fibers to a finer particle size. Thus, with
`the microcrystalline celluloses, we have a
`different class of products with different
`properties and different functions.
`
`RC and CL types of Avicel microcrystalline
`cellulose (MCC) are water-dispersible products
`for use in pharmaceutical and cosmetic prepara-
`tions. They contain sodium carboxymethylcellu-
`lose (NaCMC) to aid dispersion and to serve
`as a protective colloid.
`
`Structure and Properties
`
`There are four types of Avicel RC/CL: RC-501,
`RC-581, RC-591, and CL-611. All types are
`white, odorless, and tasteless hygroscopic
`powders. They are insoluble in organic solvents
`and dilute acids, and partially soluble in both
`dilute alkali and water (CMC fraction). Due to
`the small size of the microcrystals (about 60%
`of the crystallites in the dispersion are < 0.2µm),
`there are a large number of microcrystals packed
`in each powder particle. The large number of
`small microcrystals foster product elegance by
`slowing the rate of sedimentation, increasing
`the stability of a dispersion, and eliminating hard
`packing of settled particles. The highly compact
`nature of the powder particle is evident in the
`scanning electron micrograph as shown in
`Figure 2.
`
`To achieve maximum dispersion, RC-501 and
`RC-581 require high shear mixing while RC-591
`and CL-611 require low to moderate shear
`mixing. With RC-501, RC-581, RC-591, and
`CL-611, approximately 60% of the particles in
`the dispersion are less than 0.2µm when proper-
`ly dispersed. Concentrations of less than 1%
`solids produce fluid dispersions, while concen-
`trations of more than 1.2% solids produce
`thixotropic gels. CL-611 needs a concentration
`slightly higher than 1.2% for thixotropy.
`
`When stirred in water, Colloidal Avicel powder
`disperses to form either a colloidal sol or a white
`opaque gel, depending on the Avicel concentra-
`tion. When properly dispersed in water, the
`individual RC-591 powder particles disintegrate
`and form a dispersion of cellulose microcrystal
`aggregates. These aggregates are elongated
`solid particles that range in size from a few
`microns to a few tenths of a micron. At concen-
`trations of less than 1% solids, Avicel RC-591
`forms colloidal pseudoplastic dispersions; but
`at concentrations greater than 1%, thixotropic
`gels are formed.
`
`Even though Avicel RC-591 and RC-581 are
`equivalent in colloid content and gel strength
`when fully peptized, high shear equipment such
`as colloid mills and homogenizers are required
`for dispersion of Avicel RC-581. In this case,
`the point of complete or maximum RC-581
`peptization must be predetermined, and an “in
`process” viscosity control has to be established
`in order to equate time versus number of passes
`through a colloid mill (or homogenizer) versus
`viscosity. A consistent maximum hydration
`value must be obtained.
`
`On a practical basis, a colloid mill or Manton
`Gaulin-1000 psi homogenizer is representative
`of the most efficient equipment for processing
`Avicel RC-581 MCC dispersions. The most effi-
`cient mixer, a Waring blender, is not considered
`standard production equipment in the pharma-
`
`11
`
`000011
`
`

`

`ceutical industry. Care should be exercised not
`to lose sight of this fact when formulating
`(on a laboratory scale) a product geared for
`production. Avicel® RC-591 or Avicel CL-611,
`when used alone or with other hydrocolloids,
`is the microcrystalline cellulose of choice for
`
`the preparation of suspensions.
`
`Avicel RC-501, RC-581, RC-591, and CL-611
`are listed as Microcrystalline Cellulose and
`Carboxymethylcellulose Sodium in the U.S.
`Pharmacopoeia/National Formulary.
`
`Figure 2: Fully peptized (activated) Avicel colloidal microcrystalline cellulose
`
`1 ␮M
`
`Chemical and Physical Specifications
`
`Microcrystalline Cellulose and Carboxymethylcellulose Sodium, NF, BP
`
`Avicel RC-501
`
`Avicel RC-581
`
`Avicel RC-591
`
`Avicel CL-611
`
`*NMT 6.0
`NMT 0.001
`7.1-11.9
`+60 mesh NMT 0.1
`+200 mesh NMT 40
`6.0-8.0
`72-168
`(2.1 % solids)
`
`*NMT 6.0
`NMT 0.001
`8.3-13.8
`+60 mesh NMT 0.1
`+200 mesh NMT 35
`6.0-8.0
`72-168
`(1.2% solids)
`
`*NMT 6.0
`NMT 0.001
`8.3-13.8
`+60 mesh NMT 0.1
`+325 mesh NMT 45
`6.0-8.0
`39-91
`(1.2% solids)
`
`*NMT 6.0
`NMT 0.001
`11.3-18.8
`+60 mesh NMT O.1
`+325 mesh NMT 50
`6.0-8.0
`50-118
`(2.6% solids)
`
`NMT 5.0
`
`NMT 5.0
`
`NMT 5.0
`
`NMT 5.0
`
`Product
`Specifications
`Loss on drying, %
`Heavy metals, %
`NaCMC, %
`Sieve fraction, wt. %
`
`pH
`Viscosity, cps
`
`Residue on
`ignition, %
`
`*Not More Than
`
`12
`
`000012
`
`

`

`Microbiological Specifications
`
`Total aerobic microbial count/g........................................................................................NMT 100
`Total yeast and mold count/g.............................................................................................NMT 20
`Escherichia coli.............................................................................. None present in a 10g sample
`Staphylococcus aureus..................................................